Abstract

Large clinical trials have documented the efficacy of angiotensin-converting enzyme (ACE) inhibitors in a broad spectrum of patients with or at risk of cardiovascular disease. In particular, ACE inhibitors improve myocardial infarction- and stroke-free survival in patients with heart failure, impaired left ventricular function, acute myocardial infarction, stable coronary disease, stroke, hypertension, and diabetes. Part of this benefit is related to blood pressure reduction, but it is likely that other factors specific to ACE inhibitors also play a role. Since there are important pharmacological differences among ACE inhibitors, those with documented efficacy in specific indications should be chosen. In the combined analysis using individual data from 29 463 patients from ADVANCE, EUROPA, and PROGRESS, perindopril-based treatment has been shown to significantly reduce the risk of mortality and major cardiovascular events among patients with various levels of cardiovascular risk. Evidence for cardiovascular protection with perindopril was consistent in subgroups of patients with different clinical characteristics, concomitant medication use, and across all strata of baseline blood pressure.

Introduction

Angiotensin-converting enzyme (ACE) inhibitors were introduced a few decades ago for treatment of hypertension and heart failure. In addition to symptomatic improvement and improved survival, studies in patients with heart failure or left ventricular dysfunction demonstrated a reduction in myocardial infarction and other coronary events in patients receiving the ACE inhibitors ramipril, trandolapril, enalapril, and captopril.1–6 These observations were the basis for subsequent studies with ramipril, perindopril, and trandolapril in patients with coronary disease without significant left ventricular dysfunction, in patients with other vascular disease, and in patients at risk of coronary artery disease.7–10 Furthermore, all but one study,9 in patients with a history of cerebrovascular disease11 and diabetes mellitus,12 demonstrated a reduction in cardiovascular events during follow-up in patients receiving an ACE inhibitor.

In experimental pharmacological studies, ACE inhibitors differ, for example, in tissue penetration.13 However, it is uncertain whether these differences are meaningful in clinical practice. Nevertheless, it is prudent to select ACE inhibitors of proven clinical efficacy in the relevant patient groups.

Hypertension

The ASCOT-BPLA trial compared two treatment regimens in patients with hypertension who had a moderate risk of developing cardiovascular events.14 A total of 19 270 patients were randomized to receive either atenolol 50–100 mg, with the addition of bendroflumethiazide 1.25–2.5 mg and potassium as required, or amlodipine 5–10 mg, with the addition of perindopril 4–8 mg as required to control blood pressure. The trial was stopped after a median follow-up of 5.5 years because the amlodipine–perindopril regimen, compared with atenolol–bendroflumethiazide, reduced all-cause mortality: event rate per 1000 patient years 13.9 and 15.5, respectively, relative risk reduction (RRR) 11%, P = 0.025. Furthermore, a reduction in other cardiovascular end points was observed, including non-fatal myocardial infarction and fatal coronary heart disease, non-fatal and fatal stroke, and revascularization. Nevertheless, reduction in the primary end point (silent and non-silent myocardial infarction and fatal coronary heart disease) was not statistically significant, with event rate per 1000 patient years 9.1 and 8.2 in the atenolol- and amlodipine-based treatment groups, respectively (RRR 10%, P = 0.105). During the trial, systolic and diastolic pressures were lower in patients treated with amlodipine–perindopril than with atenolol–thiazide. The mean difference was 2.7/1.9 mmHg. Overall, the ‘new’ regimen of calcium antagonist and ACE inhibitor was superior to the ‘old’ regimen of β-blocker and diuretic.

Diabetes mellitus

In ADVANCE, 11 140 patients with type 2 diabetes were randomized to treatment with a fixed combination of perindopril plus indapamide compared with placebo in addition to current therapy.12 Perindopril–indapamide resulted in a reduction in blood pressure (5.2/2.2 mmHg). The combined primary end point of major macrovascular and microvascular events was reduced by perindopril–indapamide in comparison with placebo (15.5% vs. 16.8%, respectively, RRR 9%, P = 0.041). In particular, there was a reduction in renal events, but also in coronary events and total mortality. The results were consistent across all clinical subgroups analysed.

