Coronary Artery Disease Screening, Treatment, and Follow-up

Prim Care Clin Office Pract

33 (2006) 863–885

Coronary Artery Disease Screening,Treatment, and Follow-up

Jennifer L. Junnila, MD, MPHa,Guy P. Runkle, MD, MAb,*

aDepartment of Medical Science, Army Medical Department Center and School,

Fort Sam Houston, TX 78234, USAbDepartment of Family Medicine, Madigan Army Medical Center,

Fort Lewis, WA 98431, USA

According to the National Center for Health Statistics [1] and the Amer-ican Heart Association [2], heart disease affects more than 71 million Amer-icans and causes more than 30% of the total deaths in this countrydmorethan 900,000 deaths in 2003 alone. Advanced heart disease may exist beforethe onset of clinical symptoms; myocardial infarction or even cardiac deathmay be the first sign of serious disease. A recent prospective cohort study [3]demonstrated that one in five asymptomatic patients who have diabetes hassilent myocardial ischemia. Providing medical therapy and other appropri-ate interventions for patients in the subclinical stages of disease may allowprimary care physicians to improve the prognosis for patients at high riskfor cardiac events. Using evidence-based screening methods in the early de-tection of asymptomatic coronary artery disease (CAD) would give physi-cians the ability to identify which patients that would benefit most fromprimary prevention efforts.

The initial evaluation and management of patients presenting with acutecoronary syndrome, including unstable angina and myocardial infarction(MI), is beyond the scope of this article. Instead, the authors discuss thescreening of asymptomatic patients for suspected significant CAD, as wellas the treatment and ongoing management of those who have documentedCAD or a high suspicion of CAD. Heart disease in children and adolescentsis not discussed.

* Corresponding author.

E-mail address: [email protected] (G.P. Runkle).

0095-4543/06/$ - see front matter � 2006 Elsevier Inc. All rights reserved.

doi:10.1016/j.pop.2006.09.011 primarycare.theclinics.com

mailto:[email protected]

864 JUNNILA & RUNKLE

Coronary artery disease screening in asymptomatic patients

A provider considering a screening test for an asymptomatic patientshould also ask if the screening test will result in further testing or treatmentthat positively affects outcomes. Depending on the patient’s point of view,improved outcomes may be in terms of either quality or quantity of life. Be-fore performing a screening test, three variables should be considered: (1)the sensitivity of the test, (2) the specificity of the test, and (3) the pretestprobability of disease. That is, how likely will true, significant disease actu-ally be detected by the test? What is the probability that a negative test ac-tually reflects true absence of disease? The pretest probability of any disease,or likelihood that disease is present, will greatly affect whether a screeningtest for that disease is indicated. This is no different in screening for CAD.

The American College of Cardiology (ACC), American Heart Association(AHA) and the United States Preventive Services Task Force (USPSTF) rec-ommend against screening for either the presence of severe coronary arterystenosis or for the prediction of CAD events in adults at low risk for theseevents [4–7]. The potential harms of routine screening for CAD in adults atlow risk for disease exceed the potential benefits [6,7]. Tests in this populationare generally false-positive, especially in women, and may result in unneces-sary invasive and possibly injurious procedures and overtreatment. An appro-priate algorithm for estimating risk of CAD should be considered beforetesting for CAD in the asymptomatic patient.

Estimating probability of significant coronary artery disease

in the asymptomatic patient

There is inadequate evidence to determine the precise balance of benefits(improved CAD-related health outcomes) and harms (including overtreat-ment and unnecessary invasive procedures) in screening for significantCAD [7]. The rationale for establishing the diagnosis of CAD in asymptom-atic patients falls largely into two categories: (1) identification and furtherrisk-stratification of the patient who has multiple risk factors and whomay benefit from extensive primary prevention efforts, and (2) screeningfor critical disease in a patient at moderate or higher risk who plans to beginan exercise program.

A person’s risk for CAD can be estimated based on the presence of multi-ple risk factors. These include older age, male gender, elevated systolic bloodpressure or treatment for hypertension, smoking, elevated total cholesterol,low high-density lipoproteins (HDL), diabetes, obesity, and sedentary life-style. Estimating the probability of CAD greatly influences whether to screenfor disease. The Diamond-Forrester method for estimating pretest probabil-ity of CADwas first described in 1979 [8,9]. This method considers a person’sage, gender, and the quality of cardiac symptoms; however, it is only useful inthe symptomatic patient, and was not developed from an unselected

865CORONARY ARTERY DISEASE

population. In the asymptomatic patient, determination of 10-year (short-term) risk for developing CAD is performed using Framingham risk scoring[10]. TheAdult Treatment Panel IIIGuidelines (ATP III) of theNationalCho-lesterol Education Project recommends consideration of the FraminghamRisk Score in its treatment guidelines [11]. The Framingham score estimatesrisk of major CAD events, including MI and coronary death (Fig. 1).

