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Clinical trials update from the American Heart Association meeting:

ACORN-CSD, primary care trial of chronic disease management,

PEACE, CREATE, SHIELD, A-HeFT, GEMINI, vitamin E meta-analysis,

ESCAPE, CARP, and SCD-HeFT cost-effectiveness study

Rhidian J. Sheltona, Periaswamy Velavana, Nikolay P. Nikitina, Alison P. Colettaa,*,

Andrew L. Clarka, Alan S. Rigbya, Nick Freemantleb, John G.F. Clelanda

aDepartment of Cardiology, University of Hull, Castle Hill Hospital, Cottingham, Kingston-upon-Hull HU15 5JQ, UKbDepartment of Primary Care and General Practice, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK

Received 15 November 2004; accepted 23 November 2004

by guest on June 12, 2013http://eurjhf.oxfordjournals.org/

Abstract

This article provides information and a commentary on landmark trials presented at the American Heart Association meeting held in

November 2004, relevant to the pathophysiology, prevention, and treatment of heart failure. An open trial of the ACORN Cardiac Support

Device (CSD) showed encouraging preliminary results in patients with severe heart failure. The PEACE (Prevention of Events with

Angiotensin-Converting Enzyme inhibition) study supports data from previous studies showing that ACE inhibitors reduce vascular events in

patients at increased risk. The CREATE (clinical trial of metabolic modulation in acute MI treatment evaluation) study of patients with acute

myocardial infarction (MI) showed no mortality benefit of a glucose/insulin/potassium regimen, but treatment with reviparin reduced the

incidence of death, MI, or stroke. Azimilide was not associated with a significant reduction in shocks, but reduced the shocks or episodes of

markedly symptomatic ventricular tachycardia terminated by pacing in the SHIELD (Shock Inhibition Evaluation with Azimilide) study. The

addition of isosorbide dinitrate plus hydralazine to standard therapy improved survival in black heart failure patients in the A-HeFT (African–

American Heart Failure Trial) study. In an investigation of hypertensive patients with diabetes, carvedilol had fewer adverse effects on

diabetic control than metoprolol. A meta-analysis of high-dose vitamin E supplementation suggested an association with increased mortality.

The ESCAPE (Evaluation Study of CHF and Pulmonary Artery Catheterisation Effectiveness) study showed no benefit of pulmonary artery

catheterisation over clinical management in patients with severe heart failure. Routine prophylactic coronary revascularisation for stable

coronary disease prior to major vascular surgery showed no benefit in the CARP (Coronary Artery Revascularization Prophylaxis) study.

Analysis of data from SCD-HeFT supports the cost-effectiveness of ICDs in heart failure, although overall cost implications may be

prohibitive.

D 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Keywords: ACORN-CSD; Primary care trial of chronic disease management; PEACE; CREATE; SHIELD; A-HeFT; GEMINI; Vitamin E meta-analysis;

ESCAPE; CARP; SCD-HeFT cost-effectiveness

1. ACORN Cardiac Support Device (CSD) trial

The ACORN CSD is a high-technology fibre mesh that

can be wrapped around the heart to provide some external

1388-9842/$ - see front matter D 2004 European Society of Cardiology. Publishe

doi:10.1016/j.ejheart.2004.11.008

* Corresponding author. Tel.: +44 1482 624086; fax: +44 1482

624085.

E-mail address: a.p.coletta@hull.ac.uk (A.P. Coletta).

elastic constraint and, therefore, myocardial support in

diastole. Theoretically, this could prevent progressive left

ventricular dilatation or even reverse it by reducing diastolic

myocardial transmural stress [1]. Apart from the obvious

risks of surgery and infection, there is a theoretical risk of

producing iatrogenic pericardial restriction.

The ACORN-CSD trial enrolled 300 patients with heart

failure (NYHA II–IV, 6 MWT b150 m) and LVSD (EF

Failure 7 (2005) 127–135

d by Elsevier B.V. All rights reserved.