ADVANCE also studied a more intensive glucose-lowering therapy compared with standard therapy. The more intensive therapy, including gliclazide-MR, significantly improved the primary end point of combined micro- and macrovascular events. This was driven by the reduction in microvascular events, particularly albuminuria, while no effect of intensive glucose lowering was observed on the occurrence of cardiovascular death or myocardial infarction at 5 years of follow-up. Similarly, two other recent studies15,16 did not find a reduction in cardiovascular death, myocardial infarction, or stroke with a more intensive glucose-lowering strategy at 2–5 years of follow-up. In the ACCORD study, mortality appeared even higher with intensive glucose control. These results demonstrate that, in addition to management of glucose levels in patients with Type 2 diabetes, management of blood pressure and other measures to reduce the risk of heart disease or stroke are equally important. The optimal degree of glucose control, and the way in which normal glucose levels should be achieved, is still a matter for debate after the conflicting results of ADVANCE and ACCORD.

Cerebrovascular disease

The PROGRESS study analysed 6105 patients randomized to a regimen of perindopril or perindopril plus indapamide or placebo.11 Active treatment reduced blood pressure and reduced the primary end point of fatal and non-fatal stroke from 13.8 to 10.1% (RRR 28%, P < 0.0001). Total major vascular events were reduced in patients with elevated blood pressure and in those with normal blood pressure at entry.

Stable coronary disease

Reduction in cardiovascular death and non-fatal myocardial infarction with an ACE inhibitor was demonstrated in the HOPE and EUROPA trials with ramipril and perindopril, respectively.7,8 In contrast, no benefit was observed in patients treated with trandolapril in the PEACE study.9 Nevertheless, a meta-analysis of these three trials, with a total of 29 805 patients, clearly demonstrated a consistent reduction in all-cause mortality (7.8% vs. 8.9%, RRR 14%, P = 0.0004), non-fatal myocardial infarction (5.3% vs. 6.4%, RRR 18%, P = 0.0001), fatal and non-fatal stroke (2.2% vs. 2.8%, RRR 23%, P = 0.0004), and hospitalization for heart failure (2.1% vs. 2.7%, RRR 23%, P = 0.0007) (Table 1).10 No sound explanation could be found for the absence of benefit in PEACE. It has been suggested that this might be due to more intensive concomitant medical therapy or more frequent coronary revascularization in the latter trial, compared with HOPE and EUROPA.9 However, additional analyses of these two trials demonstrated a consistent benefit with ramipril and perindopril in all patient subgroups, across the whole spectrum of risk, independent of impaired kidney function or concomitant treatment with statins, β-blockers, or revascularization (Figure 1).7 Accordingly, the investigators concluded that the absence of treatment benefit with trandolapril in PEACE was most likely a chance finding.10

Figure 1

Consistent benefit in EUROPA, across risk levels. Consistent reduction in the primary end point (cardiovascular death, myocardial infarction, or resuscitated cardiac arrest) across the whole spectrum of risk, using a multivariate risk model.21 Patients were stratified in tertiles.

Figure 1

Consistent benefit in EUROPA, across risk levels. Consistent reduction in the primary end point (cardiovascular death, myocardial infarction, or resuscitated cardiac arrest) across the whole spectrum of risk, using a multivariate risk model.21 Patients were stratified in tertiles.

Table 1

Treatment effect in HOPE, EUROPA, PEACE

 ACE inhibitor events (%) Control events (%) Odds ratio (95% CI) P-value 
Total mortality 
 HOPE 10.4 12.2 0.83 (0.73–0.95) 0.0047 
 EUROPA 6.1 6.9 0.89 (0.77–1.02) 0.098 
 PEACE 7.2 8.1 0.88 (0.75–1.04) 0.13 
 Total 7.8 8.9 0.86 (0.79–0.94) 0.0004 
Non-fatal myocardial infarction 
 HOPE 5.9 7.5 0.77 (0.65–0.90) 0.0013 
 EUROPE 4.8 6.2 0.77 (0.66–0.90) 0.0010 
 PEACE 5.3 5.3 1.00 (0.83–1.21) 0.98 
 Total 5.3 6.4 0.82 (0.75–0.91) 0.0001 
Fatal + non-fatal stroke 
 HOPE 3.4 4.9 0.68 (0.55–0.84) 0.0003 
 EUROPA 1.6 1.7 0.96 (0.73–1.27) 0.77 
 PEACE 1.7 2.2 0.76 (0.56–1.04) 0.089 
 Total 2.2 2.8 0.77 (0.66–0.89) 0.0004 
 ACE inhibitor events (%) Control events (%) Odds ratio (95% CI) P-value 
Total mortality 
 HOPE 10.4 12.2 0.83 (0.73–0.95) 0.0047 
 EUROPA 6.1 6.9 0.89 (0.77–1.02) 0.098 
 PEACE 7.2 8.1 0.88 (0.75–1.04) 0.13 
 Total 7.8 8.9 0.86 (0.79–0.94) 0.0004 
Non-fatal myocardial infarction 
 HOPE 5.9 7.5 0.77 (0.65–0.90) 0.0013 
 EUROPE 4.8 6.2 0.77 (0.66–0.90) 0.0010 
 PEACE 5.3 5.3 1.00 (0.83–1.21) 0.98 
 Total 5.3 6.4 0.82 (0.75–0.91) 0.0001 
Fatal + non-fatal stroke 
 HOPE 3.4 4.9 0.68 (0.55–0.84) 0.0003 
 EUROPA 1.6 1.7 0.96 (0.73–1.27) 0.77 
 PEACE 1.7 2.2 0.76 (0.56–1.04) 0.089 
 Total 2.2 2.8 0.77 (0.66–0.89) 0.0004 

