Which patients would benefit the most from the perindopril–amlodipine combination?
Department of Coronary Artery Disease and Intensive Cardiac Care, Hôpital Européen Georges Pompidou, Assistance Publique des Hôpitaux de Paris, Université Paris 5 René Descartes, 20 rue Leblanc, 75015 Paris, France
* Corresponding author. Tel: +33 156093714. E-mail address: nicolas.danchin{at}egp.aphp.fr
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Abstract |
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In the recent Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm trial, the amlodipine ± perindopril strategy resulted in fewer deaths and cardiovascular events than an atenolol ± thiazide strategy. Because of the intrinsic properties of both angiotensin-converting enzyme inhibitors, particularly in terms of secondary prevention of ischaemic heart disease, and calcium-channel blockers, in terms of anti-anginal properties, the combination of amlodipine and perindopril should prove particularly beneficial in patients with coronary artery disease and either hypertension or anginal symptoms. In addition, both classes of medications have a favourable metabolic profile and have been shown to reduce the occurrence of new-onset diabetes mellitus in a variety of clinical situations. Finally, the impact of the amlodipine ± perindopril combination on central aortic pressure suggests a particular relevance in situations of increased central pulse pressure, such as elderly populations or patients with chronic kidney disease. Therefore, the amlodipine ± perindopril combination is likely to offer important clinical benefits in a number of fairly common clinical conditions.
Key Words: Combination therapy • Amlodipine • Perindopril • Coronary artery disease • Hypertension • Diabetes mellitus
The Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA) trial showed a reduction in mortality, and in a variety of important clinical endpoints, when hypertensive patients at cardiovascular risk were treated with an amlodipine ± perindopril-based regimen, compared with a reference treatment with atenolol and thiazide diuretics.1 The study population in the ASCOT trial consisted of hypertensive patients with at least three additional risk factors [including left ventricular (LV) hypertrophy, diabetes mellitus, history of stroke, or peripheral artery disease]. Patients with a history of myocardial infarction (MI) were excluded from the trial. Subgroup analyses showed that the beneficial effects of the amlodipine ± perindopril regimen were homogeneous among all subsets of patients, within the initial characteristics of the population included. But beyond the population of the ASCOT trial, there are many reasons to think that the amlodipine ± perindopril combination could be particularly relevant in specific patient populations.
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Which patients would benefit from perindopril and angiotensin-converting enzyme inhibitors? |
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Four main populations of patients benefit from angiotensin-converting enzyme (ACE) inhibitors.
Patients with hypertension
ACE inhibitors were first developed for the treatment of hypertension, for which they remain the cornerstone of therapy. Early morbidity–mortality trials of ACE inhibitors in hypertension, such as STOP-HT2 and Captopril Prevention Project, demonstrated that the benefits of ACE inhibitors are equivalent to those of earlier established antihypertensive agents—diuretics and beta-blockers. The later Antihypertensive and Lipid-Lowering treatment to prevent Heart Attach Trial (ALLHAT) trial found a similar effect on major cardiovascular outcomes with an ACE inhibitor in comparison with a thiazide diuretic, despite significantly greater blood pressure reduction with the diuretic. According to the recent guidelines, among classes of antihypertensive agents ACE inhibitors have the broadest spectrum of use, and are particularly recommended in hypertensive patients with concomitant subclinical organ damage (LV hypertrophy, microalbuminuria), clinical events (previous MI, stroke, heart failure, atrial fibrillation), or conditions (diabetes mellitus, metabolic syndrome). The Blood Pressure Lowering Treatment Trialists Collaboration (BPLTTC) meta-regression analysis (Lancet 2003) has shown reductions of 28% in stroke, 20% in coronary heart disease, and 22% in major cardiovascular events with ACE inhibitors, compared with placebo. More recently, ACE inhibitors were found to provide blood pressure-independent reduction in coronary heart disease (BPLTTC. J Hypertens 2007). Finally, the ASCOT- BPLA was the first trial to show superior effect of newer antihypertensive therapy, including ACE inhibition, on reduction of total and cardiovascular mortality in comparison with the traditional approach based on a beta-blocker and a thiazide diuretic. In ASCOT-BPLA, the amlodipine ± perindopril regimen significantly reduced total mortality by 11%, major cardiovascular events and procedures by 16%, and new-onset diabetes by 30%, in comparison with the atenolol ± thiazide regimen.