Based on the Framingham Risk Index, the risk of CAD is estimated to below (!0% risk of a major CAD event in the next 10 years), intermediate(O10% and !20%), or high (O20%) [10,11].

Fig. 1. Framingham risk scores for men. (Adapted from Wilson PW, D’Agostino R, Levy D,

et al. Prediction of coronary heart disease using risk factor categories. Circulation 1998;97:

1837–47; with permission.)


Screening methods

Typical screening tests for CAD include resting ECG, exercise treadmilltest (ETT), cardiac stress imaging, and electron-beam computerized tomog-raphy (EBCT) scanning for coronary calcium. For adults at low risk forCAD event, the USPSTF recommends against screening for disease. TheUSPSTF does not have a recommendation for or against routine screeningwith ECG, ETT, or EBCT for either the presence of severe coronary arterystenosis or the prediction of CAD events in adults at increased risk for CADevents [6,7]. Cardiac stress imaging may be appropriate in select patients. Itis important to recognize that a negative test does not rule out a future car-diac event in a patient at highest risk. These tests have limited sensitivity,and a false-negative test is more likely in a patient in the highest risk group.Techniques for performing these tests are not discussed in this article.

The ‘‘routine’’ electrocardiogram in screeningfor coronary artery disease

The resting 12-lead ECG provides valuable information about myocardialischemia in symptomatic patientswhohave knownCAD, andmayassist in theevaluation of atypical chest pain; however, there is presently no evidence thatthe routine ambulatory ECG provides reliable information concerning ische-mia in asymptomatic subjects who do not have known CAD. One studyshowed the approximately 30% of patients who have angiographically-proven CAD have a normal resting ECG [12], and the ACC/AHA guidelinesrecommend against use of a routine ECG to screen asymptomatic patients [9].

Exercise treadmill testing

No study has directly examined the effect on CAD outcomes followingscreening asymptomatic patients with exercise treadmill testing [13]. Inone meta-analysis [14], the sensitivity of exercise treadmill testing rangedfrom 23% to 100%, and the specificity ranged from 17% to 100%. Acost-effectiveness study from the late 1980s [15] estimated that screeningasymptomatic 60-year-old men who have no other risk factors has a costper life-year saved of $44,332; for 60 year-old women, the cost was$47,606. Although exercise tolerance testing correctly identifies severe coro-nary artery obstruction in up to 2.7% of those screened, most positive find-ings will be false when the risk of coronary events is low [13]. Use of the ETTto screen for CAD in asymptomatic low-to-moderate risk individuals is notindicated [7,9]; however, asymptomatic men older than age 45 and womenover age 55 who are at high risk for CAD based on estimates such as theFramingham Index may benefit from screening [9].

Cardiac stress imaging

The use of cardiac stress imaging in the asymptomatic person is generallyreserved for patients who have abnormal exercise ECG. The ACC/AHA


guidelines recommend that asymptomatic patients felt to be at low risk forCAD following exercise ECG should not have further stress imaging per-formed. A patient who has a moderate to high risk of CAD and abnormalexercise ECG may benefit from screening with exercise myocardial perfusionimaging. In a study of patients evaluated for the presence of CAD [16],stress echocardiography had better prognostic capabilities than stresselectrocardiography.

Asymptomatic patients at moderate to high risk who are unable to exer-cise can have imaging enhanced with direct vasodilators such as adenosineor dipyridamole. In patients who have limited exercise capacity and contra-indications to direct vasodilators, myocardial perfusion imaging improvesthe sensitivity of dobutamine stress echocardiography for detecting CAD[17]. Dobutamine stress nuclear myocardial perfusion imaging (DSMPI)represents an alternative, exercise-independent stress modality for the detec-tion of CAD. DSMPI is more sensitive (88%), but less specific (74%) thandobutamine stress echocardiography, and comparable with direct vasodila-tor myocardial perfusion imaging. Patients who have a normal DSMPIstudy have less than 1% annual rate of serious cardiac events [18].

The electron beam computed tomography controversy

EBCT assesses atherosclerosis by measuring the extent of vascular calci-fication. In a meta-analysis of highly selected, symptomatic groups of pa-tients [5], EBCT had a pooled sensitivity of 90.5% and specificity of49.2%. Similar data for those who have no symptoms are lacking [6]. Onestudy demonstrated that EBCT predicted silent ischemia as demonstratedby abnormal single photon emission computed tomography (SPECT) scanin asymptomatic moderate-to-high risk patients [19]. Increased coronaryartery calcium scores predict subsequent development of heart diseaseevents in the following 3.5 years in asymptomatic patients, though theincrease is not directly proportional to scores [20].

