European Heart Journal Advance Access originally published online on August 11, 2006
European Heart Journal 2006 27(18):2154-2157; doi:10.1093/eurheartj/ehl122
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Should angiotensin-converting enzyme-inhibitors be used to improve outcome in patients with coronary artery disease and ‘preserved’ left ventricular function?
1 Department of Cardiology, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK
2 University of Ferrara, Ferrara, Italy
3 McMaster University, Hamilton, Canada
4 Weill Medical College of Cornell University, New York, NY, USA
Received 19 May 2006; accepted 6 September 2006; online publish-ahead-of-print 11 August 2006.
* Corresponding author. Tel: +44 20 7351 8626; fax: +44 20 7351 8629. E-mail address: k.fox{at}rbht.nhs.uk
Abstract
Early clinical studies investigating the role of angiotensin-converting enzyme (ACE) inhibitors in the treatment of heart failure unexpectedly demonstrated a possible reduction in coronary heart disease endpoints. Two large scale clinical trials, HOPE and EUROPA, both studies in patients with coronary artery disease (CAD) but without clinical evidence of heart failure, showed a highly significant improvement in coronary heart disease outcomes on treatment with ramipril and perindopril, respectively, in contrast, in a similar population, PEACE was unable to demonstrate such benefit with trandolapril. Meta-analyses of all trials involving ACE-inhibitors showed a highly significant improvement in coronary heart disease endpoints. Current ESC guidelines recommend ACE-inhibitor therapy in CAD patients with co-existing indications for ACE-inhibitors, such as hypertension, heart failure, left ventricular dysfunction, prior MI was left ventricular dysfunction, or diabetes (class I, level of evidence A). These guidelines also recommend ACE-inhibitor therapy in all patients with angina and proven coronary disease (class IIa, level of evidence B). However, in angina patients without independent indication for ACE-inhibitor treatment, the anticipated benefit should be weighted against the costs and risks of side effects; in these patients, only agents and doses of proven efficacy for secondary prevention should be employed.
Key Words: ACE inhibitors • Stable coronary artery disease • Secondary prevention •
The Heart Outcomes Prevention Evaluation (HOPE) study showed, for the first time, reduction of cardiovascular outcomes due to angiotensin-converting enzyme (ACE)-inhibition (relative risk reduction 22%, using ramipril 10 mg daily with treatment scheduled for 5 years) in high-risk patients [coronary artery disease (CAD) without heart failure or known left ventricular systolic dysfunction1]. The EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) found a parallel result: addition of ACE-inhibitor perindopril to standard preventive therapy for patients with stable CAD (without heart failure) over 4.2 years reduces cardiovascular death, non-fatal myocardial infarction (MI), or resuscitate, cardiac arrest by 20%.2
Thus, the results of HOPE and EUROPA enable improved prognosis in patients with CAD beyond that achievable with intensive application of recommended standard therapy (antiplatelet agents, lipid-lowering drugs, and beta-blockers) and suggest that therapy with the drugs and doses employed in these trials should be considered in addition to other preventive treatments, even in the absence of heart failure, marked left ventricular dysfunction, or risk factors for all patients with documented CAD.2
Recent results of the Prevention of Events with Angiotensin Converting Enzyme inhibition (PEACE) trial indicate that addition of trandolapril to standard therapy for stable CAD with preserved left ventricular function does not further reduce cardiovascular death, MI, or coronary revascularization during 4.8 years of follow-up.3 The authors of that study concluded that ACE-inhibition (presumably irrespective of drug or dose) is not of value in patients with stable CAD who are treated with other proven preventive therapies.
We believe that the reasons for the apparent discrepancy in results and conclusions from the three trials may lie in the similarities and differences in their design and conduct.
HOPE differs from EUROPA and PEACE in focusing on patients at relatively higher cardiovascular event risk. Patients were eligible for HOPE if they were 
55 years old with a history of CAD, stroke, peripheral vascular disease, or diabetes plus one other cardiovascular risk factor (hypertension, elevated total or low high-density serum lipo-protein cholesterol concentration, cigarette smoking, or documented microalbuminuria).4 Although not focused solely on patients with CAD, the HOPE population included 80% with CAD; subgroup analysis showed clear benefit of ramipril among patients with, as well as those without, CAD at baseline.1 Recent analyses from HOPE indicate that the benefits were consistent in subgroups defined by risk and were clearly observed in high, medium, and low-risk patients.5
EUROPA assessed the effect of ACE-inhibition with perindopril in patients with documented CAD without heart failure. Many of the patients (80%) were stable, asymptomatic, or only mildly symptomatic (CCS Class I). The EUROPA results confirmed the benefits of ACE-inhibition for stable CAD without clinically evident heart failure, as previously found in HOPE. In EUROPA, as in HOPE, risk reduction by perindopril added to standard therapy was consistent among high, intermediate, and low-risk patients. Therefore, both trials demonstrated clear results overall and in patients in whom the risks of major vascular events ranged from a low of 1% to a high of 5% per year.
