NL – 01 - CADTH

Newsletter Evaluation NL – 01

Title: Evidence and Practice: COMET – Carvedilol Or Metoprolol European TrialOrganization: PrISM (Manitoba)

Summary Descriptive Information The Newsletter has 3 pages, 1592 words and is divided into 4 sections. There is partial use of colour but only in the logo on the first page. Evaluation Summary Reviewer #1 Reviewer#2#1 Referencing 5 5#2 Peer Review 5 5#3 Systematic Review 1 2#4 Statistics 4 4#5 Price and coverage 1 1#6 Graphics 3 1#7 Key Messages 4 4#8 Sections 5 3#9 Headings 2 4#10 Table Hierarchy 3 3#11 Table Editorial Consistency 3 3#12 Column Width 3 2#13 Readability 3 3#14 Justification 5 5#15 Colour 4 4#16 Main Message 4 4#17 Therapeutic Decision Support 5 3#18 Behaviour Target 4 3#19 Retrieval 2 2#20 Editorial Consistency 2 2

Reviewer's Totals 68 63

Overall Mean Score 66 Strengths The “Practice Implications” on the last page do provide an effective summary of the newsletter and supports some of the therapeutic decision making required in this area. The document received extensive peer review. Weaknesses The document fails for provide price and coverage information for the products. The price of carvedilol is a significant consideration. The document lacks a retrieval mechanism and is heavily text based. There are some editorial inconsistencies and key message are on the 3rd page.

Poole-Wilson, P.A., Swedberg, K., Cleland, J.G. et al. 2003. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomized controlled trial. Lancet 362:7-13.

COMET STUDY OVERVIEW

Design. The study was a multi-centre, double-blind, randomised parallel group trial.

Funding. The study was funded by Hoffmann La Roche and GlaxoSmithKline.

Objective. The study was designed to compare directly the effects of carvedilol and metoprolol on the mortality and morbidity in patients with mild to severe CHF.

Background. Current Guidelines recommend the combination of angiotensin converting en-zyme (ACE) inhibitors, diuretics and beta blockers (+/- digoxin) in the treatment of CHF.1 The addition of beta blockers to patients receiving ACE inhibitors has been shown to further reduce mortality and symptoms.2,3,4 Some of the beta blockers used (bisoprolol and metoprolol) have a high degree of specificity for β-1 adrenergic receptors. Carvedilol blocks a broader range of adrenergic receptors (β-1, β-2, α-1) and has also been shown to increase insulin sensitivity and have antioxidant action. 5,6,7 The overall clinical importance of these effects remains un-known. COMET was designed as the first head to head comparison with metoprolol (β-1 se-lective) in CHF.

Sample Population. A total of 3029 patients meeting the study’s criteria were randomised to carvedilol (1511 patients) or metoprolol (1518 patients).

Evidence and Practice: COMET Carvedilol Or Metoprolol European Trial

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PrISM Prescription Information Services of Manitoba

187 St. Mary’s Road ● Winnipeg, Manitoba R2H 1J2 ● Tel. (204) 231-4688 ● Email: [email protected]

Inclusion Criteria. • Symptomatic heart failure New York

Heart Association (NYHA) Class II-IV • At least one cardiovascular admission

during previous 2 years • Treated with ACE inhibitors for at least

4 weeks (unless contraindicated) • Left ventricular ejection fraction had to

be ≤35% measured in previous 3 months

Exclusion Criteria. • Recent change in treatment • Treatment with Ca channel blocker, amio-

darone or class I antiarrhythmic (past 30 days)

• Pregnancy or inadequate contraception • Known alcohol or drug abuse • Poor compliance with treatment • Uncontrolled hypertension • Contraindication to beta-blockers.

The Rural Evaluation of Academic Detailing (READ) study is an initia-tive of the Prescription Information Services of Manitoba. The study is designed to investigate the most effective means of improving profes-sional practice.

READ STUDY MATERIAL

READ STUDY MATERIAL

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Results Subjects: The mean age of patients was 62 (SD 11) years and the mean ejection fraction was 26% (SD 7%). Patients were evenly distributed between NYHA II and III. Only a small number of patients were NYHA Class IV (3 to 4%). The mean dura-tion of the study was 58 months (SD 6). Outcomes: All-cause mortality was 34% (512 of 1511) for the carvedilol group and 40% (600 of 1518) for the metoprolol group. This translates to a hazard ratio (relative risk) of 0.83 [95% CI-0.74 to 0.93; p=0.00017]. The composite end point of all-cause mortality and all-cause hospital admission occurred in 74% (1116/1511) for the carvedilol group and 76% (1160/1518) of the metoprolol group. This difference was not significant between the two groups (0.94 [0.86 to 1.02; p=0.122]). Conclusions: The authors conclude that carvedilol extends the survival of CHF pa-tients compared with metoprolol. By ex-trapolation from survival curves the authors suggest that carvedilol extend median sur-vival by 1.4 years (95% CI 0r 0.5 to 2.3).

Commentary The 5.7% absolute mortality difference [(600/1518 - 512/1511)x100%] between carvedilol and metoprolol is a large enough to effect the recommendations of beta-blocker choice. The major controversy of COMET in-volves the choice of metoprolol product and dosing regimen.8,9,10 Prior to COMET, immedi-ate release metoprolol tartrate had not been shown to reduce mortality in CHF. Previous study (MDC trial) of immediate release metoprolol showed improved symptom scores but was not designed to evaluate mortality. 11 Even in the MDC trial, TID dosing of immediate release metoprolol was used.11 The seminal trial demonstrating the mortality reduction in CHF was the MERIT Heart Failure.12 This study used an extended release metoprolol succinate that is not available in Canada. The consensus seems to be that in COMET, the dose of metoprolol may have been too low and the dosing frequency should have been higher (TID or QID). Carvedilol has a longer half-life (9 hours) than metoprolol (5hours). The result-ing small differences in heart rate reduction and blood pressure lowering may have been enough to effect the results of the study. We can conclude that carvedilol is superior to BID metoprolol in CHF. We do not know that carvedilol is better than extended release metoprolol succinate, bisoprolol or higher dose immediate release metoprolol dosed TID/QID. We still don’t know if carvedilol did better be-cause of its mixture of receptor actions or be-cause it was compared with a β-1 selective agent that was dosed inappropriately.

Statistical Analysis. All randomised pa-tients were included in the analysis as part of an intention-to-treat analysis. Patients lost to follow-up were censored at last known date. Endpoints were analyzed with a log-rank test without stratification. The relative risk (hazard ratio) and 95% confidence intervals were estimated with Cox’s proportional haz-ard model.

Intervention. Carvedilol patients received a starting dose of 3.125mg BID with titration every 2 weeks (6.25mg, 12.5mg, 25mg BID) to the target dose of 25mg BID. Metoprolol (tartrate) patients received a starting dose of 5mg BID with titration every 2 wks (12.5mg, 25mg BID) to a target dose of 50mg BID.

Outcome Measures. All-cause mortality was the primary endpoint of the study. A compos-ite endpoint of all-cause mortality and all-cause hospital admission was also included.

STUDY OVERVIEW CONTINUED

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By: Shawn Bugden BSc.Pharm, MSc. Reviewed By: Eduardo Azevedo MD, Cardiologist Ross T. Tsuyuki B.Sc.(Pharm.), Pharm.D., M.Sc., FSCHP Mark Friesen B.Sc.(Pharm.), Pharm.D.

References: 1. Liu, P., Arnold, J.M., Belenkie I., et al. The 2002/3 Canadian Cardiovascular Society consensus guideline update for the diag-

nosis and management of heart failure. Can J. Cardiology 2003 19(4):347-356. 2. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention

Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999 353:2001-2007. 3. McGavin, J.K., Keating, G.M. Bisoprolol: a review of its use in chronic heart failure. Drugs 2002 62:2677-2696. 4. Packer, M., Bristow, M.R., Cohn, J.N., et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart

failure. US Carvedilol Heart Failure Study Group. N. Engl. J. Med. 1996 334:1349-1355. 5. Gilbert E.M., Abraham W.T., Olsen, S., et al. Comparative hemodynamic , left ventricular functional, and antiadrenergic

effects of chronic treatment with metoprolol versus carvedilol in the failing heart. Circulation 1996 94:2817-2825. 6. Jacob, S., Rett, K., Wicklmayr, M., et al. Differential effect of chronic treatment with two beta-blocking agents on insulin

sensitivity: the carvedilol –metoprolol study. J. Hypertens 1996 14:489-494. 7. Yue, T.L. Cheng, Hy., Lysko, P.G. et al. Carvedilol, a new vasodilator and beta adrenoceptor antagonist, is an antioxidant and

free radical scavenger. J Pharmacol Exp Ther 1992 263:93-98. 8. Dargie, H.J. Beta blockers in heart failure. Lancet 2003 362:2-3. 9. Wikstrand, J, Fagerberg, B., Goldstein, S., Kjekshus, J., Wedel, H. COMET – Concerns about dose. Lancet 2003 362:1077 10. Hjalmarson, A., Waagstein, F. COMET – Concerns about dose. Lancet 2003 362:1077. 11. Wiklund, I., Waagstein, F., Swedberg, K., Hjalmarsson, A. Quality of life on treatment with metoprolol in dilated cardio-

myopathy: results from the MDC trial. Metoprolol in Dilated Cardiomyopathy Trial. Cardiovasc Drugs Ther. 1996 10(3):361-368.

12. Howlett, J.G., Johnstone, D.E., Sketris, I., O’Reilly, M., Horne, G.S., Cox J.L., Improving Cardiovascular Outcomes in Nova Scotia Investigators. Identifying opportunities to address the congestive heart failure burden: the Improving Cardiovascular Outcomes in Nova Scotia (ICONS) study. Can J Cardiology 2003 19(4):439-444.

13. Johnson, D., Jin, Y., Quan, H., Cujec, B. Beta-blockers and angiotensin-converting enzyme inhibitors/receptor blockers pre-scriptions after hospital discharge for heart failure are associated with decreased mortality in Alberta, Canada. J Am Coll Cardiol. 2003 42(8):1438-1445.

PrISM does not guarantee that the information is accurate or complete and is not responsible for any errors of omissions or for the result obtained from the use of such information. Use of this information will imply acknowledgement of this disclaimer and release any responsibility of PrISM or its employees. Readers are encouraged to confirm the information from other sources.

Practice Implications. • All of the subtle discussion of beta blocker choice in heart failure is irrelevant when we con-

sider that only 20 to 40% of the CHF population is on a beta blocker at all.12,13 Clearly the number one priority should be ensuring that these patients are on a beta blocker.

• Metoprolol 50mg BID is not good enough. If the choice is to use metoprolol, then higher target doses and more frequent dosing should be considered. Others may consider using short acting metoprolol for CHF inappropriate until there is more data supporting a mortality benefit using TID/QID dosing.

• Unfortunately the sustained release metoprolol succinate is not available in Canada. There are no data evaluating the Canadian metoprolol tartrate long acting products for mortality in heart failure. Although direct comparison to carvedilol has not been made, bisoprolol has been found to decrease mortality in CHF.3

• Carvedilol has shown a significant mortality benefit and could be considered a drug of choice in CHF. Cost is a consideration. The recent introduction of generic carvedilol should help a little with the higher cost of this product.

• Dose does seem to matter. CHF patients put on beta-blockers should not be forgotten and they should have regular monitoring with dosage titrations as tolerated. 8,9,10

• Target dose of carvedilol was 25mg BID. • It is important to remember that the results apply to the study population (primarily Class

II,III with ejection fraction <35%). Care should be taken in extrapolating these results to others CHF patients.

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Title: Sublingual Nifedipine in Hypertensive UrgencyOrganisation: PrISM (Manitoba)

Summary Descriptive Information This newsletter has 2 pages, 1264 words and is divided into 3 sections. There is partial use of colour but only in the logo on the first page. Evaluation Summary Reviewer #1 Reviewer#2#1 Referencing 5 5#2 Peer Review 1 1#3 Systematic Review 1 2#4 Statistics 3 1#5 Price and coverage 1 1#6 Graphics 5 4#7 Key Messages 5 5#8 Sections 5 5#9 Headings 5 5#10 Table Hierarchy 4 4#11 Table Editorial Consistency 2 2#12 Column Width 3 1#13 Readability 4 3#14 Justification 3 1#15 Colour 4 5#16 Main Message 5 4#17 Therapeutic Decision Support 5 5#18 Behaviour Target 5 4#19 Retrieval 5 4#20 Editorial Consistency 3 5


Overall Mean Score 71 Strengths The key message in this document is clearly displayed with strong decision support for therapeutic alternatives to the use of sublingual nifedipine. Weaknesses The document lacks obvious peer review and lacks comparative price information. It is heavily text-based on the opening page. In addition, there are inconsistencies in tabular format between Table 1 and 2.

The Myth: Absorption of nifedipine sublingually occurs quickly and produces a rapid reduction in blood pressure that effects all ages and sexes equally. Close monitoring of blood pressure was not recommended initially because the decrease in blood pressure was supposedly proportional to the pretreatment blood pres-sure. Hypotension was said to be rare and side effects of flushing, headache, and tachy-cardia were not life threatening. 1,2

The Reality: Nifedipine is not absorbed significantly by the sublingual route. Typically the nifedipine im-mediate release capsules are punctured and the liquid is administered sublingually. How-ever, only low plasma levels are obtained from sublingual absorption. The vast majority of the effects of the drug are due to oral absorp-tion.3,4,5 Nifedipine is well absorbed from the gastrointestinal tract and does produce a sig-nificant reduction in blood pressure within 5 to 10 minutes, with a peak effect in 30 to 60 min-utes and duration of action of approximately 6 hours. The effects are not entirely predictable and the inability to control the rate or degree of the fall in blood pressure is problematic. There have been numerous reports of serious ad-verse effects associated with the use of sublin-gual nifedipine. These include cardiovascular ischemia, stroke, severe hypotension, acute myocardial infarction, conduction disturbances and death.1,6,7,8 Even low dose sublingual nifedipine produced myocardial ischemia in 7.5% of the elderly patients treated. 9 The Cardiorenal Advisory Committee of the

FDA first made a recommendation to aban-don the use of sublingual nifedipine in 1985.10 The 7th Report of the Joint National Commit-tee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure, published in December of 2003, continues to recom-mend against the use of sublingual nifedip-ine.8 This information and other supporting literature has caused a decline in usage of sublingual nifedipine and many hospitals have removed this agent from their formular-ies. 7 However, in one chart review of 3 hos-pitals in the United States, the use of sublin-gual nifedipine occurred in 83 patients within the 2 month study window.11 Sixty-three per-cent of the orders were given on the phone for asymptomatic elevations and only 2% of the orders were subsequent to a bedside evaluation.

Definitions and Approach to Treatment

A hypertensive emergency8 is a situation where the blood pressure exceeds 180/120 mmHg and immediate lowering of blood pres-sure (not necessarily to normal limits) is re-quired to minimize or prevent end organ dam-age (hypertensive encephalopathy, intracra-nial hemorrhage, unstable angina, acute myocardial infarction, eclampsia, dissecting aortic aneurysm, acute ventricular failure with pulmonary edema). In these situations initial treatment with IV medications is appropriate (Table 1). The treatment goal is to reduce mean arterial blood pressure by no more than 25% (in 2 mins to 2 hrs), then reach 160/100 mmHg in 2 to 6 hours. This gradual reduction may help to avoid the renal, cerebral or coro-nary ischemia that may accompany more pre-cipitous falls in blood pressure. 8

Volume 1, Issue 4

Sublingual Nifedipine in Hypertensive Urgency

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Key Message The inability to control the rate or degree of blood pressure reduction with sublingual nifedipine make this agent unacceptable for the treatment of hypertensive urgency. (The Seventh Report of the Joint National Committee on Prevention, Detection, Evalua-tion and Treatment of High Blood Pressure)

PrISM is a non-profit, independent pilot project set up by the Manitoba Pharmaceutical Asso-ciation and Manitoba Health to provide educa-tion in optimal drug utilization. Funding has been provided by a government research grant and an unrestricted grant from industry.

VOLUME 1, ISSUE 4

A hypertensive urgency8 is a situation where the same eleva-tion in blood pressure (>180/120mmHg) is present but without target organ dysfunction. Patients may present with headache, shortness of breath, epistaxis or anxiety. It is desirable to lower the blood pressure in the next few hours. These situa-tions can be managed with oral doses of fast acting antihyper-tensive (Table 2). In the absence of symptoms or progressive target organ damage, elevated blood pressure alone rarely re-quires emergency treatment.

Treatment of Hypertensive Urgency8 • Rule out proximate causes (pain, dis-

tended bladder etc) • Monitor blood pressure q15-30 minutes • If blood pressure remains > 180/120mm

Hg – use oral agents (Table 2) • If high blood pressure is frequent rather

than isolated, treatment with long acting agents should be initiated.

Drug Dose Onset Duration Adverse Effects Special IndicationsVasodilatorsSodium 0.25-10mcg/kg/minute Immediate 1-2 min nausea, vomiting, most hypertensive emergenciesNitroprusside as IV infusion muscle twitching, thiocyanate caution with high intracranial

(max dose for 10 min only) and cyanide intoxication pressure or azotemiaNitroglycerin 5-100mcg/min 2-5 min 3-5min headache, vomiting, coronary ischemia

as IV infusion methemoglobinemia, tolerancewith prolonged use

Enalaprilat 1.25-5mg q6h IV 15-30min 6h precipitous fall in pressure in acute left ventricular failure,high renin states, response avoid in acute myocardial variable infarction

Hydralazine 10-20mg IV 10-20min 3-8 h tachycardia, flushing, headache, eclampsia10-50mg IM 20-30min vomiting, aggravation of angina

AdrenergicInhibitorsLabetalol 20-80mg IV bolus q 10min 5-10min 3-6h vomiting, scalp tingling, burning most hypertensive emergenciesHydrochloride 0.5-2.0mg/min IV infusion in throat, dizziness, nausea, except in acute heart failure

heart block, orthostatic hypotension

Esmolol 250-500mcg/kg/min IV bolus 1-2 min 10-20min hypotension, nausea aortic dissection, perioperativeHydrochloride then 50-100mcg/kg/min by

may repeat bolus after 5 min or increase infusion rate

Phentolamine 5-15mg IV 1-2 min 3-10min tachycardia, flushing, headache catecholamine excess

Clonidine Captopril Labetalol Dose 0.2mg PO initial 6.25mg to 50mg PO or SL 100-400mg q2 to 3 hours

0.1mg q1hour, Max: 0.8mg Onset 0.5 to 2 hours 15 minutes 0.5 to 2 hours Duration 6 to 8 hours 4 to 6 hours 4 hours Side Effects sedation, dry mouth, rash, pruritus, proteinuria, orthostatic hypotension. dizziness, loss of taste, hypotension nausea, vomiting Caution altered mental status, renal artery stenosis, congestive heart failure, severe carotid artery stenosis hyperkalemia, dehydration asthma, bradycardia References: 1. Grossman, E. et al. 1996. Should a moratorium be placed on sublingual nifedipine capsules

given for hypertensive emergencies and pseudoemergencies? JAMA. 276:1328-1331. 2. Frishman, W.H., et al. 1984. Calcium entry blockers for the treatment of severe hypertension

and hypertensive crisis. Am J Med. 77:35-45. 3. Van Harten, J., et al. 1987. Negligible sublingual absorption of nifedipine. Lancet.

1987;2:1363-1365. 4. McAllister, R.G. Kinetics and dynamics of nifedipine after oral and sublingual doses. Am J

Med. 81(S6A):2-5. 5. Diker, E., et al. 1992. Is sublingual nifedipine administration superior to oral administration in

the active treatment of hypertension? Angiology. 43:477-481. 6. Peters, F.P., et al. 1997. Prolonged QT interval and ventricular fibrillation after treatment with

sublingual nifedipine for malignant hypertension. Arch Intern Med. 157:2665-2666. 7. Messerli, F.H. 1999. The use of sublingual nifedipine: a continuing concern. Arch Intern Med.

159: 2259-2260.

8. Joint National Committee on The Detection, Evaluation and Treatment of Blood Pressure. 2003. The seventh report of the joint committee on prevention, detection, evaluation and treatment of high blood pressure. Hypertension. 42: 1206-1252.

9. Ishibashi, Y., et al. 1999. Sublingual nifedipine in elderly patients: even low dose induces myocardial ischemia. Clinical and Experimental Pharmacology and Physiology. 26: 404-410

10. Messerli, F.H., et al. 1991. Sublingual nifedipine for hypertensive emergencies. Lancet. 338:881.

11. Rehman, F., et al. 1996. “Inappropriate” physician habits in prescribing oral nifedipine capsules in hospitalized patients. American Journal of Hypertension. 9:1035-1039.

12. Gemici, K., et al. 1999. A comparison of safety and efficacy of sublingual captopril with sublingual nifedipine in hypertensive crisis. International Journal of Angiology. 8:147-149.

13. Fouzi, A., et al. 2002. The dangers of immediate release nifedipine for hypertensive crisis. P&T. 27:362-365.

Table 1. Parenteral Drugs Used to Treat Hypertensive Emergencies 8,12,13

Table 2. Oral agents used to treat hypertensive urgency8,12,13

Authors: Shawn Bugden BSc.Pharm, Kyle MacNair BSc.Pharm


Title: Benzodiazepine: Efficacy, Safety and Use ManagementOrganisation: PrISM (Manitoba)

Summary Descriptive Information This newsletter has 4 pages, 2736 words and is divided into 6 sections. There is partial use of colour but only in the logo on the first page. Evaluation Summary Reviewer #1 Reviewer#2#1 Referencing 5 5#2 Peer Review 5 5#3 Systematic Review 1 2#4 Statistics 4 3#5 Price and coverage 1 1#6 Graphics 1 1#7 Key Messages 5 5#8 Sections 2 2#9 Headings 5 5#10 Table Hierarchy 3 3#11 Table Editorial Consistency 3 3#12 Column Width 4 5#13 Readability 2 1#14 Justification 2 3#15 Colour 4 5#16 Main Message 5 4#17 Therapeutic Decision Support 3 1#18 Behaviour Target 4 3#19 Retrieval 2 1#20 Editorial Consistency 5 5


Overall Mean Score 65 Strengths The key messages for the document are highlighted on the front page. The document provides comprehensive decision support in the use of these products and there is evidence of peer review. Weaknesses The document is extremely heavy text base and there is a complete lack of graphics or tables. The document also lacks comparative pricing information.

Introduction Persons over the age of 65 years currently en-compass 12.8% of the Canadian population.1 By 2026 this demographic will make up approxi-mately 21% of the overall population.1 Appro-priate drug use in older persons has always been a concern and, as their population rises, will become an increasingly important health care issue. The use of psychotropic medica-tions, especially benzodiazepines, in this demo-graphic has been a matter of concern for many years. The purpose of this article is to briefly

describe the prevalence of benzodiazepine use, the efficacy of these agents in the man-agement of insomnia and the risks associated with benzodiazepine use in older persons. We will also provide drug management information that may aid in the appropriate utilization of these drugs in the elderly.

Benzodiazepines: Efficacy, Safety and Use Management

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The Rural Evaluation of Academic Detailing (READ) study is an initiative of the Prescription Information Services of Manitoba. The study is designed to investigate the most effective means of improving professional practice.

Key Points • Clinical efficacy of benzodiazepines in the treatment of insomnia is not well defined. • Efficacy in the treatment of insomnia with benzodiazepines has not been shown

beyond 2 weeks of therapy. • Literature evidence shows that use of benzodiazepines is associated with:

− decreased cognitive and physical function − increase in risk of falls in the elderly − increased risk of fractures in the elderly − increased risk of motor vehicle accidents

• Long-term use of benzodiazepines in the elderly has been recorded at similar lev-els in countries all over the world.

• Every effort should be taken to identify root cause of insomnia. • Every effort should be taken to insure appropriate therapy initiation and discon-

tinuation of these agents in patients when it is no longer medically necessary.

Prevalence A 5-year longitudinal cohort study gives an indi-cation of the benzodiazepine use in elderly Ca-nadians.6 The study participants were subject to 2 comprehensive health interviews (in person with study staff when possible) which included self-reported medication usage. The study found that 26.4% (769/2914) of subjects (age >65 years) were using benzodiazepines in 1991 and 25.2% (272/1081) of the study group were using them in 1996.6 Subjects in institutional residence were significantly more likely to be on a benzodiazepine than subjects living inde-pendently.6 Over 15% of the subjects were

using benzodiazepines continuously from 1991 to 1996.6

Another Canadian study looked at the long-term use of benzodiazepines in the Quebec elderly population. This 1 year sample of community-dwelling people over the age of 65 years found that 20.8% of the study population were long-term continuous users (at least 75% of the time for at least 6 months) of benzodiazepines.7 The study found that people older than 75 years were more than twice as likely to be on long-term continuous therapy compared to people 65-74 years old.7

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Prevalence (continued) In a British survey of 1020 elderly (age>65 years) people living at home, they reported 16% of those surveyed used a prescription hypnotic at least “sometimes”.8 The propor-tion of subjects taking a hypnotic agent rose with age, and 25% of the patients using a pre-

scription sleeping medication had been on them for greater than 10 years.8

The average usage of benzodiazepines in Manitoba Personal Care Homes has been recorded at slightly above 20% for the period of January 31st to March 31st of this year.9

Efficacy and Adverse Effects Considering the ubiquitous use of benzodi-azepines in the management of sleep disor-ders, there is a surprisingly small amount of literature supporting its efficacy and safety. A meta-analysis conducted by the Canadian Medical Association in 2000 examined this topic.2 They identified 8 studies (n=539 sub-jects of a wide age range) that compared ben-zodiazepines to placebo in reducing patient self-reported sleep latency and total sleep du-ration. The analysis of these 8 studies showed an overall, significant reduction in sleep latency of 11.7 minutes and a signifi-cant increase in total sleep duration of 48.4 minutes.2 Four trials (n=159) that used objec-tive measures of sleep, including EEG meas-ured sleep efficiency and wake times as well as comprehensive post-sleep questionnaires, found a non-significant 4.2 minute reduction in sleep latency and a significant 61.8 minute increase in total sleep duration.2 In terms of adverse effects, the pooled information on 502 patients showed benzodiazepine use to be associated with an 80% relative risk increase of experiencing an adverse effect.2 The most commonly documented effects were drowsi-ness, dizziness/light-headedness and cogni-tive impairment. None of the trials reviewed in the meta-analysis studied the use of benzodi-azepines for more than 2 weeks.2

The long term cognitive adverse effects of benzodiazepines in older persons also need

to be considered. A large (1176 patients), 4-year, longitudinal study examined the effects of benzodiazepine usage on cognitive func-tion in patients aged 60-70 years.10 The study found that chronic users of benzodi-azepines consistently scored worse than non-users in 4 of the 5 performance tests. The most notable of these tests was the Mini-Mental State Examination (MMSE). More chronic benzodiazepine users (26.3%) experi-enced a >3 point reduction in their MMSE over the 4 year study compared with non-user group (14.9%, OR 1.9).10 Chronic use of these agents is also associated with other intellectual impairments including anterograde amnesia, decreased short-term recall and in-creased forgetfulness.3 One study found that cognitive impairment associated with benzodi-azepine use improved following discontinua-tion of the psychoactive agent.4 In addition to cognitive impairment, use of benzodiazepines has been associated with physical impairment. Using a battery of physical tests, Gray et al. found benzodi-azepine users preformed significantly worse than non-users.11 The physical performance tests used in this study are highly predictive of subsequent falls, hospitalization and institu-tionalization.11 The type of benzodiazepine used (i.e. short vs. long half life) did not im-pact the performance test, but higher doses were correlated with worse performance scores.11

Motor Vehicle Accident A large case-control study conducted in Que-bec examined the role of benzodiazepines in motor vehicle accidents (MVA) that lead to bodily injury in drivers aged 67-84 years. The study by Hemmelgarn et al. also examined if the half-life, the dose or if the patient was newly started on the benzodiazepine had any impact on the accident rate. The study exam-ined 5579 cases with 55790 controls.16 The

study found that exposure to long-half life ben-zodiazepines was associated with a significant 3.2% absolute risk increase of MVA.16 The relative risk increase was 28%.16 The relative risk rose to 45% if the patient had started the long-acting agent within the previous 7 days.16 However, the difference in risk from baseline was still significant at 1 year suggesting that complete tolerance to the psychomotor effects of the drugs does not occur.16

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Risk of Falls and Fractures In a recent cross-sectional study of elderly (age 60-79) British women, Lawlor et al. looked at the effects of comorbidity and drug use on risk of falls.12 According to Lawlor the most important risk factor for falls was multiple comorbidities not polypharmacy.12 However, use of hypnotics and anxiolytics was inde-pendently associated with a 41% relative in-crease in at least one fall and 74% increase in 2 or more falls.12

Ray et al conducted a sampling chart review of 4501 hip fracture cases in patients (age >65 years) admitted to Saskatchewan hospitals from 1977-1985.13 The chart review showed the use of long-acting benzodiazepines (mostly diazepam, flurazepam and chlordi-azepoxide) increased the relative and abso-lute risk of hip fractures by 70% and 2% re-spectively.13 The review did not find any in-creased risk of fractures in those patients tak-ing a short acting benzodiazepine.13

A cohort study of 125,203 New Jersey Medi-caid patients aged 65 years or greater pro-vides additional valuable information about the risk of falls in the elderly.14 They identified 2312 first hip fractures over a 3 year period. The incident rate was 17.39 events per 1000 patient years for those taking any benzodi-azepine compared to 11.29 in the population not taking the agents.14 This represented a significant 54% increase in risk.14 Unlike the Ray et al. trial, this study found an increased risk of fractures in patients using short half-life benzodiazepines but not with long half-life

agents. This study also looked for any in-creased risk of hip fractures in patients re-cently started on a benzodiazepine. The inci-dent rate in the first 2 weeks after starting a benzodiazepine was 26.20 per 1000 patient years.14 This incident rate was significantly higher than those who were on the agents continuously. The authors of the study sug-gest that, “Given the cumulative published data reporting increased hip fracture risk with exposure to all types of benzodiazepines, short half-life benzodiazepines should not be considered safer than long half-life benzodi-azepines.”14

A study conducted in the Netherlands identi-fied patients aged 55 years and up with trau-matic femur fractures.15 The database review identified 458 of these fractures between 1986 and 1992. This study also found benzodi-azepine use associated with a 70% increased risk of fracture.15 However, they found the short-acting agents to be more likely to be as-sociated with fracture than the long-acting agents.15 A 150% increased relative risk was seen in patients concurrently exposed to more than 1 benzodiazepine.15 Increased risk of falling was also positively associated with higher daily doses.15

To summarize, benzodiazepines of both short and long half lives, have been associated with an increased risk of fractures in older persons. The risk appears to be higher in the first few weeks after therapy initiation and the risk in-creases greatly with the concurrent use of more than 1 benzodiazepine.

Benzodiazepine Use Management Integral to the prescribing of any medication is insuring there is clear indication for therapy initiation. This is especially important in the initiation of benzodiazepines in the elderly in light of the treatment risks. Insomnia should first be considered a symptom rather than a diagnosis.17 Psychiatric disorders such as depression or anxiety, medical disorders such as arthritis, congestive heart failure, pain and sleep apnoea, and medication use such as caffeine, alcohol and psychotropics can nega-tively impact sleep.17 Identification and man-agement of these root causes should precede pharmacological intervention. Poor sleep hy-

giene should also be considered in a patient presenting with sleep disturbance. The imple-mentation of cognitive-behavioural interven-tions in patients with poor sleep hygiene have been found to manage insomnia as well as pharmacotherapy in older patients.18 Inter-ventions such as avoidance of caffeine, to-bacco and alcohol, daytime napping, extreme temperature and noise in the bedroom are all integral to good sleep hygiene. As well, regu-lar daytime exercise, sleep restriction, consis-tent wake-up times and evening fluid restric-tion are all parts of cognitive-behavioural ther-apy that improve sleep patterns.18 If the need for pharmacological intervention is

By: Kyle MacNair BSc.Pharm, ACPR & Shawn Bugden BSc.Pharm, MSc. Reviewed By: Patrick Montgomery MD, FRCPC, Cert. Spec. (Ger Med) Ruby Grymonpré BSc.Pharm, PharmD


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established, a review article in the CMA Jour-nal recommends following these principles:17

• use only medications known to be effica-cious and safe; efficacy and safety be-yond that of placebo should be proven.

• use the lowest effective dose for the shortest period of time (less than 2 weeks), and aim for intermittent dosing.

• if use is prolonged or the dose is high, the discontinuation of sedatives should be gradual unless the patient can be ob-served for withdrawal reactions.

In many cases, benzodiazepine use in older persons is protracted with the inciting reason for prescribing being long since forgotten. In these cases, the withdrawal of benzodi-azepine can be quite difficult. Several factors such as withdrawal symptoms, fear of re-bound insomnia and anticipatory anxiety com-plicate the process.17 The use of cognitive-behavioral therapy to manage sleep and anxi-ety disorders has been found to ease the re-moval of benzodiazepines.17 There are a number of validated method of benzodi-azepine withdrawal. They all recommend a tapering schedule to minimize the possibility of withdrawal symptoms that include, but are not limited to anxiety, insomnia, restlessness and depersonalization. The tapering sched-ules usually involve one of two approaches. The first approach is to gradually reduce the

dose of the current benzodiazepine the patient is on by 10-25% per week for 6-12 weeks until off the drug.19 The disadvantage of this ap-proach is dosage forms of most benzodiazepi-nes do not lend themselves to small percent-age reductions. The second approach is to substitute an equivalent dose of diazepam (a long half-life agent) and taper by 2.5 to 5mg every 1-2 weeks.19 However, if a patient is on a short acting agent, switching to one with a long half-life may subject the patient to exces-sive daytime sedation.19 Because there are many factors to consider when tapering ben-zodiazepines (e.g. what drug the patient is on, what dosage form, how long the patient has been on it, the patient’s willingness to with-draw), it is difficult to formalize the process. It is important to remember that most patients require very gradual dosage reduction and supportive counselling with consistent follow-up in order to successfully withdraw from these medications. Patients must also be counselled that withdrawal reactions occur in approximately 1/3 of patients, but the benefits of discontinuation outweighs these transient side effects. A copy of “Tapering Benzodi-azepines”, an educational reference for physi-cians, is included with this newsletter that pro-vides information on rationale, strategies, con-siderations and example tapering regimens that we hope you will find useful.

References 1. Statistics Canada. http://www.statcan.ca/english/Pgdb/demo31d.htm , Accessed

May 7th, 2004.

2. Holbrook AM, Crowther R, et al. Meta-analysis of benzodiazepine use in the treatment of insomnia. CMAJ 2000; 162(2): 225-233.

3. Bogunovic OJ, Greenfield SF. Use of Benzodiazepines Among Elderly Patients. Psychiatric Services 2004; 55(3): 233-235.

4. Gray S, Lai K, et al. Drug-induced cognition disorders in the elderly. Drug Safety 1999; 21: 101-122.

5. Poyares D, Guilleminault C, et al. Chronic benzodiazepine usage and with-drawal in insomnia patients. J of Psychiatric Research 2004; 38: 327-334.

6. Hogan DB, Maxwell C, et al. Prevalence and potential consequences of benzo-diazepine use in senior citizens: Results from the Canadian Study of Health and Aging. Can J Clin Pharmacol 2003; 10(2): 72-77.

7. Egan M, Moride Y, et al. Long-term Continuous Use of Benzodiazepines by Older Adults in Quebec: Prevalence, Incidence and Risk Factors. J American Geriatrics Society 2000; 48: 811-816.

8. Morgan K, Dallosso H, et al. Prevalence, frequency, and duration of hypnotic drug use among the elderly living at home. BMJ 1988; 296: 601-602.

9. Cost-Resident Drug Listing by Category by PCH for the Claim Period of 2004-01-31 to 2004-03-31. Manitoba Health Publication. Received 2004-04-20.

10. Paternit S, Dufouil C, Alperovitch A, et al. Long-Term Benzodiazepine Use and Cognitive Decline in the Elderly: The Epidemiology of Vascular Aging Study. Journal of Clinical Psychopharmacology 2002; 22(3): 285-293.

11. Gray SL, Penninx BW, Blough DK, et al. Benzodiazepine Use and Physical Performance in Community-Dwelling Older Women. Journal of the American Geriatric Society 2003; 51: 1563-1570.

12. Lawlor DA, Patel R, et al. Association between falls in elderly women and

chronic diseases and drug use: cross sectional study. BMJ 2003; 327: 712-717.

13. Ray WA, Griffin MR, et al. Benzodiazepines of Long and Short Elimination Half-life and the Risk of Hip Fracture. JAMA 1989; 262(23): 3303-3307.

14. Wagner AK, Zhang F, Soumerai SB, et al. Benzodiazepine Use and Hip Frac-tures in the Elderly. Archives of Internal Medicine 2004; 164: 1567-1572.

15. Herings, RM, Bruno H, et al. Benzodiazepines and the Risk of Falling Leading to Femur Fracture. Arch Intern Med 1995; 155: 1801-1807.

16. Hemmelgarn B, Suissa S, et al. Benzodiazepine Use and the Risk of Motor Vehicle Crash in Elderly. JAMA 1997; 278(1): 27-31.

17. Holbrook AM, Crowther R, et al. The diagnosis and management of insomnia in clinical practice: a practical evidence-based approach. CMAJ 2000; 162(2): 216-220.

18. Bogunovic OJ, Greenfield SF, et al. Use of Benzodiazepines Among Elderly Patients. Psychiatric Services 2004; 55(3): 233-235.

19. Mistir J, Grymonpre R. Tapering Benzoidazepines. Educational material devel-oped for the CME departments of Canada’s medical schools as part of Health Transition Fund Project. January, 2000.

http://www.statcan.ca/english/Pgdb/demo31d.htm�


Title: Transdermal Fentanyl: Pitfalls in Drug TherapyOrganisation: PrISM (Manitoba)

Summary Descriptive Information This newsletter has 3 pages, 1450 words and is divided into 3 sections. There is partial use of colour but only in the logo on the first page. Evaluation Summary Reviewer #1 Reviewer#2 #1 Referencing 4 5#2 Peer Review 5 5#3 Systematic Review 1 1#4 Statistics 3 1#5 Price and coverage 1 1#6 Graphics 2 4#7 Key Messages 5 5#8 Sections 5 5#9 Headings 5 5#10 Table Hierarchy 3 3#11 Table Editorial Consistency 3 3#12 Column Width 4 3#13 Readability 3 4#14 Justification 3 4#15 Colour 5 5#16 Main Message 5 5#17 Therapeutic Decision Support 4 4#18 Behaviour Target 5 4#19 Retrieval 5 3#20 Editorial Consistency 4 5


Overall Mean Score 75 Strengths The key messages appear on the front page and are associated with relatively clear behaviour targets. There is clear evidence of peer review. Weaknesses Although there is some graphics within the document, it is still heavily text based. As well, the document lacks any alternative product information.

Background The fentanyl patch (Duragesic®) was intro-duced into the Canadian market in 1992.1 Its unique reservoir structure is designed to de-liver a relatively constant supply of the opioid over a 72 hour period.2 Delivery via the cuta-neous route is convenient for patients unable to swallow oral analgesics (e.g. patients with head and neck malignancies), patients who suffer from nausea and vomiting or patients with bowel obstruction.3 Fentanyl itself is a semi-synthetic opioid that was first introduced as an intravenous anaes-thetic and analgesic.4 Fentanyl is estimated to be 80 times more potent then parenteral mor-phine.4 However, the exact morphine equiva-lent dose delivered by the fentanyl patch is not known because of large inter-patient vari-ability in absorption. The company suggests that the 25mcg/hour patch, which is the low-est strength patch currently available on the Canadian market, delivers between 45 and 135mg of oral morphine equivalents over the course of 24 hours.2 Many practitioners equate topical 25mcg/hour fentanyl to 100mg/day oral morphine as a “rule of thumb”. Because of this drug’s very high potency, appropriate patient selection is cru-cial to its safe utilization.

Pitfall: Use in Opiate Naive The product monograph states that use of patch is contraindicated in the treatment of opioid-naïve patients.2 The following cases provide examples where that contraindication was not heeded. The first two cases occurred in Canada and were published in the October is-sue of the Canadian Adverse Event newsletter.5

• 15 year old female started on a 25mcg/hour fentanyl patch for management of chronic headaches. Twenty-one hours after first patch application the patient was found un-responsive. Patient was resuscitated but later died of anoxic brain injury.5

• 14 year old male started on a 25mcg/hour fentanyl patch for management of throat pain related to mononucleosis. Fourteen hours after first patch application the pa-tient was found unresponsive, efforts to re-vive the patient failed.5

Transdermal Fentanyl: Pitfalls in Drug Therapy

February, 2005

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Key Messages • The fentanyl patch is efficacious in the management of chronic, stable, cancer and non-

cancer pain. • Provision of the fentanyl patch to an opiate naïve patient can lead to severe adverse events

including death. • Safe and effective use of the fentanyl patch is dependant on appropriate patient selection and

close follow-up for therapeutic benefit and adverse effects. • The shortest interval for up-titration of the fentanyl patch should be every 3 days. Changing

the patch more frequently can predispose patients to adverse drug events.

PrISM is a non-profit, independent pilot pro-ject set up by the Manitoba Pharmaceutical Association and Manitoba Health to provide education in optimal drug utilization. Fund-ing has been provided by a government re-search grant and an unrestricted grant from industry.


187 St. Mary’s Road ● Winnipeg, Manitoba R2H 1J2 ● Tel. / Fax (204) 231-4688 ● Email: [email protected]

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• 84 year old female with multiple myeloma

presented to hospital with uncontrolled back pain. Patient was previously taking a low potency opiate (codeine) preparation. Patient was started on 50mcg/hour fen-tanyl patch and discharged, but was read-mitted 12 hours later with symptoms of dizziness, nausea, flushing and vomiting.6

• 53 year old patient with bone pain related to myelocytic leukemia. The patient was not taking opioids to manage the pain, un-til he was started on a 100mcg/hour fen-tanyl patch. The next day the patient could not be aroused and was taken to the hospital for intravenous opiate antagonist therapy. The patient recovered.7

Studies conducted in post-operative, opiate naïve patients have shown that opioid-induced respiratory depression can occur at plasma fentanyl levels as low as 1.25mcg/L.8 Pharmacokinetic studies done on the patch have seen blood levels from 0.94-1.54 mcg/L within 36 hours after application of a 25mcg/hour fentanyl patch.9 Despite the documented contraindication and the known incidence of severe adverse effects and death related to application of the fen-tanyl patch on opioid naïve patients, clinical trials have been conducted to see if carefully selected patients could be started directly on to the fentanyl patch. Trials where patients previously on no opioids or low potency opioids were started on the patch have found no increase in the risk of respiratory depres-sion or other severe adverse events.3,10,11 Pa-tient selection is key to the success of these

trials. All of the patients had severe, uncon-trolled, chronic cancer pain and patients at high risk of respiratory depression were not allowed into the trials. 3,10,11 Also key to the success of these trials is rigorous follow-up involving patient admission to hospital or fre-quent, regular communication between the physician and patient. 3,10,11

Pitfall: Dosing Titration Another common mistake that leads to ad-verse events with the fentanyl patch is dosing titration errors. Delivery through the cutane-ous route does not allow for immediate sys-temic activity of the drug. In kinetic trials looking at the absorption and distribution of the fentanyl patch, they found detectable blood levels within 1-2 hours of patch being applied.8 However, minimum effective blood concentrations of the drug to produce analge-sia are not seen for 12-16 hours and maxi-mum blood concentrations are not seen for 17-48 hours.8 There is substantial inter-patient variability in the rate of absorption as reflected by the wide ranges in time to maxi-mum blood concentrations. Because of the extended time required for the plasma concen-trations of the drug to stabilize, it is recom-mended that the shortest dosing titration pe-riod be 3 days.8 The following are case re-ports where these titration guidelines were not followed: • Elderly patient previously stabilized on an

oral high-potency opiate admitted to the hospital for increasing pain. The patient started on 50mcg/hour patch which was increased twice in 72 hours. Patient dis-charged on 100mcg/hour patch but was readmitted for somnolence, confusion and falling.7

• 72 year old female post-op surgery and ra-

diation for squamous cell carcinoma pre-scribed 25mcg/hour patch. The following day patch increased to 50mcg/hour with instructions to increase patch by 25mcg/hour each day until pain is relieved. Days later patient admitted to hospital with hal-lucinations on 125mcg/hour transdermal fentanyl.12

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Summary The Duragesic® patch has become an impor-tant therapeutic option in the management of cancer and non-cancer pain. Reports indicate that the fentanyl patch causes less constipa-tion, nausea and vomiting than oral morphine and is as effective, if not more effective, an analgesic.8 The unique delivery system allows for a convenient dosing schedule of every 3 days.2 However, aspects of the fentanyl patch, including the very large amount of high potency opioid in even the lowest dos-age of patch and the delayed onset of analge-sic activity, complicate the use of this drug. Physicians, pharmacists and patients must be aware of these nuances in order to minimize the risk of adverse events and insure that only appropriate patients are receiving the drug at the correct dose. As shown by numerous case reports, failure to respect the complexi-ties and potency of the fentanyl patch can lead to severe adverse events including pa-tient death.