In a cost-effectiveness analysis of EBCT, the marginal cost of usingEBCT to identify an additional patient ‘‘at risk’’ that had been missed bythe Framingham Risk Index is $9789. The study found that the cost perquality-adjusted life year saved was $86,752 when used to screen a popula-tion considered to be at low risk for CAD [21].

No study has examined the effect of EBCT data on clinical decisionmaking [6,22]. The ACC/AHA Writing Group does not recommendEBCT to diagnose obstructive CAD in asymptomatic patients.

Invasive testing

Coronary angiography can be used to establish the diagnosis of CAD,and may be appropriately used to evaluate patients who have typical anginalsymptoms; however, of all patients undergoing outpatient coronary angiog-raphy, an estimated 0.08% will die as a result of the procedure and 1.8%


will experience a potentially serious complication [23]. Invasive testing maybe appropriate for patients who have a high probability of CAD, and is notrecommended for patients who have a low probability of disease [9].

Biochemical markers of cardiovascular disease

Several biochemical markers of cardiovascular disease are being exploredfor use in screening asymptomatic patients. Plasma natriuretic peptide levelspredicted the risk of death and cardiovascular events in a community-basedsample of asymptomatic patients who were followed for over 5 years [24].Although this study did not specifically recommend using plasma natriureticpeptide levels as a trigger for further diagnostic tests in asymptomatic per-sons, it does raise the possibility that increased levels may aid in the earlydetection of cardiovascular disease. C-reactive protein is an inflammatorymarker that is also being evaluated. Several well-designed studies haveshown that elevated C-reactive protein levels are associated with develop-ment of nonfatal and fatal CAD in both men and women [25,26]. Other in-flammatory markers, such as tumor necrosis factor alpha and interleukin-6,did not show a strong association with development of disease whenadjusted for lipid levels. These studies concluded that the increased levelof C-reactive protein is a significant contributor to the prediction of coro-nary artery disease. This finding was not confirmed in diabetic patients[27]. For the primary care physician, the clinical utility of these markers re-mains to be proven.

Screening diabetic patients

Diabetic patients who have no symptoms of CAD may present only aftera significant CAD event, because silent ischemia is common in diabetic pa-tients [3]. The American Diabetes Association (ADA) consensus guidelinessuggest screening diabetic patients with stress testing when two or more ad-ditional CAD risk factors, including glomerular filtration rate (GFR) lessthan 90 mL/min, are present [3,27]. A newly-proposed diabetic cardiacrisk score (DCRS) considers the same factors as in the Framingham RiskIndex, as well as GFR less than 90 ml/min, presence of peripheral vasculardisease, and need for insulin. A recent study compared the DCRS to theFramingham score as well as the ADA scoring system in diabetic patientsundergoing CAD screening with exercise echocardiography [27]. TheDCRS was found to be slightly more effective than the Framingham RiskIndex in predicting which patients had positive findings of CAD on furtherscreening, identifying those asymptomatic diabetic patients at highest riskfor a significant CAD event. A diabetic patient who has no other cardiacrisk factors may benefit from screening with a stress echocardiogram, be-cause testing provides incremental data for risk stratification of diabeticswho have suspected CAD. Diabetic patients who have normal exercise


echocardiography have significantly fewer coronary events when comparedwith those who have abnormal studies [28]. Abnormal results on stress echo-cardiography are an independent predictor of cardiac death in diabeticpatients who have known or suspected CAD [29].

Screening those who impact public safety

Although there are insufficient data to justify screening, considerationsfor public safety may influence the decision to screen for CAD. The suddenincapacitation or sudden death of people in certain occupations such as air-line pilots, truckers, and heavy equipment operators may endanger thesafety of others. For the evaluation of asymptomatic men older than 45and women older than 55 who are involved in these occupations, it maybe appropriate to recommend screening with exercise testing; however, itsusefulness is not well-established [4,30].

Preparticipation testing

It is estimated that the risk of sudden death ranges from 1:15,000 joggersper year to 1:50,000 in marathon participants [31]. There are conflicting dataabout the use of exercise testing to screen low-risk participants before start-ing an exercise program. The USPSTF position on preparticipation screen-ing of asymptomatic patients notes that there is not enough evidence todetermine the balance of benefits and harms of this practice [6,7]. The Amer-ican Academy of Family Physicians (AAFP) does not recommend use ofroutine ECG as part of a periodic health or a preparticipation physicalexamination in asymptomatic patients [32]. The ACC/AHA guidelines findinadequate evidence to recommend exercise testing low-risk asymptomaticmen older than 45 and women older than 55 who plan to start vigorous ex-ercise [9]. It seems reasonable to screen older adults at moderate to high riskfor CAD before starting an exercise program [31]; however, in a prospectivecohort study of hypercholesterolemic men who were beginning an exerciseprogram, sensitivity of exercise testing for predicting coronary events was18% [33]. For the evaluation of asymptomatic persons who have diabetesand who plan to start vigorous exercise, the ACC/AHA is in favor of screen-ing with exercise testing [6,7].