PEACE was originally designed to test whether the use of the ACE-inhibitor, trandolapril, decreases cardiovascular death or non-fatal MI in 14 100 patients with CAD and left ventricular ejection fraction 40%.6 Because of lower than expected patient recruitment, the primary outcome was expanded to include revascularization. Although the population of PEACE was similar in terms of baseline characteristics to those of EUROPA, there was no apparent benefit in terms of primary endpoint reduction in the trandolapril group compared with placebo.3 Why was this?
In recent years, standard therapy for CAD has become more aggressive. Consequently, one might explain the differences between results of HOPE, EUROPA, and PEACE by better risk factor control in the PEACE population at baseline, reducing the likelihood that this low-risk population would benefit from ACE-inhibition with trandolapril. Certainly, the PEACE population more frequently had undergone coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) (39 and 42% of patients, respectively) than the HOPE population (26 and 18%) or EUROPA (29 and 29%). Nonetheless, in HOPE and EUROPA, ACE-inhibition reduced cardiac outcomes to a similar degree in patients with and without prior revascularization. Furthermore, available data indicate that the event-reducing effects of revascularization are limited: in the second Randomized Intervention Treatment of Angina (RITA-2) trial, an initial strategy of PCI improved angina and exercise tolerance but did not influence the risk of death or MI compared with pharmacological anti-anginal therapy.7 Meta-analysis of seven trials reported that although mortality was reduced by CABG, this was not apparent for the first 3 years of follow-up. Moreover, surgery has significantly improved survival only in the subset of patients with left main or three-vessel disease; little mortality-reducing benefit has been found in the broader group of patients with CAD.8 CABG has not reduced the overall incidence of non-fatal MI, although its benefits on mortality are proportional to the baseline patient risk. PCI has not been shown to improve outcomes in patients with stable CAD.9 Thus, prior revascularization does not guarantee lower risk of cardiac outcomes, nor do these procedures influence the underlying disease.
In HOPE, fewer patients received antiplatelet drugs, lipid-lowering agents, and beta-blockers (76, 29, and 40% patients, respectively) than in EUROPA and PEACE (consistent with contemporaneous registries and other evidence available at the time). However, in EUROPA, at baseline, 92, 58, and 62% of patients received antiplatelet drugs, lipid-lowering agents, and beta-blockers, respectively. At 3 years of follow-up, usage was 91, 69, and 62%. In PEACE, at baseline, 91, 70, and 60% patients received antiplatelet agents, lipid-lowering agents, and beta-blockers. Moreover, in HOPE and EUROPA, benefits of ramipril and perindopril were observed whether or not patients were taking these medications at baseline.1,2 In PEACE, lipid-lowering drug use at baseline nominally was slightly higher than that in EUROPA, but the modest magnitude of the difference could hardly explain the absence of trandolapril efficacy in PEACE. Experimentally, both ACE-inhibitors and statins retard atherogenesis; their combination has been shown to a exert synergistic effect.10 Recent findings of the post hoc analysis of the GREek Atorvastatin and CHD Evaluation (GREACE) study showed that combination of a statin and an ACE-inhibitor is significantly more effective in reduction of cardiovascular death, non-fatal MI, and revascularization than each of these drugs alone, supporting their complementary pleiotropic effect.11
In contrast to PEACE, measurement of left ventricular ejection fraction was not obligatory for inclusion in HOPE and EUROPA. Thus, the positive results of the latter studies might be partly due to the proven effect of ACE-inhibitors on left ventricular systolic dysfunction. This seems an unlikely explanation: the mean ejection fraction of the patients in the PEACE study was 58%. In EUROPA, ejection fraction was 57% in patients in whom it was measured, whereas in HOPE, it was 58%. Furthermore, retrospective analyses showed that in HOPE and EUROPA the large majority of the studied patients did not have left ventricular systolic dysfunction. In HOPE, left ventricular function was evaluated before randomization in 5193 (55.9%) patients, of whom 4772 (91.9%) had relatively well-preserved (40%) left ventricular ejection fraction; none had heart failure.12 Subgroup analysis among these 4772 patients showed relative risk reduction of 27% with ramipril compared with placebo (95% confidential interval 0.63–0.84, P<0.001).13 Retrospective analysis of EUROPA indicated that left ventricular ejection fraction was 40% in 97% of patients; event reduction was 22% on treatment with perindopril in these patients. These data suggest that ramipril and perindopril provided benefits in patients with CAD, a substantial portion of whom had normal left ventricular function and the great majority of whom did not have marked left ventricular dysfunction, whereas trandolapril failed to provide such benefit in similar patients.