References 1. Health Canada Therapeutic Drug Product

Database. Accessed November 1,2004 http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/index_drugs_dpd_e.html

2. Duragesic (fentanyl transdermal delivery sys-tem) Product Monograph. CPS 2004: 654-657.

3. Vielvoye-Kerkmeer Ans PE, Mattern C, Uitendaal MP. Transdermal Fentanyl in Opioid-Naïve Cancer Pain Patients: An Open Trial Using Transdermal Fentanyl for the Treatment of Chronic Cancer Pain in Opioid-Naïve Patients and a Group Using Codeine. Journal of Pain and Symptom Management 2000; 19(3): 185-192.

4. Hanks GW, Conno F, Cherny N, et al. Mor-phine and alternative opioids in cancer pain: the EAPC recommendations. British Journal of Cancer 2001; 84(5): 587-593.

5. Raymond B. Transdermal fentanyl (Duragesic): Respiratory arrest in adolescents. Canadian Adverse Reaction Newsletter 2004; 14(4): 1-2.

6. Ross JR, Quigley C. Transdermal fentanyl: in-formed prescribing is essential. European Jour-nal of Pain 2003; 7: 481-483.

7. Grissinger M. Fentanyl Transdermal System: Unsafe in Inexperienced Hands. P&T 2002; 27(3): 132.

8. Jeal W, Benfield P. Transdermal Fentanyl. A review of its pharmacological properties and therapeutic efficacy in pain control. Drugs 1997; 53(1): 109-138.

9. Ashburn MA, Ogden LL, Zhang J, et al. The Pharmacokinetics of Transdermal Fentanyl De-livered with and without Controlled Heat. The Journal of Pain 2003; 4(6): 291-297.

10. Mystakidou K, Tsilika E, Kouloulias V, et al. Long-term Cancer Pain Management in Mor-phine Pre-treated and Opioid Naïve Patients with Transdermal Fentanyl. International Jour-nal of Cancer 2003; 107: 486-492.

11. Tawfik OM, Bryuzgin V, Kourteva G. Use of transdermal fentanyl without prior opioid stabi-lization in patients with cancer pain. Current Medical Research and Opinion 2004; 20(3): 259-267.

12. Steinberg RB, Gilman DE, Johnson F. Acute Toxic Delirium in a Patient Using Transdermal Fentanyl. Anaesth Analg 1992; 75: 1014-1016.

Co-Authored by: Cornelius Woelk (MD, CCFP, FCFP) Kyle MacNair (BSc.Pharm, ACPR) Shawn Bugden (BSc.Pharm, M.Sc.) Reviewed by: Paul Daenick (MD, M.Sc., FRCPC)


Title: Oral Vitamin K1 in the Management of High INROrganisation: PrISM (Manitoba)

Summary Descriptive Information This newsletter has 3 pages, 1695 words and is divided into 3 sections. There is partial use of colour in the logo and figures. Evaluation Summary Reviewer #1 Reviewer#2#1 Referencing 4 5#2 Peer Review 5 5#3 Systematic Review 1 2#4 Statistics 4 4#5 Price and coverage 1 1#6 Graphics 4 5#7 Key Messages 4 5#8 Sections 5 5#9 Headings 5 5#10 Table Hierarchy 4 5#11 Table Editorial Consistency 2 3#12 Column Width 3 4#13 Readability 4 4#14 Justification 5 5#15 Colour 4 5#16 Main Message 4 5#17 Therapeutic Decision Support 5 5#18 Behaviour Target 4 4#19 Retrieval 5 4#20 Editorial Consistency 4 4


Overall Mean Score 81 Strengths This document provides good therapeutic decision support for a relatively clear behaviour target. There extensive peer-review (pharmacist experts, physician expert) is well documented. Weaknesses The key messages in the newsletter are on the 3rd page making them more difficult to find. In addition, the main treatment algorithm is provided in text when a graphic representation would be more effective.

The ability to appropriately deal with an ele-vated INR is an important clinical skill. Al-though the annual risk of bleeding for a patient on warfarin therapy is quite low at 1.1 to 8.1%1, abnormality in the INR is a major determinant of absolute bleeding risk. The bleeding risk dou-bles when comparing risk at an INR of 2 to 2.9 versus 3 to 4.4. That risk quadruples at 4.5 to 6 and quintuples at INR>7. Every 3 years the American College of Chest Physicians (ACCP) publish a comprehensive set of evidence-based guidelines on an array of topics relating to anti-coagulation. The most

recent of these guidelines were published in September of 2004.2 One aspect of these guidelines, which is of particular value to physi-cians, is the management of elevated INRs in patients on warfarin therapy. The following is a reiteration of their recommendations2:

Volume 1, Issue 3

Oral Vitamin K1 in the Management of High INR

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┼ Grade 2C: Very weak recommendation based on observational studies. Other alternatives may be equally reasonable. * Administration of fresh frozen plasma may be preferred over prothrombin complex concentrate due to its prothrombotic activity. ¶ Grade 1C: Intermediate-strength recommendations based on observational studies. May change when stronger evidence available.

INR above therapeutic range but <5; no significant bleeding: Lower dose or omit one dose, monitor more frequently, and resume at lower dose when INR

therapeutic; if only minimally above therapeutic range, no dose reduction may be required. (Grade 2C)┼

INR ≥ 5.0 but < 9.0; no significant bleeding Omit next one or two doses, monitor more frequently and resume at lower dose when INR in

therapeutic range. Alternatively, omit dose and give vitamin K1 (≤ 5 mg orally, usually 1 to 2.5mg3), particularly if at increased risk of bleeding. If more rapid reversal is required be-cause the patient requires urgent surgery, vitamin K1 (2 to 4 mg orally) can be given with the expectation that a reduction of the INR will occur in 24 h. If the INR is still high, additional vi-tamin K1 (1 to 2 mg orally) can be given. (Grade 2C) ┼

INR ≥ 9.0; no significant bleeding Hold warfarin therapy and give higher dose of vitamin K1 (5–10 mg orally) with the expecta-

tion that the INR will be reduced substantially in 24–48 h. Monitor more frequently and use additional vitamin K1 if necessary. Resume therapy at lower dose when INR is therapeutic. (Grade 2C) ┼

Serious bleeding at any elevation of INR Hold warfarin therapy and give vitamin K1 (10 mg by slow IV infusion), supplemented with

fresh plasma or prothrombin complex concentrate*, depending on the urgency of the situa-tion; recombinant factor VIIa may be considered as an alternative to prothrombin complex concentrate*; vitamin K1 can be repeated every 12 h. (Grade 1C)¶

Life-threatening bleeding Hold warfarin therapy and give prothrombin complex concentrate* supplemented with vitamin

K1 (10 mg by slow IV infusion); recombinant factor VIIa may be considered as alternative to prothrombin complex concentrate*; repeat if necessary, depending on INR. (Grade 1C) ¶

PrISM is a non-profit, independent pilot project set up by the Manitoba Pharmaceutical Associa-tion and Manitoba Health to provide education in optimal drug utilization. Funding has been pro-vided by a government research grant and an unrestricted grant from industry.

August, 2005

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A key part of these recommendations is which form of Vitamin K1 is appropriate under what circumstances. The guidelines do not discuss the use intramuscular (IM) Vitamin K1, the use of this administration route is not recommended due to erratic absorption and increased risk for hema-toma.4

Intravenous (IV) Vitamin K1 The IV use of Vitamin K1 is reserved for use in patients with serious bleeding. There are two reasons for avoiding this route in all but the most severe cases. First, there have been anaphylactic events associated with intravenous administra-tion.2 Some authors suggest the reactions can be avoided by slowing the administra-tion rate (dosing over 5-10 minutes); how-ever, anaphylactic reactions have been reported with slow administration.5 Sec-ond, IV administration leads to dramatic and persistent reductions in the INR lev-els. In 1992 Shetty et al. reported that 50% of patients with elevated INRs (6.4-17.8) had their level drop below 2 within 24 hours after administration of 1mg IV vitamin K1.6 Vitamin K1 administration can lead to "warfarin resistance", a persistent reduction in INR despite resumption of warfarin. In patients with a demonstrated high risk of clotting who need to be re-started on warfarin, one may consider starting heparin until a therapeutic INR is attained.

Subcutaneous (SC) Vitamin K1 The SC route, although touted as a safer alternative to the IV route in previous ACCP guidelines (1995,1998) has been found to be inferior to other delivery routes. In a trial by Whitling et al. that com-pared IV, SC and oral delivery, the subcutaneous route demon-strated a lack of effectiveness compared to the other 2 routes, although the study size was very small (total of 33 patients).5

Another study by Nee et al. looked at the SC versus IV administration routes.7 Pa-tients were given 0.5mg by either route for an INR of 6-10, and 3mg if the INR was above 10. Within 24 hours, the average INR in the SC group was 5.4 vs. 3.7 in the IV group. Both interventions led to INR < 3 within 72 hours. The authors concluded that the IV route was more effective at rap-idly returning patients to a therapeutic INR range. A smaller study by Raj et al. made a similar conclusion that SC administration was not as effective as IV.8

Oral Vitamin K1 The oral route is an attractive option from a safety and convenience point of view. Evi-dence from the Whitling trial as well as 3 other small non-comparative trials showed that oral vitamin K1 at doses of 1 to 2.5mg could predictably reduce moderately ele-vated INR values.2,5 It was not until 2002 that the efficacy of oral and SC delivery were compared by Crowther et al.9 The study looked at the efficacy of 1mg Vitamin K1 delivered through the 2 different routes. Figure 1 shows the reductions of INR over the 72 hours of the study and Figure 2 shows the INR reductions of each patient between the baseline and 24 hour INR sample.

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INR

Baseline 24 Hours 48 Hours 72 Hours

Oral (n=26) Subcutaneous (n=25)

Figure 1.9 Comparative INR Reductions with Oral and SC Vitamin K1

Figure 1 indicates that, at 24 hours, the likelihood of being in the therapeutic range was significantly better in the oral group compared to subcutaneous (OR 4.32 [95% CI, 1.13-17.44]). Hence, the authors concluded that oral delivery of Vitamin K1 is more effective in bringing the INR down to therapeutic lev-els (without dropping sub-therapeutic) as well as having much less inter-patient variability in the rate of INR reduction (See Figure 2).

Conclusion Guidelines produced by the American College of Chest Phy-sicians are a useful resource in the management of elevated INRs. They recommend the routine use of oral Vitamin K1 in patients with moderately elevated INRs without serious bleed-ing. In Canada, there are no single-entity oral Vitamin K1 products available on the market.9 As such, the IV formula-tion must be withdrawn from the vial and used orally, this method of administration was used in the Crowther et al. trial.9 When giving the IV formulation orally, it can be given straight, or diluted in water or juice just prior to administration.

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By: Kyle MacNair BSc.Pharm, ACPR & Shawn Bugden BSc.Pharm, MSc. Reviewed By: Catherine Moltzan MD, FRCPC Peter Toogood BSc.Pharm, ACPR

Key Messages • The use of oral Vitamin K1 is the preferred delivery route in managing moderately

elevated INR as long as the patient is not bleeding significantly. • Use of subcutaneous and intramuscular routes for administration of Vitamin K1 are

not recommended. • The use of intravenous Vitamin K1 should be reserved for elevated INR in patients

who are experiencing serious bleeding. • The use of the lowest necessary dose of Vitamin K1 as well as preferential use of

oral administration (over IV) limits the development of “warfarin resistance”.

Figure 2. 9 Twenty-four hour change in INR with oral and SC Vitamin K1

References: 1. Gallus A, Baker R, Chong B, et al. Con-

sensus guidelines for warfarin therapy: Recommendations from the Australasian Society of Thrombosis and Haemostasis. Medical Journal of Australia 2000; 172: 600-605.

2. Ansel J, Hirsh J, Poller L, et al. The Pharmacology and Management of Vitamin K Antagonists. Chest 2004; 126: 204S-233S.

3. Rosenthal B, Gin (ed). Clinical Handbook of Pharmacotherapy 2004. Health Science Centre, WRHA. Page 9.

4. Vitamin K: Adult Parenteral Drug Mono-graph. Winnipeg Regional Health Author-ity September 2004.

5. Whitling A, Bussey H, Lyons R. Compar-ing Different Routes and Doses of Phyton-adione for Reversing Excessive Anticoagu-lation. Archives of Internal Medicine 1998; 158: 2136-2140.

6. Shetty H, Backhous G, Bentley D, et al. Effective reversal of warfarin-induced excessive anticoagulation with low-dose vitamin K1. Thrombosis and Haemostasis 1992; 67: 13-15.

7. Nee R, Doppenschmidt D, Donovan D, et al. Intravenous Versus Subcutaneous Vita-min K1 in Reversing Excessive Oral Anti-coagulation. American Journal of Cardiol-ogy 1999; 83: 286-288.

8. Raj G, Kumar R, McKinney P. Time Course of Reversal of Anticoagulant Effect of Warfarin by Intravenous and Subcutane-ous Phytonadione. Archives of Internal Medicine 1999; 159: 2721-2724.

9. Crowther M, Douketis J, Schnurr T, et al. Oral Vitamin K Lowers the International Normalized Ratio More Rapidly Than Subcutaneous Vitamin K in the Treatment of Warfarin-Associated Coagulopathy. Annals of Internal Medicine 2002; 137: 251-254.



Title: Spironolactone in Heart Failure: Good for All? Organisation: PrISM (Manitoba)

Summary Descriptive Information This newsletter has 4 pages, 2014 words and is divided into 6 sections. There is partial use of colour only in logo on the first page. Evaluation Summary Reviewer #1 Reviewer#2#1 Referencing 4 5#2 Peer Review 5 5#3 Systematic Review 1 1#4 Statistics 4 5#5 Price and coverage 1 1#6 Graphics 4 3#7 Key Messages 5 5#8 Sections 1 3#9 Headings 5 5#10 Table Hierarchy 5 5#11 Table Editorial Consistency 3 4#12 Column Width 4 5#13 Readability 3 3#14 Justification 3 5#15 Colour 5 5#16 Main Message 5 5#17 Therapeutic Decision Support 3 4#18 Behaviour Target 4 4#19 Retrieval 5 3#20 Editorial Consistency 2 4


Overall Mean Score 76 Strengths The key messages for the document are highlighted on the front page, and there is clear evidence of peer review. The use of a case-based discussion threaded throughout the newsletter provides a clinical context that practitioners may find useful. Weaknesses The document is heavy text based which may not be preferred by busy practitioners. There is a lack of graphics and tabular information used within the document to convey information.

Case

Mr. HK is a 71 year old male who has been a pa-tient of your clinic for the last 10 years. You have inherited care of the patient from a colleague who recently retired. He has a complicated medical history including 2 myocardial infarctions (1999 and 2001), Type II diabetes diagnosed in 2001 and progressively worsening heart failure. His medication list is as follows: EC ASA 81mg, 1 tablet QD Ramipril 5 mg, 1 capsule QD Glyburide 5 mg, 2 tablets BID Furosemide 40 mg, 1 tablet BID Potassium Chloride 600mg, 1 tablets BID Omeprazole 20mg, 1 tablet QD Ever since his last heart attack, HK has been making an effort to live a healthier life; he follows a strict diabetic diet and walks at least ½ hour twice a week. HK comes to you today after seeing his cardiolo-gist last week. The cardiologist recommends you start the patient on spironolactone 25mg, 1 tablet once daily. Is this a reasonable recommendation from the cardiologist? What is the rationale be-hind this therapeutic decision? Discussion

Spironolactone has long been a mainstay in the management of edema and ascites associated with cirrhosis but has recently returned to the thera-peutic spotlight due to some high profile re-search. This potassium-sparing diuretic works by blocking aldosterone receptors. Aldosterone de-creases the excretion of sodium and increases the

secretion of potassium and magnesium.1 Aldoster-one is also speculated to have a negative impact on heart muscle fibres and arterial compliance.1 In 1999, the Randomized Aldactone Evaluation Study (RALES) was published in the New England Journal of Medicine.1 This study hypothesized that aldosterone plays an important role in the patho-genesis of heart failure and that ACE Inhibitors (that inhibit the renin-angiotensin-aldosterone sys-tem) did not adequately inhibit aldosterone. They randomized patients with severe heart failure, New York Heart Association (NYHA) class III-IV, to either spironolactone 25mg QD or matching pla-cebo. All of the patients were on a loop diuretic already, 95% were on an ACE Inhibitor, and about 75% were also on digoxin for their heart failure. Patients were excluded from the trial if they had a serum creatinine of greater than 221umol/L, if their serum potassium was greater then 5mmol/L or if their left ventricle ejection fraction was greater than 35%.1 Patients with certain types of valvular and congenital heart disease, unstable angina, liver failure, cancer or other life threatening diseases (besides heart failure) were also excluded. The use of spironolactone in these patients with severe heart failure resulted in a 30% reduction in the relative risk of death (11.7% absolute risk re-

Spironolactone in Heart Failure: Good for All?

April, 2005

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Key Messages

• The RALES trial has demonstrated that spironolactone is efficacious in reducing mortality in patients with NYHA class III and IV heart failure.

• The majority of patients taking spironolactone for heart failure should be on 25mg once daily. • After initiation of spironolactone, serum chemistry should initially be checked every 4 weeks for 3 months. • Failure to use spironolactone in the right patients, at the correct dose, with appropriate follow-up can ex-

pose patients to an increased risk of hyperkalemic related adverse events.

PrISM is a non-profit, independent pilot project set up by the Manitoba Pharmaceutical Association and Manitoba Health to provide education in opti-mal drug utilization. Funding has been provided by a government research grant and an unrestricted grant from industry.


187 St. Mary’s Road ● Winnipeg, Manitoba R2H 1J2 ● Tel. (204) 231-4688 ● Fax (204) 231-5964 ● Email: [email protected]

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duction).1 This indicates that you would only have to treat 9 patients with class III-IV heart failure with spironolactone to avoid one death. The trial also found a 31% reduction in the rela-tive risk of cardiac death and a 30% reduction in the relative risk of hospitalization from cardiac causes. Serious hyperkalemia occurred in only 4 more cases in the spironolactone group as com-pared with the placebo group (14 cases in 822 patients on spironolactone, 10 cases in 841 pa-tients on placebo). Gynecomastia and breast pain occurred in 10% of the men in the treat-ment group.

The highly positive results of this study have lead to widespread use of spironolactone in the man-agement of CHF. Case The patients’ serum chemistry is as follows:

Mr. HK certainly meets some of the entrance requirements of the RALES trial, but some key diagnostic criteria are as yet unknown. In addi-tion, you are a worried about potential side ef-fects. He is elderly and has diabetes which will predispose him to renal dysfunction. He also requires 40mg BID of furosemide to control his fluid levels, which is often an indicator of renal insufficiency. Although his serum creatinine is within normal limits, it is at the upper limit of normal and the patient may be at heightened risk of developing renal failure. Despite your concerns you feel that it is wise to follow the cardiologist’s advice and the patient was told that he would be starting a new drug that would make him feel better, so you write the prescrip-tion and book the patient for follow-up in 1 month. Discussion Two studies published after the RALES trial help to identify problems which can arise when positive clinical trials are put into practice. The first, conducted in a VA Hospital in Houston, Texas looked at 110 patients prescribed spiro-nolactone after September 1999.3 They found that only 25.6% of the patients started on spiro-nolactone had documented class III or IV heart failure. Over 65% had heart failure that was not classified. Just over half the patients (54.8%) had an ejection fraction less then 35%. Forty percent of the patients remained on po-tassium supplements despite having normal se-rum potassium levels, and 30.7% of patients had baseline renal dysfunction that would have made them ineligible to participate in the RALES trial.1,3 The mean dose of spironolac-tone used by patients followed in the Texas study was 40.7mg, while the mean dose in the RALES trial was 26mg.1,3 The patients were followed for 12 months. By the end of the trial period, 12% of the patients were hospitalized with severe hyperkalemia, this was far in excess of the rates seen in the RALES trial.1,3 One quarter of the study pa-tients developed renal insufficiency and 21% of the patients were taken off spironolactone. The authors suggested that one of the reasons the adverse events occurred was because the pa-

Parameter Value Normal

BUN 6.0 mmol/L 2.5-6.4 mmol/L

Creatinine 115 umol/L 53-120 umol/L

Glucose 6.3 mmol/L 3.9- 6.10 mmol/L

Sodium 137 mmol/L 136-145 mmol/L

Potassium 4.6 mmol/L 3.5-5.1 mmol/L

In assessing whether it is appropriate to start Mr. HK on spironolactone, one must consider the circumstances in which the drug had its suc-cess. You have some concerns about the ap-propriateness of this medication for this patient. The chart below highlights the RALES criteria and if Mr. HK meets them:

RALES Criteria1 Mr. HK

NYHA Class III or IV Heart Failure

Unknown (unlikely based

on activity) On an ACE Inhibitor Yes

On a Loop Diuretic Yes

EF < 35% Unknown

Free of Valvular Heart Dis. Yes

Serum Cr < 221umol/L Yes

Serum K+ < 5mmol/L Yes Free of congenital heart dis., unstable angina, liver disease, active cancer

Yes

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tients did not have rigorous enough lab follow-up. In the RALES trial, patients had their elec-trolytes tested every month for 3 months, then every 3 months for 1 year, then every 6 months thereafter.1 Only 38% of the Texas study popu-lation were follow-up appropriately. Overall it appears that the wrong patients received spiro-nolactone at too high a dose with inadequate follow-up, which likely lead to the increase in adverse events.

In the second study, a population based review, conducted in Ontario, looked at the change in spironolactone use in the province’s seniors population after publication of the RALES trial.4 They found that the number of prescrip-tion for spironolactone for patients aged ≥66 years who were on an ACE Inhibitor increased by 5 fold between early 1999 (30 per 1000 pa-tients) and late 2001 (149 per 1000 patients). The rise in spironolactone use was associated with an increase in hospital admissions for hy-perkalemia in CHF patients from 4 per 1000 patients to 11 per 1000 patients. In addition to the increases in hospital admissions, hyper-kalemia related deaths rose by almost 3 times in patients on the agent for heart failure (0.7 cases/1000 in 1999 to 2.0 cases/1000 in late 2001). Because this study is a population-based utilization review, a causal relationship between the release of the trial, the increase in spiro-nolactone use and the increase in hyperkalemia related adverse effects cannot be claimed; how-ever, a coincidental relationship seems unlikely. Case Mr. HK comes back to the clinic 1 month later. His labs are as follows:

tory and heart failure of unknown stage at risk of experiencing an adverse event related to a recently prescribed medication that you are not entirely sure is appropriate. You decide the first step is to discontinue the patient’s potassium supplement. In retrospect, since the patient’s potassium was not low when you started the spironolactone, it would have been prudent to cut-back the dose at the same time as starting the potassium sparing diuretic. The next step is to definitively assess the patient’s degree of heart failure, so you schedule the patient for a cardiac ultrasound to determine his ejection fraction. In addition, you have the patient de-scribe his heart failure symptoms in detail (symptoms at rest, symptoms with a certain amount of activity, etc). After this information is collected, it would be most appropriate to contact the cardiologist who first prescribed the drug. The cardiologist can provide the rationale why the Mr. HK was started on the drug and you can provide information on how the patient has responded to therapy. Together you can decide if the patient should continue on spiro-nolactone, despite the rising potassium, and what the appropriate follow-up should be. Discussion The marked reductions in all cause mortality, cardiovascular mortality and cardiac-related hospital admissions seen in the RALES trial make spironolactone an integral component in the management of severe heart failure. How-ever, subsequent to the publication of the trial, increases in hyperkalemia related hospital ad-missions and deaths have been noted.3,4 The low adverse event rate seen in the RALES trial shows that spironolactone can be safely admin-istered in the appropriate patient population.1 In order to safely and effectively use this agent, clinicians should be aware of the characteristics of patients in the RALES trial. Sprironolactone should be added to regular heart failure therapy, which includes an ACE Inhibitor or an ARB, in patients with class III-IV heart failure and a low ejection fraction at a dose of 25mg/day. It should be avoided in patients with significant renal dysfunction (creatinine > 221umol/L) and high serum potassium. After patients are se-lected, careful follow-up is essential to monitor for toxicity.

Parameter Value Normal BUN 6.5 mmol/L 2.5-6.4 mmol/L

Creatinine 128 umol/L 53-120 umol/L

Glucose 6.4 mmol/L 3.9- 6.1 mmol/L

Sodium 142 mmol/L 136-145 mmol/L

Potassium 5.3 mmol/L 3.5-5.1 mmol/L

He does not feel that his heart failure symp-toms have improved but they have also not gotten any worse. To summarize, you have a 71 year old man with a complex medical his-

For more information about PrISM and to access previous Spectrum Newsletters, visit us online at: www.prisminfo.org

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Co-Authored by:

Kyle MacNair BSc.Pharm, ACPR Shawn Bugden BSc.Pharm, MSc. Reviewed by:

Dr. B. Penner, Director of the Hyperten-sion and Early Risk Factor Clinic. University of Manitoba

References: 1. Pitt B, Zannad F, Remme W, et al. The Effect of Spironolactone on Morbidity and Mor-

tality in Patients with Severe Heart Failure. NEJM 1999; 341(10):709-17. 2. New York Heart Association Functional classification. http://en.wikipedia.org. Accessed

September 2, 2004. 3. Bozkurt B, Agoston I, Knowlton A. Complications of Inappropriate Use of Spironolac-

tone in Heart Failure: When and Old Medicine Spirals Out of New Guidelines. J Am Coll Card 2003; 41(2): 211-4.

4. Juurlink D, Mamdani M, Lee D, et al. Rates of Hyperkalemia after Publication of the Ran-domized Aldactone Evaluation Study. NEJM 2004; 351(6): 543-51.


Title: An Overview of IDEALOrganization: RxFiles (Saskatchewan)

Summary Descriptive Information This newsletter has 2 pages, 1343 words and is divided into 5 sections. There is full use of colour in graphics and text highlighting. Evaluation Summary Reviewer #1 Reviewer#2#1 Referencing 5 5#2 Peer Review 1 2#3 Systematic Review 1 2#4 Statistics 5 5#5 Price and coverage 1 1#6 Graphics 4 4#7 Key Messages 5 4#8 Sections 5 5#9 Headings 4 4#10 Table Hierarchy 5 4#11 Table Editorial Consistency 4 3#12 Column Width 2 1#13 Readability 2 2#14 Justification 5 4#15 Colour 3 2#16 Main Message 4 2#17 Therapeutic Decision Support 5 4#18 Behaviour Target 3 4#19 Retrieval 4 5#20 Editorial Consistency 3 2


Overall Mean Score 68 Strengths This document provides comprehensive evaluative information on the IDEAL trial in a limited amount of space. The document employs summary graphics effectively to convey the study information. Weaknesses The small font and level of detail used within the document challenges the overall readability. As well, the use of page-width columns negatively impacts the readability.

www.RxFiles.ca – Jan 2006

An Overview of IDEAL – A Comparison of Intensive Statin vs Low-Moderate Statin Therapy in stable CAD patients with a Previous MI (e.g. High-Risk Patients)

IDEAL Trial Overview 1♦ a multi-center prospective randomized open-label, blinded end-point trial to determine lipid lowering effects of high dose

atorvastatin vs low-moderate dose simvastatin on major coronary events defined as ‘coronary death/ non fatal acute MI/orcardiac arrest with resuscitation’ in previous MI patients (intention to treat analysis; all patients enrolled were included in final analysis)

♦ two treatment arms: � atorvastatin 80mg daily (↓ 40mg if side effects) (n=4439) 89% adherence to therapy � simvastatin 20-40mg daily (↑ to 40mg if total cholesterol >5 mmol/l at 24wks ) (n=4449) 95% adherence to therapy♦ 8,888 patients were followed for 4.8 years (4-5.9yrs) with the following characteristics: - males ~81% & females with previous MI (MIs: were ~21months before, with only 11% of MIs in the last 2 months) - age: mean ~62 years (<80yr) Baseline LDL levels: 3.14 mmol/l BMI: 27.3 kg/m2 BP: 137/80 mm Hg - smokers~20%, former smokers~58%, hypertension~33% & history of diabetes~12%

Table 1: IDEAL Results (atorvastatin 80mg 13% 40mg final dose daily vs simvastatin 20mg 23% 40mg final dose daily)

Endpoints Atorvastatin % (n=4439)

Simvastatin % (n=4449)

ARR % RRR % NNT/4.8 yrs

p value

1° coronary death/non fatal acute MI*/orcardiac arrest with resuscitation

9.3 10.4 1.1 11 NS 0.07

2° Nonfatal MI 6 7.2 1.2 17 84 0.022° Major cardiovascular events (10 + stroke)

12 13.7 1.7 13 59 0.02

2° Any CHD event ** 20.2 23.8 3.6 16 28 <0.0012° Any cardiovascular event *** 26.5 30.8 4.3 16 23 <0.0012° Fatal or nonfatal stroke 3.4 3.9 0.5 13 NS 0.22° All-cause mortality 8.2 8.4 0.2 2 NS 0.812° Cardiovascular mortality 5 4.9 0.1 3 NS 0.782° Noncardiovascular mortality 3.2 3.5 0.3 8 NS 0.47

* =requiring hospitalization **=coronary revascularization or hospitalization for unstable angina *** = ** plus peripheral vascular disease & hospitalizations for nonfatal HF1o=primary outcome 2o=secondary outcome ARR=absolute risk reduction CHD=coronary heart disease CV=cardiovascular GI=gastrointestinalHF=heart failure MI=myocardial infarction NNT=number needed to treat to benefit 1 patient NS= not statistically significant RRR=relative risk reduction SE=side effects

Of Note:♦ concomitant meds: ASA(79%), β-blocker(~75%), ACE-I(30%), CCB(19%), warfarin(13%), ARB(6%)

♦ LDL mean levels during treatment: atorvastatin arm: 2.1 mmol/l; simvastatin arm: 2.7 mmol/l (~75% of pts had previously beenon statins ~51% on simvastatin (pts were already simv tolerant) : LDL ↓33% in the simvastatin naïve arm & ↓49% in the atorvastatin naïve arm at 12 wks)

♦ ↓ both total cholesterol by 0.74mmol/l & ↓triglycerides by 0.67mmol/l more in the atorvastatin than the simvastatin group at year 1♦ ↑HDL by 0.03mmol/l more in the simvastatin group at year 1 (thus small HDL differences not likely clinically important)♦ SAFETY:

- Myopathy: Rate: 1 in 500; 11 simv pts & 6 atorv pts. Rhabdomyolysis: Rate: 1 in 1800; 5 cases by investigators only 2 for atorv - ALT/AST elevations >3 x ULN occurred in 1% of patients in the atorvastatin arm and 0.1% in the simvastatin arm; NNH=112

{atorvastatin 80mg vs 10mg in the TNT trial n=10,001 4.9yr: 1.2% vs 0.2% of pts had liver ALT levels >3 x ULN; NNH=100}- permanently discontinued study med: atorvastatin 14% & simvastatin 7% (most switched to a different statin)- adverse events worse with atorvastatin: D/C med 9.6 vs 4.2%; eg. myalgia 2.2 vs 1.1%, diarrhea 0.9 vs 0.2%, abdominal pain 0.8 vs 0.2% & nausea 0.5 vs 0.1%

- noncardiovascular deaths higher in TNT trial 3.2% atorv 80 vs 2.5% atorv 10, but NOT the case in IDEAL 3.2 % atorv 80 vs 3.5% simv 20

What we knew and what these results add to that knowledge:♦ Many large RCTs, including IDEAL have shown statins reduce the risk of death or CV events in high-risk patients. 13 Current

guidelines recommend reducing LDL to <2.5mmol/l in patients with CAD or diabetes � previous studies using moderate statin doses haveshown this is beneficial. TNT & IDEAL showed a ↓ in CV events but some ↑ in SE with high dose statins and resulting LDLs of ~2 mmol/l

♦ IDEAL: more aggressive lipid therapy (atorvastatin 80mg/d vs simvastatin 20-40mg/d) appears to provide greater benefit against‘major CV events & stroke’ in previous MI patients. Some adverse event rates causing discontinuation are increased with theatorvastatin 80mg which may warrant caution and/or monitoring. Magnitude of benefit was “one less major CV event &stroke for every 59 previous MI pts treated over 4.8 years”; specifically less nonfatal acute MI 6 vs 7.2% NNT=84, but NO reductionin CV mortality, all-cause mortality or the 1o outcome (major coronary events)

♦ Heads-Up: 1) previous statin exposure (75%) may pre-select for patients likely to tolerate either arm2) most simvastatin patients at 20mg/d dose whereas most simvastatin evidence lies with a 40mg dose3) benefit relies on select secondary endpoints of trial since primary was not significant.4) may not be able to extrapolate benefit of routine high-dose atorvastatin to lower risk patients

Questions Remaining: ♦ What about lower risk patients requiring high dosages to reach targets? What is the benefit mechanism (ie: is it due to ↓ LDL

only, CRP levels, anti-inflammation)? What is the long-term benefit/risk profile of higher aggressive dose statin therapy? Was itthe dose of statin or the statin they dosed?

�

Upcoming Trials:

SEARCH (The Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine tests)8: comparing simvastatin 20mg and 80mg in CHD patientsSPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels)9,10: evaluating the effects of atorvastatin 80mg/day in 4,732 patients with previous stroke or TIA, but no hx of CHDASPEN (Atorvastatin Study for the Prevention of CHD Endpoints in NIDDM)11

References:1) Pedersen TR, Faergeman O, Kastelein JJ, et al. High-Dose Atorvastatin vs Usual-Dose Simvastatin for Secondary Prevention After Myocardial Infarction: The IDEAL Study: A Randomized Controlled Trial. JAMA. 2005 Nov 16;294(19):2437-2445.2) Rath B, Jensen B, Regier L. Lipid Lowering Agents-Evidence, Questions & Comparisons. RxFiles, Feb 2002.3) Pitt B, Waters D, Brown V, et al. Aggressive Lipid-Lowering Therapy Compared with Angioplasty in Stable Coronary Artery Disease (AVERT). New Engl J Med 1999; 341:70-6.4) Schwartz G, Olsson A, Ezekowitz M, et al. Effects of Atorvastatin on Early Recurrent Ischemic Events in Acute Coronary Syndromes (MIRACL). JAMA 2001;285:1711-8.5) Nissen S, Tuzcu E, Schoenhagen P, et al. Effect of Intensive Compared with Moderate Lipid-Lowering Therapy on Progression of Coronary Atherosclerosis: A randomized Controlled Trial (REVERSAL). JAMA 2004;291:1071-80.6) Genest J, Frohlich J, Fodor G, McPherson R; Working Group on Hypercholesterolemia and Other Dyslipidemias. Recommendations for the management of dyslipidemia and the prevention of cardiovascular disease: summary of the Canadian 2003 update. CMAJ. 2003 Oct 28;169(9):921-4. http://www.cmaj.ca/cgi/data/169/9/921/DC1/1 Full Report.7) LaRosa JC, Grundy SM, Waters DD, et al.; Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005 Apr 7;352(14):1425-35. Epub 2005 Mar 8.8) Brookes L. Reversing Atherosclerosis with Aggressive Lipid Lowering. Medscape: http://www.medscape.com/viewarticle/464440 Date accessed: April 7, 2004.9) Deanfield J. Clinical Trials: Evidence and Unanswered Questions--hyperlipidaemia. Cerebrovasc Dis 2003; 16 Suppl 3:25-32.10) Amarenco P, Bogousslavsky J, Callahan A, et al. Design and Baseline Characteristics of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels Study (SPARCL). Cerebrovasc Dis 2003;16(4):389-95.11) Crespin S. What Does the Future Hold for Diabetic Dyslipidaemia? Acta Diabetol 2001;38 Suppl 1:S21-6.12) Cannon C, Braunwald E, McCabe C, et al. Comparison of Intensive and Moderate Lipid Lowering with Statins after Acute Coronary Syndromes (PROVE IT-TIMI 22). New Engl J Med 2004; 350. Online April 8, 2004.13) Baigent C, Keech A, Kearney PM, et al; Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005 Oct 8;366(9493):1267-78.

Prepared by: Brent Jensen BSP, Loren Regier BSP BA

NNT= number needed to treat NNH= number needed to harm NS= not significant (statistically) RRR= relative risk reduction ULN= upper limit of normal Tx ADR’s D/C= treatment related adverse drug reactions resulting in discontinuation of therapy


Title: An Overview of ASCOT-LLAOrganisation: RxFiles (Saskatchewan)



Overall Mean Score 69 Strengths This document provides comprehensive evaluative information on the ASCOT-LLA trial in a limited amount of space. The document employs summary graphics effectively to convey the study information. Weaknesses The small font and level of detail used within the document challenges the overall readability. As well, the use of page-with columns negatively impacts the readability.

RxFiles – Q&A Supplement www.RxFiles.ca – April 2003

An Overview of ASCOT-LLA 1,7 - Atorvastatin in Primary Prevention

ASCOT-LLA Trial Overview♦ a multi-center randomized placebo-controlled trial to determine effects of atorvastatin on ‘non-fatal MI and fatal CHD’

in high risk (eg. diabetes 24%), hypertensive patients without previous heart disease and a total cholesterol ≤6.5 mmol/l♦ two treatment arms: � atorvastatin (LIPITOR) 10mg daily plus antihypertensive medications (n=5,168)

� placebo plus antihypertensive medications (n=5,137)♦ 10,305 patients with the following characteristics:

- hypertension (mean BP 164.2/95 mmHg)- total cholesterol (mean 5.5mmol/l→4.2 mmol/L), LDL (mean 3.4mmol/l→ 2.3mmol/l)- risk factors: hypertension plus ≥3 additional CHD risk factors (Average 3.7 additional risk factors/patient)

(age ≥ 55 84%, male 81%, microalbuminuria/proteinuria 62%, smoking 33%, family history of CHD 26%, type 2 diabetes 24%,TC/HDL ≥6 14%, other ECG abnormalities 14%, LVH 14%, previous stroke/TIA 10% or peripheral artery disease 5%).age 40-79 (mean 63 years); 81% male (evenly distributed)

♦ trial halted after 3.3 years due to morbidity benefits (e.g. significant reduction in ‘non-fatal MI & fatal CHD’ & stroke)

Table 1: ASCOT-LLA results (atorvastatin 10mg daily vs placebo)

Endpoints atorvastatin % placebo % ARR % RRR % NNT p value1° fatal CHD & non-fatal MI 1.9

(100 events)3.0

(154 events)1.1 36 91 0.0005

2° total CVD events & procedures 7.5 9.5 2.0 21 50 0.00052° total coronary events 3.4 4.8 1.4 29 72 0.00052° non-fatal MI plus fatal CHD* 1.7 2.7 1.0 37 100 0.00052° mortality-all cause 3.6 4.1 0.5 12 NS 0.16492° CVD mortality 1.4 1.6 0.2 13 NS 0.50662° fatal & non-fatal stroke 1.7 2.4 0.7 29 143 0.02362° fatal & non-fatal heart failure 0.8 0.7 - - - 0.57943° chronic stable angina 0.6 1.1 0.5 45 200 0.0135

* not including silent MI 1o=primary outcome 2o=secondary outcome 3o=tertiary outcome ARR=absolute risk reduction CHD=coronary heart diseaseCVD=cardiovascular disease MI=myocardial infarction NS=not significant NNT=number needed to treat to benefit 1 patient RRR=relative risk reduction

Of Note:♦ study did not provide risk/benefit data for higher atorvastatin doses or for more aggressive treatment to target♦ short trial; lack data on long term effects; reduction in all-cause death did not reach statistical significance♦ adverse event data lacking in the publication (1 case of non-fatal rhabdomyolysis in atorvastatin arm reported)♦ benefits only in men (no benefit seen in women n=1942; rate of 1° outcome non-fatal MI & fatal CHD 1.9% atorvastatin vs 1.8% placebo p>0.7)♦ lack of significant risk reduction in diabetes; may relate to study design; 14% of diabetes-placebo arm received a statin (similar limitation seen in ALLHAT-LLT 2 trial with pravastatin 40mg daily where 26% of control group received a statin)

Comparison to WOSCOPS 3

♦ a primary prevention study of pravastatin 40mg od vs placebo in Scottish males age 45-64 with cholesterol ≥7 mmol/l♦ both had relative reductions in the primary outcome of non-fatal MI and fatal CHD (RRR= ASCOT: 36% at 3.3yrs; WOSCOPS: 31% at 4.9yrs)

♦ both had favorable all-cause mortality trends (ASCOT 4.1% � 3.6% at 3.3yrs; WOSCOPS 4.1% � 3.2 % at 4.9 yrs)

♦ LDL reduction (ASCOT 3.4 mmol/l � 2.3 mmol/l at 3.3yrs; WOSCOPS 5.0 mmol/l � 4.1 mmol/l at 4.9 yrs)

What we knew and what these results add to that knowledge:♦ 1o prevention: previous evidence supported benefit of statins (pravastatin 3 & lovastatin 4) in primary prevention of CHD in

moderate to high risk male patients with dyslipidemia. 1o & 2o prevention: in PROSPER 5, pravastatin 40mg daily reduced fatalMI & non-fatal CHD in elderly male patients (age 70-82yrs) with or at high risk of CVD; in HPS 6, simvastatin 40mg daily reducedmorbidity & mortality in male and female patients (age 40-80yrs) with or at high risk of CVD.

♦ ASCOT-LLA supports the use of atorvastatin 10mg daily for primary prevention of CHD & stroke in hypertensive malepatients (especially >60years of age) with multiple risk factors for CHD and total cholesterol levels ≤6.5 mmol/L.

Magnitude of benefit was “one less fatal CHD event or non-fatal MI for every 91 patients treated over 3.3 years”; additional reductions seen in other endpoints such as stroke.

References:1) Peter S Sever, Björn Dahlöf et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial Lancet 2003; 361: 1149-58. Online April 2, 2003.2) Major Outcomes in Moderately Hypercholesterolemic, Hypertensive Patients Randomized to Pravastatin vs Usual Care. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. JAMA. 2002;288:2998-3007.3) Shepherd J, Cobbe SM, Ford I et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia (WOSCOPS). N Engl J Med 1995;333:1383-9.4) Downs JR, Clearfield M et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. Results of (AFCAPS/TexCAPS). JAMA 1998;279:1615-22.5) Shepherd J, Blauw G et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002 Nov 23;360(9346):1623-30.6) Heart Protection Study Group.MRC/BHF HPS study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002 Jul 6;360(9326):7-22.7) http://www.ascotstudy.co.uk Prepared by: Brad Rath Pharmacy Student, Brent Jensen BSP, Loren Regier BSP BA

www.RxFiles.ca – ASCOT-LLA Overview – April 2003 – Page 2

4 /1 0/03 R x Files-L ip id A gents-H ig hlig hts 1

S ta tin s (the on ly group w ith a ll-cause m o rta lity evid ence)

8.211.5

15.922.6

0

10

20

30

4S-death 4S-CV events

Drug Tx

Placebo

3.24.1

5.5 7.9

0

10

20

30

WOSCOPS-death WOSCOPS - CV events

%patients

2° P reventionS im vasta tin 20-40m g/d

1° P reventionP ravasta tin 40m g/d

� W h o ben efits m o st?� D ifferen ces: E v id en ce? D I’s? P oten cy?

W atch for to xicity :hepatic /m yop athy .

N N T = 30 N N T =12N N T =?1 11 N N T = 42

4/10/03 RxFiles-Lipid Agents-Highlights 2

HPS Lancet, July 2002

1 2 .9 14 .6 19 .925 .4

4 .4 60 .8 0 .6

01 02 03 04 05 0

A ll-D e ath M ajV a s c Eve nts S trok e A LT > 3X U LN

D rug T xP la c e bo

2° & High-risk Prevention(CHD,PVD,Diabetes,HTN,M ale/Female,Age40-80)

Simvastatin 40mg/d%

patients

•No benefit for Vitamins E 600mg, C 250mg, or beta-carotene•Evidence for simvastatin 40mg in 2O & very high risk 1O

prevention in diabetes, stroke, age<80, women, LDL<3•Questions remaining: safety/efficacy of aggressive pursuit of targets, combination therapies, low-risk patients with ↑ LDL.