R.J. Shelton et al. / The European Journal of Heart Failure 7 (2005) 127–135128

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b35% and LVEDD N60 mm) who did not require CABG.

Of these, 193 patients were scheduled for mitral valve

surgery for mitral regurgitation. These patients were

randomised to no additional procedure (n=102) or addi-

tional CSD (n=91). A total of 107 patients did not require

mitral surgery and these were randomised to receive (n=57)

or not to receive (n=50) CSD in addition to optimal medical

therapy. The primary endpoint of the trial was a composite

of (a) death, (b) major cardiac procedures (CABG, valve

surgery, LVAD, transplant, or CRT), and (c) worsening

NYHA class.

The patients enrolled had a mean age of 52 years, 55%

were men, only 10% had IHD, mean LVEF was 27.4% (but

many had severe mitral regurgitation), and LVEDD was 72

mm. Over the following year, the ACORN-CSD reduced LV

diastolic volume by about 25 ml more than control

( pb0.01), with some evidence of increasing effect over

time. Trends to improvement in LVEF (3% v 1%) were not

significant. Quality of life scores (Minnesota and SF36)

both improved ( pb0.05 and p=0.015, respectively) but

NYHA class did not. However, the trial was unblinded and

therefore subjective measurements should be treated with

caution. Rehospitalisation and mortality were unaffected,

but major cardiac procedures were reduced and therefore the

primary endpoint was achieved (Table 1). Patients under-

going mitral surgery improved markedly even without CSD,

although trends to greater benefits were observed in those

who received the device. In patients who did not undergo

mitral surgery, the benefits of CSD compared to control

appeared greater.

In summary, this trial suggests that CSD can reduce LV

volumes and the need for other major cardiac procedures in

a highly selected group of patients with severe heart

Table 1

Outcome data from the ACORN-CSD trial

Outcome Control Intervention p

Primary composite outcome

Improved 27% 38% 0.02

No change 27% 25%

Worsened 45% 37%

Components of the primary composite outcome

Deaths No difference

Transplant (n) 16 7 0.007

LVAD (n) 8 3

CRT (n) 14 10

MVR (n) 3 1

NYHA, improved (%) 43 52 ns

NYHA, no change (%) 43 35

NYHA, worse (%) 14 13

Days of rehospitalisation 307 305 ns

LVAD=left ventricular assist device; CRT=cardiac resynchronisation

therapy; MVR=mitral valve replacement; NYHA=New York Heart

Association class.

failure. This is a very encouraging preliminary result,

although it needs to be viewed with caution since the trial

was unblinded. The possibility of the development of long-

term problems such as pericardial constriction or compres-

sion of bypass grafts needs to be excluded. Faced with a

patient who has end-stage heart failure, there is now a

range of options extending from expert manipulation of

pharmacological therapy to CRT, erythropoietin, external

counterpulsation, and LVADs. A lot more convincing data

are required before this device will be used for patients

who do not require surgery for another reason. On the

other hand, provided long-term safety and efficacy data can

be provided, the threshold to using CSD could be low as

part of the routine management of patients with heart

failure and major LV dilatation who require valve surgery

or CABG.

n June 12, 2013

2. Primary care-based trial of chronic disease

management

The management of heart failure is becoming increas-

ingly complex. In order for treatments to be delivered safely

and effectively, it seems logical to provide an organised

system of expert care [2–5]. The investigators in the present

study attempted to contact over 40,000 Medicare patients in

South Texas who had been coded for heart failure. From

this population, 1069 patients with heart failure and either

LVSD (LVEF b49%) or diastolic dysfunction (LVH or

Doppler criteria) agreed to participate in a trial comparing

usual care versus a nurse-based disease management

program. Primary care physicians made all the medical

decisions about the patients. The results have recently been

published [25].

The mean age of the patients was 71 years, 29% were

women, 62% had IHD, 39% had had a myocardial

infarction (MI), 28% had diabetes mellitus, and 72% had

hypertension. Seventy percent had LVSD (LVEF 35%:

systolic BP, 138 mm Hg) and 30% had LVDD (LVEF 62%:

systolic BP, 155 mm Hg). Fifty-seven percent were in

NYHA II and 24% were in NYHA III/IV.