Preoperative evaluation

Increased sympathetic drive combines with the cardiodepressant effectsof anesthesia to create an increased risk of coronary events in the early post-operative period. There are few randomized controlled data regarding theoptimum choice for preoperative evaluation of patients at risk for CAD.Consideration of the patient’s cardiovascular risk factors, the type and tim-ing of surgery, and an estimate of functional capacity best determine theneed for further investigation [34]. On the basis of available data, exercise


testing alone or with an imaging study remains the preferred test for preop-erative evaluation [35]. Exercise or dobutamine stress echocardiographyprovide the best validated investigations [34].

The evidence for coronary artery disease therapy

Therapy for CAD revolves around two goals: (1) secondary prevention offurthermorbidity andmortality fromCADand associated conditions; and (2)management of symptomswith the goal of improvement in quality of life. Theformer goal, for obvious reasons, is themain priority. Cornerstones in the sec-ondary prevention of CAD include identification of high-risk patients whowill obtain a mortality benefit from coronary artery bypass grafting(CABG), antiplatelet therapy or anticoagulation, use of beta blockers and an-giotensin-converting enzyme (ACE) inhibitors, exercise, smoking cessation,lipid management, and blood pressure management. Key issues in symptommanagement include revascularization and medical therapy for angina.

Antiplatelet therapy and anticoagulation

Aspirin therapy has been convincingly demonstrated to decrease the riskof adverse cardiovascular events in patients who had previous MI ([myocar-dial infarction] number needed to treat [NNT] ¼ 29), acute MI (NNT ¼ 26),and other high-risk patients (those who have stable angina, atrial fibrilla-tion, peripheral arterial disease, or diabetes, (NNT ¼ 45), although therisk of major hemorrhage is increased in patients at high risk of a vascularevent (number needed to harm [NNH] ¼ 111). Interestingly, if there isa dose response to aspirin in the prevention of vascular events, it appearsto be in favor of lower doses. A meta-analysis of over 200 trials [36] demon-strated benefit for daily aspirin doses of 75 to 325 mg, with higher doses hav-ing similar efficacy to lower doses, though doses less than 75 mg may be lesseffective (there are limited data with these doses). Lower doses are not sig-nificantly less likely to cause major hemorrhage [36]. A recently publishedmeta-analysis of aspirin use [37] confirmed a small benefit in the primaryprevention of cardiovascular events in both men and women (NNT ¼ 333women, 270 men), and risk of bleeding was low (NNH ¼ 400 for women,303 for men) [37]. The USPSTF strongly recommends discussion of aspirinchemoprophylaxis risks and benefits with patients at risk for CAD [7].

The use of thienopyridines (clopidogrel or ticlodipine) has been shown tohave a small benefit when compared with aspirin in the prevention of thecombined risk of MI, vascular death, or ischemic stroke (NNT ¼ 100),with no evident difference in the risk of hemorrhage, though they areobviously far more expensive [38]. One trial [39] showed a benefit of theaddition of clopidogrel to aspirin in reducing death from cardiovascularcauses, nonfatal MI, or stroke, as well as death from cardiovascular causes,nonfatal MI, stroke, or refractory ischemia.


High intensity anticoagulation therapy (international normalized ratio[INR] 2.8–4.8) with warfarin has also been shown to be effective in reducingthe risk of MI and stroke in patients who have CAD (NNT ¼ 10), but car-ries a significant increased risk of bleeding (NNH ¼ .26) [40]. Warfarin ther-apy alone does not appear to be more effective than aspirin alone [40]. Trialsof combination therapy with moderate- to high-intensity warfarin combinedwith aspirin have demonstrated improved cardiovascular outcomes com-pared with aspirin alone (NNT ¼ 18), but again possibly at an increasedrisk of hemorrhage (NNH ¼ 53) [40].

Despite the utility of glycoprotein (GP) IIb/IIIa inhibitors in decreasingthe likelihood ischemic events associated with angioplasty, long term trialsof oral GP IIb/IIIa inhibitors have been disappointing [41].

Lipid-lowering therapy

Serum cholesterol levels are a strong predictor of development of symp-tomatic CAD, and lipid-lowering therapy has been shown to lower the riskof ischemia in patients who have CAD in many clinical trials. A meta-analysis [42] concluded that a cholesterol reduction of only 1% could beexpected to lower coronary heart disease mortality by 1.7% (NNT ¼ 85),and all-cause mortality by 1.1% (NNT ¼ 91). Lipid-lowering therapy in pa-tients who had modest elevation of cholesterol following MI significantlydecreased the risk of recurrent events (NNT ¼ 33), need for CABG(NNT ¼ 50), and angioplasty (NNT ¼ 45) [43]. Lipid-lowering therapy inpatients who have a history of MI or unstable angina results in a decreasein all-cause mortality and death from CAD at 7 years, regardless of initialcholesterol level (NNT ¼ 53) [44].