NNT=59 NNT=18

NNT=62


ASCOTLancet, April 2003

1.93

1.72 .4

3 .6 4.1

012345

% p

ts

M I & C HD Stroke A ll-Death

Drug TxPlacebo

•Trial provided evidence for primary prevention of CHD and stroke in hypertensive male patients with multiple CHD risk factors with total cholesterol ≤6.5mmol/L•Questions remaining: women, adverse effects, long term effects, safety and efficacy of titrating dose to attain targets, magnitude/$

1o Prevention in high risk(HTN, male/female, age 40-79, TC<6.5mmol/L)

Atorvastatin 10mg/d over average 3.3yrs

NNT=91 NNT=143 NNT=NS


Title: Post-MI – Troubleshooting Practical IssuesOrganisation: RxFiles (Saskatchewan)



Overall Mean Score 73 Strengths This document provides comprehensive information on the medical management of post-MI patients in extensive detail with use of very little space. The key points highlighted on the front page are an asset. Weaknesses The small font and level of detail used within the document challenges the overall readability.

.

.

POST-MITroubleshooting Practical Issues

October 2004

The RxFiles Academic Detailing Programin collaboration with

Derek Jorgenson, Health Quality Council (HQC)

701 Queen StreetSaskatoon City Hospital

Saskatoon, SK S7K 0M7Phone 306-655-8506 ; Fax 306-655-7980

Email: [email protected]@HQC.sk.ca

Key Message:� Four types of medication (ACE-Inhibitors, beta-blockers,

statins & ASA) have been shown to reduce cardiovascularrisk in post-MI patients. 1 These benefits are in addition torisk factor management (eg. diet 2,3,4, lifestyle, exercise) andoccur regardless of the presence of hypertension,dyslipidemia, or LV dysfunction. Clinical judgment isessential to assess risk/benefit for individual patients.

How are we doing in Saskatchewan?� An analysis of Saskatchewan dispensing rates by the HQC

suggests that important drugs are underutilized (See Figure 1).

PRACTICAL ISSUES – ACE Inhibitors (ACEI)Which patients will benefit?� All post MI patients without contraindications 1 (indefinitely)� Shown to reduce risk of CV events in post-MI patients who

are high risk 5,6,7 (elderly, LV dysfunction); some benefit alsoin lower risk 8,9 patients (e.g. young, no LV dysfunction)

� Beneficial when initiated soon after acute MI 1 (~first 24hrs) AHA’04

Initiation & dosing in patients with renal dysfunction 10

� Ensure SCr is stable before initiating ACEI therapy� Start with low doses, slowly titrating towards targets with close

monitoring. A moderate rise in SCr (that stabilizes within 1week) may occur after each dose increase. (Of note: ACEIbeneficial if existing renal impairment but may consider nephrologyconsult; trials exclude patients with high SCr (e.g. >200umol/l TRACE).

� Check SCr, BUN, and lytes at baseline and 7-14 days after eachdose increase. If SCr rise (above baseline) is: 10

� <30% - continue titration / no concern� 30-50% – decrease ACEI dose by 50% and recheck SCr in

7-10 days. If SCr rise still >30%, stop the ACEI� >50% – stop ACEI� When SCr rise is >30% consider investigating for renal

artery stenosis and rule out other reversible causes.� Common reversible causes include: heart failure, aggressive

diuresis, volume depletion, NSAIDs/coxibs & dehydration.� Potassium levels above 5.6mmol/L during ACEI therapy should

prompt reassessment of ACEI.

Initiation in patients with hyperkalemia� Potassium should be ≤ 5.0mmol/L before initiating� Identify reversible causes of the baseline hyperkalemia: Concurrent NSAIDs/coxibs or potassium sparing diuretics eg. spironolactone 11, dietary indiscretion -dietician counseling may be helpful.

Role of angiotensin receptor blockers (ARBs)� Acceptable alternative when ACEIs not tolerated 1� Studied only in post-MI patients with LV dysfunction; valsartan

at very high dosage showed equivalency to ACEI VALIANT 12;losartan at lower dose was less effective than an ACEI OPTIMAL 13

� Combination of an ACEI + ARB no more effective but moreadverse effects than either ACEI or ARB alone VALIANT

Figure 1: % of Sask. Patients on Target Therapy @90days Post-MI.HQC

* ~1,700 MI’s/year; 18% on all 3 drugs at 1yr & 35% on none at 1year 2000-01;project 45 lives saved/year if benchmark 14 usage rates maintained long-term 15

PRACTICAL ISSUES – Beta-blockers (BB)Which patients will benefit?� Shown to reduce all-cause mortality in all post-MI patients

regardless of LV function, especially those at high risk (wheninitiated within 4 weeks ~ideally first 24hrs of MI and continued for up to 4 years) 1,16

� Beta-blockers may be especially underutilized in the elderly.1

Contraindications – myths and preconceptions� Many conditions that previously contraindicated the use of beta-

blockers are not “absolute”. With cautious initiation and closemonitoring, benefits may outweigh the risks in the following17:• COPD, diabetes, peripheral artery disease, & compensated HF;

mild asthma (cardioselective BBs in those well controlled with inhaled steroids)18

PRACTICAL ISSUES – StatinsWhich patients will benefit?� ALL post-MI patients appear to benefit from statin therapy

regardless of lipid levels (HPS ~40% patients post-MI history) 19, 1 AHA’04

Should “high dose” statins be used in acute MI?� Aggressive dose (atorvastatin 80mg OD) was better than moderate

dose (pravastatin 40mg OD) when initiated <10 days after acuteMI and continued for 2 years.

20 PROVE IT {LDL achieved was 1.6mmol/L.

Caution: risk of adverse effects (liver, muscle) with aggressivestatin doses 20, 21,22 MIRACL. Potentially conflicting A-Z trial data 21}

Monitoring� Guidelines recommend baseline transaminase and CK levels

before starting any patient on a statin AHA 23, ATP III 24

� Frequent laboratory monitoring may be necessary in patients athigh risk for adverse effects (ie. drug interactions, elderly, renal /hepatic dysfunction, high dose statins, niacin or fibrate combinations)

PRACTICAL ISSUES – ASA� Recommend 81mg enteric coated daily (75mg-162mg) 1 AHA’04, 25 ATC’02

� Consider H. pylori eradication and cytoprotection for patientsat high-risk of a GI bleed, even for ≤100mg ASA 26

� Minimize 1,27 regular use of ibuprofen MOTRIN, ADVIL with ASAsince antiplatelet effects may be blocked (conflicting data 28)

� High-dose NSAIDs/COXIBs may be associated with adverseheart outcomes heart failure, MI (eg. rofecoxib VIOXX 29, 30; APPROVe)

For specific drug & dosage considerations, see Page 2 - Table 1.

0

20

40

60

80

100

97-98 98-99 99-00 00-01 01-02

B-BlockerACEIStatin

Targets:85% BB & ACEI70% Statins

←Fiscal year

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Table 1: Post-MI –Drug & Dosage Considerations Prepared by D. Jorgenson, B. Jensen, L. Regier - www.RxFiles.ca - Oct 2004POST-MI TARGET DOSES CONTROLLED TRIALS $/30d BENEFITS RISKS COMMENTS

AC

EIRamipril ALTACE 10mg HS HOPE; 5mg BID AIRE 31

Trandolapril MAVIK 4mg OD TRACE 6

Lisinopril ZESTRIL/PRINIVIL 10mg OD GISSI-3 32

(high dose) ~35mg OD ATLAS 33 (HF)

Perindopril COVERSYL 8mg OD EUROPA 9

Enalapril VASOTEC 20mg OD CONSENSUS-II 34

Captopril CAPOTEN 50mg TID SAVE 7, BID in ISIS4 35

41413065454852

� all-cause mortality: 17-29% RRR whenstarted 2-16 days after event & continued for4-5 yrs in pts with LV dysfx AIRE, TRACE, SAVE;{TRACE: NNT=13 over 4yrs 42.3 vs 34.7%,n=1749}�prevents ventricular remodeling;↓proteinuria�16% RRR in all cause mortality when startedin high risk pts with remote history of MI andcontinued for 5 years HOPE ; NNT HOPE = 56

�Adverse effectsinclude cough<10%,hypotension/dizzy ~2%,hyperkalemia~2-11%,renal insufficiency (in ptswith renal artery stenosis) &angioedema 0.4%, Blacks 0.7% 36;taste changes, rash; Rare:pancreatitis & blood dyscrasias.

�AHA STEMI Guidelines2004 suggest to use ACE inhibitors in all pts indefinitely. Most benefit if anterior infarction, pulmonary congestion or EF<0.4, tachycardia, in the absence of hypotension (SBP<100mm Hg or < 30mm Hg below baseline)�Contraindicated in pts with bilateral renal artery stenosis (or unilateral stenosis if only 1 kidney), history of angioedema to ACEI, & pregnancy�Combo ACEI+ARB: option with persistent HF CHARM

(more adverse effects & no greater efficacy VALIANT)

AR

B

Valsartan DIOVAN 160mg BID VALIANT 12

Candesartan ATACAND 32mg OD CHARM (HF trial)37,38

8287

� all-cause mortality: valsartan, captopril50mg TID,or combo equally effective VALIANT, n=14703, ~2yr

� ↓ proteinuria 39 even in pts with SCr<265 40, 41

Angioedema (17 of 26 ptssafely put on ARB after ACEI)42;More: ↓BP & ↑SCr 4.9 VS 3% VALIANT

Less: cough 1.7 VS 5% VALIANT,rash & taste changes than ACEI. VALIANT

�Alternative if ACEI not tolerated & HF/LVEF<0.41

(ARB: less cough & somewhat less angioedma)�captopril 50mg TID reduced CV-death in post-MI pts more than losartan 50mg OD OPTIMAAL

β- B

LOC

KER

Metoprolol♥ LOPRESSOR 100mg BID HJALMARSON 43

≤200mg SR OD MERIT-HF 44,45

Atenolol♥ TENORMIN 100mg OD ISIS-1 46

Carvedilol COREG � 25mg BID CAPRICORN 47

Propranolol INDERAL 60-80mg TID BHAT 48

Timolol BLOCADREN 10mg BID NMCG 49

Acebutolol♥& ISA MONITAN 200mg BID APSI 50

16242058142522

� all-cause mortality: 23% RRR when startedin any pt within 5-28 days of MI & continuedfor up to 4yr;Meta-analysis: NNT=42 over 2yr

(best long-term evidence with propranolol,metoprolol & timolol) FREEMANTLE n=24,974 16

�↓ sudden death, reinfarction & arrhythmias�Less benefit: ISA agents (pindolol; acebutolol?) 1,51

�Cardioselective agents (♥) preferred for mildasthma & diabetes

Adverse effects 52

include hypotension,dizziness, bradycardia,fatigue <10%, insomnia,vivid dreams, & sexualdysfunction ~4%;PAD, cold extremities;mask hypoglycemia .

�AHA STEMI Guidelines2004 suggest to use beta- blockers in all pts indefinitely {benefit less in low-risk pts eg. ~normal left ventricular fx, successful reperfusion, absence of significant ventricular arrhythmias}�Contraindicated in pts with severe/poorly controlled asthma, 2nd or 3rd degree heart block, HR<50, SBP <90, & decompensated heart failure 53

�some believe carvedilol better than metoprolol for HF but equivalent doses may not have been used COMET 54

�CNS adverse effects (depression, impotence, fatigue) overestimated; common in placebo groups & may not be solely related to beta-blockers 52

STA

TIN

S

Simvastatin ZOCOR 20-40mg OD 4S 55, HPS 19

Atorvastatin LIPITOR 10mg OD ASCOT

(not post-MI) 56

(high-dose in ACS) 80mg OD PROVE IT 20,22

Pravastatin PRAVACHOL 40mg OD LIPID 57, CARE 58

(Rosuvastatin CRESTOR -no outcome trials yet; 59,60 10mg ODHigher levels in Asians; rhabdomyolysis cases at doses ≥10mg/d)

4667874456

� all-cause mortality: 22-29% RRR in post MIpts with ↑ cholesterol (LDL 3.9-4.9mmol/L) 4S, LIPID;

4S NNT=30 11.5 vs 8.2%, n=4444 simvastain 20-40mg/d, 5.4yr

� ↓ in major CV events NNT=18 & stroke NNT=62

in pts at high CV risk (over 5 years) HPS 19

�most trials enrolled pts >3months post-MI HPS, LIPID, CARE

�No major statin trial enrolled pts age >82yrs 61

�Adverse effectsinclude GI upset,muscle aches, elevatedLFTs <2%,myopathy <1%,rhabdomyolysis <0.2%,impotence; Rare: lupus-likesymptoms, periph neuropathy.

�AHA STEMI Guidelines2004 suggest to use statins inall patients (even when baseline LDL < 2.5mmol/L)�ATP-3 LDL target option: 1.8 mmol/L if very high risk 24

�If TG >5.6mmol/L, consider niacin or fibrate�Options for low HDL: lifestyle (exercise, ↓wt, smoking),fibrate (gemfibrozil 600mg BID VA-HIT $42) 62 or niacin�Contraindicated in pts with active liver disease, high alcohol consumption & pregnancy

A

NTI

-

PLA

TELE

T ASA 80-162mg OD

Generally start at ~ 81mg enteric coated OD; {ASA ≤100mgas effective/less bleeding than 325mg, especially with Plavix CURE} 63

{see also RxFiles Antiplatelet & Antithrombotic Chart 64}Clopidogrel PLAVIX � 75mg OD CURE 65, CAPRIE 66

Warfarin COUMADIN 1-10mg OD WARIS II 67

5

96

15

�all-cause mortality:10% RRR,NNT=91over 2yr ATC

�25% RRR in vascular events in previous MIpatients treated with antiplatelet agents for 27months ATC 25

�Stenting→ If on ASA+warfarin INR 2-3 foranticoagulation then D/C Plavix after: ≥1month-bare metal; ≥3month-sirolimus; ≥6month-paclitaxel. If onlyon ASA + Plavix →then D/C Plavix after ~1 yr. 1

�Adverse effects: GI upset, hypersensitivity, GI bleed; major bleed.�Maj bleed/ hemorrhagicstroke ~ 0.5% / 5 years(NNH=200) ATC, USPSTF 68

{high risk pts, i.e. CAPRIEASA 325mg/d 1.9 yrs; Bleeding:GI=2.7%; All severe =1.6%} 66

�AHA STEMI Guidelines2004 suggest using ASAindefinitely 75 to 162 mg/d if not contraindicated.�Contraindicated in pts with recent/active bleeding, major GI intolerance or history of ASA allergy�For pts with a true allergy to ASA consider clopidogrel 75mg OD or warfarin (INR target 2.5-3.5) as useful alternatives 1

� Combo: ASA+PLAVIX: ↑ efficacy but ↑ bleeding {CURE NNT=48, NNH 99,over 9 months; MATCH 69

post stroke NNH=77}

OTHER: Spironolactone ALDACTONE 12.5-25mg OD $8 for severe HF Class III-IV RALES 70 ;DI:↑ K+ level with ACEI,∴monitor K+ avoid if K+≥5mmol/L & renal fx. {Eplerenone in USA: for select post-MI pts with LV dysfx EPHESUS 71}$=retail cost �=Exceptional Drug Status �=male �=female A1C=glycosylated hemoglobin ACEI=angiotensin converting enzyme inhibitor ARB=angiotensin receptor blocker ATC=Antithrombotic Trialists' Collaboration ARR=absolute risk reduction BMI=body massindex BP=blood pressure CK=creatine kinase CV=cardiovascular DI=drug interaction EF=Ejection Fraction Fx=function FPG=fasting plasma glucose GI=stomach HF=heart failure HQC=Health Quality Council HR=heart rate Hx=history K+=potassium LV=leftventricular MI=myocardial infarction NNT(H)=number needed to treat (harm) PAD=peripheral arterial disease PPBG=postprandial blood glucose Pts=patients RRR=relative risk reduction SCr=Serum creatinine TG=triglycerides wk=week wt=weightRISK Factors:

72,75 Cholesterol:↑LDL (ApoB/ApoA1 ratio used in INTERHEART), Smoking, Diabetes, ↑BP esp. systolic, Abdominal obesity: waist/hip ratio (� ≥0.95; � ≥0.9), BMI >25, Waist size 73 (� >102cm,40inch; � >88cm,35inch), stress & depression; lack of vegetables, fruits, exercise (30-45mins 3-5x/week or more) & alcohol (0-2drinks/d �=14/week �=9/week); Low HDL �1, Family history of premature heart disease (Age: � <55, � <65) 73, Microalbuminuria 73, renal dysfx 74 & Age (� >55, � >65).

Targets: BP Canadian 2004 (75): General <140/90 ; Diabetes < 130/80 if no proteinuria; <125/75 if proteinuria >1g/d. LIPID

Canadian 2003 (76) Post MI/High Risk→ LDL<2.5; Total Cholesterol/HDL Ratio<4

GLUCOSE: Canadian 2003 (77) Target for most: A1C ≤7%; FPG 4-7 mmol/L; PPBG 2hr post 5-10 mmol/L if can be done safely without hypoglycemia.COPYRIGHT, DISCLAIMER, REFERENCES & ACKNOWLEDGMENTS AVAILABLE AT www.RxFiles.ca

Generally start low-dose & titrate up to target dose if tolerated. eg. ramipril 2.5mg OD x1wk, 5mg od x3wk then 10mg od HOPE >50% POST MI

Start low-dose & titrate up to target dose if tolerated, eg. metoprolol 12.5mg BID; double dose ↑ q2wk. (atenolol 25mg OD; carvedilol 3.125mg BID).Tolerability: Gradual dose titration & pt education regarding initial side effects improves tolerability. (e.g. 64% of MERIT-HF reached metoprolol 200mg/d) 45

If withdrawing beta-blocker therapy, do so gradually if possible over a few weeks to minimize risk of precipitating angina/MI.

May start at target dose unless high risk for side effects (ie. elderly, renal/hepatic dysfx, niacin or fibrate combos, drug interactions, high dose or hx of intolerance)

Generally start low-dose & titrate up to target dose if tolerated. eg. candesartan 4-8mg od, doubling ~q2wk →32mg od (>50% Ischemic Heart Disease in the CHARM Heart Failure trial)

Not recommended Post-MI: vitamin C, vitamin E & HRT 1

Lifestyle changes for DIET, EXERCISE & stop SMOKING!

.

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References: RxFiles Post-MI 1 Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (STEMI); A report of the American College of Cardiology/American Heart Association TaskForce on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of patients with acute myocardial infarction). J Am Coll Cardiol. 2004 Aug 4;44(3):E1-E211. http://www.acc.org/clinical/guidelines/stemi/index.pdf2 Knoops KT, de Groot LC, Kromhout D, et al. Mediterranean diet, lifestyle factors, and 10-year mortality in elderly European men and women: the HALE project. JAMA. 2004 Sep 22;292(12):1433-9.3 Sasks F, Svethkey L, et al. Effects on blood pressure of reduced dietary sodium and the dietary approaches to stop hypertension (DASH) diet. N Engl J Med 2001;344:3-10.4 Facts about the DASH Diet. http://www.nhlbi.nih.gov/health/public/heart/hbp/dash (access verified 24 Sept, 2004)5 Torp-Pedersen C, Kober L. Effect of ACE inhibitor trandolapril on life expectancy of patients with reduced left-ventricular function after acute myocardial infarction. TRACE. Trandolapril Cardiac Evaluation. Lancet. 1999 Jul 3;354(9172):9-12.6 Kober L, Torp-Pedersen C, Carlsen JE, et al. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE)Study Group. N Engl J Med. 1995 Dec 21;333(25):1670-6.7 Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVEInvestigators. N Engl J Med. 1992 Sep 3;327(10):669-77.8 Yusuf S, Sleight P, Pogue J, et al., The Heart Outcomes Prevention Evaluation (HOPE) Study Investigators, Effects of an Angiotensin-Converting-Enzyme Inhibitor, Ramipril, on Cardiovascular Events in High-Risk Patients. N Engl J Med 2000 342: 145-153.9 The EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease:randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 2003; 362: 782-88.10 Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: is this a cause for concern? Arch Intern Med. 2000 Mar 13;160(5):685-93.11 Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med. 2004 Aug 5;351(6):543-51.12 Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan in Acute Myocardial Infarction Trial Investigators (VALIANT). Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, orboth. N Engl J Med. 2003 Nov 13;349(20):1893-906. Epub 2003 Nov 10.13 Dickstein K, Kjekshus J. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarction with Angiotensin IIAntagonist Losartan.; OPTIMAAL Steering Committee of the OPTIMAAL Study Group. Lancet 2002 Sep 7;360(9335):752-60.14 Tran CT, Lee DS, Flintoft VF, et al.; Canadian Cardiovascular Outcomes Research Team/Canadian Cardiovascular Society; Acute Myocardial Infarction Quality Indicator Panel. CCORT/CCS quality indicators for acute myocardialinfarction care. Can J Cardiol. 2003 Jan;19(1):38-45.15 Health Quality Council: Improving the Quality of Heart Attack Care in Saskatchewan. www.hqc.sk.ca Phone: 306-668-881016 Freemantle N, Cleland J, Young P, et al. Beta Blockade after myocardial infarction: systematic review and meta regression analysis. BMJ. 1999 Jun 26;318(7200):1730-7.17 Borrello F, Beahan M, Klein L, et al. Reappraisal of beta-blocker therapy in the acute and chronic post-myocardial infarction period. Rev Cardiovasc Med. 2003;4 Suppl 3:S13-24.18 Salpeter SR, Ormiston TM, Salpeter EE. Cardioselective beta-blockers in patients with reactive airway disease: a meta-analysis. Ann Intern Med. 2002 Nov 5;137(9):715-25.19 Heart Protection Study Group.MRC/BHF HPS study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002 Jul 6;360(9326):7-22.20 Cannon C, Braunwald E, McCabe C, et al. Comparison of Intensive and Moderate Lipid Lowering with Statins after Acute Coronary Syndromes (PROVE IT-TIMI 22). New Engl J Med 2004; 350. Online April 8, 2004.

{RxFiles Q&A Summary: http://www.rxfiles.ca/acrobat/Lipid-Q&A-Prove-It.pdf }21 de Lemos JA, Blazing MA, Wiviott SD, et al.; A to Z Investigators. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA. 2004 Sep 15;292(11):1307-16.22 Schwartz G, Olsson A, Ezekowitz M, Ganz P, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes (MIRACL). JAMA 2001;285:1711-8.23 Pasternak RC, Smith SC Jr, Bairey-Merz CN, et al.; American College of Cardiology; American Heart Association; National Heart, Lung and Blood Institute. ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins. Stroke. 2002Sep;33(9):2337-41.24 NCEP Expert Panel. Executive summary-3rd national cholesterol education program on detection, evaluation and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001;285:2486-97. GrundySM, Cleeman JI, Merz CN, et al.; National Heart, Lung, and Blood Institute; American College of Cardiology Foundation; American Heart Association. Implications of recent clinical trials for the National Cholesterol EducationProgram Adult Treatment Panel III guidelines. Circulation. 2004 Jul 13;110(2):227-39. http://www.acc.org/clinical/adoptions/ncep_report.pdf25 Antithrombotic Trialists' Collaboration (ATC). Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002 Jan 12;324(7329):71-86.26 Lai KC, Lam SK, Chu KM, et al. Lansoprazole for the prevention of recurrences of ulcer complications from long-term low-dose aspirin use. N Engl J Med. 2002 Jun 27;346(26):2033-8.27 Do NSAIDs interfere with the cardioprotective effects of aspirin?. Med Lett Aug 2, 2004 Vol 46 (Issue 1188) 61-62.28 Patel TN, Goldberg KC. Use of aspirin and ibuprofen compared with aspirin alone and the risk of myocardial infarction. Arch Intern Med. 2004 Apr 26;164(8):852-6.29 Mamdani M, Juurlink DN, Lee DS, Rochon PA, Kopp A, Naglie G, Austin PC, Laupacis A, Stukel TA. Cyclo-oxygenase-2 inhibitors versus non-selective non-steroidal anti-inflammatory drugs and congestive heart failure outcomes inelderly patients: a population-based cohort study. Lancet. 2004 May 29;363(9423):1751-6.30 Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR study group. N Engl J Med 2000;343:1520-8.31 Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Lancet. 1993 Oct 2;342(8875):821-8.32 GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Gruppo Italiano per lo Studio della Sopravvivenza nell'infarto Miocardico.Lancet. 1994 May 7;343(8906):1115-22.33 Packer M, Poole-Wilson PA, Armstrong PW, et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group.Circulation. 1999 Dec 7;100(23):2312-8.34 Swedberg K, Held P, Kjekshus J, et al. Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction. Results of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II)N Engl J Med. 1992 Sep 3;327(10):678-84.35 ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. ISIS-4 (Fourth International Study of Infarct Survival)Collaborative Group. Lancet. 1995 Mar 18;345(8951):669-85.36 Major Outcomes in High-Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial(ALLHAT). The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997.37 Granger CB, McMurray JJ, Yusuf S, et al. CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzymeinhibitors: the CHARM-Alternative trial. Lancet. 2003 Sep 6;362(9386):772-6.38 McMurray JJ, Ostergren J, Swedberg K,et al.; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzymeinhibitors: the CHARM-Added trial. Lancet. 2003 Sep 6;362(9386):767-71.39 Parving HH, Lehnert H, Brochner-Mortensen J, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes (IRMA II). Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria

Study Group. N Engl J Med 2001 Sep 20;345(12):870-8.40 Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes (IDNT); Collaborative Study Group. N Engl J Med 2001 Sep 20;345(12):851-60.41 Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy; RENAAL Study Investigators. N Engl J Med 2001 Sep 20;345(12):861-9.42 Cicardi M, Zingale LC, Bergamaschini L, et al. Angioedema associated with angiotensin-converting enzyme inhibitor use: outcome after switching to a different treatment. Arch Intern Med. 2004 Apr 26;164(8):910-3.43 Hjalmarson A, Elmfeldt D, Herlitz J, et al. Effect on mortality of metoprolol in acute myocardial infarction: a double blind randomised trial. Lancet 1981;ii:823-7.44 Janosi A, Ghali JK, Herlitz J, et al.; MERIT-HF Study Group. Metoprolol CR/XL in postmyocardial infarction patients with chronic heart failure: experiences from MERIT-HF. Am Heart J. 2003 Oct;146(4):721-8.45 Hjalmarson A, Goldstein S, Fagerberg B, et al. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestiveheart failure (MERIT-HF). MERIT-HF Study Group. JAMA. 2000 Mar 8;283(10):1295-302.46 Randomised trial of intravenous atenolol among 16 027 cases of suspected acute myocardial infarction: ISIS-1. First International Study of Infarct Survival Collaborative Group. Lancet. 1986 Jul 12;2(8498):57-66.47 Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Lancet. 2001 May 5;357(9266):1385-90.48 A randomized trial of propranolol in patients with acute myocardial infarction. I. Mortality results. JAMA. 1982 Mar 26;247(12):1707-14.49 Pedersen TR. The Norwegian Multicenter Study of Timolol after Myocardial Infarction. Circulation. 1983 Jun;67(6 Pt 2):I49-53.50 Boissel JP, Leizorovicz A, Picolet H, et al. Efficacy of acebutolol after acute myocardial infarction (APSI trial). The APSI Investigators. Am J Cardiol. 1990 Sep 25;66(9):24C-31C.51 Which Beta-blocker. Med Lett 2001;43:9-11. & Drugs for Hypertension, Treatment Guidelines from the Medical Letter 2003; Vol 1 (Issue 6) 33-40.52 Ko DT, Hebert PR, Coffey CS, et al. Adverse effects of beta-blocker therapy for patients with heart failure: a quantitative overview of randomized trials. Arch Intern Med. 2004 Jul 12;164(13):1389-94.53 Borrello F, Beahan M, Klein L, et al. Reappraisal of beta-blocker therapy in the acute and chronic post-myocardial infarction period. Rev Cardiovasc Med. 2003;4 Suppl 3:S13-24.54 Poole-Wilson PA, Swedberg K, Cleland JG, et al.; Carvedilol Or Metoprolol European Trial Investigators. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol OrMetoprolol European Trial (COMET): randomised controlled trial. Lancet. 2003 Jul 5;362(9377):7-13.55 Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-9.56 Peter S Sever, Björn Dahlöf et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac OutcomesTrial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial Lancet 2003; 361: 1149-58. Online April 2, 2003. {RxFiles Q&A Summary: http://www.rxfiles.ca/acrobat/Lipid-Q&A-ASCOT.pdf }57 Long-Term Intervention with Pravastatin in Ischeamic Heart Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterollevels. N Engl J Med 1998; 339:1349-1357.58 Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels (CARE). N Engl J Med 1996;335:1001-9.59 Carswell CI, Plosker GL, Jarvis B. Rosuvastatin. Drugs. 2002;62(14):2075-85; discussion 2086-7.60 Rosuvastatin--a new lipid-lowering drug. Med Lett Drugs Ther. 2003 Oct 13;45(1167):81-3.61 Shepherd J, Blauw GJ, Murphy MB, et al.; PROSPER study group. PROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360:1623-30.62 Bloomfield Rubins A, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol(VA-HIT). N Engl J Med 1998; 339:1349-57.63 Hirsh J, Guyatt G, Albers GW, et al. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence-Based Guidelines. Chest. 2004 Sep;126(3 Suppl):172S-3S.64 RxFiles Oral Antiplatelet & Antithrombotic Comparison Chart http://www.rxfiles.ca/acrobat/cht-AntiThrombotics.pdf65 Yusuf S et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST segment elevation (Clopidogrel in unstable angina to prevent recurrent events (CURE). N Engl J Med 2001; 345: 494-502.66 CAPRIE Steering Committee. A randomized, blinded trial of clopidogrel vs aspirin in patients at risk of ischemic events (CAPRIE). Lancet 1996; 348:1329-39.67 Hurlen M, Abdelnoor M, Smith P, et al. Warfarin, aspirin, or both after myocardial infarction. (WARIS-II) N Engl J Med. 2002 Sep 26;347(13):969-74.68 Hayden M, Pignone M, Phillips C, et al. Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2002 Jan 15;136(2):161-72.69 Diener HC, Bogousslavsky J, Brass LM, et al.; MATCH investigators. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised,double-blind, placebo-controlled trial. Lancet. 2004 Jul 24;364(9431):331-7.70 Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure (the Randomized Aldactone Evaluation Study [RALES]). Am J Cardiol. 1996 Oct 15;78(8):902-7.71 Pitt B, Remme W, Zannad F, et al.; Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. (EPHESUS) Eplerenone, a selective aldosterone blocker, in patients with left ventriculardysfunction after myocardial infarction. N Engl J Med. 2003 Apr 3;348(14):1309-21.72 Yusuf S., Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004 (online version published Sept 3,2004)73 The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, & Treatment of High Blood Pressure (The JNC 7); JAMA. 2003 May;289(19):2560-72. (Complete report in Hypertension 2003;42:1206-1252)74 Anavekar NS, McMurray JJ, Velazquez EJ, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med. 2004 Sep 23;351(13):1285-95.75 The 2004 Canadian Hypertension Education Program Recommendations www.chs.md Khan NA, McAlister FA, Campbell NR, Feldman RD, et al.; Canadian Hypertension Education Program. The 2004 Canadian recommendationsfor the management of hypertension: Part II--Therapy. Can J Cardiol. 2004 Jan;20(1):41-54.76 Genest J, Frohlich J, Fodor G, et al.; Working Group on Hypercholesterolemia and Other Dyslipidemias. Recommendations for the management of dyslipidemia and the prevention of cardiovascular disease: summary of the Canadian2003 update. CMAJ. 2003 Oct 28;169(9):921-4. http://www.cmaj.ca/cgi/data/169/9/921/DC1/1 Full Report.77 Canadian 2003 Diabetes Guidelines http://www.diabetes.ca/cpg2003/download.aspx Harris SB, Lank CN. Recommendations from the Canadian Diabetes Association. 2003 guidelines for prevention and management of diabetes andrelated cardiovascular risk factors. Can Fam Physician. 2004 Mar;50:425-33. (Meltzer S, Leiter L, Daneman D, et al 1998. Clinical practice guidelines for the management of diabetes in Canada. CMAJ 1998;159 (8 Suppl)).NOTE: Additional RxFiles Related Materials & Drug Comparison Charts: see www.RxFiles.ca {eg. Lipid Landmark Trials; Comparison Charts: ACEI, Beta-Blocker, Antithrombotic, Lipid Lowering}

We would like to acknowledge the following contributors and reviewers: Dr. T. Wilson (Internal Medicine/Pharmacology), Dr. R. Basran (Cardiology), Dr. T. Laubscher (Fam. Medicine),Dr. G. Pylypchuk (Nephrology), Dr. D. Marciniuk (Respirology), Dr. B. Semchuk (Pharmacy), & the RxFiles Advisory Committee. D. Jorgenson PharmD, L. Regier BSP, BA, B. Jensen BSPDISCLAIMER: The content of this newsletter represents the research, experience and opinions of the authors and not those of the Board or Administration of Saskatoon Health Region (SHR). Neither the authors nor Saskatoon Health Region nor any other party who has been involved in thepreparation or publication of this work warrants or represents that the information contained herein is accurate or complete, and they are not responsible for any errors or omissions or for the result obtained from the use of such information. Any use of the newsletter will imply acknowledgment of thisdisclaimer and release any responsibility of SHR, its employees, servants or agents. Readers are encouraged to confirm the information contained herein with other sources. Copyright 2004 – RxFiles, Saskatoon Health Region (SHR) www.RxFiles.ca


Title: Life After Vioxx…Organisation: Independent Drug Information Service – iDiS (Harvard)

Description: This newsletter has 4 pages, 1736 words and is divided into 5 sections. There is full use of colour in graphics, tables and titles. Evaluation Summary Reviewer #1 Reviewer#2 #1 Referencing 4 5#2 Peer Review 3 2#3 Systematic Review 1 3#4 Statistics 3 1#5 Price and coverage 5 4#6 Graphics 5 5#7 Key Messages 2 3#8 Sections 5 3#9 Headings 5 5#10 Table Hierarchy 4 5#11 Table Editorial Consistency 3 4#12 Column Width 3 1#13 Readability 5 4#14 Justification 5 5#15 Colour 5 5#16 Main Message 2 4#17 Therapeutic Decision Support 5 4#18 Behaviour Target 3 5#19 Retrieval 4 3#20 Editorial Consistency 5 5


Overall Mean Score 77 Strengths The spacing and layout within the document enhance readability. The document contains appropriate comparative pricing information. Weaknesses There is a technical problem with the title of the final figure which makes it unreadable. The key messages are spread throughout the document making them difficult to find quickly.

The unexpected withdrawal of Vioxx

in September 2004, followed by Bextra

in April 2005, has led many physicians

to reassess the place of selective cox-2

inhibitors in pain management. These

concerns were heightened last spring

when the FDA applied the same “black

box warning” to all NSAIDs as well,

cautioning that they each can increase

the risk of cardiovascular events. What

is really known about the comparative

efficacy and safety of these drugs?

Balanced data about medications

Life after Vioxx…

The overwhelming evidence from clinical trials shows that selective cox-2 inhibitors do not have anystronger analgesic efficacy than conventional NSAIDs such as naproxen (e.g.,Aleve) or ibuprofen (e.g.,Motrin).1 Different patients may respond differently to different analgesics,but there’s virtually noevidence that the cox-2 drugs relieve pain any better than their older counterparts.Elaborate mediacampaigns directed at patients created an aura of superiority that was not backed up by clinical trial data.

The main advantage of drugs like Vioxx (rofecoxib) or Celebrex (celecoxib) was the expectationthat they would lower the risk of gastrointestinal bleeding compared to older NSAIDs. However…

• this protection was relative, not absolute;2,3

• concurrent use of low-dose aspirin for cardioprotection can sharply reduce the g.i. protectionoffered by these drugs;2

• only a small proportion of patients who will need chronic analgesics are at high risk of NSAID-induced g.i. bleeding in the first place;4 [see box]

• there are other effective ways of protecting patients from analgesic-induced g.i. side effects, such asadding a proton pump inhibitor to a conventional NSAID.5

There has long been concern about whether selectively inhibiting the cox-2 enzyme might increasethe risk of cardiovascular events through a variety of thrombogenic effects as well as othermechanisms. A key randomized trial of rofecoxib (Vioxx) published in 2000 unexpectedlydemonstrated a 5-fold increase in the rate of myocardial infarction in patients randomized to that drug.3

Several large observational studies since then have also found higher rates of MI in patients takingVioxx.6,7 In September 2004,a Merck-sponsored randomized clinical trial found that patients givenVioxx had twice the number of MIs or strokes that controls did.8 The company withdrew the drugfrom the market. Bextra (valdecoxib) was withdrawn seven months later.

Confusion increased when FDA warned in April 2005 that all NSAIDs and the remaining selective cox-2 inhibitor,Celebrex (celecoxib),would be required to carry the same black-box warning that they canincrease the risk of cardiovascular events.9 This created concerns for physicians and patients over thewhole class of agents,but provided little guidance on what to do or whether the risk is the same for allof these drugs.The evidence suggests that it is not.10 We have reviewed the data from all availablerandomized controlled trials (RCTs) and epidemiological (epi) studies and summarize it here:

Which patients are at most risk for g.i. side effects?• older age • history of peptic

ulcer disease• using oral steroids • taking warfarin

(Coumadin) or another anticoagulant

Clearing the air about efficacy.

A word on gastroprotection.

The tipping point for cardiovascular risk.

What about the benefits and risks of the drugs that remain?

Vioxx Considerable evidence of increased risk of MI, stroke,and other cardiovascular (rofecoxib) complications seen in RCTs and epi studies,especially at higher doses. [withdrawn

from market]

Bextra Doubling or tripling of cardiovascular events compared to placebo in two RCTs of(valdecoxib) patients undergoing cardiac surgery. Also causes potentially fatal dermatologic side

effect of Stevens-Johnson syndrome. [withdrawn from market]

Celebre x At high doses (200-400 mg b.i.d.),dose-related doubling or tripling of myocardial(celecoxib) infarction in one RCT compared to placebo,but no increase in risk found in another

RCT with a single daily dose of 400 mg/d. Several epi studies have found no elevatedrisk signal compared to Vioxx or other NSAIDs.

Motrin, etc. Conflicting evidence of risk,much less clear than with previous three drugs.However,(ibuprofen) little information is available on cardiac risk from randomized placebo-controlled trials.

aassppiirriinn:: Clear evidence of reduction in risk of MI based on large RCTs in men; less evidence ofbenefit in women.

naproxen: Evidence of slightly reduced risk of MI in many but not all RCT and epi studies.

One good outcome of the current resurgence of interest in the risks and benefits of the coxibs andNSAIDs is that many prescribers have begun to re-think their management of acute and chronicpain.11 Pain specialists and rheumatologists recommend this approach:12

1 . Start with acetaminophen (Tylenol, etc.). Because it is sold over-the-counter and has beenavailable for decades, many clinicians underestimate the utility of this drug. Unless a patient hascontraindications such as liver disease, alcoholism, or poorly controlled hypertension, consider 1 gt.i.d.-q.i.d. as an initial pain medication.This may well be adequate for a significant number ofpatients and can form the foundation of further treatment for others.

2 . Naproxen is probably the safest NSAID in terms of cardiac risk. If a non-aspirin NSAID isneeded, the bulk of evidence indicates that naproxen carries the lowest cardiac risk, and may evenbe cardioprotective to a small degree. (But it should not be used to replace low-dose aspirin for thispurpose.) Naproxen is also available at low cost from multiple generic manufacturers [see costcomparison chart]. It should be taken with meals or milk. If g.i. symptoms develop, or a patient is athigh g.i. risk [see box], consider adding an H2-blocker or a proton pump inhibitor. There is evidencethat taking omeprazole along with a conventional NSAID can provide gastroprotection comparableto that provided by Celebrex.5

3 . All patients who require cardioprotective use of low-dose aspirin should receive itr egardless of their NSAID regimen. Unfortunately, the available evidence suggests that (a) low-dose aspirin reduces the modest gastroprotective benefit of the cox-2 inhibitors, and (b) this doesnot seem to protect against the elevated risk of MI caused by the coxibs.

4 . Whatever regimen is chosen, prescribe the lowest dose that will control pain, and the shortestduration of therapy. Monitor patients for side effects including fluid retention, hypertension,reduction in renal function, and evidence of gastrointestinal toxicity (abdominal pain, black stools,fecal occult blood, anemia).

Back to basics.

References are provided in the evidence document accompanying this material.

For patients with chronic arthritis pain, rheumatologists advocate several additional strategiesto avoid having to commit a patient to years of high-dose NSAID therapy:12

1 . Protect the affected joints with a cane, brace, weight loss, and lower extremity exercise programs.

2. Evaluate the need for controlled opioid analgesics. For carefully selected patients, measureduse of codeine, tramadol, hydrocodone, or oxycodone may be a safe and appropriate choice.

3. Don’t wait too long before surgery. For some patients with severe osteoarthritis, the mosteffective treatment is joint replacement, which will usually improve function and will lessen theneed for pain medication in many cases.

References: 1. Helfand M, Peterson K, Carson SM, Drug class review on NSAIDs. Final Report: http://www.ohsu.edu/drugeffectiveness/reports/documents/NSAIDs Final Report u2.pdf. 2. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs forosteoarthritis and rheumatoid arthritis: the CLASS study:A randomized controlled trial. Journal of the American Medical Association. 2000;284(10):1247-1255.3. Bombardier C, Laine L, Reicin A, et al.VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients withrheumatoid arthritis.VIGOR Study Group. New England Journal of Medicine. 2000;343(21):1520-1528. 4. Gabriel SE, Jaakkimainen L, Bombardier C. Risk forserious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs.A meta-analysis. Annals of Internal Medicine. 1991;115(10):787-796. 5. Chan FK, Hung LC, Suen BY, et al. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients witharthritis. New England Journal of Medicine. 2002;347(26):2104-2110. 6. Solomon DH, Schneeweiss S, Glynn RJ, et al. Relationship between selective COX-2inhibitors and acute myocardial infarction in older adults. Circulation. 2004;109(17):2068-2073. 7. Solomon DH. Selective Cyclooxygenase 2 Inhibitors andCardiovascular Events.Arthritis and Rheumatism. 2005;52(7):1968-78. 8. Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated withrofecoxib in a colorectal adenoma chemoprevention trial. New England Journal of Medicine. 2005;352(11):1092-102. 9. Food and Drug Administration,April 7, 2005.Accessed at: http://www.fda.gov/cder/drug/advisory/COX2.htm 10. Antman EM, DeMets D, Loscalzo J. Cyclooxygenase inhibition andcardiovascular risk. Circulation. 2005;112(5):759-770. 11. Bennett JS, Daugherty A, Herrington D, et al.The use of nonsteroidal anti-inflammatory drugs(NSAIDs): a science advisory from the American Heart Association. Circulation. 2005;111(13):1713-1716. 12. American College of RheumatologySubcommittee on Osteoarthritis Guidelines. Recommendations for the medical management of osteoarthritis of the hip and knee.Arthritis andRheumatism. 2000;43(9):1905-1915.

Additional references documenting these recommendations are provided in the evidence document accompanying this material.

This material was produced for the Independent Drug Information Service (iDiS) by Dan Solomon, M.D., M.P.H., AssistantProfessor of Medicine at Harvard Medical School, and Jerry Avorn, M.D., Professor of Medicine at Harvard Medical School.iDiS is supported by the PACE Program of the Department of Aging of the Commonwealth of Pennsylvania. This program isnot affiliated in any way with any pharmaceutical company. These are general recommendations only; specific clinicaldecisions should be made by the treating physician based on an individual patient’s clinical condition.

©iDiS 2005 December 2005

The renewed concern about the safety and efficacy of old and new NSAIDs can provide a freshopportunity to reassess the approach to pain management. In many instances, such reassessmentwill enable patients to experience better analgesic results with lower risk of cardiovascular as wellas gastrointestinal side effects.

$100

acetaminophen1 g, q.i.d.

ibuprofen400 mg, t.i.d.

naproxen250 mg, b.i.d.

Celebrex (celecoxib)200 mg, q.d.

$80

$60

$40

$20

$0

Co

st

D ru g

Av e rage R e ta il C o s t Pe r 3 0 D ay s

$ 8 .7 0 $ 8 .7 0 $ 7 .8 0

$ 7 9 .2 0


Who really needs a cox-2 inhibitor? The recommended approach will work best for mostpatients.The available data indicate that the one cox-2 inhibitor remaining on the market,Celebrex,appears to pose less cardiac risk than did Vioxx and Bextra, and little is known about its safetycompared to older non-selective NSAIDs.However, the greater rate of cardiac events seen at highdoses in placebo-controlled trials is worrisome.Taken together, the data suggest that Celebrex bereserved for patients who require an NSAID,are at increased risk of the gastrointestinal complicationsfrom which it provides modest protection, and cannot tolerate the suggested regimens.