Overall, the disease management program reduced

mortality ( p=0.037) but not event-free survival. There was

no effect on bed days or costs. In patients with LVSD,

mortality was reduced ( p=0.012) and event-free survival

increased ( p=0.017). Patients with LVSD randomised to the

intervention lived an average of an additional 81 days. For

comparison, meta-analysis of trials of CABG suggests that

revascularisation of triple-vessel disease increases average

survival by about the same amount over 5 years [6]. There

was no effect on LVDD.

In summary, the trial shows a small benefit from a

primary care-based chronic disease management program

amongst patients with predominantly mild heart failure at

low risk of events. Beta-blocker use was high at entry to the

study. It may be that the care received in the control and

R.J. Shelton et al. / The European Journal of Heart Failure 7 (2005) 127–135 129

intervention groups was rather similar. Other studies have

suggested that specialist care might have increased benefits

further. The data are consistent with other studies that have

shown either a reduction in mortality or in rehospitalisation,

or both [2,3]. The lack of effect in patients with LVDD may

reflect the better prognosis of (and lack of effective

therapies for) this group of patients.

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3. PEACE: Prevention of Events with

Angiotensin-Converting Enzyme inhibition

The results of PEACE have already been reported [7].

Briefly, the study recruited 8290 patients aged N50 years

with proven stable coronary disease in whom a LVEF b40%

or serum creatinine N177 Amol/l had been excluded, and

who had tolerated 2 mg of trandolapril for 2 weeks. Patients

were then randomised to double-blind placebo or trando-

lapril 4 mg/day. The initial intention was to randomise

N14,000 patients with a primary endpoint of death or MI.

Due to poor recruitment, the primary endpoint was

expanded to include coronary revascularisation, and this

increase in event rate allowed a reduction in study size to

8100 patients. The mean follow-up was 4.8 years.

The mean age of the patients was 64 years, 54% had had

a MI, and 17% had diabetes. Ninety percent were receiving

aspirin, 70% lipid-lowering drugs, and 60% beta-blockers.

Seventy-two percent had undergone revascularisation prior

to entry and a further 19% underwent first or repeat

revascularisation during the course of the study.

Trandolapril did not reduce any of the primary or

preplanned secondary outcomes. Overall, there were only

six fewer cardiovascular deaths on trandolapril compared to

placebo. The trial appears resoundingly neutral—but is it

really different from HOPE and EUROPA, trials in which

the ACE inhibitors ramipril and perindopril were shown to

reduce cardiovascular events? The answer is probably not.

The confidence intervals surrounding the modest effects of

ACE inhibitor on the same endpoint in all three trials

overlap. Indeed, for the most robust outcome, all-cause

mortality, the relative benefits in PEACE (11%), EUROPA

(11%), and HOPE (16%) are very similar. Absolute benefits

were also similar but small (0.9%, 0.8%, and 1.8%,

respectively). The HOPE trial did observe a reduction in

revascularisation, where intervention was predominantly

CABG ( p=0.002), an outcome that showed a strong

positive trend in PEACE. On the other hand, revascularisa-

tion was not reduced in EUROPA and revascularisation in

this trial was probably predominantly by PCI, an outcome

on which trandolapril had no effect in PEACE. Had

coronary revascularisation been added to the primary

endpoint of EUROPA, the effects of perindopril would

have been attenuated or lost. Unfortunately, the PEACE trial

has insufficient power to show an effect on outcomes such

as CVS death, MI, or stroke because it included fewer

patients than either EUROPA or HOPE, and also had a

lower annual event rate compared to HOPE (about 2%

compared to about 3%).

In HOPE, for every 1000 patients treated for 5 years,

between 20 and 60 patients would have CVS death, MI, or

stroke prevented. In EUROPA, it would be between 15 and

40, and in PEACE, up to about 20. Of course, this means

that over 90% of patients in each of the trials obtained no

demonstrable benefit. The PEACE study should make us

reconsider the medical philosophy of treating large

numbers of patients for small benefits. Accurate targeting

of highly effective therapy to the individual patient’s needs

should be the goal of modern medicine. PEACE may mark

the beginning of the end of the era of the megatrial.