Patients who have established CAD are categorized as high risk by theATP III, and the treatment goal established by these guidelines is to obtaina low-density lipoprotein (LDL) cholesterol level less than 100, with use ofdrug treatment if LDL level is above 130 [45]. The benefits of lipid-loweringtherapy on cardiovascular mortality could be extended to high-risk patientswho have initial total cholesterol greater than 135, regardless of initial LDLcholesterol (NNT ¼ 66) [46].

In patients who have hypertriglyceridemia (triglyceride O200), non-HDLcholesterol (calculated as total cholesterol – HDL cholesterol) is the closestsurrogate marker for highly atherogenic very low-density lipoprotein(VLDL) lipoproteins readily available in clinical practice. Hypertriglyceride-mia is a secondary target for lipid-lowering therapy, and should be treatedwith a combination of lifestyle change and pharmacologic therapy [11].

Low levels of HDL cholesterol have been identified as an independentrisk factor for CAD, resulting in an increase in coronary risk of about2% for every 1% decrease in HDL cholesterol. The use of gemfibrazil totreat low HDL has been shown to lead to lower risk of fatal and nonfatalMI in patients who have normal LDL levels(NNT ¼ 23) [47]. Drugs to raise


HDL should be considered in patients who have low HDL and normal tri-glycerides. This can be accomplished with the use of fibrates, 3-Hydroxy-3-methylglutaryl coenzyme A (HMG Co-A) reductase inhibitors, or nicotinicacid [11].

Epidemiologic evidence suggests a benefit to a diet high in omega-3 fattyacids, common in fish and marine mammals. Supplementation with fish oildecreases triglycerides and has a variable effect on other lipoprotein levels[48]. Advice to eat at least two weekly portions of fatty fish results in signif-icant decreases in death caused by ischemic heart disease (NNT ¼ 7) andoverall mortality (NNT ¼ 8) [49]. A 1992 meta-analysis concluded that therewas a benefit in the use of fish oil supplements in the prevention of restenosisfollowing percutaneous intervention (PCI) (NNT ¼ 16) [50].

Hypertension treatment

Blood pressure elevation has been consistently linked with CAD mortal-ity in observational studies. Every 20 degrees of systolic blood pressure ele-vation over 115 and every 10 degrees of diastolic blood pressure elevationover 75 correlates to a doubling of CAD risk [51]. Although controlled trialsof antihypertensive treatment have not been conducted on patients whohave CAD, treatment of hypertension clearly decreases the risk of cardio-vascular events in the general population, and is considered a key elementin the management of patients who have CAD [9]. Lowering blood pressureby 12 mmHg over 10 years in patients who have established CAD will resultin a significant decline in cardiac death (NNT ¼ 9) [9].

Beta blockers

Beta blockers reduce cardiac events following MI, and more limited datasupport their use in patients who have CAD and who have not had an MI[4]. They appear to be equally to slightly more effective than calcium-channelblockers or long-acting nitrates in controlling angina symptoms, and are aswell-tolerated as calcium-channel blockers. The effects of beta blockers com-bined with nitrates or calcium channel blockers on angina are additive, butthese agents may be ineffective or harmful in treating vasospastic angina [9].

Angiotensin-converting enzyme inhibitor therapy

Several trials have also shown ACE inhibitors to decrease the risk ofcardiovascular death, MI, and stroke [4]. In high-risk patients treatedwith ramipril, significant reductions in death from cardiovascular causes(NNT ¼ 50), MI (NNT ¼ 42), revascularization (NNT ¼ 43), cardiac arrest(NNT ¼ 200), and heart failure (NNT ¼ 40) were noted, independent ofany antihypertensive effect [52]. When patients who had known CAD with-out heart failure were randomized to receive the ACE inhibitor perindoprilor placebo, the ACE inhibitor was shown to have a benefit in prevention of


a nonfatal MI (NNT ¼ 71), as well as a combined cardiovascular end pointincluding total mortality, nonfatal MI, unstable angina, and cardiac arrest(NNT ¼ 19) [53]. Addition of an ACE inhibitor to optimal beta blockadehas been shown to reduce exercise-induced myocardial ischemia in patientswho have normal left ventricular function [9,54].

Calcium channel blockers

Short-acting dihydropyridine calcium channel blockers cause a dose-related increase in the risk of mortality in patients who have a history ofMI and unstable angina [55]. Nondihydropyridine calcium channel blockersand long-acting dihydropyridines do not appear to share this risk, and canbe used to relieve the symptoms of angina [9].