In summary…

Source: www.drugstore.com


Title: An Overview of CARDS (Collaborative Atorvastatin Diabetes Study)Organization: RxFiles (Saskatchewan)

Summary Descriptive Information This newsletter has 2 pages, 1192 words and is divided into 4 sections. There is full use of colour in figures and in highlighting text. Evaluation Summary Reviewer #1 Reviewer#2#1 Referencing 5 5#2 Peer Review 1 2#3 Systematic Review 1 2#4 Statistics 5 5#5 Price and coverage 1 1#6 Graphics 4 4#7 Key Messages 5 4#8 Sections 5 5#9 Headings 4 5#10 Table Hierarchy 5 5#11 Table Editorial Consistency 3 3#12 Column Width 2 1#13 Readability 3 3#14 Justification 5 5#15 Colour 4 4#16 Main Message 4 5#17 Therapeutic Decision Support 5 4#18 Behaviour Target 4 4#19 Retrieval 4 4#20 Editorial Consistency 4 4


Overall Mean Score 75 Strengths This is a comprehensive document that interprets this trial in a clinical context. It provides important tools to allow thoughtful practitioners to evaluate the limitations and context of statin use in primary prevention for patients with diabetes. Weaknesses Column width, font, colour pattern and density of information provide serious challenges to readability to those not familiar with this style of document.

Q&A – Lipid Trials - CARDS www.RxFiles.ca – Aug 2004

An Overview of CARDS (Collaborative Atorvastatin Diabetes Study): Primary Prevention of Cardiovascular Disease with Atorvastatin in Type 2 Diabetes

CARDS Overview 1♦ a multi-center randomized placebo controlled trial to determine hard outcomes of atorvastatin 10mg vs. placebo in patients with

Type 2 diabetes, & at least 1 additional cardiovascular risk factor (RF) � (63% had 1 RF, 30% had 2 RF, 6% had 3 RF & 1% had 4 RF), LDL ≤ 4.14mmol/L, TG ≤ 6.78mmol/L, and without a history of cardiovascular, cerebrovasular or peripheral vascular disease.

� (Additional CV risk factors for inclusion were: hypertension 84% , retinopathy 30% , current smoking 23% or albuminuria 17% ; in addition, the majority of patients were male, Caucasian and over 60 years of age)

♦ 2,838 high risk patients were followed for 4 years with the following baseline demographic characteristics:- age: 40-75 (Ave=62 yrs); sex: 68% male; white ethnic origin: 94%; LDL: 3.0mmol/L; HDL: 1.4mmol/L; TG: 1.7mmol/L

♦ two treatment arms: atorvastatin LIPITOR 10mg daily (n=1428) versus placebo (n=1410)

Table 1: CARDS results - Atorvastatin 10mg daily vs placebo daily

Endpoints - (4 years) Atorvastatin % (n=1428)

Placebo % (n=1410)

ARR%

RRR%

NNT p value

1o time to 1st occurrence of:CHD death, non-fatal MI (including silent),

hospitalized for unstable angina, resuscitatedcardiac arrest, coronary revascularization or stroke

5.8(83 events)

9.0(127 events)

3.2 36 32 0.001

Acute Coronary Events 3.6 5.5 1.9 35 53 0.02 Revascularization 1.7 2.4 NS NS NS 0.2Stroke 1.5 2.8 1.3 47 77 0.022° All-cause mortality 4.3 5.8 NS NS NS 0.06

1o=primary outcome 2o=secondary outcome ARR=absolute risk reduction CV=cardiovascular CHD=coronary heart diseaseMI=myocardial infarction NNT=number needed to treat to benefit 1 patient RF=risk factor RRR=relative risk reduction

Of Note:♦ analysis by intention to treat (an average of 9% of placebo group were taking a statin compared to 85% in treatment group)♦ LDL: initial 3.0mmol/L(25% <2.5mmol/L); at follow up (4yrs): placebo arm: 3.12 mmol/l; atorvastatin arm: 2.11 mmol/l♦ SAFETY : frequency of serious adverse events did not differ between groups (uncommon muscle and liver events reported in both groups)♦ Exclusion criteria to ensure only carefully selected patients enrolled eg. serum creatinine ≥150umol/l, creatine phosphokinase ≥3x

normal, no concomitant drugs associated with rhabdomyolysis, fibrates or other interacting medications.♦ All-cause mortality: trend for benefit in atorvastatin group however, it did not reach statistical significance; trial halted early.

What we knew and what these results add to that knowledge:♦ Patients with Type 2 diabetes are at higher risk of stroke and cardiovascular events.♦ Subgroup analysis of previous secondary prevention trials have shown reductions in major CV event rates with statins.

HPS2 - diabetes subgroup CHD or CVD (2°) n=3051: Simvastatin 40m/d NNT= 18 over 4.8 yrs4S3 – diabetes & FBG ≥ 7mmol/L n=483: Simvastatin 20-40mg/d NNT = 7 over 5.4 yrs4S4 – diabetes & IFG (FBG ≥6.0mmol/L) n=678: Simvastatin 20-40mg/d NNT = 9 over 5.4 yrsCARE5 –diabetes subgroup n=586: Pravastatin 40mg/d NNT = 13 over 5 yrs

♦ Diabetes subgroup analysis of previous primary prevention trials support possible benefit of statins.HPS6 – diabetes subgroup no CVD (1°) n=2912: Simvastatin 40mg/d NNT = 24 over 4.8 yrsASCOT7 – diabetes subgroup n=2532: Atorvastatin 10mg/d Non-significant (Trend for benefit)

♦ CARDS is the first trial designed and powered to evaluate hard outcomes specifically in Type 2 diabetes patients with one ormore cardiovascular risk factors. CARDS does not provide information on patients who are younger or without risk factors.

♦ Magnitude of benefit (e.g. Number Needed to Treat) in CARDS patients (Type 2 Diabetes & risk factors):1 less patient progressed towards a major CV event over 4 years for every 32 patients treated with atorvastatin 10mg/day.

♦ CARDS supports the findings of the HPS trial that it is cardiovascular risk and not necessarily elevated LDL that predictsbeneficial outcomes in patients on statins. Similar beneficial outcomes were seen regardless of initial LDL and HDL levels.

Questions Remaining: �Would benefits be seen in younger/lower risk Type 2 diabetes patients and if so, would the numbers needed to treat justify their use?�Is there an optimal LDL target for patients with Type 2 diabetes and if so, what is it?�What effect would lipid lowering combinations (eg. statins + fibrates or ezetimibe) have on risks vs benefits?�Are there any differences in risks and benefits of various statins in this population group?�How do other lipid lowering drug classes compare to statins in patients with diabetes?

TAKE HOME: Statin treatment (atorvastatin 10mg/d) in high risk Type 2 diabetes patients with at least 1 additionalrisk factor significantly reduces their risk of CV & stroke events even when initial LDL is already ≤ 3mmol/L.

NNT= number needed to treat NNH= number needed to harm NS= not significant (statistically)RRR= relative risk reduction

References:1 Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative AtovastatinDiabetes Study (CARDS). Lancet 2004;364:685-96.2 Collins R, Armitage J, Parish S, Sleigh P, Peto R; Heart Protection Study.(HPS) Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering withsimvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet. 2003 Jun 14;361(9374):2005-16.3 Haffner SM, Alexander CM, Cook TJ, Boccuzzi SJ, Musliner TA, Pedersen TR, Kjekshus J, Pyorala K. Reduced coronary events in simvastatin-treated patients withcoronary heart disease and diabetes or impaired fasting glucose levels: subgroup analyses in the Scandinavian Simvastatin Survival Study (4S). Arch Intern Med. 1999Dec 13-27;159(22):2661-7.4 Haffner SM, Alexander CM, Cook TJ, Boccuzzi SJ, Musliner TA, Pedersen TR, Kjekshus J, Pyorala K. Reduced coronary events in simvastatin-treated patients withcoronary heart disease and diabetes or impaired fasting glucose levels: subgroup analyses in the Scandinavian Simvastatin Survival Study (4S). Arch Intern Med. 1999Dec 13-27;159(22):2661-7.5 Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels (CARE).N Engl J Med 1996;335:1001-9.6 Collins R, Armitage J, Parish S, Sleigh P, Peto R; Heart Protection Study (HPS). Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-loweringwith simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet. 2003 Jun 14;361(9374):2005-16.7 Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O'Brien E,Ostergren J; ASCOT investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-averagecholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial.Lancet. 2003 Apr 5;361(9364):1149-58.

Prepared by: Loren Regier BSP BA & Brent JensenBSP


CARDS Aug 2004

5.89

1.52.8 4.3 5.8

0

10

20

Time to 1st Major CVEvent

Stroke All-Death

AtorvPlac

Atorvastatin 10mg/day vs Placebo in Type 2 Diabeteswith 1 or more CVD risk factors, no hx of CV disease,

LDLmmol/L ≤ 4.14 (Ave 3.0), TG ≤ 6.78 (Ave 1.7)%patients

NNT=32 /4yrs

NNT=76 /4 yrs

NS

Atorvastatin benefits patients with type-2 diabetes at high riskfor CVD. Benefits regardless of higher or lower initial LDL.Average atrovastatin patients achieved LDL ~ 2mmol/L


Title: Acid-suppressing therapy: neutralizing the hypeOrganization: Independent Drug Information Service – iDiS (Harvard)

Summary Descriptive Information This newsletter has 4 pages, 2312 words and is divided into 9 sections. There is full use of colour in figures, headings and pictures. Evaluation Summary Reviewer #1 Reviewer#2#1 Referencing 5 5#2 Peer Review 2 2#3 Systematic Review 1 3#4 Statistics 2 1#5 Price and coverage 5 5#6 Graphics 5 5#7 Key Messages 2 2#8 Sections 1 2#9 Headings 5 5#10 Table Hierarchy 5 5#11 Table Editorial Consistency 4 5#12 Column Width 3 1#13 Readability 4 4#14 Justification 5 5#15 Colour 5 5#16 Main Message 2 3#17 Therapeutic Decision Support 5 5#18 Behaviour Target 4 5#19 Retrieval 4 3#20 Editorial Consistency 5 5


Overall Mean Score 75 Strengths There is good use of graphics to illustrate the concepts of PPI tapering. There is also excellent support for therapeutic alternatives with information on dosage, time to symptom relief and cost. Weaknesses The number of words per column and the number of section headings in the document exceeds the optimums defined for this evaluation.

Proton pump inhibitors (PPIs) such as omeprazole (Prilosec),

esomeprazole (Nexium) and pantoprazole (Protonix) have become some

of the most widely used drugs in the country, in large part because of

aggressive marketing to both doctors and patients. The drugs suppress

stomach acid production almost completely, and as such are useful in

patients with severe gastroesophageal reflux disease (GERD) or peptic

ulcer. However,when taken p.r.n. (as many patients use them), they can

require up to 24 hours to produce full symptom relief. Regular use can

result in painful rebound hyperacidity when the drug is stopped if it is not

tapered properly (see back page).

PPIs are often used unnecessarily in patients who do not require

total suppression of acid production. This is of particular concern in light

of two recent reports. The Journal of the American Medical Association

reported in December 2005 that PPI use triples the risk of potentially

dangerous Clostridium difficile diarrhea in primary care patients.1 In the

same month the federal Agency for Healthcare Research and Quality

released an exhaustive overview of treatments for GERD. It concluded

that while PPIs are the most effective medication for patients who actually

have this condition, they caused more side effects than the H2 blockers

(particularly headache,diarrhea,and abdominal pain).2 Because these

drugs are so costly, they can also have important adverse effects on

patients’budgets, as well as on fiscally-strapped public programs that help

patients pay for their prescriptions.

Despite the usefulness of PPIs when truly needed, there are solid

reasons for reassessing PPI regimens in many patients. The more

prescriptions a patient has to juggle, the greater the likelihood of reduced

compliance with essential drugs.3 A longer medication list also puts

patients at greater risk of medication errors and adverse drug reactions,4,5

especially in older patients. For those without drug insurance,a year of

PPIs can cost about $1500. Even for patients with health insurance, their

deductibles,dispensing fees,and monthly co-payments can impose a

significant financial burden for those on fixed incomes.


Acid-suppressing therapy:neutralizing the hype

Although PPIs are often taken on an as-needed basis, they do not work well p.r.n. because they canrequire over 24 hours to achieve clinically useful levels of acid suppression.6 By contrast, antacids actlocally on irritated mucosal surfaces and are effective within 5-20 minutes. H2 blockers work within 30-60 minutes.

Only a few categories of patients require a PPI as initial treatment: those with severe GERD,documented peptic ulcer disease, or Zollinger-Ellison syndrome, and those being given a regimen toeradicate H. pylori. All PPIs work about as well as one another for these indications; reviews of theliterature have produced no convincing evidence that any one of them is superior.2,8

Gastroesophageal reflux disease (GERD): The American Gastroenterological Association reviewednumerous randomized trials in patients with mild to moderate GERD, and concluded in its guidelinesthat H2 blockers and antacids should be used as first-line therapy, and will produce a 60-70% rate ofsymptom relief.7

Non-ulcer (“functional”) dyspepsia (NUD): In this vague but common condition, patients complainof epigastric discomfort but have no endoscopic evidence of ulcer or GERD. Large randomized studiesof NUD have found little difference between the effectiveness of PPIs vs. H2 blockers.9 The cause of this condition is often multifactorial; many patients benefit from promotility drugs rather than acid suppression.10 There is conflicting evidence as to whether PPIs are any better than placebo for this indication.11

Lifestyle modifications are a key component of any treatment plan, and can be the most effectivecomponent of the regimen:

• for acid suppression: avoid products that increase acid production or damage mucosal defenses:NSAIDs, alcohol, tobacco, caffeine.

• to reduce reflux: eliminate substances that reduce tone in the lower esophageal sphincter: caffeine,nicotine, chocolate; avoid large meals right before bedtime; elevate the head of the bed; replace tightclothing that constricts the abdomen; don’t recline within 2-3 hours after a meal; lose weight.

When patients understand the downsides of potentially unnecessary PPI therapy and experience rapidsymptom relief with non-PPI medications, they are likely to accept being tapered off of their PPIs. Forthose with severe and relapsing GERD or PUD, chronic PPIs are an appropriate part of the medicalregimen. But for a large proportion of patients, tapering PPIs and education about how to use H2blockers and antacids will provide excellent control of symptoms. It will also reduce patients’ out-of-pocket expenses and make it easier for them to comply with other medications.

For acute use, ‘PPI p.r.n.’ may not spell ‘relief’

Rarely required as first-line therapy7

Alternative initial choices for other indications

Non-prescription alternatives work as well for many patients

>24 hrsTime to symptom relief6 30-60 minutes 5-20 minutes

Proton Pump Inhibitors H2 Blockers Antacids

Identifying and treating H.pylori can achieve a cure in patients with peptic ulcer disease and may eliminatethe need for lifelong therapy.12 All patients with clinical evidence of an ulcer should be tested for H.pylori.Testing in the setting of functional dyspepsia is controversial, and should be accompanied by patientcounseling.13-15 Recent American College of Gastroenterology practice guidelines suggest that in areas of highulcer or H.pylori prevalence (e.g., immigrant populations) patients should be tested and treated for H.pylori,while in areas of low ulcer or H.pylori infection prevalence (e.g.,high socio-economic areas),empiricevidence and anti-secretory therapy is appropriate,with testing for H.pylori in patients who do not respondto therapy.16 If the patient is to undergo endoscopy,a biopsy is the test of choice. Otherwise,urea breathtests or stool antigen tests are currently the most accurate non-invasive diagnostic tools.16 Serum antibodyserology (ELISA antibody test) may not be locally validated and has suboptimal sensitivity and specificity inpractice.16 The regimen of choice for eradicating H.pylori is triple therapy with a proton pump inhibitor(standard dose twice daily), amoxicillin (1 g twice daily) and clarithromycin (500 mg twice daily) for 10 days(7 days therapy is approved with rabeprazole).16 Prepackaged regimens (e.g.,Prev-Pac) are available tosimplify prescribing.

Clinically, it doesn’t matter much. All available PPIs have similar efficacy. At comparable doses, there is little or no therapeutic difference between them in the treatment of gastroesophageal reflux disease (GERD),gastric or duodenal ulcers, and Zollinger-Ellison syndrome.17-21 This conclusion was recently confirmed inseveral large reviews of all existing clinical trials.2,8,22,23 However, these drugs can differ substantially in their cost:

Only a few conditions will require long-term chronic use of PPIs:GERD with ongoing symptoms orcomplications such as Barrett’s esophagus,24 severe peptic ulcer disease with recurrent episodes,and theuncommon Zollinger-Ellison Syndrome. More typical patients should be evaluated after 6 to 8 weeks.Most will do well with step-down therapy at that point (see iDiS materials to help with this transition).Plan on tapering and then discontinuing PPIs in these common conditions:

• GERD patients who are symptom-free after 4 weeks of therapy;

• patients with peptic ulcer disease after 8 weeks of therapy and H.pylori eradication;

• non-ulcer dyspepsia (NUD) patients who are symptom-free for 2 weeks on PPI therapy.

If the clinical picture suggests peptic ulcer disease, eradicate H. pylori

Aciphex(rabeprazole)

20 mg

>24 hrs

60-70

91

>24 hrs

$122

—

—

—

$9

Time to symptom relief6

Complete symptom relief (% of patients)

Esophageal healing at 8 weeks (% of patients)

Duration of action

Rx brand (cost per 30 days)*

Rx generic (cost per 30 days)*

OTC brand (cost per 30 days)*

OTC generic (cost per 30 days)*

Co-pay for PACE enrollees

Prilosec(omeprazole)

20 mg

>24 hrs

60-70

86

>24 hrs

$116

$94

$21

—

$9

Prevacid(lansoprazole)

30 mg

>24 hrs

60-70

87

>24 hrs

$124

—

—

—

$9

Protonix(pantoprazole)

40 mg

>24 hrs

60-70

91

>24 hrs

$111

—

—

—

$9

Nexium(esomeprazole)

40 mg

>24 hrs

60-70

92

>24 hrs

$124

—

—

—

$9

e.g., Zantac(ranitidine)

75 mg

30-60 min

60-70

50

12 hrs

$120-240

$33 (150 mg)

$15 (75 mg)

$7 (75 mg)

Over the counter

e.g., Maalox and

generics

5-20 min

20

—

1-2 hrs

—

—

$2 (500 mg)

$1 (550 mg)

Over the counter

Proton Pump Inhibitors H2RA Antacid

If first-line treatments fail, which PPI to choose?

*Source: www.drugstore.com

When starting a course of PPI…

References: 1. Dial S, Delaney JA, Barkun AN, Suissa S. Use of Gastric Acid-Suppressive Agents and the Risk of Community-Acquired Clostridium difficile-Associated Disease. JAMA. 2005; 294(23):2989-2995. 2. Comparative effectiveness of management strategies for Gastroesophageal Reflux Disease.AHRQ Pub No. 06-CH003. December 1, 2005. Available at: http://effectivehealthcare.ahrq.gov/repFiles/GERD%20Final%20Report.pdf. 3. Chapman RH,Benner JS, Petrilla AA,Tierce JC, Collins SR, Battleman DS, Schwartz JS. Predictors of adherence with antihypertensive and lipid-lowering therapy. Archives ofInternal Medicine. 2005;165:1147-52. 4. Atkin PA, Veitch PC,Veitch EM, Ogle SJ.The epidemiology of serious adverse drug reactions among the elderly. Drugs& Aging. 1999;14:141-52. 5. Schneeweiss S, Hasford J, Gottler M, Hoffmann A, Riethling AK,Avorn J.Admissions caused by adverse drug events to internalmedicine and emergency departments in hospitals: a longitudinal population-based study. European Journal of Clinical Pharmacology. 2002;58:285-91.6. Spechler S, Peikin S, El-Serag H. Medication strategies for heartburn.American Gastroenterological Association. September 16, 2002. 7. Peterson WL.Improving the management of GERD. Evidence-based therapeutic strategies. Consensus Opinion in Gastroenterology,American Gastroenterology Association.2004. 8. McDonagh MS, Carson S, for the Oregon Evidence-based Practice Center. Drug class review on proton pump inhibitors.April 2004. 9. Blum AL,Arnold R, Stolte M, Fischer M, Koelz HR. Short course acid suppressive treatment for patients with functional dyspepsia: results depend on Helicobacter pyloristatus.The Frosch Study Group. Gut. 2000;47:473-80. 10. Allescher HD, Bockenhoff A, Knapp G,Wienbeck M, Hartung J.Treatment of non-ulcer dyspepsia: ameta-analysis of placebo-controlled prospective studies. Scandinavian Journal of Gastroenterology. 2001;36:934-41. 11. Talley NJ, Lauritsen K.The potentialrole of acid suppression in functional dyspepsia: the BOND, OPERA, PILOT, and ENCORE studies. Gut. 2002;50 Suppl 4:iv36-41. 12. Gisbert JP, Khorrami S,Carballo F, Calvet X, Gene E, Dominguez-Munoz JE. H. pylori eradication therapy vs. antisecretory non-eradication therapy (with or without long-termmaintenance antisecretory therapy) for the prevention of recurrent bleeding from peptic ulcer. Cochrane Database Syst Rev. 2003;(4):CD004062. 13. HowdenCW, Hunt RH. Guidelines for the management of Helicobacter pylori infection.Ad Hoc Committee on Practice Parameters of the American College ofGastroenterology. Am J Gastroenterol. 1998;93:2330-8. 14. Talley NJ, Hunt RH.What role does Helicobacter pylori play in dyspepsia and nonulcer dyspepsia?Arguments for and against H. pylori being associated with dyspeptic symptoms. Gastroenterology.1997;113:S67-77. 15. Blum AL, Talley NJ, O'Morain C, vanZanten SV, Labenz J, Stolte M, Louw JA, Stubberod A,Theodors A, Sundin M, Bolling-Sternevald E, Junghard O. Lack of effect of treating Helicobacter pyloriinfection in patients with nonulcer dyspepsia. Omeprazole plus Clarithromycin and Amoxicillin Effect One Year after Treatment (OCAY) Study Group. N Engl JMed. 1998;339:1875-81. 16. Talley NJ, Vakil N; Practice Parameters Committee of the American College of Gastroenterology. Guidelines for the managementof dyspepsia. Am J Gastroenterol. 2005 Oct;100(10):2324-37. 17. Langman MJ. Which PPI? Gut. 2001;49:309-10. 18. Stedman CA, Barclay ML. Reviewarticle: comparison of the pharmacokinetics, acid suppression and efficacy of proton pump inhibitors.Alimentary Pharmacology & Therapeutics. 2000;14:963-78. 19. Vanderhoff BT, Tahboub RM. Proton pump inhibitors: an update. American Family Physician.2002;66:273-80. 20. Welage LS, Berardi RR. Evaluationof omeprazole, lansoprazole, pantoprazole, and rabeprazole in the treatment of acid-related diseases. Journal of the American Pharmaceutical Association.2000;40:52-62; quiz 121-3. 21. Carswell CI, Goa KL. Rabeprazole: an update of its use in acid-related disorders. Drugs. 2001;61:2327-56. 22. Hutchinson TA,Shahan DR, eds. Drugdex system.Vol. 116. Greenwood Village, CO. Micromedex; edition expires 2003.06. 23. Chan J, Acid-peptic therapy. In:Anderson PO,Knoben JE,Troutman WG, eds. Handbook of clinical drug data. 10th ed.Toronto: McGraw-Hill; 2002:528-52. 24. DeVault KR, Castell DO,American College ofGastroenterology. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. American Journal of Gastroenterology.2005;100:190-200. 25. Qvigstad G, Waldum H. Rebound hypersecretion after inhibition of gastric acid secretion. Basic & Clinical Pharmacology & Toxicology.2004;94:202-8. 26. Inadomi JM, McIntyre L, Bernard L, Fendrick AM. Step-down from multiple- to single-dose proton pump inhibitors (PPIs): a prospectivestudy of patients with heartburn or acid regurgitation completely relieved with PPIs. American Journal of Gastroenterology.2003;98:1940-4.

Additional references documenting these recommendations are provided in the evidence document accompanying this material.

This material was produced for the Independent Drug Information Service (iDiS) by Sebastian Schneeweiss, M.D., Sc.D.,Associate Professor of Medicine at Harvard Medical School, and Michael Fischer, M.D., M.S., Instructor in Medicine atHarvard Medical School. iDiS is supported by the PACE Program of the Department of Aging of the Commonwealth ofPennsylvania. This program is not affiliated in any way with any pharmaceutical company. These are generalrecommendations only; specific clinical decisions should be made by the treating physician based on an individualpatient’s clinical condition.

©iDiS 2006 January 2006

Because they shut down essentially all acid production,PPIs can lead to a hypergastrinemic state whichleads to hypertrophy of parietal and enterochromaffin-like cells. This can result in hypersecretion ofacid when the PPI is stopped. As a result,once PPIs have been started, they can be difficult for somepatients to discontinue.25 Patients treated with PPIs at higher doses or for a longer duration are morelikely to suffer this complication.25 These symptoms are usually short-lived.Solid clinical evidencedemonstrates that over half of patients can be successfully tapered off of PPIs,with particularly goodsuccess rates in elderly patients.26 A tapering regimen followed by H2 blockers can control reboundsymptoms and offers the best chance of successfully stopping PPIs. Once the PPI is discontinued,many patients will not require long-term maintenance therapy and can be successfully managed withp.r.n.doses of H2 blockers or antacids.

6


Beware the purple pill habit

Patient onhigh-dosePPI:e.g.,pantoprazole 40 mg

Reduce doseby half fortwo weeks:e.g.,pantoprazole 20 mg

Stop PPIPrescribe rescuetherapy

• H2 blockers(e.g., ranitidine 150 mg)

• p.r.n.antacids

Long Te rmAs symptomsimprove, slowlydecrease dose and frequency ofH2 blockers andantacids

How to taper ‘PPI addicts’ to reduce rebound symptoms


Title: Dyslipidemia Clinical Notes SummariesOrganization: Alberta Drug Utilization Program (Alberta)

Summary Descriptive Information This newsletter has 4 pages, 1494 words and is divided into 11 sections. The document is in black and white. Evaluation Summary Reviewer #1 Reviewer#2#1 Referencing 1 1#2 Peer Review 1 1#3 Systematic Review 1 1#4 Statistics 3 1#5 Price and coverage 3 1#6 Graphics 1 3#7 Key Messages 1 2#8 Sections 1 1#9 Headings 5 5#10 Table Hierarchy 5 5#11 Table Editorial Consistency 4 5#12 Column Width 1 2#13 Readability 2 4#14 Justification 5 5#15 Colour 4 5#16 Main Message 1 3#17 Therapeutic Decision Support 2 2#18 Behaviour Target 1 1#19 Retrieval 2 2#20 Editorial Consistency 4 5


Overall Mean Score 52 Strengths This document was developed from questions received from physicians. It directly addresses the stated informational needs. Weaknesses The document’s strength is also its greatest weakness. It’s question format does not allow it to fully address clinical issues in the same manner as a focussed newsletter. Lack of referencing and obvious peer review also threatens the document’s face credibility.

Prepared for Alberta Drug Utilization Program by the Health Care Professional Drug Consultation Service of

Alberta Poison and Drug Information Service (PADIS). 944-1222 for Calgary only, 1-800-332-1082 for Alberta,

Page 1 of 4

Dyslipidemia Clinical Notes Summaries

________________________________________________________________________ If you are interested in obtaining complete supporting evidence with references,

please contact your academic detailer or visit the Alberta Drug Utilization Program website www.uofaweb.ualberta.ca/adup.

Does freshly squeezed orange juice lower LDL? In contrast to animal studies, there is no evidence that freshly squeezed orange juice lowers LDL in humans. Large amount of orange juice (750mL per day) may increase HDL and decrease the LDL-HDL ratio. However, due to the large amount of calories contained in this volume of orange juice (approximately 20% of daily energy), patients should not be advised to routinely drink this amount of orange juice. They should instead be encouraged to consume a variety of fruits and vegetables in order to obtain an equivalent amount of cardio protective nutrients. Do the fat-soluble statins have a greater effect on the endothelial lining than water-soluble statins? The statins have beneficial effects on the endothelial lining by increasing nitric oxide production, reducing smooth muscle cell migration and proliferation, and altering the inflammatory process. Although it is logical to suspect that due to their increased ability to enter cells other than hepatocytes, the lipophilic statins would be better able to affect endothelial cells, there is a lack of animal and human studies to support this hypothesis. Do statins cause increased lipase levels, and, if so, how? Increased lipase levels due to statins in the absence of acute pancreatitis have not been found. Case reports have been found wherein statin use has been associated with acute pancreatitis, and its associated elevated lipase levels. Clinical course was generally mild, requiring only supportive treatment; however, more severe cases have also been reported. Duration of exposure and dosing did not seem to be contributing factors. Drug interactions may potentially be the trigger, but were not present in all cases reported. Since there were no comparative or theory-based studies, it cannot be determined whether different statins carry different risks. It can also not be determined based on the available evidence if pancreatitis is a class effect.



Page 2 of 4

To what extent do the various available statins interact with warfarin? If a stabilized warfarin patient is to be started on pravastatin, it is unlikely a drug interaction will occur. Stabilized warfarin patients are best to avoid lovastatin, simvastatin or rosuvastatin, and probably atorvastatin and fluvastatin, unless PT/INR are monitored closely on starting and after any changes. Advise patients to watch for any signs of bleeding and/or unexplained muscle pain, tenderness or weakness.

MEDICATIONS WARFARIN

METABOLIC

PATHWAY CYP 3A enzymes, 2C9

LOVASTATIN CYP 3A4

All case reports found that warfarin/lovastatin given concurrently increases PT/INR. Many, but not all, individuals experience an increase in INR/PT without bleeding.

SIMVASTATIN CYP 3A4

Simvastatin when added to a stabilized warfarin regime resulted in variable effects on INR and in clinical course. One case report was of a questionable nature and another also resulted in simvastatin-induced adverse outcomes.

ATORVASTATIN CYP 3A4

Conflicting literature - it is theorized that it may interact with warfarin due to common metabolic pathways. No case reports exist. CYP 3A4 metabolism is to a lesser extent than lovastatin and simvastatin.

FLUVASTATIN CYP 2C9 Few case reports show increased INR alone, in patients on warfarin/fluvastatin, although some conflicting studies exist.

ROSUVASTATIN CYP 2C9, 2C19 Accumulated data appears to indicate that rosuvastatin can interact with warfarin by increasing the INR/PT and occasional bleeding.

PRAVASTATIN SULFATION Evidence indicates that pravastatin does not appear to induce a hypoprothrombinemic response and/or cause bleeding.

Are atorvastatin or the other statins of benefit during outbreaks of influenza (possibly due to their anti-inflammatory effects)?

Although the statins may possess some anti-inflammatory properties, there appears to be no compelling evidence that they are of benefit during infection with the influenza virus.



Page 3 of 4

What evidence is there to support the use of psyllium to lower cholesterol levels? What degree of cholesterol and/or triglyceride lowering can be expected and is HDL affected? There is ample evidence from randomized, placebo-controlled, double blinded trials that psyllium lowers LDL and total cholesterol. In general, a dose of 10.2g/day of psyllium lowers LDL by 6-13% and total cholesterol by 4-8% (although higher and lower values have been reported in individual trials). HDL and triglyceride levels do not appear to be significantly affected by psyllium. Although this degree of cholesterol lowering is suggested as being appropriate in patients with mild to moderate hyperlipidemia, it may be too modest for patients with severe dyslipidemia and thus not appropriate as mono-therapy in this population.

Any evidence on using the combination of statins and psyllium to lower cholesterol levels?

In a study of 68 patients, three 5 gram servings of psyllium daily were added to the diet of patients already taking simvastatin. After 8 weeks, psyllium lowered LDL-C levels by 6% in addition to the lowering results seen with the statin, and the lowering results were equal to those from doubling the statin dose. HDL levels were unchanged, and adverse effects were reported more in the placebo group than by patients taking psyllium. Does the timing of alcohol ingestion influence triglyceride levels? Evidence supports avoiding ethanol for at least 24 hours prior to obtaining fasting triglyceride levels. Studies comparing varying durations of abstinence could not be located and there does not appear to be any compelling evidence for avoiding alcohol for 48 hours prior to measuring serum triglycerides. Will statins interact with macrolide antibiotics? If a patient is on the statins fluvastatin, pravastatin or rosuvastatin they would be unlikely to interact with a macrolide antibiotic such as erythromycin, clarithromycin or azithromycin; so the macrolide antibiotic could be used. Advise patients to watch for any unexplained muscle pain, tenderness or weakness. If a patient is on lovastatin, simvastatin or atorvastatin they should refrain from using a macrolide antibiotic as the macrolide antibiotics are potent inhibitors of the CYP3A4 enzyme.



Page 4 of 4

I have heard that taking ASA before a dose of niacin can reduce flushing. What dose of ASA is required for this effect and how soon before a dose of niacin should ASA be administered? ASA is effective at reducing niacin flushing. It does this by inhibiting the synthesis of the prostaglandins responsible for this side effect. Although there are many references to the use of ASA for this purpose, relatively few studies have been conducted to determine the ideal dose required for this effect. Of the studies located, 325mg of ASA appears to be superior to doses of 80-165mg. Doses higher than 325mg (such as 650mg) may not provide any additional effect. The ideal timing of ASA dosing prior to niacin has not been studied. In the studies found, ASA was given 30 minutes prior to the niacin dose which supports the 30-60 minutes advised in the literature. This correlates with the usual onset of action of aspirin. The efficacy of once daily doses of ASA not given within an hour of niacin has not been studied and therefore cannot be assured to reduce niacin flushing. What is the Calgary Health Region’s practice in starting statins after an acute coronary event? At the Rockyview Hospital, Calgary Health Region, a patient with an acute coronary event is immediately put on a statin. Statins are initiated without waiting for the results of lipid testing. At the Foothills Hospital, Calgary Health Region, it is recommended that statins be started within 24 to 48 hours of a patient having an acute coronary event and based on an immediate fasting lipid profile confirming hyperlipidemia. Thus far, at Foothills Hospital, statins are not started post-acute coronary syndrome in the absence of hyperlipidemia. Recommendations suggest that the patient should be started on a statin in the coronary care unit. It is thought that this will increase compliance as the patient will realize this is an essential treatment plus tolerability can be assessed. If the patient was on a statin prior to having an acute coronary event the patient would be kept on the statin. At the Peter Lougheed Hospital, Calgary Health Region, statins are started as soon as a patient comes to the cardiac unit with an acute coronary event and preferably within 48 hours of coming to hospital. A patient lipid profile does not necessarily have to be done before the statin is started.


Title: COPD: Interventions for Better OutcomesOrganization: National Prescribing Service – Prescribing Practice Review (Australia)

Summary Descriptive Information This newsletter has 4 pages, 1912 words and is divided into 4 sections. The document uses full colour for titles, logo and headings. Evaluation Summary Reviewer #1 Reviewer#2#1 Referencing 5 5#2 Peer Review 5 5#3 Systematic Review 1 2#4 Statistics 3 4#5 Price and coverage 2 1#6 Graphics 1 2#7 Key Messages 5 5#8 Sections 4 5#9 Headings 5 5#10 Table Hierarchy 3 3#11 Table Editorial Consistency 3 3#12 Column Width 4 4#13 Readability 2 4#14 Justification 5 5#15 Colour 4 3#16 Main Message 4 5#17 Therapeutic Decision Support 3 3#18 Behaviour Target 4 4#19 Retrieval 5 5#20 Editorial Consistency 4 5


Overall Mean Score 75 Strengths A relatively complete assessment of major treatment challenges in COPD contained in less than 2000 words. Key messages are easily obtained from the document. Weaknesses The document is almost entirely text based and might benefit from some graphics to illustrate key points. The document does not consider cost for medications. Colour and some aspects of formatting interfere with readability.

National Prescribing Service LimitedABN 61 082 034 393 l Level 7/418A Elizabeth Street Surry Hills NSW 2010 l PO Box 1147 Strawberry Hills NSW 2012

Phone: 02 8217 8700 l Fax: 02 9211 7578 l email: [email protected] l web: www.nps.org.au

Prescribing Practice Review | For Primary Care May 2006

PPR thirty three

COPD: interventions for better outcomes

• Diagnose early using spirometry.

• Keep motivating patients to quit smoking by using brief interventions.

• When using bronchodilators and/or inhaled corticosteroids, plan a trial period and assess response objectively

— Stop treatment if no response.

• Reserve antibiotics for acute exacerbations with purulent sputum plus increased sputum volume and/or dyspnoea.

In early COPD, airflow limitation is often asymptomatic.1,2 Patients usually seekmedical help at a stage of dyspnoea when airflow limitation may already bemoderate to severe.1,2

Consider a diagnosis for patients with other smoking-related conditions; there is a high prevalence of COPD in patients with vascular disease and smoking-related carcinomas.1

Spirometry demonstrates airflow limitation. Physical examination or peakexpiratory flow measurements alone are not diagnostic.1,2 Airflow limitation is not fully reversible when, after administering a bronchodilator:

• FEV1 (forced expiratory volume in one second) is < 80% predicted, and

• FEV1 to FVC (forced vital capacity) ratio is < 70%.1,2

Spirometry also identifies patients at risk; an early indicator of COPD is whenFEV1 is > 80% but FEV1/FVC is < 70%.1

A clinically significant response to a bronchodilator is an increase in FEV1 > 200 mLand > 12% above pre-bronchodilator level.1,2 Consider referral to a respiratoryphysician to exclude other diagnoses or complications.1

Chronic obstructive pulmonary disease (COPD) is mostly caused by smoking, which leads to progressiveirreversible airflow limitation. Optimal drug treatment can reduce exacerbations and improve quality of life.

Key Messages

Use spirometry to diagnose COPD early

Consider a diagnosis of COPDfor any current or ex-smokerover the age of 35 years1,2

Spirometry is needed to confirm the diagnosis1,2

Consider asthma if there arereversible components

NPS is an independent, non-profit organisation for Quality Use of Medicines funded by the Australian Government Department of Health and Ageing.

OKA4582 NPS PPR 33 COPD 18/4/06 12:06 PM Page 2

Use a long-acting anticholinergic (tiotropium [Spiriva]) or long-acting beta2agonist (eformoterol [Foradile, Oxis] or salmeterol [Serevent])† if symptomsare not controlled by short-acting bronchodilators.1,9,10 If symptoms persist,try a different long-acting bronchodilator or combine a long-actinganticholinergic and beta2 agonist.9

Step up to a long-actingbronchodilator if needed

Stopping smoking is the most important intervention

Brief intervention by ahealthcare professional helpssmokers to quit

Offer intensive interventionand/or pharmacotherapy

Use nicotine replacementtherapy with brief orintensive interventions

Provide brief counselling (3–5 minutes) on smoking cessation by using the 5As approach:

• Ask and identify smokers at every visit

• Advise about the risks of smoking and benefits of quitting

• Assess the motivation to quit

• Assist cessation

• Arrange follow-up within a week of the quit date and one month after.1–3

Telephone counselling (e.g. Quitline), group behavioural therapy, orcounselling by a smoking cessation specialist can help smokers to quit.3

Consider adding pharmacotherapy to counselling and support if patientssmoke more than 10 cigarettes/day: cessation rates after 6–12 monthsrange from 5–15% with placebo and 10–30% with either nicotinereplacement therapy or bupropion (Zyban SR).3–7

Choose one nicotine product (gum, tablets or lozenges, patches or inhaler)and continue for up to 12 weeks.8 Heavy smokers may benefit from using a higher dose.3,8

Only use bupropion withintensive intervention

Bupropion* only has evidence for an effect in conjunction with intensivecounselling and support.3,6 Start bupropion at least 7 days before the quitdate and continue for 7–9 weeks.8

Combine therapies forsmokers who relapse

Offer a combination of nicotine products (e.g. patches and gum) and/orintensify counselling and support, if one nicotine product is ineffectivealone.3,8 Add bupropion if a further relapse occurs.3,5

Drug treatments improvesymptoms and quality of life

Monitor patients for changes in symptoms, daily activities and exercisecapacity; improvements can occur without changes in FEV1.1,2,9,10 For patients with COPD and asthma, treat as for asthma.1

Start with inhaled short-acting bronchodilators

Use a short-acting beta2 agonist (salbutamol [Airomir, Asmol, Epaq] orterbutaline [Bricanyl]) or anticholinergic (ipratropium [Atrovent]) asneeded.1,2,9,10 Start regular treatment if symptoms worsen.10 Ipratropium is suitable for regular use because it has a relatively long duration ofaction.1,10 If needed, combine salbutamol or terbutaline with ipratropium†

to improve symptom control and limit adverse effects.1,10

Introduce stepwise drug treatment in stable COPD

* Refer to the Schedule of Pharmaceutical Benefits for restrictions for prescribing bupropion (Zyban SR). Patients are only subsidised on the Pharmaceutical Benefits Scheme (PBS) for onetreatment course (two Authority prescriptions) per year.


Tiotropium reduces exacerbations in patients with moderate to severeCOPD — treating 14 patients with tiotropium for 1 year, instead ofipratropium or placebo, prevents 1 exacerbation.11 Tiotropium is more likely than ipratropium to cause anticholinergic side-effects, particularly dry mouth; it may be unsuitable for patients intolerant of ipratropium.8,11

Tiotropium may be of morebenefit than ipratropium topatients with frequentexacerbations

The effects of long-acting beta2 agonists are generally small andinconsistent between studies.12–24 Patients with the greatest response to long-acting beta2 agonists have some reversible airflow limitation.13–17

Stop salmeterol or eformoterol if there is no change after 4 weeks.9,10,25

Restart if symptoms worsen; consider adding tiotropium to improvesymptom control.9,10

Reassess response to long-acting beta2 agonists if patients report noimprovement

Instruct patients to rinse their throat and mouth with water, and spit out,after inhalation.8,10 Advise patients who use a metered-dose inhaler (MDI)that a spacer reduces the risk of dysphonia.8,10

Inhaled corticosteroids at high doses can increase the risk of osteoporosis,especially in patients with COPD; bruising and cataracts may also occur.1,8,10

Minimise systemic absorptionof inhaled corticosteroids

Use theophylline for patients who do not respond to short-acting and/or long-acting bronchodilators, or who cannot use inhaled therapy.1,9,10 Only slow-release preparations have shown benefit in COPD.1,2 For furtherguidance on stepwise drug treatment for stable COPD see NPS News 45.

Consider theophylline ifsymptoms persist despiteinhaled bronchodilators

Optimal technique can be achieved with an MDI, breath-activated inhaler(e.g. Autohaler) or dry powder inhaler (DPI); however, ability to use variesand can decline within 2 months of first instruction.9,10,30 Where possible,minimise the different types of inhaler that the patient needs to use.

Check inhaler technique regularly

Use a spacer if the patient has difficulty with inhaler devices.8,9 Reservenebulisers for symptoms which persist despite maximum inhaled therapy —nebulisers do not improve lung function compared with an MDI (with orwithout spacer) or DPI.9,10,30

Nebulisers do not improve lung function

Start an inhaled corticosteroid, with or without a long-acting beta2 agonist†,for patients with:

• a documented response to a short course (2 weeks) of oral corticosteroid, or

• 2 or more exacerbations per year requiring treatment with antibiotics or oral corticosteroids.1,2,9,10

Oral corticosteroids do not predict the response to inhaled corticosteroids andshould not be used to identify patients for such treatment.1,9,10 Assess response toinhaled corticosteroids by monitoring FEV1 and symptoms every 2 weeks; stop ifthere is no improvement after 6 weeks.10 Inhaled corticosteroids reduceexacerbations compared with placebo (relative risk reduction 30%, 95% CI 16%to 42%).26 This has been shown in patients with reversible or irreversible airflowlimitation, but only with high doses and only in moderate to severe COPD.26–28

Combining an inhaled corticosteroid and a long-acting beta2 agonist improvessymptoms and health-related quality of life, compared with inhaledcorticosteroids alone.22–24,29

Consider inhaledcorticosteroids in moderateto severe COPD (FEV1 ≤ 50%)

† Note: Tiotropium is the only long-acting bronchodilator subsidised on the PBS for COPD. Long-acting beta2 agonists, inhaled corticosteroids, and combination inhaled corticosteroids andlong-acting beta2 agonists (budesonide/eformoterol [Symbicort] and fluticasone/salmeterol [Seretide]) are not listed on the PBS for COPD. Combination salbutamol and ipratropium(Combivent) is listed on the RPBS for COPD. Inhaled corticosteroids (excluding fluticasone/salmeterol) are not approved by the Therapeutic Goods Administration for COPD.


National Prescribing Service Limited provides accurate, balanced, evidence-based information and services to help people choose if, when and how to use medicines to improve their health and wellbeing.

We are member-based and work in partnership with health professionals, government, pharmaceutical industry and consumers.

The information contained in this material is derived from a critical analysis of a wide range of authoritative evidence.Any treatment decisions based on this information should be made in the context of the clinical circumstances of each patient.