Reduction by ACE inhibitors of major cardiovascular events (mortality, myocardial infarction, and stroke) in three trials in patients with stable coronary artery disease, other vascular disease, or at high risk of cardiovascular disease. Adapted from Dagenais et al.10

Meta-analysis of trials with perindopril-based regimens

A recent meta-analysis of the three largest trials studying perindopril or a perindopril-based regimen (EUROPA, ADVANCE, PROGRESS) demonstrated a significant reduction in all-cause mortality (7.4% vs. 8.2%, RRR 11%, P = 0.006), cardiovascular mortality (4.1% vs. 4.8%, RRR 15%, P = 0.004), and myocardial infarction (3.3% vs. 4.1%, RRR 20%, P < 0.001) compared with placebo therapy.17 The reduction in cardiovascular events was observed irrespective of the type of patients (diabetes mellitus, cerebrovascular disease, or coronary disease, and the level of risk) (Figure 2 and Table 2). These findings were in agreement with the previous meta-analysis of trials in stable coronary disease (Table 1).

Figure 2

Survival in ADVANCE, EUROPA, PROGRESS. Time course of total mortality (upper panel) and major cardiovascular events (lower panel, cardiovascular mortality, myocardial infarction, or stroke) in a combined analysis of three trials of perindopril-based therapy. Adapted from Brugts et al.17

Figure 2

Survival in ADVANCE, EUROPA, PROGRESS. Time course of total mortality (upper panel) and major cardiovascular events (lower panel, cardiovascular mortality, myocardial infarction, or stroke) in a combined analysis of three trials of perindopril-based therapy. Adapted from Brugts et al.17

Table 2

Treatment effect in ADVANCE, EUROPA, PROGRESS

 Perindopril-based regimen events (%) Placebo events (%) Hazard ratio (95% CI) P-value 
Total mortality 
 ADVANCE 7.3 8.5 0.86 (0.75–0.98) 0.026 
 EUROPA 6.1 6.9 0.89 (0.77–1.02) 0.098 
 PROGRESS 10.0 10.4 0.96 (0.82–1.12) 0.596 
 Total 7.4 8.2 0.89 (0.82–0.96) 0.006 
Non-fatal myocardial infarction 
 ADVANCE 2.4 2.4 1.01 (0.80–1.29) 0.91 
 EUROPE 4.8 6.2 0.77 (0.66–0.90) 0.001 
 PROGRESS 2.0 3.1 0.62 (0.44–0.86) 0.003 
 Total 3.3 4.1 0.80 (0.71–0.90) 0.001 
Fatal + non-fatal stroke 
 ADVANCE 3.9 3.9 0.98 (0.82–1.19) 0.76 
 EUROPA 1.6 1.7 0.96 (0.73–1.27) 0.77 
 PROGRESS 10.1 13.8 0.72 (0.62–0.83) 0.001 
 Total 4.2 5.0 0.82 (0.74–0.92) 0.002 
 Perindopril-based regimen events (%) Placebo events (%) Hazard ratio (95% CI) P-value 
Total mortality 
 ADVANCE 7.3 8.5 0.86 (0.75–0.98) 0.026 
 EUROPA 6.1 6.9 0.89 (0.77–1.02) 0.098 
 PROGRESS 10.0 10.4 0.96 (0.82–1.12) 0.596 
 Total 7.4 8.2 0.89 (0.82–0.96) 0.006 
Non-fatal myocardial infarction 
 ADVANCE 2.4 2.4 1.01 (0.80–1.29) 0.91 
 EUROPE 4.8 6.2 0.77 (0.66–0.90) 0.001 
 PROGRESS 2.0 3.1 0.62 (0.44–0.86) 0.003 
 Total 3.3 4.1 0.80 (0.71–0.90) 0.001 
Fatal + non-fatal stroke 
 ADVANCE 3.9 3.9 0.98 (0.82–1.19) 0.76 
 EUROPA 1.6 1.7 0.96 (0.73–1.27) 0.77 
 PROGRESS 10.1 13.8 0.72 (0.62–0.83) 0.001 
 Total 4.2 5.0 0.82 (0.74–0.92) 0.002 