Although large studies may provide tight confidence

intervals around their result, the clinical relevance of any

intervention that requires a large long-term study to show a

statistical effect must be questioned. In other words, large

studies are only really useful when they are neutral or

when they are stopped early.

However, it is possible that the trials had genuinely

different results. Trandolapril reduced mortality in the

TRACE study and cannot be considered ineffective, but

important differences between ACE inhibitors are possible.

It may be that higher doses are required in the patient group

recruited to PEACE, although the dose of ramipril was only

10 mg/day in HOPE. On the other hand, differences in

treatment or patients may be important. Diabetes was more

common in HOPE, but no benefit in this subgroup was

observed in PEACE. Most of the benefits in HOPE were

confined to the 25% of patients who were not taking aspirin

(Fig. 1). High aspirin use may have accounted for the trend to

lesser benefit observed in EUROPA and PEACE. However,

the rate of death or MI on active treatment in EUROPA and

PEACE was similar despite a much higher rate of

revascularisation in the latter trial. Could it be that the

benefits of revascularisation and ACE inhibitors are also

similar but not additive?

New-onset diabetes mellitus was common in PEACE

(one in eight patients) and almost twice as common as in

HOPE, which can only be partially accounted for by the

higher baseline prevalence of diabetes in HOPE. The high

rate may reflect changing criteria or improved surveillance

for diabetes. The small reduction in the number of patients

developing diabetes on trandolapril in PEACE is a

consistent feature of trials of ACE inhibitors as well as

ARBs. It is not clear whether this reflects a direct effect on

cellular function or an indirect effect mediated through

changes in weight and body composition.

The PEACE study reported that about one in every 25

patients had heart failure as the primary cause of death or

hospitalisation. Extrapolating from epidemiological data and

from the HOPE study, this finding suggests that about three

times as many patients may have exhibited new-onset heart

failure in other ways than was reported, making it potentially

the most common serious CVS event in PEACE. Again, the

consistency between the trials is remarkable.

Fig. 1. Figure showing the effect of aspirin on the effect of enalapril on mortality in the SOLVD studies and on the effect of ramipril on the composite primary

outcome measure (death, nonfatal MI, or nonfatal stroke) in the HOPE study [Cleland, J.G.F. Is aspirin dthe weakest linkT in cardiovascular prophylaxis. The

surprising lack of evidence supporting the use of aspirin for cardiovascular disease. Prog. Cardiovasc. Dis. 44 (2002) 275–292].

R.J. Shelton et al. / The European Journal of Heart Failure 7 (2005) 127–135130

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There has been much controversy as to whether the

results from these trials, particularly HOPE, simply

reflected blood pressure reduction, or represented a specific

ACE inhibitor effect. There is some evidence to suggest that

the blood pressure effect may have been more profound

than widely known in HOPE [8], and, in PEACE, there

seems to have been little difference in blood pressure

between the treated and placebo groups. The neutral

outcome in PEACE is thus consistent with the blood

pressure argument.

Fig. 2. (a) Meta-analysis of all-cause mortality data from the HOPE, EUROPA, a

diabetes, and heart failure from the HOPE, EUROPA, and PEACE studies.

A meta-analysis of outcome data from the HOPE,

EUROPA, and PEACE studies is shown in Fig. 2a and b.

In summary, PEACE reinforces the notion that ACE

inhibitors reduce vascular events in patients at increased

risk. The effect in all three studies is modest but consistent.

Society and the medical profession should decide what

absolute level of risk and absolute benefit justifies taking an

extra tablet each day. Controversially, trials comparing the

safety and efficacy of revascularisation with contemporary

interventions to that of medical therapy are urgently

nd PEACE studies. (b) Meta-analysis of data for CVS death, CVS events,

by guest on June 12, 2013/

R.J. Shelton et al. / The European Journal of Heart Failure 7 (2005) 127–135 131

required since this is an area of medical practice that lacks

an adequate evidence base.