One explanation of the discrepancies among the results of the three trials may be in the medications, themselves, and/or the dose regimens that were employed. Although all three drugs are ACE-inhibitors, it is well established that ACE-inhibitors manifest a large number of pharmacological effects that may differ among individual agents;14 the dose–response relations for shared effects, and the relative magnitude of various shared effects at any given dose, may differ as well. In addition, though it is hypothesized that effects of ramipril and perindopril on coronary events result specifically from some aspect of ACE-inhibition, this hypothesis never has been rigorously tested, nor is it known whether some combination of pharmacological effects, specific to one or another ACE-inhibitor, may be necessary in order to achieve the desired clinical benefit. The latter is a potentially important consideration: the clinical effects of any drug are the net result of all its pharmacological actions, not necessarily of any one action that is of particular interest to investigators.15 Given the presumed basis of the benefits of ramipril and perindopril on coronary events, it is not possible to know a priori the dose of another ACE-inhibitor to achieve the same effects, assuming that the same benefits would result from that drug. Indeed, for coronary events, as opposed to blood pressure (which can be measured), no biomarker has been identified that can be employed to select an effective dose. As an example of the possible difficulties in extrapolating from results with ramipril or perindopril to trandolapril, the duration of action of a single dose, bioavailability, and high affinity to tissue ACE may contribute to the long-term benefits of ACE-inhibition and differ among the drugs. Penetration into an atherosclerotic plaque requires both high lipophilicity and adequate blood concentration of the ACE-inhibitor. In contrast, treatment of hypertension and heart failure (from which doses used in PEACE were derived) appears to require adequate plasma concentration with lesser need for tissue penetration.
Although differences in specific pharmacological properties may help explain different outcomes among trial results, differences in the trial designs themselves provide the most plausible explanation for the different findings. In HOPE and EUROPA, patients were assigned to receive relatively high doses of ramipril (10 mg) and perindopril (8 mg), and these doses were achieved rapidly and in a high proportion of patients. In PEACE, trandolapril was up-titrated to the target 4 mg (the dose associated with a 22% reduction in all-cause mortality and a trend towards decreased incidence of MI during a 2-year follow-up in the earlier TRACE study16) only 6 months after randomization, and only 57.8% of patients assigned to trandolapril received target dose at 3 years.3 At 3 years, in a similar population, 93% of patients were at target dose of perindopril in EUROPA. Additionally, the statistical power of the PEACE study may have been inadequate to demonstrate outcome improvement compared with the larger (and longer on target dose) HOPE and EUROPA. The event rate was lower than that predicted in PEACE; consequently, revascularization (a relatively ‘soft ’ or non-disease-specific endpoint that depends on practice styles and therefore is potentially insensitive to treatment) was added to the primary endpoint as the trial progressed. Finally, a greater number of patients lost to follow-up in PEACE than in the earlier trials aggravates the possibility of a type II error (failure to detect a difference when an actual difference exists).
Thus, PEACE did not show benefits from adding trandolapril to current customary medication of patients with CAD and relatively well-preserved left ventricular function. However, these results cannot be employed to draw inferences about the effects of ramipril or perindopril in patients with clinically stable CAD corresponding to the populations in which they were tested in HOPE and EUROPA, which overlap importantly with the PEACE population. Furthermore, there have now been a number of meta-analyses published summarizing the results of long-term randomized controlled trials investigating the effects of ACE-inhibitors in patients with CAD without heart failure or left ventricular systolic dysfunction.17–19 The evidence provided by these meta-analyses continue to show a favourable outcome in terms of major vascular events in such patients. Importantly, these positive findings in patients normally considered to be in intermediate risk complement the findings already obtained in much higher risk patients with heart failure or left ventricular dysfunction.
Consistent with this view, both the European Medicines Agency (EMEA) and the United States Food and Drug Administration (USFDA), which approved ramipril for secondary prevention for CAD shortly after the HOPE results became available, recently extended the indication of perindopril similarly: on 27 July 2005, the EMEA found that perindopril is indicated for reduction of cardiac events in patients with stable CAD with prior MI and/or revascularization; less than 1 month later, on August 23, the USFDA approved the use of perindopril for patients with stable CAD to reduce the risk of cardiovascular mortality or non-fatal MI (irrespective of prior MI and/or revasculatization), noting specifically that the drug can be used together with antiplatelet, antihypertensive, or lipid-lowering therapy.
Which patients with CAD but without heart failure or left ventricular dysfunction should be given these drugs will depend on physician and patient preferences as well as on pharmoco-economic considerations.20,21 Nevertheless, at the very least, among patients with CAD and other indications for ACE-inhibition employed in HOPE and EUROPA [hypertension, diabetes, and/or CAD with reasonably well-preserved left ventricular function and moderate (1%/year) to high (5%/year) risk of future events], perindopril and ramipril, in doses derived from the clinical trials, should be considered for prevention of coronary events consistent with their current labelling.22
Conflict of interest: K.F., R.F., and J.S.B. are paid consultants to Laboratoires Servier; S.Y. has consulted with Aventis and Abbott Laboratories. None of the authors has a stock ownership, equity, or contract of employment, position on a company board, or holds or is applying for a relevant patent. The manuscript was generated specifically by the interest of the authors and not by request from any manufacturer. None of the authors was paid by any source external to the medical schools of which they are faculty members for writing this article. All authors contributed to the conceptualization and writing/editing of this article and approved the final version.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
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