Major cardiovascular events (mortality, myocardial infarction, and stroke) in three trials with perindopril-based treatment. Adapted from Brugts et al.17

Although the reduction in vascular events was consistent across the trials, it should be appreciated that patients with a history of disease involving a specific vascular bed are at increased risk for recurrent events in the same area. Thus patients with a history of coronary disease, as in EUROPA, are at greater risk of (recurrent) myocardial infarction, while stroke is infrequent. In contrast, stroke rates are high in patients with a history of cerebrovascular disease, as in PROGRESS and HOPE.

Angiotensin-converting enzyme inhibitors and/or angiotensin II blockers

ACE inhibitors and angiotensin II receptor blockers have different effects on the renin–angiotensin–aldosterone system. The former reduce the formation of angiotensin and the latter block the main effect of angiotensin. Both approaches result in lowered blood pressure. Furthermore, ACE inhibitors increase the level of bradykinin. The different pharmacological effects of these two classes of drugs are also likely to affect their clinical effects, and it has been suggested that a combination of the two might be particularly effective. Yet several trials in patients with heart failure did not find a benefit with such a combination, while event rates were similar in patients receiving an ACE inhibitor or an angiotensin II receptor blocker (Table 3).18,19 So far, no comparative trials have been conducted in patients with diabetes or stable coronary disease. Accordingly, in such patients, ACE inhibitors remain the drugs of choice, with angiotensin II receptor blockers as an alternative in patients who do not tolerate the former.

Table 3

ACE inhibitors and angiotensin II receptor blockers

 ACE inhibitor events (%) ARB events (%) Combination events (%) 
Total mortality 
 ONTARGET 11.8 11.6 12.5 
 VALIANT 16.0 16.8 16.9 
CV mortality, myocardial infarction, stroke, or heart failure 
 ONTARGET 16.5 16.7 16.3 
 VALIANT 33.4 32.8 32.1 
 ACE inhibitor events (%) ARB events (%) Combination events (%) 
Total mortality 
 ONTARGET 11.8 11.6 12.5 
 VALIANT 16.0 16.8 16.9 
CV mortality, myocardial infarction, stroke, or heart failure 
 ONTARGET 16.5 16.7 16.3 
 VALIANT 33.4 32.8 32.1 

Total mortality and major cardiovascular events in two trials comparing an ACE inhibitor, an angiotensin II receptor blocker and a combination of both. No significant differences were observed among the treatment groups.

Effects of angiotensin-converting enzyme inhibitors beyond blood pressure lowering

Although ACE inhibitors are effective blood pressure-lowering agents, the ASCOT-BPLA investigators suggested that part of the benefit of the amlodipine–perindopril regimen might be independent of blood pressure.14 Indeed, the reduction in cardiovascular events in ADVANCE, EUROPA, and PROGRESS was observed in patients with mild hypertension and in patients with normal blood pressure.17 The meta-analysis by the Blood Pressure Lowering Treatment Trialists' Collaboration suggested that ACE inhibitors reduce events more than might be expected from the effect on blood pressure alone.20 This might be an advantage of ACE inhibitors over angiotensin II receptor blockers, although in comparative trials similar event rates were observed for both groups of drugs, as summarized in Table 3. Additional studies of the pharmacology of both classes of drugs, and of clinical efficacy in different groups of patients, are warranted, including a pharmacogenetic approach.

In conclusion, ACE inhibitors remain the drugs of choice for a broad spectrum of patients with or at risk of cardiovascular disease. Since there are important pharmacological differences among ACE inhibitors, those with documented efficacy, such as ramipril and perindopril, should be chosen.

Funding

Netherlands Heart Foundation.

Conflict of interest: none declared.

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