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4. CREATE: clinical trial of metabolic modulation in

acute MI treatment evaluation

This study of more than 20,000 patients tested two

hypotheses in patients with acute MI. The first hypothesis

was that a glucose/insulin/potassium regimen would reduce

mortality (it did not). Major morbidity was also not reduced

and there were more adverse events. The second hypothesis

was to test the effect of a low-molecular-weight heparin,

reviparin, on 7- and 30-day incidence of death, MI, or

stroke. Reviparin reduced the composite outcome at both

time points, mainly due to an effect on death and MI.

The benefit from reviparin was greater the earlier it was

given. The majority of these patients received thrombolysis

with streptokinase, in whom antithrombotic treatment is

commonly withheld or delayed for several hours (as

compared with patients receiving alteplase/tenecteplase).

CREATE should encourage earlier use of low-molecular-

weight heparin in patients who have received streptokinase.

by guest on June 12, 2013eurjhf.oxfordjournals.org/

5. SHIELD: Shock Inhibition Evaluation with Azimilide

Azimilide is an antiarrhythmic drug with potassium

channel-blocking properties that prolongs the cardiac

action potential and refractory periods and is theoretically

useful for the prevention of VT/VF. This double-blind,

placebo-controlled trial randomised patients (mean LVEF

34%) with an ICD and recent VT or VF to azimilide (at

two dose levels) or placebo and followed them for 1 year.

Azimilide was not associated with a significant reduction

in shocks but did reduce shocks or episodes of markedly

symptomatic VT terminated by pacing (Table 2). Mortal-

ity was not reduced, but cardiovascular hospitalisations,

including those for heart failure, were reduced by the

lower dose. The reduction was either due to fewer ICD

shocks (which may cause myocardial damage) or sup-

pression of supraventricular and ventricular arrhythmias.

There were five patients in the azimilide group and one

patient in the placebo group who developed torsades de

Table 2

Efficacy data from the SHIELD study

Placebo

(n=214)

Azimilide,

75 mg (n=220)

Azimilide,

125 mg (n=199)

p

All-cause shock

Patients 113 (53%) 106 (48%) 91 (46%) ns

Events 613 472 480

Shocks or episodes of markedly symptomatic VT terminated by pacing

Patients 124 (58%) 114 (52%) 100 (50%) 0.005

Events 1459 665 737

pointes. Because the patients had ICDs, they were

protected from the worst effects of this outcome.

6. A-HeFT: African–American Heart Failure Trial

This study has recently been published in the New

England Journal of Medicine [9,10]. Briefly, 1050 African–

American patients with NYHA III/IV heart failure were

randomised to placebo or Bidil (a combination of hydrala-

zine/isosorbide dinitrate) on top of treatment with ACE

inhibitors, beta-blockers, and diuretics. The rationale for this

was the observation that only African–American patients

received benefit with the combination in V-HeFT I [11] and

that dBidilT outperformed enalapril in this subgroup in V-

HeFT II [11]. African–American patients may not have

benefited from enalapril in SOLVD [12], although data on

this latter point are conflicting [13]. However, in neither V-

HeFT trial was there a significant interaction on mortality

between race and treatment (Table 3).

The primary endpoint of the study included death,

hospitalisation, and patient well-being. The study was

stopped early by its DSMB after only 86 deaths had

occurred and only a mean of 10 months of follow-up

accrued due to a 43% reduction in mortality with Bidil. This

is unfortunate since studies stopped early for benefit tend to

overestimate effects, and the number of deaths is not large

enough to convince all observers. However, the result is

encouraging. The use of ACE inhibitors and beta-blockers

other than carvedilol [14] must now be questioned in this

population. Whether Bidil is effective in other racial groups

is presumably the next big question. Data have not so far

provided convincing evidence that either nitrates or

hydralazine used alone adds to the benefits of ACE

inhibition [15].