Nitrates

Nitrates relieve the symptoms of angina without increasing risk; however,nitrates do not improve mortality in patients who have CAD. Nitrates havebeen shown effective in improving exercise tolerance in patients who havechronic stable angina, and result in improved control of anginal symptomswhen combined with beta blockers or calcium channel blockers. Sildenafilshould not be used within 24 hours of administration of a nitrate productbecause of the high risk of severe hypotension. Prolonged use of nitratesleads to tolerance of the antianginal effects of the drug, which is generallyprevented by maintaining an 8 to 12-hour nitrate-free interval [9].

Revascularization

Revascularization can involve CABG using internal mammary arterygrafts or vein grafts, or may involve PCI with or without stenting.

Early randomized trials comparing CABG with medical management in-dicated that patients likely to receive a survival advantage from CABG arethose who have left main coronary artery disease (NNT ¼ 10), multivesseldisease (NNT ¼ 4), or proximal LAD stenosis (NNT ¼ 16) [56]. Patients de-termined to be at high risk by clinical criteria such as angina severity, historyof hypertension, history of MI, and ST depression at rest as measured by analgorithm developed in the Veterans Administration cooperative study alsobenefit from revascularization (NNT ¼ 9) [56]. Because these trials wereconducted, there have been advances in therapy, particularly the use of ar-terial grafts, and survival after CABG appears to have improved on the ba-sis of observational studies [57].

Based on a meta-analysis, PCI may be superior to medical management inthe management of anginal symptoms (NNT¼ 9), but is more likely to resultin the patient proceeding to CABG (NNH ¼ 33) [58]. In a study comparingpercutaneous transluminal coronary angioplasty (PTCA) to medical therapyin patients considered suitable for either treatment regimen [59], no difference


was observed in mortality; however, the use of stents was uncommon in thisstudy, and patients undergoing PTCA were more likely to have a nonfatalMI, (sometimes in conjunction with their procedure) (NNH ¼ 31). Patientsrandomized toPTCAwere alsomore likely to requireCABG(NNT¼ 48) [59].

Ambulatory ECG monitoring may be able to identify a subgroup ofpatients likely to obtain a survival benefit from revascularization. Patientsundergoing revascularization had improved survival when compared withpatients treated medically to relieve anginal symptoms (NNT ¼ 18), aswell as when compared with patients treated medically to relieve ischemicchanges documented on ambulatory ECG (NNT ¼ 30) [60]. Patients whohad asymptomatic ischemia on ambulatory ECG monitoring were morelikely to have multivessel disease (58.3% versus 37.1%), or complex plaques(34.2% versus 18.5%) when compared with controls who did not have am-bulatory ischemia, possibly explaining the survival benefit observed [61]. Onthe other hand, medical therapy coupled with aggressive lipid lowering ther-apy, although less effective in management of angina symptoms (NNT ¼ 8),results in fewer significant ischemic events (NNT ¼ 13) [62].

One study randomized patients who had three-vessel disease to receive ei-ther PCI or CABG [63]. The trial failed to show a survival benefit of CABGat 5 years (with the important exception of the subpopulation of diabeticpatients who did obtain a survival advantage with CAGB (NNT ¼ 6); how-ever, patients who underwent PCI were much more likely to require repeatrevascularization by 5 years after the procedure (NNT ¼ 15), and were morelikely to subsequently require CABG (NNT ¼ 56) [63]. By 7 years afterrandomization, a survival benefit for CABG was seen in the nondiabeticpatients as well (NNT ¼ 8) [64].

Another study randomized patients who had severe proximal stenosis of theleft anterior descending artery and stable angina to receivemedical therapy, bal-loon angioplasty, or bypass surgery using the left internal mammary artery [65].The study demonstrated prolonged event-free survival in the patients receivingsurgery when compared with patients undergoing PCI (NNT¼ 3), whereas pa-tients undergoing medical therapy had intermediate results (NNT ¼ 4). Therewas no significant difference in mortality among the comparison groups [65].In a trial that used stenting in addition to angioplasty in the PCI group, therewas no survival advantage of CABG, though PCI patients were still more likelyto require further revascularization (NNT ¼ 8) [66].

Risk factor modification

Smoking cessationThe link between smoking and the development of cardiovascular disease

has been firmly established in numerous observational studies [67]. Smokingalso increases the risk of recurrence of MI and increases the risk of suddendeath in patients with angina [68]. Smoking has a dose-response relationshipin the development of cardiovascular events, and its effects are additive to


other risk factors [69,51]. In an observational study, smoking cessation de-creased the risk of cardiovascular events within 5 years in patients who hadCAD (NNT ¼ 7) [70]. Risk reduction is evident within a year following MIand increases over time, despite evidence of increased infarct severity in pa-tients who quit [68]. Although because of ethical considerations randomizedtrials of smoking cessation have not been conducted in patients who haveestablished CAD and who smoke, it remains a key component to reductionof cardiovascular risk in patients who have CAD. Following a cardiac event,patients are particularly receptive to smoking cessation interventions [9].