ReviewerAssoc Prof David McKenzie, Head of Department,Respiratory and Sleep Medicine,Prince of Wales Hospital, Randwick

References1. Australian Lung Foundation and Thoracic Society

of Australia and New Zealand. The COPD-X Plan:Australian and New Zealand guidelines for themanagement of chronic obstructive pulmonary disease. Australian Lung Foundation, 2005.

2. Global Initiative for Chronic Obstructive Lung Disease(GOLD COPD). Global strategy for the diagnosis,management, and prevention of chronic obstructivepulmonary disease. GOLD COPD, 2005.

3. Miller M, Wood L. Smoking cessation interventions:review of evidence and implications for best practice inhealth care settings. Canberra: Australian GovernmentDepartment of Health and Ageing, 2002.

4. The Royal Australian College of General Practitioners(RACGP). Smoking, Nutrition, Alcohol and Physicalactivity (SNAP). A population health guide to behaviouralrisk factors in general practice. Melbourne: RACGP, 2004.

5 Jorenby DE, et al. N Engl J Med 1999;340:685–91.6. Woolacott NF, et al. Health Technol Assess 2002;6(16).7. Tashkin D, et al. Lancet 2001;357:1571–5.8. Australian Medicines Handbook 2006.9. National Institute for Clinical Excellence (NICE).

Chronic obstructive pulmonary disease: managementof chronic obstructive pulmonary disease in adults inprimary and secondary care. London: NICE, 2004.

10. Therapeutic Guidelines. Respiratory, 2005.11. Barr R, et al. Cochrane Database Syst Rev

2005;(2):CD002876.12. Brusasco V, et al. Thorax 2003;58:399–404.13. Aalbers R, et al. Eur Resp J 2002;19:936–43.14. Mahler DA, et al. Chest 1999;115:957–65.15. Appleton S, et al. Cochrane Database Syst Rev

2001;(4):CD001104.16. Rossi A, et al. Chest 2002;121:1058–69.17. Hanania NA, et al. Chest 2003;124:834–43.18. Donohue JF, et al. Chest 2002;122:47–55.

19. Shukla V, et al. Long-acting beta-2-agonists formaintenance therapy of stable chronic obstructivepulmonary disease: a systematic review. Ottawa:Canadian Coordinating Office for Health TechnologyAssessment, 2002.

20. Wadbo M, et al. Eur Resp J 2002;20:1138–46.21. Boyd G, et al. Eur Resp J 1997;10:815–21.22. Szafranski W, et al. Eur Resp J 2003;21:74–81.23. Calverley P, et al. Lancet 2003;361:449–56.24. Calverley PM, et al. Eur Resp J 2003;22:912–9.25. Institute for Clinical Systems Improvement (ICSI). Chronic

Obstructive Pulmonary Disease. Health Care Guideline.Bloomington: ICSI, 2005.

26. Alsaeedi A, et al. Am J Med 2002;113:59–65.27. Burge PS, et al. BMJ 2000;320:1297–303.28. Vestbo J, et al. Lancet 1999;353:1819–23.29. Nannini L, et al. Cochrane Database Syst Rev

2004;(3):CD003794.30. Brocklebank D, et al. Health Technol Assess 2001;5(26).31. Wood-Baker R, et al. Cochrane Database Syst Rev

2005;(1):CD001288.

NPSP0152

Complete a COPD action plan for acute exacerbations

Detect and manageexacerbations early toprevent deterioration and hospital admission1

Give a COPD action plan to patients and/or their carers (available from theAustralian Lung Foundation, www.lungnet.org.au). Consider supplying oralcorticosteroids and/or antibiotics as part of the patient’s management plan,to assist early treatment. Instruct patients to start treatment if there is anincrease in 1 or more symptoms of: cough, wheeze or breathlessness;sputum purulence and/or volume; or fever.1,2,9,10

Increase use of short-actingbronchodilators1,10

Only use a nebuliser for exacerbations if symptoms persist using a spacer;if bronchodilators are needed more than 3 hourly, tell the patient to getmedical attention.1,10 Step down treatment when symptoms resolve andreview management.

Start a short course of oral corticosteroid

Use oral prednisolone 30–50 mg daily for 7–14 days then stop without taper; where continuous treatment is needed use the lowest dose.1,9,10 Oralcorticosteroids prevent hospital re-admission or changes to therapy, restorelung function and improve dyspnoea in patients with acute exacerbations.31

Use antibiotics only if sputumpurulence is present withincreased sputum volumeand/or dyspnoea10

Prescribe amoxycillin or doxycycline for 5–10 days; only use a macrolideantibiotic (e.g. erythromycin, roxithromycin), cephalosporin or amoxycillinplus clavulanic acid if there is no response to these and only use a macrolide if Haemophilus influenzae has been excluded.1,2,10 There is no evidence forantibiotic prophylaxis.1,2

Influenza vaccinations reduce the relative risk of exacerbations, hospitalisationand death by 50%.1,2 Pneumococcal vaccination is also recommended.1,2,10

Online citations available at www.nps.org.au/healthpro



Title: Managing Depression in Primary CareOrganization: National Prescribing Service – Prescribing Practice Review (Australia)



Overall Mean Score 79 Strengths Key messages are displayed on first page. The document tackles the difficult issue of suicide risk and lack of efficacy of therapies in children. Overall format allows for rapid retrieval of the most important information. Weaknesses The document lacks pricing information and does not provide full support for the required therapeutic decisions. Its number of section exceeds the defined optimum of five sections.

PPRPrescribing Practice Review — PPR

No

vem

ber

200

5

thirtytwo

For General Practice



Key messages

Use non-drug therapy first in mild depression, as it is unclear if antidepressantsare better than placebo

The evidence that antidepressants are better than placebo is in moderate to severe depression

Continue antidepressants in moderate to severe depression for at least 6 months after symptoms improve

Advise patients what to expect from drug therapy: likely adverse effects, up to 4–6 weeks for effect and the expected duration of treatment

Always ask about suicidal thoughts and assess risk, especially during initial treatment

Managing depression in primary care

Assess symptoms,severity, functioning and suicide risk

“The main deficiencies in prescribing these drugs[antidepressants] have been the undertreatment of patients with major depression and the inappropriate treatment of patients who are not clearly depressed.” — Therapeutic Guidelines:Psychotropic, 2003

Establish the diagnosis of depression and its severity then treat accordingly

The evidence for efficacy of antidepressants is in moderate to severe major depression.1,2

There is insufficient evidence in mild depression to support the use of antidepressants, and non-drug therapy is first line.1–3

Mild depression involves fewer symptoms* and minimal functionalimpairment. With increasing severity, there are more symptoms, of greater intensity (including suicidal intent) and more significantfunctional disability.4

Assess drug and alcohol use when making the diagnosis; substance abusemay be primary or comorbid and affect treatment (see Table 1 for illicitdrugs involved in serotonin syndrome). Also, check for psychosocialstressors that require non-drug interventions (e.g. bereavement).

Seek psychiatric assessment and treatment for patients with significantsuicide risk (urgent); psychotic symptoms; marked psychomotor agitation or retardation, which may suggest more severe (melancholic) depression;history of mania or evidence of bipolar depression.3

* A diagnosis of major depression according to the DSM-IV requires at least 5 symptoms. Either depressed mood or loss of interest orpleasure must be present; other symptoms are appetite or weight change, insomnia or hypersomnia, psychomotor agitation orretardation, fatigue, feelings of worthlessness or guilt, impaired thinking or concentration, indecisiveness, and suicidal thoughts orthoughts of death.4

NPSPPR_32_8pp.qxd 25/10/05 9:23 AM Page 3

Evaluating suicide risk is a key aspect of assessing depression

Always ask about suicide — asking does not cause suicidal behaviour5

In children and adolescents,antidepressants mayincrease suicidal behaviour— and have a poor benefitto harm ratio

In adults, a definitive linkhas not been establishedbetween SSRIs andsuicidal behaviour

When assessing suicide risk, consider:

suicidal ideation

suicidal intent

whether there is a plan, or rehearsal of a plan

access to means of suicide

if there is a history of self-harm or suicide attempts.3,5

Seek urgent psychiatric assessment and treatment for those withsignificant risk and closely monitor others.

In children and adolescents, antidepressants have little evidence ofefficacy but an increased risk of suicidal thoughts and behaviour — 4%for antidepressants compared with 2% for placebo (relative risk, 1.78;95% CI, 1.14 to 2.77).6,7 Fluoxetine has some evidence of efficacy butsimilar risk. No antidepressant is approved for paediatric depression in Australia.8

Regulatory review in adults9 continues — key findings so far are:

there is not conclusive evidence from randomised trials that selectiveserotonin reuptake inhibitors (SSRIs) increase suicidal ideation andbehaviour compared with placebo, but an increased risk in someindividuals cannot be completely ruled out10–12

for most adults with major depression treated with SSRIs, likely benefitsoutweigh likely harms10,11

observational data show no apparent difference in rates of suicidalbehaviour or self-harm between patients prescribed SSRIs or otherantidepressants.10,11 Such data cannot determine causality.

Monitor suicide risk —especially in the earlystages of treatment.Worsening depressionand emergence ofsuicidality may occur with treated or untreateddepressive illness

The Adverse Drugs Reactions Advisory Committee advises that when anantidepressant is prescribed to an adult, child or young person:

closely monitor patients for suicidality (suicidal thoughts andbehaviours) in the first weeks of treatment and when changing dose

consider changing or discontinuing therapy if there are new orworsening symptoms of suicidality

advise patients and caregivers to monitor for worsening illness, suicidal or self-harm-related thoughts or behaviours and to seek medical assistance immediately if these occur.10

In mild depression non-drug therapies are first line

Provide information and education about depression to all patients with depression.

The following non-drug strategies have some evidence supporting their use in mild depression:

brief cognitive behavioural therapy (CBT) or interpersonal therapy (IPT)(6–8 sessions)

Consider the role of non-drug treatments in the management plan


The goal of acute treatment is to reduce symptoms and improvefunctioning. The aim in the continuation and maintenance phase of treatment is to prevent relapse.

Relapse is most likely in the early stages of recovery. About 40% of patients in antidepressant trials relapsed in the first 6–12 months afterinitial improvement, but the rate was halved in those who continuedantidepressants, compared with those switched to placebo (odds ratio, 0.30;95% CI, 0.2 to 0.4). This was mostly in those with a high risk of recurrence.15

The likelihood of further depressive episodes increases with eachrecurrence; guidelines state that subsequent episodes require longermaintenance therapy of 2–3 years.1,2 When reviewing ongoing need,consider the number of prior episodes, their proximity, related functional impairment and the presence of residual symptoms.1,2

Continue antidepressanttreatment for at least6–12 months in moderateto severe depression

Treat depression beyond the acute phase of symptom remission

In moderate major depression, CBT and IPT have the best publishedevidence. These can be an effective alternative to antidepressants (16–20 sessions over 6 months).1,3

Consider CBT and IPT inmoderate depression

In more severe depression, long-term or recurrent depression (chronicdepression), antidepressants are usually required but a combination ofpsychological treatment and antidepressant drugs shows evidence ofbetter outcomes than either therapy alone.1

Combine antidepressantswith psychologicaltreatment in chronic and recurrent depression

Some antidepressant effect is usually observed after 1–2 weeks, but fulleffects may take 4–6 weeks.3 If there is a partial response after 4–6 weeks, a longer trial or increased dose of the same drug is reasonable. If there isno response at all after 4 weeks, response is unlikely.1,14

Older people should be started at a lower dose and may take longer torespond; lower maximum doses may apply.

If response to an adequate trial of the initial medication is poor, switch to adifferent drug class after checking compliance, correct diagnosis and othercontributing factors.3 If changing treatment because of adverse effects, it isreasonable to try another drug in the same class (see TherapeuticGuidelines: Psychotropic for comparative adverse effects).

Monitor response totreatment in the first 4–6 weeks to guideongoing treatment

Full response to antidepressant drug treatment may take 4–6 weeks

problem-solving therapy

physical exercise (structured, supervised 2–3 sessions per week)

guided self-help books based on CBT principles

computer-based CBT (e.g. www.moodgym.anu.edu.au)

supportive counselling by a GP or other health professional.1,13

These may also be considered as adjuncts to antidepressants in moderate depression.


If residual symptoms exist after adequate treatment, or there was a longperiod of illness (≥ 2 years), adding CBT or IPT to continuing drug treatmentcan further reduce the risk of relapse for up to 4 years.1,16–18

Booster sessions in the maintenance phase may preserve improvement inthose who have responded to treatment. For example, 3–4 booster CBTsessions in the 12 months after remission was equivalent to ongoing drugtherapy in preventing relapse, in a recent trial.19

Consider psychologicaltherapy for relapseprevention

Persistence with follow-up to achieve remission and prevent relapse may be more important than initial treatment choice.2

Patients may be less likely to actively seek help when they are no longeracutely depressed.21 Encourage patients to recognise signs of recurrence,avoid likely triggers and seek help early if symptoms recur.22

Depression can be achronic condition20 —follow up and monitor

The Better Outcomes in Mental Health Care initiative includes:

education and training for GPs: required for participation

the 3 Step Mental Health Process: a Service Incentive Payment for GPs

focussed psychological strategies: MBS item numbers for trained GPsproviding these therapies

access to allied psychological services: funding of additionalpsychological services through participating local divisions of general practice

access to psychiatrist support: new MBS items (291 and 293) forpsychiatrists to provide a one-off assessment and GP management plan.Access to non-urgent psychiatric opinion through GP Psych Support(www.psychsupport.com.au or call 1 800 200 588).

See www.racgp.org.au/mentalhealth or your local division of generalpractice for more information.

GPs can access extra remuneration,training and servicesfor treating depression

Advise patients about what to expect from antidepressant drugs

Empower patients by treating them as active partners inunderstanding andmanaging depression

In Australia, 1 in 2 patients who start antidepressant therapy will no longerbe taking any antidepressant 2 months later.24

People with depression may respond negatively to the suggestion ofantidepressant medicine from their doctor, be unconvinced of benefits orfeel stigmatised by the prescription.21 The health professional’s convictionthat treatment can be effective may help counter negative thoughts andattitudes due to depression.

“I just think what’s the point in going back to see [the doctor]? He can’t do anything. Nobody can doanything. It’s just ... something I’ve got to work through myself isn’t it?”

— Person with depression when asked about her need for GP review23

“I feel if I had not been asked specifically to come back, I would not have done so … when you arevery depressed your self-esteem is in the gutter and you feel that no one is interested in how you aregetting on. Taking tablets endlessly makes you feel that there is no end in sight and you need constantencouragement”

— 57-year-old woman with depression21


Be familiar with theadverse effects ofantidepressants andaddress concerns atfollow-up visits

Advise patients:

that some adverse effects are likely, describe what these are and thatmost will subside after 1–2 weeks

it can take up to 4–6 weeks for antidepressants to work fully

that antidepressants will need to be continued for at least 6 monthsafter symptoms improve, to prevent a relapse

to return to their doctor if they are concerned by adverse effects they experience

that there are other treatments that can be tried

not to stop taking antidepressants abruptly, as this can cause unpleasantadverse effects

that non-prescription and complementary medicines may interact withantidepressants.

Reinforce medication advice at subsequent visits or with writteninformation. Suggest or provide the consumer medicine information (CMI)for the drug prescribed.

An information leaflet for patients who have been prescribed anantidepressant has been developed by NPS; photocopy the enclosed insertor download from www.nps.org.au/healthpro (follow the links to this PPR).

Anxiety and agitation are common adverse effects of SSRIs and venlafaxine,especially at initiation. To limit these and other adverse effects, start with alower dose (50% of the usual starting dose) and titrate over 2–4 weeks,especially in patients with comorbid anxiety.22

See the Australian Medicines Handbook for a list of common adverse effects.25

Start low to limit adverse effects

Encourage patients to:

– tell other doctors and pharmacists about theirantidepressant when another drug is prescribed or purchased

– ask if they are safe to use together

Serotonin syndrome (see Table 2) is not an idiosyncratic response; it is atoxic effect resulting from too much serotonin. It has been observed with:

overdose of a single agent (usually SSRIs)

simultaneous use of two drugs that increase serotonin levels or serotonergic transmission

failing to observe an adequate washout period when switching antidepressants.26

Fatalities have most often occurred through use of two drugs with differentmechanisms for increasing serotonergic activity — for example monoamineoxidase inhibitors (MAOIs) or moclobemide used with any drug that inhibits re-uptake of serotonin (SSRIs, some tricyclic antidepressants (TCAs), tramadol).The first drug may have been discontinued weeks earlier in some cases —hence the need for washout periods.26

Risky situations include prescribing of interacting drugs by other doctors,use of over-the-counter (OTC) medicines such as St John’s wort ordextromethorphan, and use of illicit drugs such as ecstasy (see Table 1).

Watch for serotonin syndrome


National Prescribing Service Limited (NPS) is a member-based organisation providing accurate, balanced, evidence-based information and servicesto health professionals and the community on Quality Use of Medicines (QUM). To achieve this we work in partnership with GPs, pharmacists,

specialists, other health professionals, government, pharmaceutical industry, consumer organisations and the community. NPS is an independentnon-profit organisation funded by the Australian Government Department of Health and Ageing.


ReviewersDr Chris HolmwoodDirector, South Australian Prison Health ServiceAssociate Professor Geoff RileyHead, School of Psychiatry and Clinical NeuroscienceFaculty of Medicine and DentistryUniversity of Western Australia

References1. National Institute for Clinical Excellence. Depression:

management of depression in primary and secondarycare. Clinical Guideline 23. London: NICE, 2004.http://www.nice.org.uk/pdf/CG023NICEguideline.pdf(accessed 20 June 2005).

2. Ellis PM, et al. Med J Aust 2002;176 (Suppl):S77–83.3. Therapeutic Guidelines: Psychotropic. Version 5, 2003.4. Diagnostic and statistical manual of mental disorders.

4th edn. Washington DC: American PsychiatricAssociation, 1994.

5. American Psychiatric Association. Am J Psychiatry2003;160 (Suppl):1–60.

6. FDA Center for Drug Evaluation and Research.FDA Public Health Advisory. Suicidality in children and adolescents being treated with antidepressantmedications. Washington: US Department of Health

and Human Services, 2004. http://www.fda.gov/cder/drug/antidepressants/SSRIPHA200410.htm(accessed September 2005).

7. Hammad TA. Review and evaluation of clinical data.FDA Center for Drug Evaluation and Research, 2004.http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4065b1-10-TAB08-Hammads-Review.pdf (accessedSeptember 2005).

8. Adverse Drug Reactions Advisory Committee. Use ofSSRI antidepressants in children and adolescents(Dated 15 October 2004). Canberra: Commonwealthof Australia, 2004. http://www.tga.gov.au/adr/adrac_ssri.htm (accessed September 2005).

9. FDA Center for Drug Evaluation and Research. FDAPublic Health Advisory. Suicidality in adults beingtreated with antidepressant medications. Washington:US Department of Health and Human Services, 2005.http://www.fda.gov/cder/drug/advisory/SSRI200507.htm (accessed August 2005).

10. Adverse Drug Reactions Advisory Committee. Aust AdvDrug Reactions Bull 2005;24.

11. Committee on Safety of Medicines. Report of the CSMExpert Working Group on the safety of selectiveserotonin reuptake inhibitor antidepressants, 2004.https://www.mca.gov.uk/ourwork/monitorsafequalmed/safetymessages/SSRIfinal.pdf (accessed January 2005).

12. Gunnell D, et al. BMJ 2005;330:385–9.13. Jorm AF, et al. Med J Aust 2002;176 (Suppl):S84–96.14. Quitkin FM, et al. Arch Gen Psychiatry

1996;53:785–92.15. Geddes JR, et al. Lancet 2003;361:653–61.16. Paykel ES, et al. Psychol Med 2005;35:59–68.17. Klein DN, et al. J Consult Clin Psychol 2004;72:681–8.18. Fava GA, et al. Am J Psychiatry 1996;153:945–7.19. Hollon SD, et al. Arch Gen Psychiatry 2005;62:417–22.20. Andrews G. BMJ 2001;322:419–21.21. Nolan P, Badger F. J Psychiatr Ment Health Nurs

2005;12:146–53.22. American Psychiatric Association. Am J Psychiatry

2000;157:1–45.23. Gask L, et al. Br J Gen Pract 2003;53:278–83.24. McManus PM, et al. Aust N Z J Psychiatry

2004;38:450–4.25. Australian Medicines Handbook 2005.26. Gillman K, Whyte IM. Serotonin syndrome.

In: Haddad P, et al, eds. Adverse syndromes and psychiatric drugs: a clinical guide. Oxford:Oxford University Press, 2004; pp. 37–49.

NPSP0151

Antidepressants MAOIs, mirtazapine, moclobemide, SSRIs, TCAs (especially clomipramine, imipramine), venlafaxine

Analgesics dextropropoxyphene, pethidine, tramadol

OTC and complementary medicines

brompheniramine, chlorpheniramine*, dextromethorphan (in many cough/cold preparations),panax ginseng , St John’s wort, S-adenosylmethionine (SAMe)

Stimulants diethylpropion, hallucinogenic amphetamines, methylphenidate, phentermine

Anti-migraine drugs dihydroergotamine, naratriptan, sumatriptan, zolmitriptan

Others buspirone, linezolid, lithium, selegiline, sibutramine, tryptophan

Illicit drugs MDMA (ecstasy), LSD, cocaine

Table 1: Drugs that may be involved in serotonin syndrome25,26

* Reported cases have involved intravenous chlorpheniramine (not available in Australia).26

Mental confusion, agitation, hypomania, hyperactivity, restlessness

Neuromuscular clonus† (spontaneous, inducible or ocular), hyperreflexia, hypertonia, ataxia, tremor

Autonomic hyperthermia, sweating, tachycardia, hypertension, mydriasis, flushing, shivering

Table 2: Clinical features of serotonin syndrome26

† Hypertonia and clonus are symmetrical and more obvious in lower limbs to begin with; clonus is the most important distinguishing feature in diagnosis.



Title: Ischemic Heart DiseaseOrganization: National Prescribing Service – Prescribing Practice Review (Australia)



Overall Mean Score 77 Strengths Key messages are displayed on first page. The side-heading format allows for rapid retrieval of the most important points in the newsletter. Weaknesses The document is heavily text based and lacks graphics to enhance readability and impact. It lacks pricing information and does not provide full support for the required therapeutic decisions. Its number of section exceeds the defined optimum of five sections.

PPRPrescribing Practice Review — PPR

Sep

tem

ber

200

5

thirtyone

For General Practice



Key messages

Inform the patient early of the need for multiple medications

Use the simplest possible drug regimen: minimise the number of medicationsand daily doses

Use low-dose aspirin in all patients with ischaemic heart disease; restrictclopidogrel to true aspirin intolerance

Use beta blockers after myocardial infarction and in angina

Continue ACE inhibitors after myocardial infarction in patients with left ventricular dysfunction or heart failure; consider in others at high cardiovascular risk

Manage all cardiovascular risk factors including dyslipidaemia, hypertension and diabetes

Ischaemic heart disease

Medication compliance is a significant issue in ischaemic heart disease because this requiresmanagement with multiple medications to reduce the risk of myocardial infarction or death.

Aspirin, HMG-CoA reductase inhibitors (statins), beta blockers andangiotensin-converting enzyme (ACE) inhibitors can prevent myocardialinfarction and death. However, poor medication compliance is a problem in ischaemic heart disease; ensure the patient understands the benefits of treatments.1–3

Inform the patient early of the benefits of multiple medications

Limiting the number of daily doses can improve medication compliance.4

When possible, time doses with the patient’s routine (e.g. meals) and limitthe number of medications when they can treat co-existing conditions (e.g. a beta blocker can manage both angina and hypertension).

Guidance for health professionals to assist their patients with medicationcompliance is available in NPS News 41 ‘Targeting ischaemic heartdisease: improving health outcomes with multiple medications’(www.nps.org.au/healthpro, go to ‘Newsletter Index’).

Simplify dosage regimensby limiting the number of daily doses

Multiple medications are necessary in ischaemic heart disease

NPS PPR_31.qxd 18/8/05 4:01 PM Page 3

Manage hypertension, dyslipidaemia and diabetes to reduce theburden of ischaemic heart disease

Manage multiple riskfactors concurrently to reduce total risk

Modifiable risk factors for ischaemic heart disease include smoking,elevated blood pressure and cholesterol level, physical inactivity andobesity.5 Managing risk factors can have additive effects in reducingmyocardial infarction and death.6,7 Lifestyle interventions and drugtreatments shown to reduce the risk of cardiovascular morbidity andmortality are also detailed in NPS News 41.

Depression is an independent risk factor that often coexists with ischaemic heart disease.7 Assess all patients for depression and manage with psychological and drug treatments when indicated.7

Treat all patients with ischaemic heart disease with aspirin6–8

Use aspirin 75–150 mgdaily, unless contra-indicated or nottolerated

Manage aspirinintolerance in thosewho should use aspirin

Restrict clopidogrel* to patients with trueaspirin intolerance6–8,10

When is aspirin contra-indicated?

Low-dose aspirin is the antiplatelet drug of first choice. It is effective, has an established safety profile and is inexpensive.8 In a meta-analysis thatincluded patients with ischaemic heart disease, aspirin prevented 36 seriousvascular events (myocardial infarction, stroke or vascular death) per 1000patients treated for 2 years.9 This outweighs the risk of major extracranialbleeding or haemorrhagic stroke (1–2 events per 1000 patients treated over 1 year).9

Aspirin is contra-indicated in patients with a history of intracranialhaemorrhage, active or recent peptic ulcer disease, allergy to aspirin or bleeding disorder.10–12

Assess the signs and symptoms of aspirin allergy as reported by the patient,as they may describe intolerance that is not an allergy. Allergic reactions toaspirin include13,14:

rhinorrhoea, bronchospasm and/or laryngospasm

urticaria, with or without angioedema

anaphylaxis (e.g. hypotension, laryngeal oedema, pruritus).

Severe dyspepsia, upper gastro-intestinal ulceration and/or bleeding aresigns of aspirin intolerance.6,10,11 Advise patients with dyspepsia to take their aspirin with food and when possible avoid exacerbating medications(e.g. NSAIDs).10 Lowering the dose to 75 mg or using an enteric-coatedformulation may also improve tolerance to aspirin but will not reduce the risk of gastro-intestinal bleeding.10,15

Clopidogrel (Iscover, Plavix) should not replace aspirin as the antiplatelet drugof first choice. It is as effective as aspirin in reducing serious vascular events,and as well tolerated, but is less cost effective.8 In the CAPRIE study, whichincluded patients with ischaemic heart disease, the annual rate of myocardialinfarction, ischaemic stroke or vascular death was 5.3% with clopidogrel and5.8% with aspirin; there were also similar rates of gastro-intestinal bleeding(2.0% vs 2.7%) and intracranial bleeding (0.4% vs 0.5%).16


Should aspirin andclopidogrel be usedtogether?

Clopidogrel may be considered when patients have recurrent vascularevents while using aspirin.6,7 Check first that the patient has been compliantwith aspirin therapy. Adding clopidogrel to aspirin increases the risk ofmajor bleeding8,17,18 but the benefits outweigh the risks in unstable anginaand non-ST segment elevation myocardial infarction, and when used for upto 12 months after coronary stent implantation.18–20

Ticlopidine (Ticlid, Tilodene) may be used when there is intolerance to both clopidogrel and aspirin, but it may cause more serious adverse effects(e.g. neutropenia).6,10 Dipyridamole (Persantin) does not reduce the risk ofmyocardial infarction or death compared with aspirin; combined dipyridamoleand aspirin (Asasantin SR) reduces the risk of non-fatal stroke and may be usedfor patients at high risk of cerebral ischaemic events.8,21,22

* Refer to the Schedule of Pharmaceutical Benefits for criteria for prescribing clopidogrel on the PBS (authority required).

Statins prevent seriousvascular events anddeath from any cause inpatients with ischaemicheart disease

In the Heart Protection Study23 involving 20 536 patients at highcardiovascular risk (e.g. history of angina or myocardial infarction),treatment with simvastatin (40 mg daily for 5 years) compared with placebo reduced the absolute risk of:

any death by 1.8% (NNT† = 56)

myocardial infarction, stroke, or any revascularisation by 5.4% (NNT = 19)

any stroke by 1.4% (NNT = 71).

Patients with ischaemic heart disease had the greatest absolute riskreductions for serious vascular events (5.7%, NNT = 18).23 These benefitswere additional to those of aspirin, beta blockers and ACE inhibitors andwere irrespective of pretreatment cholesterol levels.‡23

† Number needed to treat (NNT) = number of patients who need to be treated with one therapy compared to another therapy for a period of time to prevent one event.

‡ Note that total cholesterol > 4 mmol/L is required for PBS subsidy of lipid-lowering drugs for patients with existing ischaemic heart disease.

Start a statin irrespective of the cholesterol level

Beta blockers improve survival after myocardial infarction

Beta blockers after myocardial infarction reduce re-infarction, suddendeath, all-cause mortality and cardiovascular mortality.8 In a systematicreview24, beta blockers given immediately after myocardial infarction andcontinued for 6 months to 4 years reduced the annual rate of death fromany cause by 1.2% (NNT for 2 years = 42). Benefits persist for as long astreatment is taken.8

Beta blockers (atenolol or metoprolol) are usually begun in hospital;however, GPs may still need to adjust the dose or initiate therapy.6 Avoidbeta blockers with intrinsic sympathomimetic activity (oxprenolol, pindolol)as they have not shown benefit after myocardial infarction.10,24

Continue beta blockersindefinitely aftermyocardial infarction,unless contra-indicated§


Choose bisoprolol (Bicor), carvedilol (Dilatrend, Kredex) or metoprololcontrolled release (Toprol-XL) for patients after myocardial infarction who have left ventricular dysfunction or chronic heart failure.6–8,10 Thesebeta blockers reduce the absolute risk of all-cause mortality, cardiac death or myocardial infarction by 3–6% when used with ACE inhibitors in these patients.25–27

Start beta blockers at a low dose and slowly titrate upwards.6,8

If beta blockers must be stopped, reduce the dose gradually over 2 weeks, or 4–6 weeks if treatment has continued for many years.10

Abrupt withdrawal can worsen angina or cause rebound hypertension or re-infarction.10

Adverse drug reactions are common with beta blockers.8 Using less lipid-soluble beta blockers (e.g. atenolol, bisoprolol) may alleviate adverse effects such as insomnia and nightmares.8,10 Taking the dose at night may reduce postural hypotension, tiredness or lethargy.8

Those with beta-1-receptor selectivity (e.g. atenolol, bisoprolol, metoprolol) may cause less bronchospasm, peripheral vasoconstriction and changes in blood glucose and may be suitable for patients who experience theseadverse effects with other beta blockers.10

§ Contra-indications to beta blockers include reversible airways disease (e.g. asthma, COPD), bradycardia, second- or third-degree heartblock, sick sinus syndrome, cardiogenic or hypovolaemic shock, severe hypotension, uncontrolled heart failure.8,10

Start an ACE inhibitor within 24–48 hours of myocardial infarction inpatients with6–8,10:

previous myocardial infarction

left ventricular dysfunction or heart failure

anterior infarction

heart rate > 80 beats per minute

diabetes mellitus or hypertension.

In a systematic review, these patients had the greatest reductions inmortality when an ACE inhibitor was started early after myocardialinfarction together with conventional treatment (e.g. beta blockers).28

Consider starting an ACE inhibitor in other patients after myocardialinfarction, as this review showed the absolute risk of mortality at 30 days was reduced by 0.5%.28

In patients with left ventricular dysfunction or heart failure, long-termtreatment reduces the absolute risk of death, myocardial infarction or re-admission for heart failure by 7.2% (NNT for 3 years = 14).29

Use an ACE inhibitorlong term aftermyocardial infarction in patients with leftventricular dysfunctionor heart failure6,8

ACE inhibitors provide additional benefit after myocardial infarction


Observe a 10–12 hournitrate-free interval with all regular nitratepreparations

To avoid the development of tolerance to the anti-anginal effects of nitrates,ensure a daily nitrate-free interval of 10–12 hours when symptoms are lesslikely (e.g. overnight).6,10 The formulation of sustained-release isosorbidemononitrate tablets allows for this interval.10 When using glyceryl trinitratepatches or isosorbide dinitrate tablets, dosing must be timed to incorporate a nitrate-free interval.10 Do not combine long-acting nitrate preparations asthis leads to the rapid development of tolerance.6

Prevent the symptoms of angina and relieve acute attacks

Beta blockers are firstline for stable angina

Start a beta blocker (atenolol or metoprolol).6 Use short-acting nitratepreparations, such as glyceryl trinitrate spray, for acute anginal attacks or before any exertion likely to cause chest pain.6

Other drugs used for angina are as effective as beta blockers for symptomcontrol.10 However, there is no evidence that nitrates or calcium-channelblockers (other than verapamil) prevent cardiovascular events.7,8,10

Use calcium-channelblockers, nitratesand/or nicorandil when beta blockers are contra-indicated or do not controlangina

When a beta blocker is contra-indicated, use a long-acting calcium-channelblocker that reduces heart rate (diltiazem or verapamil).6 Isosorbidemononitrate sustained-release tablets, glyceryl trinitrate patches ornicorandil (Ikorel) may also be substituted for a beta blocker.6

When a beta blocker alone does not control angina, add a long-actingdihydropyridine calcium-channel blocker (amlodipine or controlled-releasenifedipine), a nitrate or nicorandil.6 Avoid using verapamil (use diltiazemwith caution) with a beta blocker due to the risk of severe bradycardia andheart block.6,10

Use combinations of a calcium-channel blocker, nitrate and/or nicorandilwhen these drugs alone do not control symptoms.6 Perhexiline (Pexsig) is used when angina is refractory to drug treatment or surgery (e.g. revascularisation) but can cause serious adverse effects such as peripheral neuropathy.6,10

Patients with ischaemic heart disease with normal ventricular function but at greatest cardiovascular risk (e.g. elevated total cholesterol, coexisting diabetes or hypertension) achieve the greatest absolute benefits from ACE inhibitors.30–32 In the HOPE study30, ramipril reduced the absolute risk of cardiovascular mortality, myocardial infarction or stroke by 3.8% (NNT for 5 years = 26) in high-risk patients ≥ 55 years of age.

Start ACE inhibitors at a low dose and titrate slowly according to blood pressure; hypotension can be significant, especially for patients ≥ 75 years of age.6,10,28 Check serum creatinine and electrolytes at baselineand 1–2 weeks later.6,10 Renal dysfunction is uncommon but can occur in the presence of existing renal disease.6,29

Angiotensin II receptor antagonists may be used when patients cannottolerate ACE inhibitors.7

Consider long-term ACE inhibitors inpatients with normalventricular function but at greatest risk


Are all patients using aspirin (or an alternative if aspirin is contra-indicated or not tolerated)?

Are all patients using a beta blocker (unless contra-indicated)?

Are all patients using a statin (unless contra-indicated)?

Have all patients with angina been prescribed a rapid-onset short-actingnitrate (sublingual glyceryl trinitrate, sublingual isosorbide dinitrate) forrelief or prevention of acute angina attacks?

Are target levels for blood pressure and lipids being achieved, and is blood glucose controlled?

Is the interval between prescription renewals consistent with good compliance?

Questions to review medication use in ischaemic heart disease

National Prescribing Service Limited (NPS) is a member-based organisation providing accurate, balanced, evidence-based information and servicesto health professionals and the community on Quality Use of Medicines (QUM). To achieve this we work in partnership with GPs, pharmacists,

specialists, other health professionals, government, pharmaceutical industry, consumer organisations and the community. NPS is an independentnon-profit organisation funded by the Australian Government Department of Health and Ageing.


ReviewerProf Peter Fletcher

Professor of Cardiovascular Medicine, Faculty of Health,School of Medical Practice and Population Health,University of Newcastle

Professor and Head of Cardiovascular Medicine,John Hunter Hospital, Newcastle

References1. Jackevicius CA, et al. JAMA 2002;288:462–7.2. Butler J, et al. J Am Coll Cardiol 2002;40:1589–95.3. Haynes RB, et al. JAMA 2002;288:2880–3.4. McDonald HP, et al. JAMA 2002;288:2868–79.5. Heart, stroke and vascular diseases – Australian facts

2004. AIHW Cat. No. CVD 27. Australian Institute ofHealth and Welfare and National Heart Foundation ofAustralia (Cardiovascular Disease Series No. 22), May2004. http://www.aihw.gov.au/publications/cvd/hsvd04/hsvd04.pdf (accessed 13 April 2005).

6. Therapeutic Guidelines: Cardiovascular, Version 4.

Melbourne: Therapeutic Guidelines Limited, 2003.7. National Heart Foundation of Australia and Cardiac

Society of Australia and New Zealand. Reducing risk in heart disease 2004 – guidelines for preventingcardiovascular events in people with coronary heartdisease. National Heart Foundation of Australia.Revised March 2005.http://www.heartfoundation.com.au/downloads/RRIHD_fullguide_update_010405.pdf (accessed 4 May 2005).

8. The assessment and management of cardiovascular risk: evidence-based best practice guideline 2003.Wellington: New Zealand Guidelines Group,December 2003. http://www.nzgg.org.nz/guidelines/0035/CVD_Risk_Full.pdf (accessed 13 April 2005).

9. Antithrombotic Trialists’ Collaboration. BMJ 2002;324:71–86.

10. Australian Medicines Handbook, 2005.11. Hankey GJ, Eikelboom JW. Med J Aust 2003;

178:568–74.12. Hung J. Med J Aust 2003;179:147–52.13. Gollapudi RR, et al. JAMA 2004;292:3017–23.14. Ramanuja S, et al. Circulation 2004;110:e1–4.

15. Derry S, Loke YK. BMJ 2000;321:1183–7.16. CAPRIE Steering Committee.

Lancet 1996;348:1329–39.17. Diener HC, et al. Lancet 2004;364:331–7.18. Yusef S, et al. N Engl J Med 2001;345:494–502.19. Steinhubl SR, et al. JAMA 2002;288:2411–20.20. Mehta SR, et al. Lancet 2001;358:527–33.21. De Schryver EL, et al. Stroke 2003;34:2072–80.22. Leonardi-Bee J, et al. Stroke 2005;36:162–8.23. Heart Protection Study Collaborative Group.

Lancet 2002;360:7–22.24. Freemantle N, et al. BMJ 1999;318:1730–7.25. Dargie HJ. Lancet 2001;357:1385–90.26. Janosi A, et al. Am Heart J 2003;146:721–8.27. CIBIS-II Investigators and Committees.

Lancet 1999;353:9–13.28. ACE Inhibitor Myocardial Infarction Collaborative

Group. Circulation 1998;97:2202–12.29. Flather MD, et al. Lancet 2000;355:1575–81.30. Yusef S, et al. N Engl J Med 2000;342:145–53.31. Fox KM, et al. Lancet 2003;362:782–8.32. Braunwald E, et al. N Engl J Med 2004;351:2058–68.

NPS0150



Title: Ezetimibe with Simvastatin (Vytorin) for DyslipidemiaOrganization: National Prescribing Service – RADAR (Australia)

Summary Descriptive Information This newsletter has 5 pages, 2586 words and is divided into 6 sections. The document uses full colour for titles, logo and headings.

Evaluation Summary Reviewer #1 Reviewer#2#1 Referencing 5 5#2 Peer Review 1 1#3 Systematic Review 1 1#4 Statistics 3 1#5 Price and coverage 3 3#6 Graphics 2 2#7 Key Messages 3 5#8 Sections 2 2#9 Headings 5 5#10 Table Hierarchy 3 3#11 Table Editorial Consistency 3 3#12 Column Width 5 3#13 Readability 3 3#14 Justification 5 5#15 Colour 4 3#16 Main Message 3 5#17 Therapeutic Decision Support 5 4#18 Behaviour Target 2 4#19 Retrieval 3 3#20 Editorial Consistency 4 5


Overall Mean Score 66 Strengths This newsletter provides a comprehensive review of a new medication combination with summary information clearly displayed on the first page. The inclusion of benefit and dosing information aids in therapeutic decision making. Weaknesses The document is heavily text based and lacks graphics to enhance readability and impact. It lacks pricing information and peer review. This is not a traditional newsletter directed at a behavioural target and its evaluation reflects this difference in purpose.

April 2006

Galantamine (Reminyl)

01

Ezetimibe with simvastatin (Vytorin) for dyslipidaemia(eh-ZET-eh-mibe with SIM-va-stat-in)

Summary

Ezetimibe with simvastatin combination tablets could be considered for: people already taking ezetimibe and a statin, or people receiving statin monotherapy who need their low-density lipoprotein–cholesterol (LDL-C) concentration lowered further and for whom adding ezetimibe is an appropriate choice.

Compared with ezetimibe and simvastatin taken separately, the combination tablets are cheaper for the patient (because only one co-payment is required) and may be more convenient (because only one tablet is needed).

For people taking statins other than simvastatin who need additional lowering of LDL-C concentration, consider whether the cost and potential convenience advantages of switching to ezetimibe with simvastatin warrant a change in statin therapy rather thanadding ezetimibe as a separate prescription.

The adverse-effect profile of ezetimibe plus simvastatin in clinical trials was similar to that of simvastatin monotherapy. However, ezetimibe is a relatively new drug so its full adverse-effect profile may not yet be known.

Ensure that patients understand that they must stop taking their previous individual statin and ezetimibe tablets before beginning ezetimibe with simvastatin combination tablets.

PBS listingEzetimibe with simvastatin combination tabletscontaining ezetimibe 10 mg and either simvastatin40 mg or simvastatin 80 mg are listed on thePharmaceutical Benefits Scheme (PBS). Ezetimibe with simvastatin tablets containing simvastatin 20 mg are available but are not PBS listed.

Authority required

1. Initial treatment, in conjunction with dietary therapyand exercise, in patients who have coronary heartdisease or diabetes mellitus and whose cholesterollevels are inadequately controlled with an HMG-CoAreductase inhibitor (statin).

Inadequate control with a statin is defined as acholesterol level greater than the initial threshold for PBS subsidy according to the General Statementfor Lipid-Lowering Drugs in the Schedule ofPharmaceutical Benefits after at least 3 months oftreatment at a daily statin dose of 40 mg or more.

2. Continuing treatment in patients with coronary heart disease or diabetes mellitus whose cholesterollevels were inadequately controlled with a statin and who have previously received an authorityprescription for either ezetimibe with simvastatintablets or the combination of ezetimibe and 40 mg or more of a statin.

3. Patients with homozygous familial hyper-cholesterolaemia who are eligible for PBS-subsidised lipid-lowering medication.

Refer to the Schedule of Pharmaceutical Benefitsfor full details of the authority requirements.

Reason for PBS listingThe Pharmaceutical Benefits Advisory Committee (PBAC) recommended ezetimibe with simvastatin tablets for listing on the basis of similar efficacy, safety and cost to those of ezetimibe and simvastatinadministered separately (that is, cost minimisation).1,2

OKA4501NPS RADAR March06.qxd 22/3/06 4:10 PM Page 1

Place in therapyEzetimibe with simvastatin tablets are an alternative to a statin plus ezetimibe administered separately. They could be considered for:

• people already taking ezetimibe and a statin, or

• people receiving statin monotherapy who need their LDL-C concentration lowered further and forwhom adding ezetimibe is an appropriate choice.

Ezetimibe with simvastatin tablets are bioequivalent tothe two drugs co-administered separately.3,4 The maineffect of ezetimibe is to reduce LDL-C levels by inhibitingthe absorption of biliary and dietary cholesterol acrossthe intestinal wall. It has little effect on high-densitylipoprotein–cholesterol or triglyceride levels.

In studies in which patients were randomised to receiveeither ezetimibe, a statin, or a combination of the two,the combination reduced LDL-C concentration by about15% more than statin monotherapy.5–7 In studies in which ezetimibe 10 mg was added to ongoing statin therapy in patients who had not achieved lipidtargets, ezetimibe reduced LDL-C concentration by up to 25% compared with placebo.8,9

Compared with ezetimibe and simvastatin taken separately,the combination tablets are cheaper for patients (because only one co-payment is required) and may be more convenient (because only one tablet is needed),which may help patients to take their medicines correctly.

When is adding ezetimibe an appropriate choice?

Ezetimibe is an alternative to other non-statin drugs for people who have had an adequate trial of statinmonotherapy and need additional drug therapy to reach LDL-C goals. There is no need to consider addingezetimibe for patients who have reached lipid goals andare tolerating statin monotherapy.

Non-statin lipid-modifying drugs include bile-acid resins(cholestyramine and colestipol), fibrates (gemfibrozil andfenofibrate) and nicotinic acid. Ezetimibe is a new lipid-modifying drug that was first PBS listed in August 2004.Clinical experience with it is therefore limited comparedwith that for other lipid-modifying drugs. The effect ofezetimibe on the incidence of coronary heart diseaseevents in people at risk is unknown.

Any combination therapy should only be initiated after a trial of statin monotherapy at an adequate dose for a sufficient duration.