7. GEMINI: glycemic effects in diabetes mellitus:

carvedilol–metoprolol comparison in hypertensives

This randomised study of 1235 hypertensive patients

suggested that carvedilol (target dose 25 mg, bid; mean

achieved dose 17.5, mg bid) had fewer adverse effects on

insulin sensitivity and diabetes control compared to meto-

prolol tartrate (target dose 200 mg, bid; mean achieved dose

128 mg, bid). There were more problems with bradycardia

in those assigned to metoprolol [16]. It is unclear as to what

extent the difference observed is due to dose or drug,

although its findings are in keeping with other studies in

heart failure [17,18].

8. Vitamin E meta-analysis

This meta-analysis suggested that high-dose vitamin E

supplements were associated with increased mortality,

Table 3

Comparison of the effect of race on outcome in the V-HeFT I, V-HeFT II, SOLVD, and A-HeFT studies

White Black

V-HeFT I

n Placebo=192 H–I=132 Placebo=79 H–I=49

Deaths 85 (18.8% pa) 56 (16.9% pa) 35 (17.3% pa) 15 (9.7% pa)#

Hospitalisation with HF 49 (25.5%) 32 (24.2%) 12 (23.0%) 11 (22.4%)

Hospitalisation for any reason 67 (34.9%) 56 (42.4%) 21 (40.4%) 20 (40.8%)

V-HeFT II

n Enalapril=292 H–I=282 Enalapril=106 H–I=109

Deaths 90 (11.0% pa) 112 (14.9% pa)* 39 (12.8% pa) 39 (12.9% pa)

Hospitalisation with HF 51 (17.5%) 51 (18.1%) 24 (22.6%) 23 (21.1%)

Hospitalisation for any reason 181 (62.0%) 165 (58.5%) 65 (61.3%) 59 (54.1%)

SOLVD: effect of enalapril versus placebo

n 5719 800

Hospitalisation for HF 40 (95% CI: 32–47)% reduction 14 (95% CI: +16–36)% reduction

Death 14 (95% CI: 3–24)% reduction 15 (95% CI: +14–36)% reduction

A-HeFT

n Placebo=532 H–I=518

Deaths 54 (10.2%) 32 (6.2%)##

Hospitalisation with HF 130 (24.4%) 85 (16.4%)**

Hospitalisation for any reason Not reported

Note that percentages for hospitalisation in all trials and mortality in A-HeFT are NOT annualised.

CI=confidence intervals around the difference; (+) 95% CI includes a worse outcome; H–I=hydralazine/isosorbide dinitrate.

* p=0.02.

** p=0.001.# p=0.04.## p=0.01.

R.J. Shelton et al. / The European Journal of Heart Failure 7 (2005) 127–135132

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although these data may not apply to patients with heart

failure who were poorly represented in the analysis [19].

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9. ESCAPE: Evaluation Study of CHF and Pulmonary

Artery Catheterisation Effectiveness

This randomised controlled trial assessed the value of a

pulmonary artery catheter (PAC) for the management of

patients admitted to hospitals with severe heart failure not

already treated with inotropic agents [20]. Only patients with

LVEF b30% and systolic blood pressure b125 mm Hg were

included to ensure higher risk, but patients with serum

creatinine N3.5 mg/dl (about 300 Amol/l) were excluded as

these patients might not have tolerated effective treatments for

heart failure. The immediate therapeutic goal in the clinically

managed group was resolution of the symptoms and signs of

heart failure. The immediate goal in the intervention groupwas

the same but also to reduce the PCWP to b15mmHg and right

atrial pressure to b8 mm Hg. The primary outcome was the

number of days dead or hospitalised over 6 months.