Weight lossObesity is associated with increased risk of coronary artery disease mor-

tality, but it appears that most of the risk is caused by other associated riskfactors, including impaired glucose tolerance, hypertension, and hyperlipid-emia. Obesity, however, remained associated with increased risk of coronarymorbidity in the Framingham cohort after adjusting for other known co-morbidities, and was predictive of adverse coronary events, even in the smallsubset of patients who had obesity alone. In addition, weight loss was asso-ciated with a significant reduction in morbidity [71].

Exercise trainingExercise training has a beneficial effect on lipid profiles, including triglycer-

ides, LDL, and total cholesterol [72], and is useful in the management of othercoronary risk factors, including diabetes, hypertension [73], and obesity. Lackof exercise is a risk factor formorbidity fromCAD, andmost of the benefit canbe obtained by moderate levels of physical activity [74]. Regular exercise canprevent CAD, and improves symptoms in patients who have establishedCAD[75,76]. Following MI, cardiac rehabilitation programs involving exercise de-creases cardiovascular mortality (NNT¼ 56) and total mortality (NNT¼ 47)[77]. Improvements in exercise tolerance have been clearly documented for is-chemic heart disease patients treated with exercise in randomized clinical tri-als. There is no clear long-term benefit of higher intensity exercise programs,but these programs may be more effective when they involve exercise at leastthree times per week and last for at least 12 weeks [77]. Even suggestions bya physician on exercise can have benefit [78]. Prescription and supervision ofexercise to patients with CAD can reduce mortality, but patient adherenceto these regimens remains a problem [75]. There is no significant increase incardiovascular complications or other serious outcomes demonstrated inCAD patients engaging in exercise programs [77], although patients engagingin regular physical activity are more likely to be injured than those who aresedentary (NNH ¼ 11) [79].

CounselingType A behavior has been firmly established as an independent risk fac-

tor for cardiovascular mortality, and appears to be amenable to counseling,


resulting in decreased recurrence of cardiac events following MI (NNT ¼ 12)[80].

Moderate alcohol intakeOne study demonstrated a benefit of current alcohol consumption when

compared with never drinking (NNT ¼ 72) and compared with former alco-hol consumption (NNT ¼ 39) in men of Japanese ancestry living on Oahu[81]. Moderate alcohol intake (1.5 gm/d to 14.9 gm/d) in women is protec-tive against the development of fatal or severe heart disease, although it isassociated with an increased risk of subarachnoid hemorrhage [82]. Acase-control study has suggested that increases in HDL cholesterol withalcohol intake may be the source of the observed association with lowercardiovascular morbidity [83].

Cardiac rehabilitationCardiac rehabilitation services are defined as ‘‘comprehensive, long-term

programs involving medical evaluation, prescribed exercise, cardiac risk fac-tor modification, education, and counseling’’ [77]. These programs are de-signed to avoid morbidity and mortality and to enhance functioning incardiac patients. Such services are recommended on the basis of improve-ments in exercise tolerance, symptoms, lipid levels, cigarette smoking, psy-chosocial well-being and reduction of stress, and mortality [77].

Nurse-led, secondary prevention clinics focusing on use of aspirin, bloodpressure and lipid management, lifestyle factors, and behavioral changewere able to demonstrate improvements in aspirin therapy, blood pressuremanagement, low fat diet, and exercise at 1 year. All improvements but ex-ercise were sustained at 4 years, with subsequent improvements in survival[84].

Education, counseling, and behavioral modification training as part ofcardiac rehabilitation have been demonstrated to improve rates of smokingcessation and prevent relapse, improve lipid levels, reduce anginal symp-toms, and improve psychological outcomes, and may promote regressionof atherosclerosis and prevent reinfarction. Education alone is unlikely toresult in weight loss, but modest weight loss can be attained when educa-tional programs are combined with behavioral interventions. These strate-gies have not been demonstrated to be effective in improving exercisetolerance, controlling blood pressure, or hastening return to work [77].

Alternative therapies

Spinal cord stimulation appears to be effective in reducing anginal symp-toms in patients refractory to standard therapy, resulting in increased exer-cise capacity and decreased frequency of angina. Interestingly, ischemicepisodes on ambulatory ECG monitoring were also decreased with therapy[85]. In a randomized trial of CABG compared with spinal cord stimulation


in patients refractory to maximal medical therapy, there was no survivaladvantage to CABG, and the results in symptom relief were similar [86].Enhanced external counterpulsation appears effective in angina symptommanagement as well [87].