Before starting combination therapy, assess compliancewith statin therapy because people often discontinuelipid-modifying drugs.10 Careful questioning aboutcompliance in a non-threatening non-judgmentalmanner — for example, ‘People often have difficultytaking their pills for one reason or another. Have youever missed any of your pills?’ — will identify more than half of those with low compliance.11

To reduce modifiable risk factors, patients should makediet and lifestyle changes before starting drug therapyand continue these throughout treatment.

An alternative to adding a second drug is to increase thedose of statin monotherapy. The cost and convenienceadvantages of this option must be weighed against thefact that increasing the statin dose increases the risk of adverse effects and has relatively modest effects on cholesterol levels (each doubling of the statin doseachieves in the order of an additional 6% lowering of LDL-C concentration).12 Generally, more than 80% of the lipid-modifying effects of a statin can be achievedwith 50% of the maximum dose.13

It should be noted that although lowering cholesterolhas been shown to reduce the risk of coronary heartdisease events, optimal lipid targets have not beenestablished. Therefore, the benefits of titrating therapyto a particular goal are unknown.

See the August 2004 issue of NPS RADAR for moredetail about the place of ezetimibe in managingdyslipidaemia.

Changing from another statin to ezetimibewith simvastatin combination tablets

For people taking ezetimibe with statins other thansimvastatin, consider whether the cost and potentialconvenience of switching to the combination tabletswarrant a change in statin therapy. Adding ezetimibe as a separate prescription may be preferable.

Adding ezetimibe to monotherapy with any statin usuallylowers LDL-C concentration by about 15%.5 However,different statins produce different reductions in LDL-Cconcentration per milligram. Therefore, switching from

April 2006

02

Ezetimibe with simvastatin (Vytorin)


April 2006

03

another statin to ezetimibe with simvastatin combinationtablets may lower LDL-C concentration by more or less than adding ezetimibe to the original statin.Simvastatin has greater LDL-C-lowering effects permilligram than pravastatin or fluvastatin but is lesspotent than atorvastatin.13 Patients whose LDL-Cconcentrations are inadequately controlled onatorvastatin monotherapy could have a greater overallreduction in LDL-C concentration if ezetimibe is added to atorvastatin than if they switch to ezetimibe withsimvastatin combination tablets.

See the NPS RADAR review ‘Atorvastatin (Lipitor) for the management of lipid disorders’ for a discussion of the lipid-modifying effects of atorvastatin comparedwith those of other statins.

Safety issuesThe adverse-effect profile of ezetimibe plus simvastatin in clinical trials was similar to that of simvastatinmonotherapy.5,7,14 However, ezetimibe is a relatively new drug so its full adverse-effect profile may not yet be known.

Elevated liver enzyme concentrations appear to be more frequent with the combination of ezetimibe and simvastatin than with simvastatin alone.4

Muscle disorders are known adverse effects ofsimvastatin and have been reported with ezetimibe.15,16

Report suspected adverse reactions to the Adverse Drug Reactions Advisory Committee (ADRAC) online (see www.tgasime.health.gov.au) or by using the ‘BlueCard’ distributed with the Schedule of PharmaceuticalBenefits and Australian Prescriber. For information aboutreporting adverse drug reactions, see the TherapeuticGoods Administration website (www.tga.gov.au).

Be vigilant for signs of muscle adverse effects

Simvastatin can cause muscle pain and weakness and rarely rhabdomyolysis. See Box 1 for informationabout preventing statin myopathy. More recently, muscle disorders have been reported with ezetimibeused alone.15,16 It is not known if ezetimibe can cause rhabdomyolysis.

ADRAC has received 44 reports of muscle disorders,including myalgia, muscle cramp, weakness and pain, with ezetimibe.15 Almost half of the cases occurred within

2 weeks of starting ezetimibe. Five cases included elevatedserum creatine kinase (CK) concentration. Twenty-onecases were in patients with a history of muscle disorders or elevated CK concentration with a statin. In 5 casesezetimibe was given with a statin; ADRAC suggests thatthese cases were consistent with an interaction betweenezetimibe and the statin, with the symptoms of myalgia or CK-concentration increase developing within 3 monthsof the addition of ezetimibe to long-term statin treatment.Two published cases also describe myopathy associatedwith the combination of ezetimibe and a statin, withmuscle and tendon pain and/or CK-concentrationelevation detected within 2 months of adding ezetimibe to longstanding statin treatment.16

Monitor transaminase concentrations

Elevated serum transaminase concentrations occurred in patients taking the combination of ezetimibe andsimvastatin more frequently than in those on simvastatinmonotherapy in clinical trials.4 These adverse effectsappeared to be related to the dose of simvastatin, wereoften asymptomatic and generally resolved after eitherdiscontinuing treatment or during continuing therapy.

Similar precautions apply as with statin treatment.Measure transaminase concentrations before startingezetimibe with simvastatin therapy and periodically


Box 1: Reducing the risk of statin myopathy17–19

• Monitor for signs and symptoms of myopathy (unexplained muscle pain, tenderness or weakness).

• Use the lowest statin dose required to achieve therapeutic goals.

• Ask patients to report muscle symptoms promptly,particularly if accompanied by malaise, fever and/or dark urine.

• Avoid, or use cautiously, in combination with drugs knownto increase the risk of statin myopathy (e.g. fibrates,cyclosporin, azole antifungals, macrolide antibiotics).

• Use statins with caution in patients at particular risk ofmyopathy (older people, particularly older women; patientswith multisystem disease; patients with diabetes and chronic renal failure; patients taking multiple medications).

• Suspend statin therapy temporarily when conditionspredispose to rhabdomyolysis (e.g. major surgery, trauma,acute renal failure).


April 2006

04


during treatment, particularly in patients takingezetimibe with simvastatin 10 mg / 80 mg. Stop treatmentif transaminase concentrations are persistently abovethree times the upper limit of normal.12

It is usually recommended that restarting statintreatment be considered after transaminaseconcentrations have returned to normal, becausetransaminase elevations often do not recur atrechallenge.12 The likelihood of transaminaseconcentration elevation recurring on rechallengewith ezetimibe with simvastatin tablets is unknownbecause clinical experience with the combination is more limited. If ezetimibe is restarted, monitortransaminase concentrations closely.

Avoid ezetimibe with simvastatin in people with active liverdisease or unexplained persistent transaminase elevationsand use caution in those with a past history of liver diseaseor who consume excessive amounts of alcohol.3

Consider drug interactions with simvastatin

Drug interactions for simvastatin apply to ezetimibe withsimvastatin. Inhibitors of CYP3A4 (such as ketoconazole,verapamil and grapefruit juice) can increase simvastatinlevels and elevate the risk of adverse effects.

The manufacturer recommends that ezetimibe withsimvastatin tablets not be used with fibrates (gemfibrozil,fenofibrate) because the combination of simvastatin and a fibrate increases the risk of myopathy and thesafety of ezetimibe in combination with fibrates has not been established.3

Dosing issuesEach ezetimibe with simvastatin combination tabletcontains ezetimibe 10 mg. Combination tabletscontaining simvastatin doses of 20 mg, 40 mg and 80 mg are available in Australia. Only the ezetimibe withsimvastatin 10 mg / 40 mg and 10 mg / 80 mg strengthsare listed on the PBS.

Patients should not take more than one ezetimibe withsimvastatin tablet at a time because there is noadvantage to using ezetimibe doses above 10 mg.20

The manufacturers suggest starting at a dose ofezetimibe with simvastatin of up to 10 mg / 40 mg* and individualising dose based on response.3

People already taking simvastatin can switch directly to the corresponding dose of ezetimibe with simvastatin.The manufacturer does not provide any specific dosing recommendations for people switching fromother statins to ezetimibe with simvastatin tablets. Itwould seem reasonable to switch to the same milligramstatin dose in the fixed-dose combination tablets (for example, from atorvastatin 40 mg to ezetimibe with simvastatin 10 mg / 40 mg). Assess response andadjust dose as required.

If lipid goals are not reached using ezetimibe withsimvastatin 10 mg / 40 mg, LDL-C concentration can be further reduced by up to 6% by titrating up to the higher strength containing simvastatin 80 mg.5,21

Information for patientsExplain the symptoms of possible adverse effects onmuscle of ezetimibe with simvastatin. Ask patients toreport unexplained muscle pain or weakness promptly.

Ensure that patients understand that they must stoptaking their previous statin and ezetimibe tablets beforebeginning ezetimibe with simvastatin combinationtablets and that they should not take more than oneezetimibe with simvastatin tablet at a time.

Discuss the importance of lifestyle changes in reducingoverall cardiovascular risk. Information about lifestylechanges for patients is available from the HeartFoundation’s national telephone information service,Heartline (Ph 1300 36 27 87) or online(www.heartfoundation.com.au).

For more detailed information about ezetimibe withsimvastatin, suggest or provide the Vytorin consumermedicine information (CMI).

* Except for people with homozygous familial hypercholesterolaemia, who should start atan ezetimibe with simvastatin dose of either 10 mg / 40 mg or 10 mg / 80 mg.


April 2006

05


Date prepared: January 2006

The information contained in this material is derived from a critical analysis of a wide range of authoritative evidence. Any treatment decisions based on this information should be made in the context of the clinical circumstances of each patient.

1. Pharmaceutical Benefits Advisory Committee. July 2005PBAC outcomes — positive recommendations.Canberra: Australian Government Department of Healthand Ageing, 2005. http://www.health.gov.au/internet/wcms/publishing.nsf/Content/pbacrec-jul05-positive(accessed 30 August 2005).

2. Pharmaceutical Benefits Advisory Committee. March2005 PBAC outcomes — positive recommendations.Canberra: Australian Government Department of Healthand Ageing, 2005. http://www.health.gov.au/internet/wcms/publishing.nsf/Content/pbacrec-mar05-positive(accessed 30 August 2005).

3. Merck Sharp and Dohme (Australia) Pty Ltd. Vytorinproduct information. 12 August 2005.

4. Therapeutic Goods Administration. Vytorin(ezetimibe/simvastatin) request for ADEC advice.Canberra: Australian Government Department of Health and Ageing, 30 August 2004.

5. Bays HE, et al. Clin Ther 2004;26:1758–73.6. Feldman T, et al. Am J Cardiol 2004;93:1481–6.7. Goldberg AC, et al. Mayo Clin Proc 2004;79:620–9.8. Pearson TA, et al. Mayo Clin Proc 2005;80:587–95.9. Farnier M, et al. Int J Cardiol 2005;102:327–32.10. Simons L, et al. Med J Aust 1996;164:208–11.11. Stephenson BJ, et al. JAMA 1993;269:2779–81.12. National Cholesterol Education Program Expert Panel

on Detection, Evaluation, and Treatment of High BloodCholesterol in Adults. Final report. Bethesda, Maryland:National Institutes of Health — National Heart Lungand Blood Institute, 2002. http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3_rpt.htm (accessed 30 August 2005).

13. Australian Medicines Handbook 2005.14. Masana L, et al. Clin Ther 2005;27:174–84.

15. Adverse Drug Reactions Advisory Committee.Australian Adverse Drug Reactions Bulletin 2005;24:15.

16. Fux R, et al. Ann Intern Med 2004;140:671–2.17. Pasternak R, et al. J Am Coll Cardiol 2002;40:567–72.18. Hamilton-Craig I. Med J Aust 2001;175:486–9.19. Thompson P, et al. JAMA 2003;289:1681–90.20. Center for Drug Evaluation and Research. Zetia

(ezetimibe) tablets approval package. Rockville,Maryland: United States Food and Drug Administration,2002. http://www.fda.gov/cder/foi/nda/2002/21445_Zetia.htm (accessed 30 August 2005).

21. Ballantyne CM, et al. Am Heart J 2005;149:464–73.

References



Title: Eplerenone (Inspra) for Use After Acute Myocardial Infarction Complicated by Heart Failure

Organization: National Prescribing Service – RADAR (Australia) Summary Descriptive Information This newsletter has 5 pages, 2315 words and is divided into 6 sections. The document uses full colour for titles, logo and headings. Evaluation Summary Reviewer #1 Reviewer#2#1 Referencing 5 5#2 Peer Review 1 1#3 Systematic Review 1 1#4 Statistics 4 2#5 Price and coverage 3 1#6 Graphics 3 2#7 Key Messages 3 5#8 Sections 2 2#9 Headings 5 5#10 Table Hierarchy 5 5#11 Table Editorial Consistency 5 5#12 Column Width 5 3#13 Readability 4 3#14 Justification 5 5#15 Colour 4 3#16 Main Message 3 5#17 Therapeutic Decision Support 4 5#18 Behaviour Target 3 4#19 Retrieval 3 3#20 Editorial Consistency 4 5


Overall Mean Score 71 Strengths This document provides a complete review of the role of eplerenone in therapy including safety and monitoring concerns. Benefit information is provided and there is good support for therapeutic decision making. Weaknesses The document is heavily text based and suffers from some readability challenges. It lacks pricing information and peer review. This is not a traditional newsletter directed at a behavioural target and its evaluation reflects this difference in purpose.

April 2006

06

Eplerenone (Inspra) for use after acute myocardialinfarction complicated by heart failure(ep-LAYR-eh-nown)

Summary

Eplerenone is an aldosterone-receptor antagonist similar to spironolactone.

When added to standard therapy in people with heart failure soon after myocardial infarction, there is evidence that eplerenone reduces mortality in both the short and long term. Standard ongoing therapy should include aspirin, a beta blocker, an angiotensin-converting enzyme inhibitor and a statin.

To be eligible for PBS subsidy, eplerenone must be started 3–14 days after an acute myocardial infarction. Evidence of a left ventricular ejection fraction ≤ 40% is also required.Eplerenone will usually be initiated in hospital and continued indefinitely.

Eplerenone increases the risk of serious hyperkalaemia. Careful monitoring of serum potassiumis essential.

Eplerenone should be avoided in people with moderate to severe renal impairment.

Spironolactone is the aldosterone-receptor antagonist of choice in severe chronic heart failure.

PBS listing

Authority required

Heart failure with a left ventricular ejection fraction of 40% or less after an acute myocardial infarction.Treatment with eplerenone must be started 3–14 daysafter an acute myocardial infarction to be eligible forsubsidy. PBS-subsidised therapy may begin after this timeif it is a continuation of eplerenone treatment that wasinitiated within the 3–14-day time limit (e.g. in hospital).

Reason for PBS listingEplerenone reduces mortality in people with leftventricular dysfunction after myocardial infarction when added to optimal medical therapy.1 The PBACrecommended listing on the basis of acceptable costeffectiveness compared with placebo.2

The PBAC recommended an authority-required listing for eplerenone.3 Participants in the key clinical trial had a left ventricular ejection fraction of 40% or lower,symptomatic heart failure or diabetes, and were startedon eplerenone between 3 and 14 days after acute

myocardial infarction.1 The authority restrictions are toensure that people using eplerenone fulfil these criteria,and so match the population in which a cost-effectivebenefit has been demonstrated.4

The PBAC accepted that the appropriate comparator for eplerenone was placebo rather than spironolactone(which is pharmacologically similar to eplerenone).Spironolactone has not been studied in patients whohave had an acute myocardial infarction complicated by heart failure and is currently used in only a smallproportion of these cases.4

Place in therapyEplerenone is an aldosterone-receptor antagonist similarto spironolactone. As with spironolactone, eplerenone is a potassium-sparing diuretic at higher doses and hasbeen registered as an antihypertensive overseas.

In Australia the sole registered indication for eplerenoneis to reduce the risk of death in patients who haveevidence of heart failure and left ventricular impairmentsoon after an acute myocardial infarction; eplerenoneshould be added to the standard drug regimen for these


April 2006

07

Eplerenone (Inspra)

patients. The indication was established in the EPHESUS trial, in which more than 6000 peoplereceived eplerenone or placebo in addition to standardtherapies for an average follow-up of 16 months.1

Other than EPHESUS, there are no published trials of eplerenone in heart failure and no head-to-headcomparisons with spironolactone for this indication.

Eplerenone can be added to standardtherapy after myocardial infarction

It is expected that eplerenone will most commonly bestarted in hospital along with standard managementafter myocardial infarction. This includes aspirin, a beta blocker, an angiotensin-converting enzyme (ACE)inhibitor and a statin5; all reduce the risk of death (see NPS Prescribing Practice Review 31: Ischaemic heart disease). People with heart failure are likely to be receiving a diuretic and possibly digoxin5 (see Druginteractions), and these may also be used in combinationwith eplerenone.1,6

Participants in the EPHESUS trial had a left ventricularejection fraction ≤ 40%.1 Eplerenone was initiatedbetween 3 and 14 days after acute myocardial infarction.At 1 year of follow-up the risk of death in the eplerenonegroup was 11.8%, compared with 13.6% in the placebogroup. This means that 56 people with heart failure after myocardial infarction would need to be treatedwith eplerenone for 1 year to avoid 1 death.

Continue eplerenone indefinitely

Eplerenone should be continued indefinitely aftermyocardial infarction, as there is currently no evidencethat the mortality benefit disappears in the longer term.More than half of the deaths avoided with eplerenonetreatment in the EPHESUS trial were in the first 30 days1,7;however, there was evidence of a benefit for the durationof the trial, which continued for an average follow-up of16 months.1 Nevertheless, patients should be reassessedafter no longer than 12 months, and options for themanagement of chronic heart failure considered.8

Use spironolactone in severe chronic heart failure

Guidelines recommend low-dose spironolactone(12.5–50 mg/day) in severe heart failure.5 In people with severe heart failure of at least 6 weeks’ duration,addition of low-dose spironolactone to treatment with

an ACE inhibitor and a loop diuretic reduced mortalitysubstantially9 (see NPS News 36: A step-wise approachto heart failure management). Eplerenone andspironolactone should not be co-administered.

The evidence for eplerenone is in people with a diagnosisof heart failure soon after myocardial infarction. Morethan 4 in 5 participants in EPHESUS had only mild heartfailure symptoms (New York Heart Association Class I or II).6 Although eplerenone is an aldosterone-receptorantagonist similar to spironolactone, it is unclear frompublished trials if spironolactone and eplerenone haveequivalent benefits in heart failure.6,10

The mortality benefits seen in EPHESUS and withspironolactone in severe heart failure might suggest a role for an aldosterone-receptor antagonist in all peoplewith mild to moderate heart failure symptoms; however,there are insufficient data to recommend this, as there aresafety concerns that may outweigh any potential benefit.

Safety issuesThe risk of serious hyperkalaemia is the primary safetyconcern with eplerenone. As with spironolactone,eplerenone should only be used in patients with heartfailure if serum potassium is regularly monitored.Eplerenone is contraindicated in moderate to severe renalfailure, or in combination with potassium-sparing diuretics(such as amiloride, triamterene or spironolactone).

Report suspected adverse reactions to the Adverse Drug Reactions Advisory Committee (ADRAC) online (see www.tgasime.health.gov.au) or by using the ‘BlueCard’ distributed with the Schedule of PharmaceuticalBenefits and Australian Prescriber. For information aboutreporting adverse drug reactions, see the TherapeuticGoods Administration website (www.tga.gov.au).

Be aware of the risk of serious hyperkalaemia

Eplerenone therapy may cause life-threateninghyperkalaemia. Monitor serum potassium:

• before initiating therapy

• within the first week

• 1 month after starting treatment or adjusting the dose

• every 3 months thereafter.


April 2006

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Eplerenone (Inspra)

If serum potassium concentration is ≥ 5.5 mmol/L, the dose of eplerenone should be reduced or withheld(see Dosing issues).

Consider other risk factors for hyperkalaemia whenprescribing or reviewing eplerenone therapy, such as:

• diabetes

• renal dysfunction (which may develop over time)

• increases in dietary potassium intake or use ofpotassium supplements.

In the EPHESUS trial the incidence of serioushyperkalaemia (≥ 6.0 mmol/L) in eplerenone-treatedparticipants was 5.5% over the course of the trial,compared with 3.9% in the placebo group; no deathsdue to hyperkalaemia were recorded in the eplerenonegroup.1 In other populations, or with less intensivemonitoring, the incidence of serious hyperkalaemia may be greater, as seen with spironolactone.

Analysis of hospital and prescribing data in Canadarevealed an estimated 5% admission rate forhyperkalaemia in spironolactone-treated heart failurepatients, and evidence of associated mortality.11 Theresults indicate that hyperkalaemia is considerably morecommon in practice than it was in the one large-scale trialof spironolactone in heart failure, in which the incidenceof serious hyperkalaemia was 2%.9 Perhaps for this reasonthe widespread adoption of spironolactone treatmentdescribed in the Canadian study did not lead to anydecrease in all-cause mortality in the period from 1999 to2001, despite the expectation of a substantial benefit.11

Eplerenone may cause sex-hormone-relatedadverse effects

Eplerenone may cause adverse effects similar to thoseseen with spironolactone, such as gynaecomastia or breast pain in men, or abnormal vaginal bleeding in women.6,12 Eplerenone has a lower affinity for progesterone and androgen receptors thanspironolactone13, but the lack of long-term head-to-head trials means that it is not known how much these adverse effects are reduced.

The incidence of sex-hormone-related adverse events in the EPHESUS trial was less than 1% and did not differ from that for placebo.1,8 However, in other trials,patients receiving up to 400 mg/day eplerenoneexperienced a low rate of gynaecomastia and abnormalvaginal bleeding, while these were not reported with

placebo.12 On average, gynaecomastia took almost 2 years to appear in the trial of low-dose spironolactone in heart failure6,9 while average follow-up in EPHESUSwas 16 months.1

Contraindications for eplerenone

Eplerenone should not be used:

• if initial serum potassium concentrationis > 5.5 mmol/L

• if creatinine clearance is < 50 mL/min or estimatedglomerular filtration rate (eGFR) is < 60 mL/min/1.73 m2

(i.e. moderate to severe renal impairment)

• in severe hepatic insufficiency

• with potassium-sparing diuretics (amiloride,spironolactone or triamterene)

• with potent CYP3A4 inhibitors (clarithromycin,itraconazole, ketoconazole, nelfinavir or ritonavir).8,12,14

Drug interactions

Potassium supplementation should be reduced or discontinued.15

Nonsteroidal anti-inflammatory drugs (NSAIDs — bothnon-selective and COX-2 selective) should be used withcaution in people receiving eplerenone. NSAIDs maycause fluid retention and exacerbate heart failure. A drug interaction study of eplerenone with an NSAIDhas not been conducted, but the combination mayincrease the risk of hyperkalaemia or kidney failure.8,14

Use of low-dose aspirin does not appear to be a hazard.1

Co-administration of an ACE inhibitor or angiotensin II-receptor antagonist with eplerenone will be usualpractice; be mindful of the increased risk ofhyperkalaemia with this combination in patients at risk for impaired renal function, such as those aged 65 years or older. Close monitoring of serum potassiumand renal function is recommended.14

Mild to moderate CYP3A4 inhibitors (e.g. amiodarone,cimetidine, diltiazem, erythromycin, fluvoxamine,miconazole or verapamil) may increase the serumconcentration of eplerenone.14 Potent CYP3A4 inhibitors are contraindicated (see Contraindications for eplerenone). Co-administration with potent CYP3A4 inducers (carbamazepine, phenobarbitone,phenytoin, rifampicin or St John’s wort) may reduce theeplerenone concentration.14 Monitor serum potassiumclosely and adjust the eplerenone dosage if necessary(see Dosing issues).


Systemic digoxin exposure (AUC) is increased by 16%with concomitant use of eplerenone.14 Use cautionwhen digoxin dosing is near the upper limit of thetherapeutic range. Note that hyperkalaemia increases the risk of digoxin-induced arrhythmias.

Dosing issuesInitiate at 25 mg once daily and, if the serum potassium concentration is < 5.0 mmol/L, titrate to the recommended target dose of 50 mg once daily within 4 weeks, as tolerated by the patient.8,14

Reduce the dose if serum potassiumconcentration is high

If monitoring indicates hyperkalaemia (see Safety issues),the dose should be reduced or withheld according to the scheme in Table 1. Serum potassium concentrationshould be measured again after 1 month and the doseadjusted further as needed.

Information for patientsAdvise people receiving eplerenone to:

• avoid salt tablets, ‘low sodium’ salt substitutes and dietary supplements containing potassium;glucosamine sulfate preparations (available over the counter for arthritis) may contain a significantquantity of potassium

• avoid over-the-counter painkillers containing aspirin orNSAIDs: diclofenac (Voltaren Rapid, Diclac); ibuprofen(Nurofen, Tri-Profen, Herron Blue, Advil, Actiprofen,Compufen, Bugesic, Panafen, Rafen); mefenamic acid(Ponstan); or naproxen (Naprogesic, Alleve, Nurolasts).Suggest paracetamol for minor complaints such asheadache and fever

• drink sufficient fluids during hot weather and whenexercising, and, if dehydration occurs (e.g. because of vomiting or diarrhoea), stop taking eplerenone and consult a medical practitioner promptly.

Explain that not following this advice can increase theblood potassium level, which may result in dangerouschanges in the rhythm or rate of the heartbeat.

For more detailed information about eplerenone, suggest or provide the Inspra consumer medicineinformation (CMI).

April 2006

Galantamine (Reminyl)

09

Eplerenone (Inspra)

Table 1: Dose adjustment according to serumpotassium concentration

Serumpotassiumconcentration(mmol/L) Action

Dose adjustmentfrom current dose

≥ 6.0 Withhold* —

5.5–5.9 Decrease If 50 mg daily then 25 mg daily

If 25 mg daily then 25 mg everyalternate day

If 25 mg everyalternate day then withhold*

5.0–5.4 Maintain No dose adjustment

< 5.0 Increase If 50 mg daily then no adjustment

If 25 mg daily then 50 mg daily

If 25 mg everyalternate day then 25 mg daily

* After withholding because of serum potassium concentration ≥ 6.0 mmol/L, when theconcentration has fallen to < 5.5 mmol/L dosing can restart at 25 mg every alternate day.


April 2006

10

Eplerenone (Inspra)

Date prepared: January 2006.

The information contained in this material is derived from a critical analysis of a wide range of authoritative evidence. Any treatment decisions based on this information should be made in the context of the clinical circumstances of each patient.

1. Pitt B, et al. N Engl J Med 2003;348:1309–21.2. Pharmaceutical Benefits Branch. Eplerenone public

summary document. http://www.health.gov.au/internet/wcms/publishing.nsf/Content/pbac-psd-eplerenone (accessed 31 October 2005).

3. Department of Health and Ageing. July 2005 PBAC outcomes — positive recommendations.http://www.health.gov.au/internet/wcms/publishing.nsf/Content/pbacrec-jul05-positive (accessed 29 August 2005).

4. Pharmaceutical Benefits Branch and Pfizer Australia.Data on file.

5. Therapeutic Guidelines: Cardiovascular. Version 4, 2003.

6. Inspra (eplerenone) approval package. Company: GDSearle LLC, Application No: 021437, Approval Date:10/07/2003. http://www.fda.gov/cder/foi/nda/2003/21-437s002_Inspra.htm (accessed 16 August 2005).

7. Pitt B, et al. J Am Coll Cardiol 2005;46:425–31.8. Pfizer Australia. Inspra product information,

20 June 2005.9. Pitt B, et al. N Engl J Med 1999;341:709–17.10. Jessup M. N Engl J Med 2003;348:1380–2.11. Juurlink DN, et al. N Engl J Med 2004;351:543–51.12. GD Searle LLC [USA]. Inspra (eplerenone) prescribing

information, 7 October 2003. http://www.fda.gov/cder/foi/label/2003/21437se1-002_inspra_lbl.pdf(accessed 12 August 2005).

13. de Gasparo M, et al. J Pharmacol Exp Ther1987;240:650–6.

14. Pfizer Limited [UK]. Inspra summary of productcharacteristics, 21 September 2005.http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=16746 (accessed 18 October 2005).

15. Hunt SA, et al. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failurein the adult. http://www.acc.org/clinical/guidelines/failure/index.pdf (accessed 31 August 2005).

References



Title: Aggressive High Dose Statin TherapyOrganization: Community Drug Utilization Program (British Columbia)

Summary Descriptive Information This newsletter has 3 pages, 1644 words and is divided into 3 sections. The document uses partial colour for its logo and in one table. Evaluation Summary Reviewer #1 Reviewer#2#1 Referencing 5 5#2 Peer Review 5 5#3 Systematic Review 1 2#4 Statistics 5 5#5 Price and coverage 1 1#6 Graphics 4 3#7 Key Messages 4 2#8 Sections 4 2#9 Headings 5 5#10 Table Hierarchy 5 5#11 Table Editorial Consistency 3 4#12 Column Width 5 5#13 Readability 2 2#14 Justification 1 1#15 Colour 4 5#16 Main Message 3 3#17 Therapeutic Decision Support 4 4#18 Behaviour Target 2 3#19 Retrieval 3 4#20 Editorial Consistency 4 4


Overall Mean Score 70 Strengths This document provides a complete literature background on the benefits and limitations to aggressive statin therapy. It also includes an important discussion of safety. Therapeutic equivalent dosing chart linked to study outcomes provides an important decision support for prescribers. Weaknesses The first page if heavily text based and the key messages are difficult to obtain quickly. Full justification of the columns interferes with readability. The lack of pricing information is notable.


Title: Restless Legs SyndromeOrganization: Prescription Information Services of Manitoba – PrISM (Manitoba)

Summary Descriptive Information This newsletter has 3 pages, 1974 words and is divided into 5 sections. The document uses partial colour for its logo on the first page. Evaluation Summary Reviewer #1 Reviewer#2#1 Referencing 5 5#2 Peer Review 3 2#3 Systematic Review 1 1#4 Statistics 3 1#5 Price and coverage 1 1#6 Graphics 4 3#7 Key Messages 3 2#8 Sections 5 5#9 Headings 5 5#10 Table Hierarchy 4 4#11 Table Editorial Consistency 5 5#12 Column Width 1 1#13 Readability 1 2#14 Justification 4 5#15 Colour 4 5#16 Main Message 4 2#17 Therapeutic Decision Support 4 4#18 Behaviour Target 2 2#19 Retrieval 3 2#20 Editorial Consistency 4 5


Overall Mean Score 64 Strengths The table provides good support for therapeutic decision making. Weaknesses The document has readability challenges because of its heavy text base and page-width columns. The lack of pricing information is notable. There is not a clear behaviour target apparent in this document. The lack of a key message section impedes the rapid uptake of the main messages of the document.

PrISM (Prescription Information Services of Manitoba)

Restless Legs Syndrome It is Wednesday morning at your pharmacy when a very tired looking elderly gentleman comes to the counter asking about OTC sleep aids. He wants to know which is the �strongest�. Being the thorough pharmacist you are, you inquire as to why he is having trouble sleeping. He informs you that it is not him that is having the problem, it is his wife, she is constantly moving around in bed. �It seems like she is walking 10 miles in her sleep every night, her legs never stop moving.� Consequently, neither of them sleeps well, and they are considering sleeping in separate beds. You think this sounds familiar and then you remember the Spectrum Newsletter you read on Restless Legs Syndrome. What is it? Restless Legs Syndrome (RLS) was first identified in the medical literature over 300 years ago.1 For many years the condition was believed to be a peripheral disorder of the lower extremities; however, recent improvements in imaging modalities and response to specific pharmacotherapy has lead researchers to conclude that this is more likely a neurological disorder.2 Estimates of prevalence of RLS vary but appear to be approximately 5-15%.1 However, there is significant geographic disparity in prevalence with studies in Singapore and Hong Kong showing rates below 1%.1 There appears to be no gender difference in prevalence. The syndrome has been recognized in patients as young as 18 years old (3% estimated rate in ages 18-29) and rates rise modestly with age.2 The International Restless Leg Study Group have determined the minimum diagnostic criteria of RLS to be:1

• a distressing desire to move the legs, usually associated with akathisia (distressing, irritable need to move the legs)

• motor restlessness • symptoms should be brought on by rest or worsen by rest and there should be at least a

partial (but temporary) relief with activity • symptoms should worsen in the evening or at night

In addition to these diagnostic criteria, patients often report involuntary limb movement while awake and periodic limb movement (PLM) while asleep (seen in about 80% of patients with RLS).1 Patients with the syndrome are categorized into 2 different pathological groups, primary (idiopathic) and secondary RLS. The pathogenesis of the primary syndrome is unknown. Although, recent functional imaging studies of patients with RLS have demonstrated dysfunction in the binding and uptake of dopamine in the basal ganglia of the brain.2 The efficacy of exogenous dopamine and dopamine agonists in treatment of RLS also solidifies the presumption that the pathology is related to

Spectrum A Drug Information Newsletter

For Pharmacists

May 2004

dopamine in the central nervous system. Forty percent of patients with primary RLS have a family history which suggests a genetic predisposition to the disorder.2 Secondary Restless Legs Syndrome is brought about by a number of different conditions. One important secondary cause is uremia; hence patients on dialysis must be closely monitored for this condition. The prevalence of RLS in patients on dialysis have been reported as high as 62%.3 There seems to be no difference in rates between hemodialysis and peritoneal dialysis patients.3 Another condition linked to RLS is iron deficiency anaemia. A number of case reports and studies have linked RLS with low serum and spinal fluid levels of ferritin.2 Other secondary causes include diabetic neuropathy2, rheumatic diseases2, pregnancy2, venous insufficiency2 and use of certain medications (ex. metoclopramide, lithium and tricyclic antidepressants) that affect dopamine in the brain.1 What can be done? Lifestyle and non-pharmacological activities can improve RLS. Reduction or removal of caffeine and alcohol intake as well as smoking cessation have been shown to help reduce symptoms.4 Elevating the legs when at rest, massage therapy (including the use of vibrating massage devices), flexion-extension exercises should also be considered part of RLS management.4 Whether these activities impact the pathology of RLS or just improve sleep in general is not know. The cornerstone of management of secondary RLS is dealing with the secondary causes. Removal or reduction of medications that exacerbate RLS should be considered. If patients have iron deficiency, correction of the deficiency with oral or IV iron therapy has been found effective in symptom reduction.3 In patients with end-stage renal disease, dialysis itself does not improve symptoms, but kidney transplant may eliminate RLS.3 For those who remain on dialysis, those who have secondary causes that cannot be modified or removed and those who have primary RLS, pharmacological intervention often required. Please see Appendix 1 for a summary chart of drugs and doses used in the management of RLS. Dopamine Analogues The use of levodopa plus a peripheral decarboxylase inhibitor (carbidopa or benserazide) have long been considered the �gold-standard� in the treatment of RLS. Levodopa used at doses between 50-200mg/day have been shown to reduce periodic leg movements and improve sleep.1 A problem with the use of regular release levodopa is a �wearing-off� affect where symptoms return after approximately 4 hours after the patient goes to bed.1 This phenomenon can be alleviated by giving a short acting plus a long acting levodopa preparation at the same time before going to bed5 or by giving a second dose of regular-release if symptoms recur during the night.1 A further problem with the use of levodopa is the development of augmentation symptoms with prolonged use. Development of more severe RLS symptoms, return of symptoms earlier in the day and spread of symptoms to different parts of the body (ex. to upper limbs) despite increasing doses of levodopa are all common manifestations of augmentation.3 In a recent 1-year prospective study of levodopa for restless legs syndrome, over 50% of patients discontinued therapy before the end of the trial due to augmentation symptoms.6 Dopamine Agonists Because of problems with long-term efficacy of dopamine analogues, the use of dopamine agonists has become more popular in the management of RLS. The first dopamine agonists studied for this indication was ergotamine derivative, pergolide (Permax®). Several placebo controlled trials have shown pergolide�s superiority in both subjective and objective measures of sleep.2 However, side effects of the ergot-derivatives dopamine agonists (pergolide and cabergoline - Dostinex®) such as nausea/vomiting and orthostatic hypotension, and the risk of pulmonary fibrosis (with pergolide) limits the usefulness of these agents.2 The non-ergot dopamine agonists ropinirole (ReQuip®) and pramipexole (Mirapex®) have also shown promising activity in RLS with less dose-limiting side-

effects.2 Recently, the value of ropinirole was tested in the largest placebo-controlled trial to date conducted for treatment of RLS.7 Over the course of this 12 week trial, ropinirole was superior to placebo in improving all sleep measures and patient quality of life.7 The risk of augmentation from long-term therapy with dopamine agonists still exists but appears to be lower then with levodopa. In a 1 year study with pergolide, augmentation symptoms were seen in 25% of subjects.1

Other Treatment Options Benzodiazepines have proven efficacious in RLS management in a few, small open labelled trials. Diazepam and clonazepam have both been shown to improve symptoms and sleep quality.1 However, long term use of benzodiazepines can lead to concerns of dependence, and long term use in the elderly, carries with it risk of falls and fractures.8 The trials examining benzodiazepines in the management of RLS also identified over-sedation and �hang-over� effects as potential problems with long-term use.1 Opiods, including codeine, methadone and oxycodone have all been found to be helpful in management of RLS.2 They positively impact number of sleep arousals, PLM frequency and sleep efficiency.2 In addition, long-term sleep studies have shown that narcotics maintain their efficacy.1 However, concerns over side effects and the potential for dependence and abuse of these agents make them a second-line therapy for those patients who have failed on, or do not tolerate safer alternatives.2 Gabapentin and carbamazepine are the final group of agents that can be used in the management of RLS. Both these agents have been studied in placebo-controlled trials.1 Although both improved subjective and objective measures of sleep quality, over-sedation was a concerning side-effect, especially with carbamazepine.1 A common misconception is that quinine is effective in managing symptoms of restless legs syndrome. While there has been at least one case report of its use in one person with this condition,9 its value has never been shown in any placebo-controlled or open label trials. Quinine has been found useful in the management of leg cramps which is very different from RLS. Leg cramps are an involuntary, painful contraction of muscles in the legs (usually the calf) that is believed to be caused by an over-excitation of motor neurons in the legs or spine.10 The Bottom Line Restless legs syndrome is a common condition that adversely affects patients sleep and sleep-related quality of life. The pathology is either idiopathic or secondary to a number of other medical conditions. The identification of the syndrome as well as any factors that may be causing or worsening the condition is key to appropriate management. Pharmacotherapeutic management is often required, with new dopamine agonists being the preferred therapy. References 1. Schapira AH. Restless Legs Syndrome: An Update on Treatment Options. Drugs 2004; 64(2): 149-158. 2. Tarsy D, Sheon RP. Restless Leg Syndrome. UpToDate Online 12.1. www.uptodate.com, Accessed 5/4/2004. 3. Kavanaugh D, Siddiqui S, et al. Restless Legs Syndrome in Patients on Dialysis. American Journal of Kidney Diseases 2004;

43(5): 763-771. 4. Restless Leg Syndrome � Drugs of Choice. Micromedex Healthcare Series. www.micromedex.com, Accessed 5/4/2004. 5. Collado-Seidel V, Kazenwadel J, et al. A controlled study of additional sr-L-dopa in L-dopa-responsive restless legs syndrome with

late-night symptoms. Neurology 1999; 52(2): 285-290. 6. Trenkwalder C, Seidel VC, et al. One-year Treatment with Standard and Sustained-Release Levodopa: Appropriate Long Term

Treatment of Restless Legs Syndrome? Movement Disorders 2003; 18(10): 1184-1189. 7. Trenkwalder C, Garcia-Borreguero D, et al. Ropinirole in the treatment of restless legs syndrome: results from the TREAT RLS 1

study, a 12 week, randomised, placebo controlled study in 10 European countries. Journal Neurology, Neurosurgery and Psychiatry 2004; 75: 92-97.

8. Ray WA, Griffin MR, et al. Benzodiazepines of Long and Short Elimination Half-life and the Risk of Hip Fractures. JAMA 1989; 262(3): 3303-3307.

9. Snyder S. Restless Legs Syndrome Treated with Quinine Sulfate. Journal of Psychiatric Treatment and Evaluation 1983; 5: 385-6. 10. Riley JD, Anthony SJ. Leg Cramps: Differential Diagnosis and Management. American Family Physician 1995; 52(6):1794-1798.

Appendix 1

Drugs Used in the Management of Restless Legs Syndrome┼

Drug Initial Dose

Recommended Maximum Dose

Common Side Effects

Dopamine Analogues

Levodopa (+ carbidopa or benserazide)

50 mg 400mg, in divided doses*

Nausea/vomiting, orthostatic hypotension, hallucinations, augmentation of symptoms, insomnia

Dopamine Agonists

Pergolide 0.025mg 0.5mg, in 2-3 divided doses**

Same as levodopa plus nasal congestion and fluid retention. Health Canada Advisory: sudden onset of sleep, �sleep attacks�***

Pramipexole 0.125mg 1.5mg, in 2-3 divided doses**

Same as pergolide without sudden onset of sleep

Ropinirole 0.25mg 3 mg, in 2-3 divided doses**

Same as pergolide without sudden onset of sleep

Other Options

Clonazepam 0.25mg 2mg, at bedtime Tolerance, over-sedation

Diazepam 2 mg 10mg, at bedtime Same as clonazepam

Gabapentin 300mg 3600mg, in 3 divided doses

Sedation, dizziness, fatigue, somnolence, ataxia

Codeine 30mg 180mg, in 2-3 divided doses

Sedation, pruritus, constipation, nausea/vomiting, dry mouth, dependence

Oxycodone 5mg 20-30mg, in 2-3 divided doses

Same as codeine

Oxycodone � extended release

10mg 20-30mg, in 2-3 divided doses

Same as codeine

Methadone 2.5mg 20mg, in 2 divided doses

Same as codeine

┼ Table adapted from: Early, CJ. Restless legs syndrome. NEJM 2003; 348: 2103. * Information from Trenkwalder et al. One-year Treatment with Standard and Sustained-Release Levodopa: Appropriate Long Term Treatment of Restless Legs Syndrome. Movement Disorders 2003; 18(10): 1188. ** Evening dose to be taken at least 2 hours before bedtime *** Health Canada, Advisories for Health Professionals. Important Safety Information Regarding the Antiparkinson Drug Permax®: Sudden Onset of Sleep. February 2004. Written by Kyle MacNair, Clinical Pharmacist, PrISM. Thanks to Cali Orsulak, Clinical Pharmacist, Health Sciences Centre and Shawn Bugden, Executive Director, PrISM for reviewing this newsletter.


Title: Statin Therapy: Decisions and DilemmasOrganization: Prescription Information Services of Manitoba – PrISM (Manitoba)

Summary Descriptive Information This newsletter has 4 pages, 2959 words and is divided into 7 sections. The document uses full colour for its logo and tables. Evaluation Summary Reviewer #1 Reviewer#2#1 Referencing 5 5#2 Peer Review 5 5#3 Systematic Review 3 2#4 Statistics 5 5#5 Price and coverage 4 5#6 Graphics 5 4#7 Key Messages 4 5#8 Sections 1 2#9 Headings 5 5#10 Table Hierarchy 5 3#11 Table Editorial Consistency 4 2#12 Column Width 3 4#13 Readability 4 2#14 Justification 5 4#15 Colour 4 5#16 Main Message 3 4#17 Therapeutic Decision Support 5 5#18 Behaviour Target 4 3#19 Retrieval 2 2#20 Editorial Consistency 5 5


Overall Mean Score 79 Strengths The boxed key messages help to ensure main messages can be obtained relatively quickly. The dosing and pricing information help to support therapeutic decision making. Weaknesses The document has a relatively heavy text base and multiple messages that diffuse the ability to target specific behaviours. The document has more than the optimal five sections.


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Statin Therapy: Decisions and Dilemmas

The Basics Table 1 summarizes the current Canadian Guidelines for target lipid levels.3 Recent trials have suggested potential benefits of higher statin doses and lower lipid targets that may in-fluence future guidelines.4,5 At present, mixed study results and concerns about safety of high-dose therapy limit wide-spread adoption of ag-gressive treatment to lower targets. The degree to which the statins lower choles-terol varies depending on the different agents and dosages. It is important to realize that the different statins can achieve similar cholesterol reductions when given in equivalent doses.6 The “high potency” agents (atorvastatin and ro-suvastatin) only differ from the other statins in the ability of their highest doses to lower choles-terol by 50% or more, an endpoint which may not be needed in all patients. Table 2 provides a comparison between the LDL lowering ability of the various statins available on the Canadian market. LDL cholesterol is a surrogate endpoint so it is important to focus on the evidence for clinical endpoints in a review of statin efficacy. Major cardiac events (normally defined as non-fatal MI or death from coronary heart disease) and over-all mortality were the most commonly used trial endpoints. We have applied meta-analytic tech-niques to determine pooled number-needed-to-treat (NNT) results for a variety of subgroups of interest (Table 3). We will look at statins used in both the primary (patients without established vascular disease) and secondary (patients with established vascular disease) prevention setting as they pertain to 4 specific patient populations: men, women, elderly and diabetic patients.