A total of 218 patients were randomised to clinical

management and 215 to the PAC. The mean age of the

patients was 56 years, 26% were women, and 56% had

ischaemic heart disease. Themean ejection fraction was 19%,

systolic BP 106 mm Hg, sodium 136 mmol/l, and creatinine

1.5 mg/dl (about 130 Amol/l). The 6-min walk test was 400 ft

(the patients could walk) and Minnesota QoL score was 74

(versus 75 in REMATCH [21]). PCWP was 25 mm Hg

(dropping to 17 mm Hg on therapy), right atrial pressure 14

mm Hg (dropping to 10 mm Hg on therapy), and cardiac

index 1.9 l/min/m2 (rising to 2.4 l/min/m2). Patients

randomised to clinical care tended to receive more diuretics

and beta-blockers.

During 6 months follow-up, patients spent a median of

about 11 days in hospital (average 17 days); mortality was

about 19% and 21% of the 180 days of follow-up (average

38 days; median 13 days) were lost due to death or

hospitalisation (Table 4). Patients managed clinically had

fewer serious adverse events and tended to have a lower

mortality; but otherwise, there was no difference in outcome.

There was no difference in index hospitalisation duration

(about 8 days). Eighteen percent of control patients crossed

over to catheterisation. There were no PAC-related deaths.

In conclusion, this result suggests that clinicians should be

conservative about their use of pulmonary catheters. How-

ever, pulmonary catheterisation may still have a place in the

management of hypotensive patients (i.e., those with systolic

BP b100 mm Hg). No subgroup analyses were presented.

10. CARP: Coronary Artery Revascularization

Prophylaxis trial

This study investigated the use of routine prophylactic

coronary revascularisation by CABG or PCI for stable

Table 4

Outcome data from the ESCAPE study

Clinical PAC

Number of patients 218 215

Days dead or hospitalised

(average/median)

36

(20%)/13 (6%)

38

(21%)/13 (6%)

Mortality 17.4% 20.9%

Rehospitalisation (per patient) 2.1 2.1

Days in hospital (average/median) 16 (7%) /11

(6%)

17 (8%)/11

(6%)

Pulmonary complications of PAC (%) 0 1.0

Infected PAC (%) 0 1.9

Antibiotic for infection (%) 9.2 13

Cardiac arrest (%) 2.3 4.2

30-day mortality (%) 5 4.7

PAC=pulmonary artery catheterisation.

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coronary disease prior to major surgery for abdominal aortic

(33%) or peripheral (leg) vascular disease [22,23]. The

primary endpoint was long-term all-cause mortality. The

study was adequately powered for this endpoint. A total of

5859 patients were screened for inclusion and 80% were

excluded mainly because the patient/procedure was consid-

ered to have such a low risk that angiography was not

necessary, or because the vascular surgery was urgent and

had to proceed without delay. A total of 1190 had an

angiogram. This showed no coronary obstruction in only

5%, no revascularisable lesion in 20%, and left main

coronary disease in 8%. These patients were excluded.

Eventually, 510 were randomised. Thirty-five percent of this

group had three-vessel coronary disease, 44% had myocar-

dial perfusion imaging indicating moderate or high risk, and

their mean age was 66 years. Eighty percent of patients were

on a beta-blocker and 50% on a statin. Coronary revascu-

larisation was by percutaneous intervention in 59% of cases

and 41% had CABG. Coronary revascularisation led to

about 7 weeks delay (versus 1–3 weeks in the control group)

in vascular surgery during which 10 patients died.

Perioperative outcome following peripheral vascular

surgery was similar in each group in terms of mortality

and MI. During a median follow-up of 2.7 years, all-cause

mortality was similar in the two groups at about 23%. Only

25% of deaths were from coronary disease in each group

(Table 5).

These data suggest, with few caveats, that routine

preoperative revascularisation for vascular—and probably

by extension of other types—surgery is not warranted.

Preoperative assessment by stress echo or nuclear cardiol-

ogy tests will identify patients at increased risk, but as

Table 5

Outcome data from the CARP study

No revascularisation Revascularisation

n 252 258

30-day mortality (%) 3.4 3.1

Mortality at 2.7 years (%) 23 22

Postoperative MI (%) 14.3 11.6

intervention has not been shown to decrease risk, the value

of such tests should be questioned. However, noninvasive

techniques could have a role in excluding left main coronary

disease. It may be better to focus on the use of beta-blockers

and statins in this setting rather than investigating and

intervening on coronary disease.