For patients with refractory angina not amenable to conventional revas-cularization, laser transmyocardial revascularization has been found to besignificantly more effective in improving anginal symptoms and improvingquality of life than continued medical therapy at 3 months (NNT ¼ 2–3)and persisting to 12 months (NNT ¼ 3–5) without observed difference inmortality [88–90]. In one study [91], difference in mortality rate did notreach statistical significance, but favored medical therapy (NNH ¼ 16),leading the authors to recommend against the procedure. Another trial[92] used a percutaneous catheter for transmyocardial revascularization ver-sus continued medical therapy and demonstrated significant improvement inangina (NNT ¼ 5), with no significant difference in survival between groups.

Garlic has been shown to decrease cholesterol in the short, but not longterm, and there are no data to support its effect on cardiovascular events.Vitamin B6, B12, and folate may lower serum homocysteine levels, whichare higher in patients with CAD and may be associated with higher morbid-ity and mortality; however, the use of such treatment has not been studied inthe prevention of coronary events. Acupuncture may increase time to anginawith exercise and improve work capacity, though the results of randomizedcontrolled trials are nonhomogeneous. Controlled trials of Chinese herbaltherapy have also shown improvements in angina symptoms. Chelationtherapy has not been shown to be effective in the treatment of angina [9].

Monitoring patients with known coronary artery disease

In the patient who has chronic stable angina, routine testing is of little usewithout a change in history or physical examination. There is little evidenceregarding the follow-up of patients who have known CAD. Based on expertopinion, the ACC/AHA recommends clinical evaluation every 4 to 6months during the first year of therapy, with annual evaluations to follow.Rather than refer all patients to cardiologists, primary care physicians areencouraged to comanage their patients with alternating visits.

The ACC/AHA suggests five questions that should be answered regularlyduring the follow-up of a patient who is receiving treatment for chronicstable angina (Fig. 2) [93]:

� Has the patient’s level of physical activity decreased since the last visit?� Have the patient’s anginal symptoms increased in frequency or becomemore severe since the last visit?� How well is the patient tolerating therapy?� How successful has the patient been in modifying risk factors andimproving knowledge about ischemic heart disease?


Fig. 2. Chronic stable angina. (From Texas Tech University Managed Health Care Network

Pharmacy & Therapeutics Committee. Chronic stable angina. University of Texas Medical

Branch Correctional Managed Care; 2003. � Copyright 2003 University of Texas Medical

Branch Correctional Managed Care.)


� Has the patient developed any new comorbid illnesses, or has the severityor treatment of known comorbid illnesses worsened the patient’s angina?

Use of cardiac testing during follow-up

Cardiac testing should only be considered based on a clinical change inthe patient’s status. The ACC/AHA writing committee consensus concludedthat the following studies are indicated [93]:

� Repeated echocardiogram when therapy with medications affecting car-diac conduction are initiated or changed, or when anginal pattern haschanged, symptoms or findings suggest a dysrhythmia or conductionabnormality, or near or frank syncope occurs� Chest radiography for patients who have evidence of new or worseningcongestive heart failure (CHF). The American College of Radiologyconcurs with this recommendation, noting that typical findings ofCHF are often noted on radiograph, and that diseases other thanCHF may present with one or more of the signs or symptoms of CHF[94].� Assessment of left ventricular ejection fraction and segmental wall mo-tion by echocardiography or radionuclide imaging in patients who havenew or worsening CHF or evidence of intervening MI by history or elec-trocardiography. One retrospective cohort study [95] confirms thatpatient history, ECG results, and chest radiograph can all be used topredict the absence of systolic dysfunction. Patients who have normalfindings are very unlikely to have left ventricular systolic dysfunctionand do not need echocardiography [95].� Echocardiography for patients who have evidence of new or worseningvalvular heart disease� Treadmill exercise test for patients who had no previous revasculariza-tion who have a significant change in clinical status, can exercise, andhave none of the following electrocardiogram abnormalities: pre-excita-tion (Wolff-Parkinson-White) syndrome, electronically paced ventricu-lar rhythm, more than 1 mm of ST-segment depression at rest, orcomplete left bundle-branch block. The Duke Treadmill Score predictssubsequent cardiac events. Techniques for calculating the Duke Scoreare described elsewhere [96].� Stress radionuclide imaging or stress echocardiography procedures forpatients who had or did not have previous revascularization and whohave a significant change in clinical status and cannot exercise, or whohave any of the electrocardiogram abnormalities listed above� Stress radionuclide imaging or stress echocardiographyprocedures for pa-tients who have a significant change in clinical status and required a stressimaging procedure on their initial evaluation because of equivocal orintermediate-risk results with exercise electrocardiography testing


� Coronary angiography in patients who have marked limitation of ordi-nary activity despite maximal medical therapy. Evidence confirms theutility of angiography in patients who have severe stable or unstableanginal symptoms that are resistant to medication [97].

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Coronary Artery Disease Screening, Treatment, and Follow-up

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