Introduction In 2004, atorvastatin was the most prescribed drug in Canada and statins are now the 6th most prescribed therapeutic class.1,2 With the amount of healthcare resources spent on reducing cho-lesterol it is not surprising that the market is rife with both information and drug options that practi-tioners must sift through. In this newsletter we attempt to provide some practical tips that clini-cians can apply in their day-to-day practice, highlight some therapeutic controversies related to statin therapy and provide evidence-based realities to assist practitioners in finding the most ap-propriate therapeutic strategies for their patients.

Men The majority of patients in statin trials have been men. Because of this abundance of re-search data, we can make very definitive statements about the benefits of statin therapy in males. Four large randomized controlled trials have documented absolute reductions in all-cause mortality with statins used in secon-dary prevention in men.7,8,9,10 The NNT for reducing mortality is relatively low at 39 (Table 3). In the primary prevention setting, four trials have found that treating men with risk factors for cardiovascular disease can reduce the in-cidence of major cardiac events (the combina-tion of non-fatal MI or fatal coronary heart dis-ease).11,12,13,14 The NNT to prevent one major cardiac event is higher for primary prevention (57) compared to secondary prevention (27).

Table 1: The Canadian Guidelines for the Management of Dyslipidemia3

Key Messages • Statin therapy reduces cardiac death, non-

fatal MI and overall mortality in men with a history of vascular disease.

• For men with risk factors but no history of vascular disease, there is strong evidence that statins reduce cardiac death and non-fatal MI.

10 year risk of CAD

Target Levels

LDL-C HDL-C ratio

High Risk ≥20% <2.5 <4 diabetes, atherosclerosis

Moderate Risk 11-19% <3.5 <5 Low Risk <10% <4.5 <6

Women Large randomized controlled statin trials have tended to enroll far less women than men. The benefits of statins in women are therefore more difficult to evalu-ate. In the secondary prevention setting, four major randomized controlled trials have included women.7,8,9,15 Only 2 of the 4 major trials have shown a significant reduction in CHD death or non-fatal MI. This may be related to the smaller number of women in these trials. Meta-analysis can be used to pool these results and indicates a significant benefit in women with previous atherosclerotic disease with a NNT of 35. These results are consistent with other published meta-analysis.17,21 Neither the individual trials, nor the meta-analysis found any ability of statins to reduce all-cause mortality in women with a history of vascular disease. In the primary prevention setting five randomized con-trolled trials included women without documented ves-sel disease.10,12,13,15,22 However, only two of them pro-vide fully usable data (provided key outcomes data on the women subgroup).12,13 Pooled estimates (CHD death and non-fatal MI) from these two studies did not show a significant benefit (Relative Risk (RR) of 0.85 - 95% CI 0.51 to 1.45). Published meta-analysis that included these trials along with the Heart Protection Study (HPS), female subgroup (many of whom had diabetes and/or existing vascular disease) came to the same conclusion.21 We have insufficient evidence to conclude that statin therapy reduces major coronary events or over-all mortality in women without a previ-ous history of vascular disease.

Key Messages • There is good evidence that statin therapy can re-

duce the incidence of major cardiovascular events in women with a history of vascular disease.

• Statin therapy has not been conclusively proven to reduce incidence of important cardiovascular end-points in women at high risk for their first vascular event.

Elderly (Men and women over 65 years of age)

Five major RCTs have reported on coronary heart disease (CHD) death or non-fatal MI for pa-tients 65 years of age or older (up to 80 yrs) with a history of vascular disease, and two of the trials also documented rates of all-cause mortal-ity.7,8,9,10,15 Approximately 80% of all coronary heart disease deaths occur in people over the age of 65.16 The higher event rates found in eld-erly patients produce larger absolute impacts from cholesterol treatment than in younger indi-viduals. It is, therefore, not surprising that meta-analysis suggests clear benefit of statins in these elderly patients with a very low NNT of 26 for the prevention of major cardiac events and also a low NNT for preventing all-cause mortality (Table 3). Other published meta-analysis concur with these results.17,18

Study of primary prevention in the elderly (> 65) has been limited. Several primary prevention tri-als have included patients >65 but most have not reported the data for this age group separately. The PROSPER trial was the only trial to report primary prevention results for those > 65.15 PROSPER did not show significant reductions in coronary death, MI or stroke in the primary pre-vention elderly population. Primary prevention in elderly patients would benefit from further study, but at present we have insufficient evidence to demonstrate a significant benefit of statins in this patient population. A retrospective cohort study from Ontario of eld-erly patients at high risk of cardiovascular dis-ease (>80% had a history of cardiovascular dis-ease with or without diabetes) looked at statin prescribing.19 The authors found only 19% of pa-tients monitored were prescribed a statin; further, there was an inverse relationship between base-line risk and the likelihood of receiving lipid lower-ing therapy. This paradoxical relationship of un-der-treating high-risk and over-treating low-risk patients is an ineffective use of available re-sources.20

Key Messages • Treatment of high risk (history of vascular dis-

ease) elderly patients is strongly supported with evidence for reduction of important car-diovascular endpoints and over-all mortality.

• Treatment of lower risk elderly patients (no history of vascular disease) has not been con-clusively proven to reduce incidence of impor-tant cardiovascular endpoints.

Diabetes Diabetic patients who also have a history of vascular events are at an extremely high risk of having subse-quent events. In an epidemiological study by Haffner et al. the risk of a future MI in patients with diabetes and previous MI was measured at 45 events/100 pa-tient years.23 Secondary prevention trials that include diabetic patients have demonstrated substantial re-ductions in major cardiovascular events requiring treatment of only 13 patients to prevent one major car-diac event.7,9 Reductions in all-cause mortality have not been found with secondary prevention in diabetics.

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Fluvastatin(mg) Pravastatin(mg) Lovastatin(mg) Simvastatin(mg) Atorvastatin(mg) Rosuvastatin(mg) %LDL ↓ 20 40 80 10 20 40 80 20 40 80∆ 5 10 20 40 80 10 20 40 80 10 20 40 20-25% 26-30% 31-35% 36-40% 41-45% 46-50% 51-55% Cost/mo┼ 31 42 48 31 37 44 85 36 70 137 22 40 49 49 49 61 76 81 81 51 63 72 Saving/mo N/A^ N/A N/A 11 14 N/A N/A 0 N/A N/A 0 14 23 23 N/A 22 34 39 N/A 18 25 N/A

∆Lovastatin 80mg generated by two lovastatin 40mg tablets ┼Cost/month in CAN dollars, assume disp. fee of $9, prescriptions filled quarterly, all prices based on Manitoba Pharmacare Reimbursement Price. ^ Not Applicable, dosage form can not be split or it is the largest dosage form available.

Diabetes (continued) The Canadian Lipid Guidelines recommend that all patients with diabetes be considered High Risk for cardiovascular disease regardless of the presence of other risk factors.3 Based on these recommenda-tions, patients with diabetes would be treated the same if they have had a vascular event or not. Per-sons with diabetes have been included in 3 primary prevention trials.10,13,14 The HPS trial did not report on endpoints of major cardiac events or mortality in the diabetic populations.10 The other trials, CARDS (diabetes and ≥1 other risk factor) and the ASCOT-LLA diabetic subgroup (diabetes, hypertension and ≥2 other risk factors), provide more insight into the potential benefits of therapy in these patients.13,14 Meta-analysis of the results of these trial show a NNT of 64 to prevent one major cardiac event; how-ever the very wide confidence interval (34-588) pro-

Key Messages • Statin therapy can reduce the incidence of ma-

jor cardiovascular events in people with a his-tory of diabetes and vascular disease.

• Statin therapy in diabetics without a history of vascular disease in addition to at least one other risk factor is marginally preventative of major cardiac events.

Written By: Shawn Bugden BSc.Pharm, MSc. Kyle MacNair BSc.Pharm, ACPR Mike Allen MD Reviewed By: Mark Friesen, BSc.Pharm, PharmD David Mymin, MD, MRCP, FRCSC

Summary Statins have been tested in many thousands of patients yet uncertainty remains regarding their effectiveness in some patient groups (women, elderly – without previous vascular disease). It is hoped that this newsletter

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will assist clinicians as they decide when treatment is justified. The expo-nential rise in NNT with lower risk patients is an important consideration. For patients where treatment is clearly justified (secondary prevention) the challenge is to ensure long-term compliance to statin therapy. Since cost can be a barrier in this goal, tablet splitting may be an effective way to limit costs in motivated patients.

Practical Considerations Although the statins are very effective at lowering cholesterol, their relatively high cost can be a barrier to adherence. Statin adherence is a large concern with rates measured at as low as 34% after 1 year of ther-apy.24 One of the most important factors implicated in non-adherence is patient’s out-of-pocket costs for therapy with one study showing a >3-fold drop in adherence for patients with co-payments of ≥$20 vs. <$10 .25 For patients that are cost-conscious dose splitting is a pragmatic option that can save patients’ hun-dreds of dollars per year. Because none of the tablets are scored, patients who wish to split their dose will likely have to use a tablet splitter, available at all retail pharmacies. Included in Table 2 is an estimate of monthly savings that could be achieved by splitting tablets.

vide an indication of the imprecision of these re-sults. Considering that no trial has tested the appli-cation of lipid lowering therapy in patients with dia-betes as a sole cardiovascular risk factor, the treat-ment of all persons with diabetes suggested in the Canadian Lipid Guidelines should be subject to clinical judgement for patients with diabetes as their only risk factor.

Table 2: LDL-C Reduction and Tablet Splitting Cost Savings

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Major Cardiac Events Non-fatal MI, deaths from CHD All Cause Mortality

Primary Prevention1 Drugs and trials NNT for 5 years

(95% CIs) Drugs and trials

NNT for 5 years

(95% CIs)

All men

39 (30-57)

All women

19 (12-40)

People with diabetes3

Major Cardiac Events Non-fatal MI, deaths from CHD All Cause Mortality

Primary Prevention1 Drugs and trials NNT for 5 years

(95% CIs) Drugs and trials

NNT for 5 years

(95% CIs)

All men PravastatinWOSCOPS LovastatinAFCAPS/TexCAPS AtorvastatinASCOT-LLA

57 (44-84)

PravastatinWOSCOPS LovastatinAFCAPS/TexCAPS AtorvastatinASCOT-LLA

All women LovastatinAFCAPS/TexCAPS AtorvastatinASCOT-LLA LovastatinAFCAPS/TexCAPS

Elderly (≥ 65 years) PravastatinPROSPER PravastatinPROSPER

People with diabetes Atorvastatin CARDS, ASCOT-LLA 65 (34-588) AtorvastatinCARDS

Secondary Prevention1

All men PravastatinLIPID, CARE Simvastatin4S, HPS

27 (22-33)

PravastatinLIPID Simvastatin4S, HPS

2 39

(30-57)

All women PravastatinCARE, LIPID4

Simvastatin4S, HPS 35

(25-59) PravastatinLIPID Simvastatin4S

Elderly (≥ 65 years) PravastatinCARE, LIPID, PROSPER Simvastatin4S, HPS

26 (21-34)

Simvastatin4S PravastatinCARE

19 (12-40)

People with diabetes3 PravastatinLIPID4

Simvastatin 4S 13

(8-32) Simvastatin4S

Evidence indicating statistically sig-nificant benefit.

Evidence insufficient to confirm benefit or no benefit because numbers of subjects or events were small.

Table 3: Summary of Outcomes from Statin Studies This table summarizes evidence for efficacy of statins from double-blind RCTs and sub-group analyses of them in the outcomes of major cardiac events and all-cause mortality for different populations.

1. Includes major statin trials for which there are specific data for CHD death and non-fatal MI. Generally these are limited to trials categorized as First Tier by Oregon Evidence-Based Practice Centre (good or fair-to-good quality with primary endpoints of cardio-vascular health outcomes).

2. Values are from overall results since they were 75-85% men and men were not reported separately. 3. HPS not included because it did not report outcomes specifically for non-fatal MI/CHD death or primary/secondary prevention. 4. No statistically significant benefit shown from drug therapy.

References 1. Lipitor Product Monograph. CPS 2004: p 1080-1082. 2. IMS Health Canada. What’s New. www.imshealthcanada.com. Accessed July 21, 2005. 3. Genest J et al. Recommendations for the management of dyslipidemia and the prevention of

cardiovascular disease: 2003 update. CMAJ 2003; 169(9): Online1-10. 4. LaRosa JC et al. Intensive Lipid Lowering with Atorvastatin in Patients with Stable Coro-

nary Disease (TNT). NEJM 2005; 5. Lemos JA et al. Early Intensive vs. A Delayed Conservative Simvastatin Strategy in Pa-

tients with Acute Coronary Syndromes: Phase Z of AtoZ Trial. JAMA 2004; 292:1307-16. 6. Helfand M et al. Drug class review on HMG-CoA reductase inhibitors (statins). Updated

final report #2 (Drug effectiveness review project). Oregon health & science university: Oregon evidence-based practice centre; 2004. www.oregonrx.org.

7. LIPID Study Group. Prevention of Cardiovascular Events and Death with Pravastatin in Patients with Coronary Heart Disease and a Broad Range of Initial Cholesterol Levels. NEJM 1998; 339: 1349-1357.

8. Sacks, F.M. et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. 1996. NEJM 335:1001-1009.

9. Scadinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease. Lancet. 1994. 344:1383-1389.

10. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of choles-terol lowering with simvastatin in 20536 high-risk individuals: a randomised placebo controlled trial. The Lancet 2002; 360: 7-22.

11. Shepard J et al. Prevention of coronary heart disease with pravastatin in men with hypercho-lesterolemia. West of Scotland Prevention Study Group. NEJM 1995; 333(20): 1301-1307.

12. Downs JR et al. Primary Prevention of Acute Coronary Events with Lovastatin in Men and Women with Average Cholesterol Levels. JAMA 1998; 279: 1615-1622.

13. Sever PS et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average to lower-than-average cholesterol concentrations, in the Ango-

Scandinavian Cardiac Outcomes Trial – Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. The Lancet 2003; 361: 1149-1158.

14. Colhoun HM et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Studye (CARDS): multicentre random-ised placebo-controlled trial. Lancet 2004; 364: 685-696.

15. Shepherd J et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. The Lancet 2002; 360: 1623-1630.

16. Dalal D et al. 2002 Management of Hyperlipidemia in the Elderly Population: An Evi-dence-Based Approach. Southern Medical Journal 95:1255-1261.

17. LaRosa JC et al. Effect of Statins on Risk of Coronary Disease: A Meta-analysis of Ran-domized Controlled Trials. JAMA 1999; 282: 2340-2346.

18. Sacks FM et al. 2000. Effect of pravastatin on coronary disease events in subgroups defined by coronary risk factors. The Prospective Pravastatin Pooling Project. Circulation 102:1893-1900.

19. Ko DT et al. Lipid-Lowering Therapy with Statins in High-Risk Elderly Patients: The Treatment-Risk Paradox. JAMA 2004; 291(15): 1864-1870.

20. Manuel DG et al. The 2003 Canadian recommendations for dyslipidemia management: Revisions are needed. CMAJ 2005; 172(8): 1027-1031.

21. Walsh JM et al. Drug Treatment of Hyperlipidemia in Women. JAMA 2004; 291: 2243-52. 22. Major Outcomes in Moderately Hypercholesterolemic, Hypertensive Patients Randomized

to Pravastatin vs Usual Care (ALLHAT-LLT). JAMA 2002; 288: 2998-3007. 23. Haffner SM et al. Mortality from Coronary Heart Disease in Subjects with Type 2 Diabetes

and in Nondiabetic Subject with and Without and Without Prior Myocardial Infarction. NEJM 1998; 339: 229-234.

24. Benner JS et al. Association between short-term effectiveness of statins and long-term adherence to lipid-lowering therapy. Am J Health-Syst Pharm 2005; 62: 1468-1475.

25. Ellis JJ et al. Suboptimal Statin Adherence and Discontinuation in Primary and Secondary Prevention Populations. J Gen Intern Med 2004; 19: 638-645.

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Results are given as approximate numbers needed to treat (NNT) for 5 years and 95% confidence intervals (95% CIs) and are calculated as an estimate from all the studies listed. For ex-ample, if NNT = 25, you would need to treat 25 patients for 5 years to prevent one bad outcome; and if the 95% CIs = 10-40, if the study were repeated 100 times using the same sample size, 95 times out of 100 the true NNT will lie between 10-40.

PrISM does not guarantee that the information is accurate or complete and is not responsible for any errors of omissions or for the result obtained from the use of such information. Use of this informa-tion will imply acknowledgement of this disclaimer and release any responsibility of PrISM or its employees. Readers are encouraged to confirm the information from other sources.

http://www.imshealthcanada.com/�

http://www.oregonrx.org/�


Title: Chronic Atrial FibrillationOrganization: Community Drug Utilization Program (British Columbia)

Summary Descriptive Information This newsletter has 6 pages, 3485 words and is divided into 4 sections. The document uses partial colour for its logo and tables. Evaluation Summary Reviewer #1 Reviewer#2#1 Referencing 5 5#2 Peer Review 5 5#3 Systematic Review 1 2#4 Statistics 4 5#5 Price and coverage 5 5#6 Graphics 3 3#7 Key Messages 4 5#8 Sections 5 5#9 Headings 4 5#10 Table Hierarchy 5 5#11 Table Editorial Consistency 4 5#12 Column Width 5 4#13 Readability 2 4#14 Justification 1 1#15 Colour 4 3#16 Main Message 4 5#17 Therapeutic Decision Support 5 5#18 Behaviour Target 4 4#19 Retrieval 4 5#20 Editorial Consistency 2 4


Overall Mean Score 81 Strengths The document provides comprehensive support for therapeutic decision making in chronic atrial fibrillation. Referencing, peer review and pricing are all evident. Weaknesses The separation of table and text impedes readability, interrupts flow and provides for a heavy text based first section. The full justification of columns also impedes readability.


Title: COPD – Updated Guidelines for PharmacotherapyOrganization: Community Drug Utilization Program (British Columbia)



Overall Mean Score 74 Strengths The document and chart provide comprehensive support for therapeutic decision making in the management of COPD. Referencing, peer review and pricing are all evident. Weaknesses The document presents only limited statistical information. The full justification of columns impedes readability. The behaviour target is not immediately clear.


Title: Statin UpdateOrganization: Community Drug Utilization Program (British Columbia)



Overall Mean Score 77 Strengths The integration of pricing, dosing and clinical information provides a powerful support for therapeutic decision making. Both referencing and peer review are evident. Weaknesses The number of headings and some editorial inconsistency interfere with readability of the document. The full justification of columns is an added impediment to readability. The document would also be improved by better integration of the tabular information and the text.


Title: Management of Dyslipidemia and the Prevention of Cardiovascular DiseaseOrganization: Alberta Drug Utilization Program (Alberta)

Summary Descriptive Information This newsletter has 2 pages, 881 words and is divided into 3 sections. The document uses full colour for its logos and figures. Evaluation Summary Reviewer #1 Reviewer#2#1 Referencing 1 1#2 Peer Review 1 1#3 Systematic Review 1 2#4 Statistics 2 1#5 Price and coverage 1 1#6 Graphics 5 5#7 Key Messages 1 2#8 Sections 5 5#9 Headings 5 5#10 Table Hierarchy 5 5#11 Table Editorial Consistency 3 3#12 Column Width 2 1#13 Readability 3 5#14 Justification 5 5#15 Colour 4 4#16 Main Message 3 3#17 Therapeutic Decision Support 4 5#18 Behaviour Target 3 3#19 Retrieval 2 2#20 Editorial Consistency 4 4


Overall Mean Score 62 Strengths The document provides very good support for risk assessment and drug choices in dyslipidemia. Weaknesses This is not a traditional newsletter and its scoring reflects this alternate purpose. The lack of multiple referencing and peer review are evident. The column width exceed the defined optimum. The provision of pricing information would have enhanced decision support.

MONITORING

• Lipid Levels- It is generally recommended that lipid levels be rechecked 4 - 6 weeks after the commencement of therapy.- Treatment goal reached: recheck lipid profile every 6 - 12 months depending on the risk profile of the patient.- Treatment goal not reached: recheck lipid profile 4 - 6 weeks after each dosage change.

• CK and ALT- Baseline CK and ALT levels (prior to initiating drug therapy) should be obtained.- It is generally recommended that CK and ALT levels be rechecked 4 to 6 weeks after the commencement

of therapy.- After 6 weeks, routine monitoring of CK and ALT may not be required in patients receiving statin therapy.- Patients with unexplained symptoms of weakness, muscle aches, and soreness should have statin therapy

stopped and prompt laboratory investigation of CK and ALT.- With a CK level between 5 - 10 times the upper limit of normal (ULN), clinical judgement should dictate

whether to continue therapy or not. If CK is elevated greater than 10 times ULN in a symptomatic patientthen the drug should be discontinued.

- For patients receiving a statin with an interacting medication it may be prudent to monitor CK every 6 monthsdue to the increased risk of myopathy.

- Inform patients of possible side-effects of medications (e.g., myalgia with statins) and when to contactprescribing doctor.

TREATMENT• Diet: An important focus should be on decreasing energy consumption, in particular by reducing intake of refined

carbohydratesand sugar to achieve and maintain a body mass index of less than 25 kg/m2.

• Exercise: Recommend at least 30 minutes of physical activity (such as walking) per day, most days of the week.

• Medication:- In people at high risk of coronary artery disease, treatment should be started immediately, concomitant with

diet and therapeutic lifestyle changes.- For patients at low and moderate risk, pharmacological treatment should be initiated if target lipid levels

(Table 1) are not met after 3 and 6 months respectively, of lifestyle therapy.

Lipid Lowering Medications:Relative Lipid Lowering Effects

Drug

StatinsResinsEzetimibeFibratesNiacin

LDL-C

↓18-55%↓15-30%↓17%↓5-20%↓5-25%

HDL-C

↑5-15%↑3-5%↑1.3%↑10-35%↑15-35%

Triglycerides

↓7-30%No change or increase↓ 6%↓20-50%↓20-50%

Lipid Profile

↑↑ LDL↑↑ LDL, ↑ TG↑ LDL, ↓ HDL↑ LDL, ↑↑ TG↓ HDL, ↑ TG

2nd Choice

Resin or ezetimibeFibrate or niacinCombination therapyCombination therapyCombination therapy

1st Choice

StatinStatinFibrate or statinFibrate or niacinFibrate or niacin

Drugs of Choice for Management

Approximate Equivalent Doses Based on LDL-C Lowering EffectAtorvastatin

5 mg

Fluvastatin

40 mg

Lovastatin

20 mg

Pravastatin

20 mg

Rosuvastatin

2.5 mg

Simvastatin

10 mg

ASSESSING RISK AND SCREENING

• A patient’s 10-year risk of coronary artery disease can be estimated using the model provided in the 2003 guidelines(and also found at http://www.topalbertadoctors.org/guidelines/guidelinespdf.aspx). The three categories of risk andcorresponding target lipid levels are outlined in Table 1.

• Routinely screen men over age 40 and women who are postmenopausal or over age 50.Note: Although there are no evidence-based recommendations regarding the optimal frequency forscreening, it is reasonable to suggest asymptomatic patients with previously normal lipids be screenedevery 5 years after age 40 (men) or 50 (women).

• Screen those with diabetes mellitus; risk factors such as hypertension, smoking or abdominal obesity; a strongfamily history of premature cardiovascular disease; manifestations of hyperlipidemia; or evidence of symptomaticor asymptomatic atherosclerosis.

• Patients of any age may be screened at the discretion of the physician, particularly when lifestyle changes areindicated.

TARGET LEVELLDL-C level

mmol/LTotal cholesterol

HDL-C ratio

RISK CATEGORY

High(10 year risk of coronaryartery disease ≥ 20%, orhistory of diabetes mellitus;any atherosclerotic diseaseincluding CAD, PAD, CVD;chronic kidney disease orthose undergoing long termdialysis)

Moderate(10 year risk 11% - 19%)

Low*(10 year risk ≤ 10%)

<2.5 and

<3.5 and

<4.5 and

<4.0

<5.0

<6.0

Table 1Risk Categories and Target Lipid Levels

Table 2Clinical Identification of the

Metabolic Syndrome*

Risk factor Defining levelAbdominal obesity

Men

Women

Triglyceride level

HDL-C levelMenWomen

Blood pressure

Fasting glucose level

Waist circumference > 102cm (40in)

Waist circumference > 88cm (35in)

≥ 1.7 mmol/L

< 1.0 mmol/L < 1.3 mmol/L

≥ 130/85 mm Hg

6.2 - 7.0 mmol/L

* In the very low risk stratum, treatment may be deferred if the10-year estimate of cardiovascular disease is <5% and the LDL-C is<5.0 mmol/L.Apolipoprotein B can be used as an alternative measurement,particularly for follow-up of patients treated with statins. Anoptimal level of Apo-B in a patient at high risk is <0.9 g/L,moderate risk <1.05 g/L and low risk <1.2 g/L.

* Criteria: 3 or more of the risk factors. If metabolic syndrome isdiagnosed, consider increasing calculated risk by one category

MANAGEMENT OF DYSLIPIDEMIA AND THE PREVENTIONOF CARDIOVASCULAR DISEASE

Summary of the “Recommendations for the management of dyslipidemia and the prevention of cardiovascular disease: 2003 update.”

• The clustering of cardiovascular risk factors is recognized asbeing an important health issue.

• The metabolic syndrome is defined in qualitative terms andencompasses abdominal obesity, insulin resistance, elevatedplasma triglyceride levels, low HDL-C levels and high bloodpressure.

For complete guideline: http://www.cmaj.ca/cgi/reprint/169/9/921References available upon request.

www.topalbertadoctors.org

AlbertaDrugUtilizationProgram


Title: Anti-Infective Drug Utilization Review in Alberta – Respiratory Track InfectionsOrganization: Alberta Drug Utilization Program (Alberta)

Summary Descriptive Information This newsletter has 6 pages, 2296 words and is divided into 8 sections. The document uses full colour for its logos, figures, graphics and text boxes. Evaluation Summary Reviewer #1 Reviewer#2#1 Referencing 5 5#2 Peer Review 1 1#3 Systematic Review 1 2#4 Statistics 5 5#5 Price and coverage 3 2#6 Graphics 5 5#7 Key Messages 3 3#8 Sections 1 1#9 Headings 4 5#10 Table Hierarchy 5 5#11 Table Editorial Consistency 3 3#12 Column Width 2 3#13 Readability 4 4#14 Justification 3 1#15 Colour 5 4#16 Main Message 2 2#17 Therapeutic Decision Support 5 4#18 Behaviour Target 2 2#19 Retrieval 5 5#20 Editorial Consistency 2 3


Overall Mean Score 66 Strengths This document provides a comprehensive review of Alberta practice compared with guideline recommendations in the management of CAP. The document has chunked text and figures to produce a readable framework. Retrieval information has been made available. Weaknesses This document is not a traditional newsletter and its scoring reflects this alternate purpose. The number of section in the document exceeds our defined optimum of five. Splitting information on an indication between pages also challenges readability. There are some editorial differences between chart format in different sections of the document.

ALBERTA DRUG UTILIZATION PROGRAM REPORT Volume 4, No. 1 Alberta Management Committee on Drug Utilization January 2004

Anti-Infective Drug Utilization Review in Alberta - Respiratory Tract Infections

The purpose of the review was to examine anti-infective drug utilization according to the standards set in the Alberta Clinical Practice Guidelines (CPGs) Program. As respiratory tract infections (RTIs) account for 75% of all antibiotic prescriptions (4), RTIs selected for the study were acute pharyngitis, acute otitis media, sinusitis, bronchitis and community acquired pneumonia. This newsletter will focus on three of the RTIs: acute otitis media, acute pharyngitis and community acquired pneumonia. Objectives The specific objectives of the DUR were to quantify the extent that:

“Appropriate” oral antibiotics (i.e. selection of drug of choice according to CPGs) were prescribed for selected RTIs;

Physicians collected a throat swab where the diagnosis was acute pharyngitis;

Differences in selected variables, such as specialty, impacted the prescribing of antibiotics for treatment of selected RTIs.

Methods This drug utilization review (DUR) was done retrospectively using administrative claims databases as data sources. The study was limited to the population with drug benefits covered by Alberta Health & Wellness (AHW) who received outpatient antibiotic prescriptions between October 1st and March 31st of three consecutive years: 1997-1998, 1998-1999, and 1999-2000. Beneficiaries from three AHW government sponsored Alberta Blue Cross (ABC) plans include seniors, widows/widowers and non-group individuals. These programs provide prescription drug benefits to approximately 450,000 Albertans.

Anonymous patient data with appropriate ICD9 diagnoses were extracted from physician billing claims (AHCIP database) and matched to prescription claims for anti-infective agents (ABC drug database). DUR subjects (matched cases) were identified by having the same patient identification and date of ABC anti-infective prescription claim within 7 days of the physician visit. Matched cases were reviewed to determine use of first and second line agents, and “other” agents that are not appropriate for the indication. Expert user groups assisted in developing research protocols for the study as well as in analyzing data, reviewing reports and formulating recommendations. Criteria for Determining Adherence to Guidelines Criteria for determining adherence to guidelines were selected from standards recommended by the Alberta CPGs (http://www.albertadoctors.org) and are summarized in Table 1 (5-11). It is important to note that the study period (1997-2000) was before the distribution of all the CPGs, except acute pharyngitis (fall 1999), to physicians and pharmacists in the province.

AlbertaDrugUtilizationProgram

“Antibiotic use in RTIs that have a significant viral etiology needs to be reduced.”

“Acute Otitis Media had the best guideline adherence for first line agent use.”

Over the three-year period, with respect to guideline adherence to first line anti-infective use, Acute Otitis Media had the best result (64%) followed by Community Acquired Pneumonia (50%), Acute Pharyngitis (36%), Acute Sinusitis (31%), Acute Exacerbation of Chronic Bronchitis (25%) and Chronic Sinusitis (13%).

Antibiotic use in RTIs that have a significant viral etiology (e.g. acute bronchitis, acute pharyngitis) needs to

be reduced.

The inappropriate use of broad-spectrum macrolides (azithromycin, clarithromycin), and quinolones (ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin), and some cephalosporins in the various RTIs studied needs to be reduced.

In most of the RTIs studied, anti-infective agents were prescribed by general practitioners (> 80%).

Media*

Over the three- year period, prescribing of first line anti-infective agents for all age groups (1 month-19 years old) was 64% (69% in children < 5 yrs old), the highest adherence rates to CPGs of the five RTIs studied.

Amoxicillin was the most common first line agent used (72%-80%).

The use of second line agents for initial cases increased from 7% to 17% with clarithromycin being the most

common second line agent during the study period.

The use of other antibiotics considered inappropriate for AOM (e.g. cephalosporins and erythromycin) decreased slightly during the study period from 29% to 20%.

The rate of first line agent use by general practitioners (GPs), who prescribed over 90% of the prescriptions,

stayed relatively constant (62-65%) while the rate for pediatricians consistently improved (70-80%). Percentage Breakdown of Agents Prescribed

in Acute Otitis Media

0%20%40%60%80%

100%

1997 -98

1998-99

1999-00

Year (Oct 1 - Mar 31)

Perc

ent Other Agents

Second LineAgents

First Line Agents

Anti-Infective DUR in RTIs/ Key Findings

Acute Otitis Media Antibiotic Use in Acute Otitis Media

Percentage Breakdow n of Firs t Line Agents for Treatm ent of Acute Otitis M edia

(Oct 1, 1999 - M ar 31, 2000)

15%

3%

1%

80%

Amoxicillin

TMP-SMX

Erythromycin-sulf isoxazole

Pivampicillin

*Percentage does not equal 100% due to rounding.

Prescribing of first line anti-infective agents over the three-year period for all age groups (4-35 years old) was low at 25%, or 36% when amoxicillin was allowed

as a first line agent for children < 10 years old.

Penicillin V was the most common first line agent prescribed and its use increased from 54-56% to 66% over the study period.

Cefaclor, cephalexin, and clarithromycin were the most frequently used “other” agents.

TMP-SMX, which has no activity against Group A Strep, was prescribed for 2% to 4% of cases during the

study period.

From October 1st 1999 to March 31st 2000, a throat swab was done in only 24.2% of cases diagnosed as acute pharyngitis; 44% of these were positive for Group A Strep.

Over the three- year period, prescribing of first line agents for all age groups (1 month and older with > 99% of matched cases aged > 17 years) was 50%, the second best rate of the five RTIs studied.

Macrolides were the most common first line agents used (92%-97%).

The use of second line agents for initial cases increased from 20% to 30%.

Acute Pharyngitis Antibiotic Use in Acute Pharyngitis

Community Acquired Pneumonia Antibiotic Use in Outpatient Community

Acquired Pneumonia

Percentage Breakdown of Agents Prescribed in Acute Pharyngitis

0

20

40

60

80

100

1997-98 1998-99 1999-00


Perc

ent Other Agents

First Line Agents

Percentage Breakdown of First Line Agents for Treatment of Acute Pharyngitis

(Oct 1, 1999 - Mar 31, 2000)

66%

28%

6%

Penicillin V

Erythromycin

Clindamycin

There was a low use of second line agents (20% - 26%) for repeat cases of CAP.

The use of antibiotics considered inappropriate for CAP (e.g. other agents) decreased from 33% to 19% during

the study period.

In their daily practice, clinicians can play an important role to support the appropriate use of antibiotics and control the development of antibiotic resistance by:

becoming familiar with the antibiotic therapy recommendations for RTIs through various sources such as Alberta CPG Program, Bugs & Drugs Antimicrobial Pocket Reference 2001, CAP Pathway, National Information Program on Antibiotics (NIPA), Canadian Committee on Antibiotic Resistance (CCAR), Canadian Bacterial Surveillance Network (CBSN), and Alliance for the Prudent Use of Antibiotics (APUA). Further details and links are available on the ADUP website (www.ualberta.ca/~adup);

displaying various posters in patient care areas, distributing patient leaflets on RTIs and talking to patients

about the three key messages provided in the Do Bugs Need Drugs? project;

participating in various educational programs (e.g. continuing medical education sessions, academic detailing visits) and discussions with peers;

participating in various research projects and finding new approaches to implement the findings in

practice in order to improve patient outcomes.

More information To receive further information or a copy of the full report entitled Anti-Infective Drug Utilization Review in Respiratory Tract Infections contact ADUP at (780) 492-0110 or email [email protected].

Percentage Breakdown of First Line Agents for Treatment of CAP

(Oct 1, 1999 - Mar 31, 2000)

66%7%

24%

3%

Clarithromycin

Erythromycin

Azithromycin

Doxycycline

What can you do, as a clinician, to improve the appropriate use of antibiotics?

Percentage Breakdow n of Agents Prescribed in CAP

0%

20%

40%

60%

80%

100%

1997-98

1998-99

1999-00


Perc

ent

Other Agents

Second LineAgents

First Line Agents

Table 1. Drug treatment of respiratory tract infections (RTIs) according to the Alberta Clinical Practice Guidelines (CPGs) (5-11)

RTI/ CPG (Date of

Publication)

First Line Agents

Second Line Agents

Comments

Acute pharyngitis (July 1999)

Viral: No antibiotics recommended Group A Strep: ▪Penicillin V ▪Amoxicillin (<10 years old*) B-lactam allergy: ▪Clindamycin ▪Erythromycin

None recommended

Up to 85% of patients with acute pharyngitis do not have Group A Streptococcal (Strep) pharyngitis. Antibiotics are not recommended unless 2 or more symptoms are present,a throat swab for culture is done, and is found positive. * Due to palatability issues with penicillin suspension, for the DUR assume amoxicillin is also an acceptable first line agent in <10 years olds.

Acute Otitis Media (AOM) in Children (Feb. 2000/ Reviewed Nov. 2001)

▪Amoxicillin B-lactam allergy: ▪Erythromycin-sulfisoxazole ▪TMP/SMX

▪Amoxicillin-clavulanate +/- amoxicillin ▪Cefuroxime axetil B-lactam allergy: ▪Erythromycin-sulfisoxazole ▪Azithromycin ▪Clarithromycin

Children less than 24 months: Treat with antibiotics. Children aged 2 years or older: Most cases of AOM resolve with symptomatic treatment alone and do not require antibiotics. If symptoms worsen, or fail to respond to symptomatic treatment with systemic analgesics after 48-72 hours, treat with antibiotics.

Acute Sinusitis (Dec. 2000)

▪Amoxicillin B-lactam allergy: ▪Erythromycin-sulfisoxazole ▪TMP/SMX

▪Amoxicillin-clavulanate +/- amoxicillin ▪Cefuroxime axetil B-lactam allergy: ▪Erythromycin-sulfisoxazole ▪Azithromycin ▪Clarithromycin Adults only ▪Levofloxacin ▪Gatifloxacin† ▪Moxifloxacin†

Studies indicate that up to 60% of cases will resolve spontaneously without antibiotics.

Chronic Sinusitis (Dec. 2000)

▪Amoxicillin-clavulanate ▪Clindamycin

Acute Bronchitis (Dec. 2000)

Almost exclusively viral: No antibiotics recommended‡

‡ Up to 80-90% of all cases of acute bronchitis are viral (12-13). Meta-analyses have shown no benefit of antibiotics in patients with acute bronchitis (14).

Acute Exacerbation of Chronic Bronchitis (Dec. 2000)

▪Amoxicillin B-lactam allergy: ▪Doxycycline ▪Tetracycline ▪TMP/SMX

▪Amoxicillin-clavulanate ▪Cefuroxime axetil B-lactam allergy: ▪Azithromycin ▪Clarithromycin

Because of their broad spectrum & potential for increasing resistance in S. pneumoniae, quinolones should be reserved for patients who have failed recent antibiotic therapy or with advanced lung disease & severe AECB. Ciprofloxacin should be reserved for Pseudomonas infections only.

Community Acquired Pneumonia (CAP)/ Outpatient: Adults (16 yrs and over) (Feb. 2002)

▪Azithromycin ▪Clarithromycin ▪Erythromycin ▪Doxycycline ▪Tetracycline

▪Levofloxacin§ ▪Gatifloxacin†§ ▪Moxifloxacin†§ ▪Cefuroxime axetil + macrolide

§ Because of their broad spectrum & potential for increasing resistance in S. pneumoniae, quinolones should be reserved for patients who have failed recent antibiotic therapy or are elderly and with significant comorbidities.

Community Acquired Pneumonia (CAP)/ Outpatient: Pediatric (Jan. 2002)

3 months - 5 yrs: ▪Amoxicillin B-lactam allergy: ▪Azithromycin ▪Clarithromycin 5-16 years old: ▪Azithromycin ▪Clarithromycin ▪Erythromycin

Previous β-lactam and macrolide therapy are risk factors for penicillin resistant S. pneumoniae.

† Not listed in the AHWDBL at the time of the study.

Limitations: Various limitations apply to a retrospective DUR using administrative databases as data sources. This DUR only includes those antibiotics covered by ABC as listed on the AHWDBL during the time periods of the study. A major limitation of this study was the inability to accurately and completely match the AHCIP practitioner payment data and the ABC drug data resulting in a significant loss of evaluable data. Another limitation is the accuracy of ICD9 coding by physicians or other office personnel. Except for the throat swab for culture, other relevant information like chest x-ray findings, comorbidities, dosage or duration of antibiotic therapy, adverse reactions or allergy to one of the first line agents, could not be evaluated in the present study. An adequate antibiotic-free period before the antibiotic treated episode analysis would also be important to consider in future studies. Acknowledgments: The AMCDU wants to acknowledge the Anti-Infective DUR Advisory Committee members and the Protocol Committee for their scientific and clinical expertise throughout the realization of this study. DUR Advisory Panel: Ms. Diane Blais Dr. Anita Carrie Ms. Susan Fryters Dr. Tajdin Jadavji

Ms. Jodi Kluchky Dr. Harold Lopatka Ms. Sharon Mitchell

References: 1. Alberta Management Committee on Drug Utilization. Alberta Drug

Utilization Program Report. 2000;2(2):1-2. 2. Canadian Committee on Antibiotic Resistance (CCAR). Optimal

Antibiotic Use [online] 2000. Available from: URL:http://www.ccar-ccra.org (Accessed 13 December 2002).

3. Arnold SR, Evans M, Straus SE. Interventions to improve antibiotic prescribing practices in ambulatory care (Protocol for a Cochrane Review). In: The Cochrane Library, Issue 3, 2002. Oxford: Updated Software.

4. McCaig LF, Hughes JM. Trends in antimicrobial drug prescribing among office-based physicians in the United States. JAMA 1995;273:214-9.

5. The Alberta Clinical Practice Guidelines Program. Guideline for The Diagnosis and Treatment of Acute Pharyngitis. Edmonton, AB: Alberta Medical Association (AMA);1999(Jul):1-6.

6. The Alberta Clinical Practice Guidelines Program. Guideline for The Diagnosis and Treatment of Acute Otitis Media in Children. Edmonton, AB: AMA;2000(Feb), Rev.2001(Nov):1-10.

7. The Alberta Clinical Practice Guidelines Program. Guideline for The Diagnosis and Management of Acute Bacterial Sinusitis. Edmonton, AB: AMA;2000(Dec):1-15.

8. The Alberta Clinical Practice Guidelines Program. Guideline for The Management of Acute Bronchitis. Edmonton, AB: AMA;2000(Dec):1-6.

9. The Alberta Clinical Practice Guidelines Program. Guideline for The Management of Acute Exacerbation of Chronic Bronchitis (AECB). Edmonton, AB: AMA;2000 (Dec):1-7.

10. The Alberta Clinical Practice Guidelines Program. Guideline for The Diagnosis and Management of Community Acquired Pneumonia: Pediatric. Edmonton, AB: AMA;2002(Jan):1-11.

11. The Alberta Clinical Practice Guidelines Program. Guideline for The Diagnosis and Management of Community Acquired Pneumonia: Adult. Edmonton, AB: AMA; 2002(Feb):1-15.

12. Gonzales R, Malone DC, Maselli JH, et al. Excessive antibiotic use for acute respiratory infections in the United States. Clin Infect Dis 2001;33:757-62.

13. Boldy D, Skidmore S, Ayres J. Acute bronchitis in the community: clinical features, infective factors, changes in pulmonary function and bronchial reactivity to histamine. Respiratory Medicine 1990;84:377-85.

14. Smucny JJ, Becker LA, Glazier RH, et al. Are antibiotics effective treatment for acute bronchitis? A meta-analysis. J Fam Pract1998;47:453-60.

15. Bonertz L. Choosing the Right Antibacterial. Pharmacy Practice 2002;18(9):1-8.

16. Alberta Management Committee on Drug Utilization. Anti-Infective Utilization Review in Respiratory Tract Infections. Technical Report. Edmonton, AB: Alberta Drug Utilization Program 2003.

For questions or further information about the ADUP program or Drug Utilization Review, please contact Harold Lopatka, Program Director, Alberta Drug Utilization Program, University of Alberta, 305

Campus Tower, 8625-112 Street, Edmonton, Alberta T6G 1K8. Bus: (780) 492-0110, Fax: (780) 492-0027, e-mail: [email protected], website: www.ualberta.ca/~adup.

Explain to patients the risks of antibiotic therapy – side effects, drug interactions, allergies and subsequent

risk of antibiotic resistance.

Stress the importance of preventative measures such as smoking cessation,

handwashing, influenza and pneumococcal vaccinations.


Title: Emergency ContraceptionOrganization: Community Drug Utilization Program (British Columbia)

Summary Descriptive Information This newsletter has 3 pages, 1016 words and is divided into 3 sections. The document uses partial colour in its logo and tables. Evaluation Summary Reviewer #1 Reviewer#2#1 Referencing 5 5#2 Peer Review 5 5#3 Systematic Review 1 2#4 Statistics 5 4#5 Price and coverage 5 5#6 Graphics 4 3#7 Key Messages 4 5#8 Sections 5 5#9 Headings 4 5#10 Table Hierarchy 3 5#11 Table Editorial Consistency 3 5#12 Column Width 5 4#13 Readability 4 3#14 Justification 1 1#15 Colour 4 4#16 Main Message 5 5#17 Therapeutic Decision Support 5 5#18 Behaviour Target 4 5#19 Retrieval 4 4#20 Editorial Consistency 4 5


Overall Mean Score 83 Strengths This document provides excellent therapeutic decision making support. Peer review and referencing are obvious. Pricing information is integrated into the document. The document is relatively short and key messages can be obtained quickly. Weaknesses Full justification of column is an impediment to readability. Key messages / Summary might be more visible on first page. The document would benefit from better integration of text and table (i.e. first page is text heavy).