11. SCD-HeFT cost-effectiveness study

Governments increasingly use estimates of cost-effec-

tiveness to decide which interventions to adopt. These

calculations should be performed on locally derived data

since costs (mainly salaries) may vary widely. However,

estimates from one country provide a starting point for

others. In the United States and UK, a cost per life year

gained (LYG) of less than US$50,000 is generally consid-

ered cost-effective, whilst costs in excess of US$100,000

would generally be considered cost-ineffective. However,

governments implement many interventions that are not

cost-effective (for instance, air bags in cars or some railway

safety measures, both of which are thought to cost in excess

of 1 million per LYG).

This analysis of the SCD-HeFT trial [24] suggested that

ICDs were fairly cost-effective. The analysis assumed that

the average cost of a simple device with leads but not

implantation costs in the United States was US$17,500

(range US$13,000–23,700) and that the average cost of

5-year management in the control group was about

US$43,000 and in the ICD group was US$62,000 per

patient (Table 6). The primary analysis extrapolated the

within-trial follow-up to lifetime expectation. The median

longevity in the control group was estimated to be 8.4 years,

rising to 10.9 years with an ICD.

On this basis, the calculation suggests that the cost per

life year gained is US$33,000, similar to that estimated for

MADIT II (about US$50,000 per LYG). There was a

powerful interaction between NYHA class and outcome

( p=0.0002). ICDs did not appear effective (and therefore

not cost-effective) in patients who had NYHA III heart

failure. Patients with milder NYHA II heart failure had a

cost of US$26,000 per LYG. If this interaction was ignored

and the benefits were assumed to be the same regardless of

NYHA class, the cost-effectiveness was still higher in

NYHA III patients (US$35,000 vs. US$45,000). If only cost

over the lifetime of the study is considered, the cost rises to

US$77,000 per LYG. If quality-adjusted life years (QALY)

Table 6

Cost of ICD therapy and control in the SCD-HeFT trial

Control (US$) ICD (US$)

Hospital costs 30,691 46,804

Outpatient costs 2863 3745

Pharmacological therapy 8019 9026

Total 43,077 61,967

ICD=implantable cardioverter defibrillator.

R.J. Shelton et al. / The European Journal of Heart Failure 7 (2005) 127–135134

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are considered, then the estimated cost per QALY was about

US$35,000. Analysis of other subgroups including age N65

years, LVEF b30%, and QRS width N120 ms showed little

variation in cost-effectiveness.

Clearly, this analysis suggests that ICDs are cost-effective

by current criteria. Are there any reasons not to implant them

in most patients with low ejection fraction heart failure? In

fact, there are many reasons to be cautious. Firstly, ICDs are

not as cost-effective to implement as ACE inhibitors, beta-

blockers, or spironolactone, nor as cost-effective as some

other measures, such as heart failure nurses or telemonitor-

ing. Implementation rates for these effective, inexpensive

treatments are low. Only once an adequate protocol for the

implementation and monitoring of pharmacological treat-

ment is in place should ICDs be considered. Secondly, new

technologies such as CRT may provide most or all of the

mortality benefits of ICDs at lower cost, whilst also

improving patient symptoms. Thirdly, it is possible that

properly informed patients may decide that they do not want

a device, knowing that more than 90% of recipients will not

benefit from the device over 5 years and that 10–20% of

patients will get inappropriate shocks. Finally, only consid-

ering new cases of heart failure and assuming that only 25%

of patients receive an ICD because the patient has refused the

device or is considered too frail then a regional centre

covering a population of 2 million people will need to

implant about 500 devices per year. Once steady state has

been reached, the excess treatment costs may be about o20

million per year, based on this model. Even though ICDs

might be cost-effective, it is possible that health services will

be unable to afford to implement therapy.

Ultimately, the best solution is to target ICD use more

accurately. Unfortunately, no technology or strategy has

convincingly shown that it can usefully detect who will and

who will not benefit from an ICD.

2, 2013

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