Title: Asthma Treatment – Questions, Tips, Pearls & ComparisonsOrganization: RxFiles (Saskatchewan)

Summary Descriptive Information This newsletter has 2 pages, 3490 words and is divided into 14 sections. The document uses full colour in its logo, headings and highlights. Evaluation Summary Reviewer #1 Reviewer#2#1 Referencing 5 5#2 Peer Review 5 5#3 Systematic Review 2 2#4 Statistics 4 2#5 Price and coverage 4 5#6 Graphics 4 2#7 Key Messages 1 2#8 Sections 1 2#9 Headings 5 5#10 Table Hierarchy 5 5#11 Table Editorial Consistency 5 5#12 Column Width 5 5#13 Readability 2 4#14 Justification 5 5#15 Colour 3 3#16 Main Message 2 2#17 Therapeutic Decision Support 5 4#18 Behaviour Target 3 2#19 Retrieval 4 4#20 Editorial Consistency 3 4


Overall Mean Score 73 Strengths There is a massive amount of information (and words) packed into the 2 page document. Referencing is extensive and full peer review is evident. Weaknesses The nature and purpose of the document (question and answer) challenges the evaluative structure suggested for newsletters. The document is divided into 14 sections far exceeding the optimum of 5. The readability of the document is challenged by the density of information for those not accustomed to the RxFiles format.

Asthma Treatment “Questions, Tips, Pearls & Comparisons”

March 2006

The RxFiles Academic Detailing Program Saskatoon City Hospital

701 Queen Street, Saskatoon, SK S7K 0M7 www.RxFiles.ca

See also: Asthma Drug Chart, Devices & Action Plan.

What is acceptable control of asthma? 1

Asthma is often under-controlled or even unrecognized. Three reasons for poor control are 1) non-compliance, 2) other causes such as hyperventilation, or 3) worsening asthma. Asking questions to assess asthma control is essential. E.g. Does the patient have nocturnal symptoms? How much are they using their PRN reliever? See also Table 1.

Table 1: What constitutes acceptable control of asthma?

PARAMETER FREQUENCY or VALUE Symptoms (dyspnea, cough,

tightness, wheezing, ↑sputum) Day: <4 day/week Night: none

Physical activity Normal Exacerbations Mild, infrequent Absent (work/school) None due to asthma Need for a ß2 agonist (Reliever medication)

<4 doses/week (1 dose/day before exercise is acceptable)

FEV1 or PEF ≥90% of personal best FEV1=forced expiratory volume in 1 second PEF=peak expiratory flow

What is the role of an “action plan”? Comprehensive education programs work, but the role of the written action plan alone is still inconclusive.2,3 Benefits have included reductions in hospital admissions, emergency visits & days off work.4,5 Patients should monitor their symptoms and have action plans for self-management.1,6 (PEF can be an insensitive measure of airway obstruction, effort dependent & less sensitive than symptoms for exacerbations; may be useful in select cases e.g. poor perceivers, occupational asthma, aid to caregiver).7,8

Action plan: What to change with poor control? Increasing the inhaled corticosteroid (ICS) dose is an option, although one should first assess for non-compliance.

In patients who regularly take an ICS, doubling the maintenance dose may not have a beneficial effect on the pattern of the exacerbation.9,10 Some specialists use up to 3-4x the maintenance ICS dose until control is restored.

Alternately consider oral steroids depending on severity of exacerbation or failure to respond to more intensive controller therapy given for at least a few days.1,11,12,13

Tapering is not required for short term steroids. Prednisone: Adults 30-60mg po od x 7-10day; Kids 1-2mg/kg/d x 3-5day; Max 50mg.

Viral exacerbations often respond poorly to steroids.

Do inhaled steroids affect growth? ICS do not appear to have a long term affect on total height but may decrease short term growth rate. 14,15,16,17,18,19 {Observational data: budesonide 400ug/d x 9.2years kids attained normal adult height20. A longer term randomized control trial found a ~1cm decrease in growth mainly in the 1st year 21 Camp 4.3yr}.

ICS: Use regularly in mild persistent asthma? Yes. ICS (eg. budesonide Pulmicort, fluticasone Flovent, beclomethasone QVAR) are the most effective therapy.22, 23 Long acting ß2 agonists (LABAs) should not be a substitute for ICS.

However, for those unable or unwilling to take ICS, leukotriene receptor antagonists (LTRAs eg. montelukast Singulair) appear reasonable.24 One preliminary trial has evaluated the effect of intermittent ICS in mild persistent asthma. Intermittent therapy with ICS, appeared as effective as continuous therapy with budesonide or zafirlukast Accolate (but worse inflammatory markers).25 Impact However, patients had a clear action plan when breathless. {Recent SK data found that 37% of the poorly controlled asthmatics did NOT fill an ICS prescription26}. ICS: Are they safe in pregnancy? Yes. Failure to control asthma during pregnancy may lead to poor outcomes.27 Control with ICS or even systemic steroids may be required. Prospective ICS cohorts & trials managed by NAEPP guidelines have shown no evidence of increased maternal or fetal morbidity or mortality, especially with budesonide.28,29 A recent review found viral illness and ICS nonadherance led to 6% of all pregnant asthma patients requiring hospitalization for asthma.30 Is monotherapy with salmeterol reasonable? No. A US study SMART n=26,355 28weeks comparing salmeterol Serevent or placebo added to usual asthma therapy, showed no primary difference for respiratory-related deaths or life-threatening experiences, but more asthma-related deaths and other serious respiratory-related outcomes with salmeterol. {Post hoc analysis: ↑risk in patients who did not report using ICS at study entry and in African-American’s.} Data for formoterol generally does not suggest ↑risk,31,32 but the FDA Advisory Committee could not exclude that the risk may apply to all long-acting ß2 agonists including the faster acting formoterol Oxeze.33 Which is better: increasing the corticosteroid dose or adding a LABA or a LTRA? Adding a LABA is often preferred.34 In asthmatic adults poorly controlled on low dose ICS, the addition of LABA is superior to LTRA for preventing exacerbations requiring systemic steroids, and for improving lung function, symptoms, and use of rescue ß2-agonists.35,36,37,38 In adults with chronic asthma, using moderate to high maintenance doses of ICS, the addition of LABA may have a ICS-sparing effect.39 ICS: Is high dose necessary? Low maintenance doses of ICS will be adequate for many patients. Some evidence suggests that ICS have a fairly flat dose-response curve (e.g. much of the benefit at doses of 200ug/day fluticasone40 & 400ug/day budesonide41). When initiating ICS therapy, starting with a moderate dose (fluticasone ≤500ug/d; budesonide ≤800ug/d) is equivalent to starting with a high dose and stepping down. Initial moderate ICS doses appear to be more effective than an initial low ICS dose.42,43,44 High dose ICS may be most effective for airway hyper-responsiveness or to reduce dependence on oral steroids. A Cochrane review found no benefit

http://www.rxfiles.ca/acrobat/CHT-AsthmaTx.pdf

http://www.rxfiles.ca/acrobat/AsthmaDevices.pdf

http://www.rxfiles.ca/acrobat/AsthmaActionPlan.pdf

when doubling doses in subjects with stable asthma.45 Novel ways to reduce ICS are being studied.46,47 (eg. nitric oxide)

Combination products: What are their roles? Budesonide/formoterol Symbicort & fluticasone/salmeterol Advair

are recommended for moderate-severe persistent asthma, when moderate dose ICS alone is not controlling symptoms. Combinations may not be beneficial in mild asthma.48,49 Optima Availability of samples may lead to overuse in such patients; however, when add-on therapy necessary, these products may be cost-effective. Company sponsored trials have found:

Symbicort regular and as necessary was better than fixed dose regimens of either Symbicort or budesonide with a PRN short acting β2-agonist (SABA) as reliever.50 Stay, 51 With Advair, control was more rapid and at a lower ICS dose than in the fluticasone only arm.52 Goal In another trial, stable Advair dosing was better than adjustable dose Symbicort but often dosed OD in persistent adult asthma.53 Concept

What herbal options are available for asthma? There is not enough evidence to assess the possible role of herbal medicine or homeopathy in asthma therapy.54,55,56 (ASHMI-

3 herbs?) Popularity aside, there is an urgent need for relevant clinical trials. Some natural products may contain constituents/impurities that exacerbate asthma.

What about concerns about drug cost? ↓Cost: Giving SABA~$20 separately with Pulmicort<$50 minimizes cost; Symbicort$80-100 may be cheaper than Advair$90-150 depending on dose. Combivent $30 & Theophylline ~$25 Uniphyl are options in rare cases. ↑Cost: nebulizers salbutamol $70, Combivent $120; Singulair

$80; Spiriva $80; Xolair

$600/vial ; & although expensive Oxeze $45-60 is usually cheaper than Serevent $70.

Should we be using wet nebulization options? MDI with spacer/holding chambers have been shown to be equivalent to nebulizer therapy 57,58,59,60,61,62. In Nova Scotia 63 & BC 64 restrictions on neb coverage reduced costs without extra GP visits and hospitalizations. The decision of which type of device to choose should be based on the practical considerations of the patient’s performance and preference.65 (At least 1200 patients in Sask.~5% use nebs especially 6-9yr olds HQC-2005 26)

Do kids require lower doses of ICS? No. In very young kids, medication lung deposition is about a tenth of an adult dose.66,67 This reflects an “auto-scaling” of dosage. Nevertheless, strive for the lowest effective dose.

We would like to acknowledge the following contributors and reviewers: Dr. D. Cockcroft (Int Med SHR), C. Bayliff, PharmD (London, ON), D. Turner (RT, PA), Dr. T. Laubscher (FM SHR), Dr. J. Alport (FM), H. Sharpe RN,

MN, CAE (AB), J. Pilla MScPhm (ON), D. Jorgenson PharmD (SHR/HQC), & the RxFiles Advisory Committee. B. Jensen BSP, L. Regier BSP, BA DISCLAIMER: The content of this newsletter represents the research, experience and opinions of the authors and not those of the Board or Administration of Saskatoon Health Region (SHR). Neither the authors nor Saskatoon Health Region nor any other party who has been involved in the preparation or publication of this work warrants or represents that the information contained herein is accurate or complete, and they are not responsible for any errors or omissions or for the result obtained from the use of such information. Any use of the newsletter will imply acknowledgment of this disclaimer and release any responsibility of SHR, its employees, servants or agents. Readers are encouraged to confirm the information contained herein with other sources. Copyright 2006 – RxFiles, Saskatoon Health Region (SHR) www.RxFiles.ca

References 1 a) Lemiere C, et al. Adult Asthma Consensus Guidelines Update 2003. Can Respir J. 2004 May-Jun;11(Suppl A):9A-18A. http://www.pulsus.com/Respir/11_SA/supp_A.pdf ; b) Becker A, et al.; Asthma Guidelines Working Group of the Canadian Network For Asthma Care. Summary of recommendations from the Canadian Asthma Consensus guidelines, 2003. CMAJ. 2005 Sep 13;173(6 Suppl):S3-11.; c) Global Initiative for Asthma (GINA) 2005 update http://www.ginasthma.com; d) Treatment Guidelines: Drugs for Asthma. Medical Letter: May 2005 e) Currie GP, et al. Recent developments in asthma management. BMJ. 2005 Mar 12;330(7491):585-9 f) Mintz M. Asthma update: Part II. Medical management. Am Fam Physician. 2004 Sep 15;70(6):1061-6. g) Joint Task Force on Practice Parameters, American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology and Joint Council of Allergy, Asthma and Immunology. Attaining optimal asthma control: a practice parameter. J Allergy Clin Immunol. 2005 Nov;116(5):S3-11. http://www.jcaai.org/pp/Attaining_Optimal_Asthma_Control.pdf ; h) Health Knowledge Central 1 page Asthma Tool http://www.healthknowledgecentral.org/onepagers/asthma.pdf ) 2 Toelle BG, Ram FS. Written individualised management plans for asthma in children and adults. Cochrane Database Syst Rev. 2004;(2):CD002171. 3 Powell H, Gibson PG. Options for self-management education for adults with asthma. Cochrane Database Syst Rev. 2003;(1):CD004107. 4 Gibson PG, et al. Self-management education and regular practitioner review for adults with asthma. Cochrane Database Syst Rev. 2003;(1):CD001117. 5 Agrawal SK, Singh M, Mathew JL, Malhi P. Efficacy of an individualized written home-management plan in the control of moderate persistent asthma: A randomized, controlled trial. Acta Paediatr. 2005 Dec;94(12):1742-6. 6 Guevara JP, Wolf FM, Grum CM, Clark NM. Effects of educational interventions for self management of asthma in children and adolescents: systematic review and meta-analysis. BMJ. 2003 Jun 14;326(7402):1308-9. 7 Reddel HK, Marks GB, Jenkins CR. When can personal best peak flow be determined for asthma action plans? Thorax. 2004 Nov;59(11):922-4. 8 Wensley D, Silverman M. Peak flow monitoring for guided self-management in childhood asthma: a randomized controlled trial. Am J Respir Crit Care Med. 2004 Sep 15;170(6):606-12. Epub 2004 Jun 7. 9 FitzGerald JM, et al. Canadian Asthma Exacerbation Study Group. Doubling the dose of budesonide vs maintenance treatment in asthma exacerbations. Thorax. 2004Jul;59(7):550-6. 10 Harrison TW, et al. Doubling the dose of inhaled corticosteroid to prevent asthma exacerbations: randomised controlled trial. Lancet. 2004 Jan 24;363(9405):271-5. 11 Gibson PG, Powell H. Written action plans for asthma: an evidence-based review of the key components. Thorax. 2004 Feb;59(2):94-9. 12 Feuillet-Dassonval C, Gagnayre R, Rossignol B, Bidat E, Stheneur C. [Written asthma action plans: a useful tool for self-management] Arch Pediatr. 2005 Dec;12(12):1788-96. Epub 2005 Aug 26. 13 PAACT 2006 Respiratory Guidelines (in press). 14 NAEPP Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma—Update on Selected Topics 2002 http://www.nhlbi.nih.gov/guidelines/asthma/asthmafullrpt.pdf 15 Allen DB, Bronsky EA, LaForce CF, et al. Growth in asthmatic children treated with fluticasone propionate. Fluticasone Propionate Asthma Study Group. J Pediatr. 1998 Mar;132(3 Pt 1):472-7. 16 Gillman SA, et al. One-year trial on safety and normal linear growth with flunisolide HFA in children with asthma. Clin Pediatr (Phila). 2002 Jun;41(5):333-40. 17 Leone FT, Fish JE, Szefler SJ, West SL. Systematic review of the evidence regarding potential complications of inhaled corticosteroid use in asthma: collaboration of American College of Chest Physicians, American Academy of Allergy, Asthma, and Immunology, and American College of Allergy, Asthma, and Immunology. Chest. 2003 Dec;124(6):2329-40. 18 Sharek PJ, Bergman DA. The effect of inhaled steroids on the linear growth of children with asthma: a meta-analysis. Pediatrics. 2000 Jul;106(1):E8. 19 Oregon Evidence-based Practice Center: Drug Class Review on Inhaled Corticosteroids Jan/06 http://www.ohsu.edu/drugeffectiveness/reports/documents/_ICS%20Final%20Report%20Update%201.pdf 20 Agertoft L, Pedersen S. Effect of long-term treatment with inhaled budesonide on

adult height in children (n=211) with asthma. N Engl J Med. 2000 Oct 12;343(15):1064-9.

21 Long-term effects of budesonide (200ug bid) or nedocromil in children (n=1041) with asthma. The Childhood Asthma Management Program Research Group. (CAMP trial) N Engl J Med. 2000 Oct 12;343(15):1054-63.

22 Zeiger RS, et al.; Childhood Asthma Research & Education Network of the National

Heart, Lung, & Blood Institute. Response profiles to fluticasone & montelukast in mild-to-moderate persistent childhood asthma. J Allergy Clin Immunol. 2006 Jan;117(1):45-52.

23 Sin DD, et al.. Pharmacological management to reduce exacerbations in adults with asthma: a systematic review and meta-analysis. JAMA. 2004 Jul 21;292(3):367-76. 24 Ducharme FM. Inhaled glucocorticoids versus leukotriene receptor antagonists as single agent asthma treatment: systematic review of current evidence. BMJ. 2003 Mar 22;326(7390):621. 25Boushey HA, Sorkness CA, King TS, et al, for the National Heart, Lung, and Blood Institute's Asthma Clinical Research Network. IMPACT trial. Daily versus as-needed corticosteroids for mild persistent asthma. N Engl J Med 2005; 352: 1519-528 (Ramey JT, Ledford D. Daily corticosteroids were not better than as-needed corticosteroids in mild persistent asthma. ACP J Club. 2005 Nov-Dec;143(3):60.) 26 Heatlh Quality Council Sep 2005 Breathing Easier: Opportunities to improve the quality of asthma care in Saskatchewan. http://www.hqc.sk.ca 27 Dewyea VA, Nelson MR, Martin BL. Asthma in pregnancy. Allergy Asthma Proc. 2005 Jul-Aug;26(4):323-5. (Poor outcomes: loss of asthma control & increases in maternal morbidity, perinatal mortality, preeclampsia, preterm birth, & low birth weight infants) 28 Silverman M, Sheffer A, Diaz PV, Lindmark B, et al.. START Investigators Group. Outcome of pregnancy (n=319) in a randomized controlled study of patients with asthma exposed to budesonide (~400ug/d). Ann Allergy Asthma Immunol. 2005 Dec;95(6):566-70. 29 Busse, W.W., Managing Asthma During Pregnancy: NAEPP Recommendations for Pharmacologic Treatment--Update 2004 {NAEPP = National Asthma Education & Prevention Program} http://www.nhlbi.nih.gov/health/prof/lung/asthma/astpreg.htm 30 Murphy VE, Clifton VL, Gibson PG. Asthma exacerbations during pregnancy: incidence and association with adverse pregnancy outcomes. Thorax. 2006 Feb;61(2):169-76 31 Wolfe J, Laforce C, Friedman B, et al.. Formoterol, 24ug bid, & Serious Asthma Exacerbations: Similar Rates Compared With Formoterol, 12ug bid, With and Without Extra Doses Taken on Demand, and Placebo. Chest 2006;129:27-38. n=2,085 16wks 32 Formoterol FDA Nov/05 http://www.fda.gov/cder/drug/InfoSheets/HCP/formoterolHCP.htm 33 a) Health Canada Sep/05 Salmeterol: http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/medeff/serevent_2_hpc-cps_e.pdf ; b) Health Canada Salmeterol Aug/03 http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/medeff/serevent_hpc-cps_e.pdf; c) Health Canada Sep/05 Formoterol: http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/oxeze_hpc-cps_e.html d) GlaxoSmithKline Clinical trial registry SLGA5011: http://ctr.gsk.co.uk/Summary/salmeterol/studylist.asp & e) Nelson HS, et al. The salmeterol multicenter asthma research (SMART)trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest. 2006 Jan;129(1):15-26. f) Martinez FD. Safety of long-acting beta-agonists--an urgent need to clear the air. N Engl J Med. 2005 Dec 22;353(25):2637-9. 34 Masoli M, Weatherall M, Holt S, Beasley R. Moderate dose inhaled corticosteroids

plus salmeterol versus higher doses of inhaled corticosteroids in symptomatic asthma. Thorax. 2005 Sep;60(9):730-4. 35 Ram F, Cates C, Long-acting beta2-agonists vs anti-leukotrienes as add-on therapy

to inhaled corticosteroids for chronic asthma. Cochrane Database Syst Rev. 2005 Jan 25;(1):CD003137. (Smith B. Review: adding long-acting beta2-agonists to inhaled corticosteroids reduces asthma exacerbations more than adding antileukotrienes. ACP J Club. 2005 Jul-Aug;143(1):20.) 36 Ni CM, Greenstone I, Danish A, et al. Long-acting beta2-agonists versus placebo in addition to inhaled corticosteroids in children and adults with chronic asthma. Cochrane Database Syst Rev. 2005 Oct 19;(4):CD005535. 37 Currie GP, Lee DK, Srivastava P. Long-acting bronchodilator or leukotriene modifier as add-on therapy to inhaled corticosteroids in persistent asthma? Chest. 2005 Oct;128(4):2954-62. 38 O'Connor RD, Rosenzweig JR, Stanford RH, et al. Asthma-related exacerbations, therapy switching, and therapy discontinuation: a comparison of 3 commonly used controller regimens. Ann Allergy Asthma Immunol. 2005 Dec;95(6):535-40. 39 Gibson P, Powell H, Ducharme F, Gibson P. Long-acting beta2-agonists as an inhaled corticosteroid-sparing agent for chronic asthma in adults and children. Cochrane Database Syst Rev. 2005 Oct 19;(4):CD005076. 40 Masoli M, Weatherall M, Holt S, Beasley R. Clinical dose-response relationship of fluticasone propionate in adults with asthma. Thorax. 2004 Jan;59(1):16-20. 41 Masoli M, Holt S, Weatherall M, Beasley R. Dose-response relationship of inhaled budesonide in adult asthma: a meta-analysis. Eur Respir J. 2004 Apr;23(4):552-8. 42 Adams N, Bestall J, Jones P, et al. Inhaled fluticasone at different doses for chronic asthma in adults & children. Cochrane Database Syst Rev. 2005;20:CD003534. 43 Adams N, Bestall J, Lasserson T, et al. Fluticasone versus placebo for chronic asthma in adults and children. Cochrane Database Syst Rev. 2005;19:CD003135. 44 Powell H, Gibson PG. Initial starting dose of inhaled corticosteroids in adults with asthma: a systematic review. Thorax. 2004 Dec;59(12):1041-5.

45 Powell H, Gibson PG. High dose versus low dose inhaled corticosteroid as initial starting dose for asthma in adults and children. Cochrane Database Syst Rev. 2004;(2):CD004109. 46 Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR. Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med. 2005 May 26;352(21):2163-73. Epub 2005 May 24. 47 Deykin A, Lazarus SC, et al.; Asthma Clinical Research Network, National Heart, Lung, and Blood Institute/NIH. Sputum eosinophil counts predict asthma control after discontinuation of inhaled corticosteroids. J Allergy Clin Immunol. 2005 Apr;115(4):720-7. 48 Overbeek SE, et al. Formoterol added to low-dose budesonide (100ug bid) has no additional antiinflammatory effect in asthmatic patients. Chest. 2005;128(3):1121-7. 49 O'Byrne PM, et al. Low dose inhaled budesonide & formoterol in mild persistent asthma: OPTIMA trial. Am J Respir Crit Care Med. 2001 Oct 15;164(8 Pt 1):1392-7. (Thus, in corticosteroid-free patients, low dose inhaled budesonide alone reduced severe exacerbations and improved asthma control, and in patients already receiving inhaled corticosteroid, adding formoterol was more effective than doubling the corticosteroid dose.) 50 O'Byrne PM, Bisgaard H, Godard PP, et al. Budesonide/formoterol combination therapy as both maintenance and reliever (Adults: 80/4.5ug bid & prn) medication in asthma. Am J Respir Crit Care Med. 2005 Jan 15;171(2):129-36. (STAY trial) 51 Rabe KF, Pizzichini E, Stallberg B, et al. Budesonide/Formoterol in a Single Inhaler for Maintenance and Relief in Mild-to-Moderate Asthma: A Randomized, Double-Blind Trial. Chest. 2006 Feb;129(2):246-56. 52 Bateman ED, et al. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL Study(GOAL).Am J Respir Crit Care Med 2004;170:836-44. (Max Diskus dosages were Advair 50/500ug bid vs Flovent 500ug bid) 53 FitzGerald JM, Boulet LP, Follows RM. The CONCEPT trial: a 1-year, multicenter, randomized,double-blind, double-dummy comparison of a stable dosing regimen of salmeterol/fluticasone propionate (Diskus: 50/250ug bid )with an adjustable maintenance dosing regimen of formoterol/budesonide in adults with persistent asthma. Clin Ther. 2005 Apr;27(4):393-406. 54 McCarney RW, et al. An overview of two Cochrane reviews of complementary

treatments for chronic asthma: acupuncture & homeopathy. Respir Med. 2004 Aug;98(8):687-96. 55 Huntley A, Ernst E. Herbal medicines for asthma: a systematic review. Thorax. 2000 Nov;55(11):925-9. 56 Wen MC, et al.Efficacy & tolerability of anti-asthma herbal medicine intervention in adult patients (n=91 4weeks)with moderate-severe allergic asthma. J Allergy Clin Immunol. 2005 Sep;116(3):517-24. http://www.acupuncturetoday.com/archives2005/dec/12fratkin.html 57 Cates CC, et al. Holding chambers versus nebulisers for beta-agonist treatment of

acute asthma. Cochrane Database Syst Rev. 2003;(3):CD000052. 58 Mandelberg A, Tsehori S, Houri S, Gilad E, Morag B, Priel IE. Is nebulized aerosol treatment necessary in the pediatric emergency department? Chest. 2000 May;117(5):1309-13. 59 Newman KB, Milne S, Hamilton C, Hall K. A comparison of albuterol administered by metered-dose inhaler and spacer with albuterol by nebulizer in adults presenting to an urban emergency department with acute asthma. Chest. 2002 Apr;121(4):1036-41. 60 Castro-Rodriguez JA, et al. Beta-agonists through metered-dose inhaler with valved holding chamber vs nebulizer for acute exacerbation of wheezing/asthma in children <5year of age: a systematic review with meta-analysis. J Pediatr. 2004 Aug;145(2):172-7. 61 Sannier N, Timsit S, Cojocaru B, Leis A, Wille C, Garel D, et al.. [Metered-dose inhaler with spacer vs nebulization for severe and potentially severe acute asthma treatment in the pediatric emergency department.] Arch Pediatr. 2006 Jan 16 62 Vella C, Grech V. Assessment of use of spacer devices for inhaled drug delivery to asthmatic children. Pediatr Allergy Immunol. 2005 May;16(3):258-61. 63 Kephart G, Sketris IS, Bowles SK, Richard ME, et al.. Impact of a criteria-based reimbursement policy on the use of respiratory drugs delivered by nebulizer and health care services utilization in Nova Scotia, Canada. Pharmacotherapy. 2005 Sep;25(9):1248-57. 64 Schneeweiss S, et al. Clinical & economic consequences of a reimbursement restriction of nebulised respiratory therapy in adults: direct comparison of randomised & observational evaluations. BMJ. 2004 Mar 6;328(7439):560. Epub 2004 Feb 24. 65 Dolovich MB, Ahrens RC, Hess DR, et al. Device selection and outcomes of aerosol therapy: evidence-based guidelines: American College of Chest Physicians/American College of Asthma, Allergy, and Immunology. Chest 2005 Jan;127(1):335-71. 66 Tal A, Golan H, Grauer N, et al. Deposition pattern of radiolabeled salbutamol

inhaled from a metered-dose inhaler by means of a spacer with mask in young children with airway obstruction. J Pediatr 1996;128(4):479-84.[ 67 Onhoj J, Thorsson L, Bisgaard H. Lung deposition of inhaled drugs increases with age. Am J Respir Crit Care Med 2000;162(5):1819-22.


Title: Chronic Obstructive Pulmonary DiseaseOrganization: Dalhousie – Academic Detailing Service (Nova Scotia)

Summary Descriptive Information This newsletter has 2 pages, 914 words and is divided into 2 sections. The document is laminated and uses full colour in its table. Evaluation Summary Reviewer #1 Reviewer#2#1 Referencing 4 4#2 Peer Review 1 2#3 Systematic Review 1 2#4 Statistics 1 1#5 Price and coverage 1 1#6 Graphics 5 5#7 Key Messages 2 3#8 Sections 4 5#9 Headings 5 5#10 Table Hierarchy 5 5#11 Table Editorial Consistency 5 4#12 Column Width 2 2#13 Readability 4 4#14 Justification 5 5#15 Colour 5 5#16 Main Message 2 3#17 Therapeutic Decision Support 4 3#18 Behaviour Target 3 3#19 Retrieval 3 2#20 Editorial Consistency 5 5


Overall Mean Score 68 Strengths This document is part of a strong evidence-based review of COPD management evaluating both the literature and the CTS guidelines. Aspects of support for therapeutic decision making are well covered. Weaknesses This document was evaluated as an independent newsletter but it actually forms part of a much larger package. Some of its deficits need to be considered in this context. The inclusion of pricing information related to drug choices would be an asset. There is limited statistical information presented and the behaviour targets are not easy to define.

AAcademic DDetailing SService

CHRONIC OBSTRUCTIVE PULMONARY DISEASE

• Spirometry is the most useful method of diagnosing COPD. Full pulmonary function tests are generally not required.

• Diagnosis of COPD requires both • Post-bronchodilator FEV1 of less than 80% of the predicted normal value, and

• FEV1/FVC ratio of less than 70%.

• In order to establish early diagnosis in individuals at risk of COPD, targeted spirometry is recommended for smokers or ex-smokers 40 years of age and older with • Persistent cough with or without sputum production, or

• Frequent respiratory tract infections, or

• Progressive activity-related shortness of breath.

• The CTS encourages classification of COPD based on the Medical Research Council (MRC) scale for dyspnea and disability assessment. Table 3 shows the CTS and MRC classifications with the approximate relations to lung function. Lung function and symptoms may not always correlate. Expert opinion suggests that symptoms are a better predictor of disease severity.

Table 3: Classification of severity of COPD CTS Stage

MRC Grade*

Symptoms FEV1**

FEV1/FVC

At risk ---- Asymptomatic smoker, exsmoker, or chronic cough/sputum

≥ 80% ≥ 0.7

Mild 2 SOB hurrying on the level or walking up slight hill

60-79%

<0.7

Moderate 3-4 SOB making patient stop after walking 100m or after a few minutes on the level

40-59%

<0.7

Severe 5

SOB making patient unable to leave the house or breathlessness after undressing or chronic respiratory failure or right heart failure

<40% <0.7

* MRC grade 1 = breathless with strenuous exercise ** Post-bronchodilator values

• COPD is largely caused by smoking. Smoking cessation is the single most effective intervention to reduce the risk of developing COPD and the only intervention that has been shown to slow its progress.

Figure 1. Effects of smoking cessation on lung function.

Anthonisen NR, Connett JE, Murray RP. Am J Respir Crit Care Med 2002; 166(5):675-679.

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ben

efit o

f lo

ng-a

ctin

g

bro

nch

odila

tors

ove

r ip

ratr

opiu

m in d

yspnea

or

qual

ity

of

life.

-

The

additio

n o

f ip

ratr

opiu

m t

o t

iotr

opiu

m is

no

t re

com

men

ded

. N

OTE:

Bro

nch

odila

tors

should

not

be

pre

scri

bed

without

inhal

ed c

ort

icost

eroid

s if t

her

e is

a

poss

ibili

ty o

f an

ast

hm

atic

com

ponen

t.

With m

oder

ate

to s

ever

e per

sist

ent

sym

pto

ms

-

Com

bin

ation o

f a

long-a

ctin

g

antich

olin

ergic

an

d a

LABA

Continue

SABA p

rn f

or

imm

edia

te

sym

pto

m r

elie

f

- Level

of

evid

en

ce 3

A

- CTS s

tate

s th

e re

sults

of

ongoin

g s

tudie

s on t

he

effe

ct o

f th

is c

om

bin

ation o

n v

ario

us

hea

lth

outc

om

es a

re n

ot

yet

avai

lable

.

- W

e fo

und n

o s

tudie

s to

support

this

rec

om

men

dation,

confirm

ing it

has

lev

el 3

evi

den

ce.

- Exp

ert

opin

ion s

tate

s th

is s

tep is

gen

eral

ly p

refe

rred

to I

CS.

With s

ever

e sy

mpto

ms

des

pite

use

of

both

a long-a

ctin

g

antich

olin

ergic

and a

LABA

- A long-a

ctin

g o

ral th

eophyl

line

Monitor

theo

phyl

line

blo

od lev

els

for

adve

rse

effe

cts

and d

rug inte

ract

ions

- Level

of

evid

en

ce 3

B

- W

e did

not

revi

ew t

hes

e ag

ents

. -

Exp

ert

opin

ion s

ugges

ts t

hat

risk

s m

ay e

xcee

d b

enef

it.

With m

oder

ate

to s

ever

e CO

PD

w

ho e

xper

ience

≥ 3

ex

acer

bations/

year

esp

eci

all

y

tho

se r

eq

uir

ing

ora

l co

rtic

ost

ero

ids

- In

hale

d c

ort

icost

eroid

s

-

CTS s

tate

s th

at in c

ontr

ast

to a

sthm

a, I

CS s

hould

not

be

use

d a

s firs

t lin

e m

edic

ation in C

OPD

.

Level

of

evid

en

ce 1

D

- CTS s

tate

s th

at t

he

pote

ntial fo

r lim

ited

ben

efits

in m

any

pat

ients

contr

ast

ed s

har

ply

with t

he

hig

h

likel

ihood o

f ad

vers

e ef

fect

s w

hen

ICS a

re u

sed in h

igh d

ose

s fo

r pro

longed

per

iods

of

tim

e,

par

ticu

larly

in t

he

elder

ly.

Level

of

evid

en

ce 3

A

- W

e ag

ree

with t

he

above

sta

tem

ents

.

- CTS s

tate

s th

at r

egula

r use

of

hig

h d

ose

IC

S a

lone

should

be

consi

der

ed o

nly

in p

atie

nts

with

moder

ate

to s

ever

e CO

PD

who h

ave ≥

3 e

xace

rbat

ions

per

yea

r, e

spec

ially

those

req

uirin

g o

ral

ster

oid

s.

Level

of

evid

en

ce 1

A

- Exp

ert

opin

ion e

mphas

izes

: -

Exa

cerb

atio

ns

should

be

seve

re e

nough t

o r

equir

e ora

l st

eroid

s bef

ore

consi

der

ing I

CS.

- Pa

tien

ts’ th

erapy

should

be

re-a

sses

sed w

hen

sta

ble

, ab

out

4-6

wee

ks a

fter

an e

xace

rbat

ion.

Rem

ain b

reath

less

des

pite

op

tim

al

bro

nch

od

ilato

r th

erap

y

- Com

bin

ation L

ABA/I

CS b

ut

this

sh

ould

be

consi

der

ed o

n a

n indiv

idual

bas

is

Level

of

evid

en

ce 3

A

- CTS s

tate

s th

ere

is n

ot

suffic

ient

evid

ence

for

a g

ener

al r

ecom

men

dation a

t th

is t

ime.

Als

o,

ICS/L

ABA c

om

bin

ations

should

be

pre

scribed

as

a m

att

er o

f co

nve

nie

nce

for

pat

ients

alrea

dy

rece

ivin

g L

ABAs

and I

CS s

epara

tely

. -

We

agre

e w

ith t

he

above

sta

tem

ents

.

1.

Can

Res

pir

J V

ol 10 N

o 4

May

/June

2003 p

.183-1

85 2.

See

han

dout

pag

e 3.

3.

Can

Res

pir

J V

ol 10,

Supp A

May

/June

2003 p

.5A-6

5A.

CTS =

Can

adia

n T

hora

cic

Soc

iety

; IC

S =

Inhal

ed C

ort

icost

eroi

d;

LABA =

long-a

ctin

g b

eta 2

-agonis

t; S

ABA =

short

-act

ing b

eta 2

-agonis

t


Title: Management of Community Acquired Pneumonia in Adults: Summary 2006 Update

Organization: Alberta Drug Utilization Program (Alberta) Summary Descriptive Information This newsletter has 2 pages, 1176 words and is divided into 4 sections. The document is uses full colour in its logos, title, headings and tables. Evaluation Summary Reviewer #1 Reviewer#2#1 Referencing 1 1#2 Peer Review 1 1#3 Systematic Review 1 2#4 Statistics 1 1#5 Price and coverage 1 1#6 Graphics 5 5#7 Key Messages 2 3#8 Sections 5 5#9 Headings 5 5#10 Table Hierarchy 5 5#11 Table Editorial Consistency 4 4#12 Column Width 4 3#13 Readability 3 3#14 Justification 5 5#15 Colour 4 4#16 Main Message 2 3#17 Therapeutic Decision Support 5 5#18 Behaviour Target 3 2#19 Retrieval 1 2#20 Editorial Consistency 4 5


Overall Mean Score 64 Strengths This newsletter provides detailed information and decision support on the stratification of risk and management options in community acquired pneumonia. Detailed dosage information is an important strength. Weaknesses The lack of referencing and peer review are evident. The absence of pricing information is also notable. The font and density of information challenge readability and the absence of key points section slows the retrieval of the main messages.

Management of Community Acquired Pneumonia in Adults: Summary 2006 update

• Analgesics/antipyretics for control of pain/fever• Ensure adequate hydration• Oxygen therapy is indicated for hypoxemia

General Management

Antibiotic Management

• Patients with pleural effusions complicating pneumonia should be referred• Pleural empyema should be drained• Chest physiotherapy is controversial

No Comorbid Factors1

Doxycycline ORAzithromycin ORClarithromycin ORErythromycin

200 mg PO first dose then 100 mg PO bid 7 to 10 days500 mg PO first day then 250 mg PO daily 4 days250 to 500 mg PO bid 7 to 10 days OR XL 1g PO daily 7 to 10 days500 mg PO qid 7 to 10 days

Comorbid Factors1

Failure of 1st Line Agents [Hemodynamic compromise (see in-patient recommendations below and consider admission to hospital)OR clinical deterioration after 72 hours of antibiotic therapy OR no improvement after completion of antibiotic therapy.] Choose aregimen not previously used as a first line therapy or within previous 3 months if possible.[Amoxicillin-clavulanate ORCefuroxime axetil] PLUS[Azithromycin ORClarithromycin ORErythromycin]AlternativeGatifloxacin ORLevofloxacin ORMoxifloxacin

Doxycycline ORAzithromycin ORClarithromycin

Recent antibiotic therapy (past 3 months)2 Choose a different class of agent than previously used and ADDAmoxicillin ORAmoxicillin-clavulanate3

200 mg PO first dose then 100 mg PO bid 7 to 10 days500 mg PO first day then 250 mg PO daily 4 days250 to 500 mg PO bid 7 to 10 days OR XL 1g PO daily 7 to 10 days

High dose 1g PO tid 7 to 10 days875 mg PO bid 7 to 10 days

875 mg PO bid 7 to 10 days500 mg PO bid 7 to 10 days

500 mg PO first day then 250 mg PO daily 4 days250 to 500 mg PO bid 7 to 10 days OR XL 1g PO daily 7 to 10 days500 mg PO qid 7 to 10 days

400 mg PO daily 7 to 10 days500 mg PO daily 7 to 10 days OR 750 mg PO daily 5 days400 mg PO daily 7 to 10 days

Recent antibiotic therapy (past 3 months)2 Choose a different class of agent than previously used and ADDAmoxicillin High dose 1g PO tid 7 to 10 days

[Cefuroxime ORCefotaxime ORCeftriaxone]PLUS[Doxycycline OR

Macrolide4]

AlternativeRespiratory Quinolone5

750 mg IV q8h 10 days1g IV q8h 10 days1g IV daily 10 days

200 mg PO first dose then 100 mg PObid 10 days

Severe[Cefotaxime ORCeftriaxone]PLUS[Macrolide4 OR

Respiratory Quinolone6]

1g IV q8h 10 to 14 days1g IV daily 10 to 14 days

10 to 14 days (exception isazithromycin for 5 days4)

Cephalosporin Allergy

10 to 14 days (exception isazithromycin for 5 days4)

Prevention• Smoking cessation and avoidance of environmental tobacco smoke• Limit the spread of viral infections (e.g., hand washing)• Influenza vaccine (annually) and pneumococcal vaccine are recommended for high risk patients• Rehabilitation and nutritional programs where appropriate

1. Comorbid/risk factors include: asthma, lung cancer, COPD, diabetes, alcoholism, chronic renal failure or liver failure, CHF, chronic corticosteroid use, malnutrition or acute weight loss (>5%),hospitalization in past 3 months, HIV, smoking

2. Antibiotic therapy within the previous 3 months is a risk factor for resistant S. pneumoniae. Amoxicillin provides the best coverage of all oral ß-lactams against S. pneumoniae, even penicillin-intermediate strains.3. Amoxicillin-clavulanate preferred over amoxicillin if Gram negative (alcoholism, recent hospitalization) or Staph (diabetes, recent influenza infection) species are a concern.

4.. Macrolide: Azithromycin (500 mg IV/PO 1st day then 250 mg PO daily 4 days), Clarithromycin (500 mg PO bid 10 days), or Erythromycin (0.5 - 1g IV q6h/500 mg PO qid 10 days)5. Respiratory Quinolone: Gatifloxacin (400 mg IV/PO daily 10 days), Levofloxacin (500 mg IV/PO daily 10 days OR 750 mg IV/PO daily 5 days), or Moxifloxacin (400 mg IV/PO daily 10 days)6. Respiratory Quinolone: Gatifloxacin (400 mg IV/PO daily 10 to 14 days), Levofloxacin (500 mg IV/PO daily 10 to 14 days), or Moxifloxacin (400 mg IV/PO 10 to 14 days).

Out-Patient

In-Patient

Respiratory Quinolone6

PLUSAnother antibiotic(clindamycin, macrolide4,vancomycin)

Diagnosis of Community Acquired Pneumonia in Adults: Summary 2006 Update

History of:• Fever +/- chills• New onset of cough (may or may not be productive)• Pleuritic chest pain• Constitutional symptoms (fatigue, headache, nausea/vomiting, abdominal pain, myalgias)Physical findings of:• Temperature >37.8OC (may be lower in frail elderly)• Tachypnea: respiratory rate ≥ 25/minute (must be counted for full minute)• Signs of consolidation: diminished chest expansion, increased tactile and vocal fremitus, dullness on

percussion, diminished air entry, bronchial breath sounds, whispering pectoriloquy, localized crackles,pleural rub

NB: Up to 80% of patients with CAP are treated as outpatients. HOSPITALIZE IF: severe hemodynamic instability, activecoexisting conditions that require hospitalization, acute hypoxemia or chronic oxygen dependency, and inability to takeoral medications. See PSI score (in full text guideline) to aid in decision.

Investigations: All patients• Chest x-ray, PA and lateral - if infiltrate treat as bacterial pneumonia• CBC with differential if risk factors for poor outcome• Sputum Gram stain and culture (if productive cough) may be useful• Blood cultures for those who present to ER with history of chills/rigors• Pulse oximetry should be performed on all patients with possible CAP who present to an ERAdditional tests: Hospitalized patients• Blood cultures (1 set blood cultures = 3 vials, 2 sites, same time)• Chemistry (glucose, electrolytes, creatinine, ALT)• Pulse oximetry• Arterial blood gas if O2 sat <90%, patient has COPD or is receiving chronic oxygen• Patients with pleural effusion complicating pneumonia should be assessed for empyema. If the effusion

is >1cm on a lateral decubitus chest x-ray the fluid should be aspirated and sent for WBC, cytology,culture, glucose, LDH. If the results indicate empyema consultation with a surgeon is necessary

DIAGNOSIS

6

Administered by theAlberta Medical Association

For full-text guideline refer to the TOP Website:www.topalbertadoctors.org

Identify Comorbidities and Risk Factors• Lung disease: smoking, asthma, lung cancer, COPD• Other: diabetes, alcoholism, chronic renal or liver failure, congestive heart failure, chronic

corticosteroid use, malnutrition or acute weight loss, HIV, immunosuppression, recent hospitalization(within past 3 months)

• Comorbidities are important to identify for appropriate antibiotic selection (see reverse)

6

6

• See reverse for general management and antibiotic management (patients with or without comorbidities)• Empiric therapy is recommended for all patients with physical findings of pneumonia and new infiltrate

on chest x-ray (viral etiology cannot be reliably differentiated from bacterial)• Ask the patient if they have had recent (within the past 3 months) antibiotics for ANY infection (see

reverse for recommendations if recent exposure)

6Follow-up• Post therapy chest x-ray (at 6 weeks) is recommended to ensure resolution and exclude underlying

diseases such as empyema, lung abscess, and malignancy if:- Extensive/necrotizing pneumonia, smoker, alcoholism, COPD, >5% weight loss in past month, >50

years old

Management

6


Title: Management of Type 2 DiabetesOrganization: Drug and Therapeutics Information Service (Kentucky)

Summary Descriptive Information This newsletter has 2 pages, 1225 words and is divided into 7 sections. The document is uses full colour in its logos, title, headings, figures and tables. Evaluation Summary Reviewer #1 Reviewer#2#1 Referencing 5 5#2 Peer Review 1 1#3 Systematic Review 2 2#4 Statistics 2 3#5 Price and coverage 1 1#6 Graphics 5 5#7 Key Messages 2 3#8 Sections 2 3#9 Headings 5 5#10 Table Hierarchy 5 4#11 Table Editorial Consistency 4 4#12 Column Width 5 4#13 Readability 5 5#14 Justification 5 5#15 Colour 5 5#16 Main Message 3 4#17 Therapeutic Decision Support 4 4#18 Behaviour Target 5 3#19 Retrieval 2 4#20 Editorial Consistency 3 4


Overall Mean Score 73 Strengths This is a well constructed newsletter that packs a lot of information in 2 pages while maintaining readability. This is achieved through careful balance of graphics and chunks of text. It provides strong support for therapeutic decision making in diabetes. Weaknesses Peer review is not evident. Providing relative pricing information for treatment options would strengthen the document. Key messages are lacking but the document is structured almost entirely of key messages.

NL – 01 - CADTH

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