Patients with coronary artery disease
ACE inhibitors have long demonstrated their efficacy in patients with coronary artery disease (CAD) and LV dysfunction. Several meta-analyses,2–4 based on the results of the Studies of Left Ventricular Dysfunction, Survival and Ventricular Enlargement, Acute Infarction Ranipril Efficacy, and TRAndolapril Cardiac Evaluation trials, have shown that using ACE inhibitor therapy in CAD patients with LV dysfunction led to a 20% reduction in all-cause mortality, with concomitant reductions in severe cardiac events such as re-infarction or re-admission for congestive heart failure. More recently, three large, randomized, controlled trials [Heart Outcomes Prevention Evaluation (HOPE), European Trial on Reduction of Cardiac events with Perindopril in stable coronary Artery disease (EUROPA), Prevention of Events with Angiotensin-Converting Enzyme Inhibition (PEACE)] and four additional smaller trials tested the hypothesis that ACE inhibitors should also be beneficial in patients without LV dysfunction. In the meta-analyses of these trials,4,5 the use of ACE inhibitors was associated with a 14% reduction in all-cause mortality, a 19% decrease in cardiovascular mortality, an 18% decrease in (re)infarction, and a 23% decrease in the risk of stroke (Table 1). The EUROPA trial specifically tested the role of high-dose perindopril (8 mg/day) in stable CAD patients without signs of heart failure or LV dysfunction.6 The use of perindopril was associated with a 20% decrease in the primary endpoint of the trial (cardiovascular death, myocardial infraction, or resuscitated cardiac arrest) at 4.2 years. Interestingly, a favourable trend was noted for all individual components of the primary endpoint, and the benefit was homogeneous, whatever concomitant medications were used. In particular, there was no heterogeneity whether the patients received calcium-channel blockers or not at baseline. The PERindopril-Thrombosis, InflammatioN, Endothelial Dysfunction and Neurohormonal Activiation Trial and PERindopril's proSPective Effect of Coronary aTherosclerosis by IntraVascular ultrasound Evaluation substudies of EUROPA have shown that perindopril has beneficial effects on endothelial function and atherosclerotic plaque composition, which provides insight into the mode of action of ACE inhibition in CAD (references: Ceconi, Cardiovasc Res 2007; Rodriguez-Granillo, Eur Heart J 2007). Finally, early use of ACE inhibitors in patients with acute MI was also beneficial, with a 7% reduction in 30-day mortality and a reduction in the risk of developing heart failure.7
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These compelling results led to the recommendation that patients with CAD should receive ACE inhibitors, whatever their LV systolic function might be. In the recent guidelines of the European Society of Cardiology for patients with stable angina, which were prepared before the results of the most recent meta-analyses were published, ACE inhibitor treatment is considered a level I-A recommendation for patients with concomitant indications for their use (i.e. patients with hypertension, diabetes, previous MI, and LV systolic dysfunction) and a level IIa-B recommendation for all the patients with stable angina and proven CAD.8
Patients with congestive heart failure
There is overwhelming evidence of the benefits of ACE inhibitor therapy in patients with congestive heart failure, whatever their underlying cardiac conditions might be.9 All guidelines recommend the use of ACE inhibitors as first-line therapy for all patients with heart failure and LV systolic dysfunction, and no specific contraindication. However, a recent population-based study doubted a class effect of ACE inhibitors in elderly patients with congestive heart failure, as the probability of survival at 2 years was significantly lower for patients who were prescribed with enalapril or captopril (Pilot, Can Med Assoc J 2008), suggesting that some ACE inhibitors may have a more powerful effect than others.
Patients with diabetes
There is a strong interaction between the renin–angiotensin system and glucose metabolism. In the HOPE and PEACE trials, ACE inhibitor therapy was shown to decrease the occurrence of new-onset diabetes in non-diabetic patients with stable CAD.5 In an analysis of published trials, testing the effect of different antihypertensive medications in hypertensive patients, use of ACE inhibitors was associated with a lower risk of developing diabetes during the course of the trials, compared with placebo; in contrast, diuretics and beta-blockers were associated with a higher risk of developing new-onset diabetes.10
More importantly still, ACE inhibitors have been shown to reduce microvascular complications in hypertensive patients with either type 1 or type 2 diabetes mellitus. The recent ESC–EASD guidelines11 recommend that intensive antihypertensive treatment be used in diabetic patients and that either ACE inhibitors or angiotensin receptor blockers be part of the therapeutic regimen (type IA recommendation). They suggest that these drugs should also be used preferentially in patients with impaired fasting glucose or the metabolic syndrome.
More recently, the Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation trial12 has shown that type 2 diabetic patients with associated risk factors had a lower rate of combined microvascular and macrovascular endpoint when they received a combination of perindopril and indapamide on top of their usual treatment. This beneficial effect was observed in both hypertensive and normotensive patients. In addition, a significant reduction in all-cause mortality was observed.
Overall, there is strong evidence of the beneficial effects of ACE inhibitor therapy in many subsets of diabetic atients.
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Which patients would benefit from amlodipine and calcium-channel blockers? |
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Patients with hypertension
Controlled ONset Verapamil InvestigatioN of Cardiovascular End points (CONVINCE)13 and ALLHAT14 were two large trials for hypertensive patients, which compared a calcium antagonist antihypertensive treatment (verapamil in CONVINCE, amlodipine in ALLHAT) with a conventional strategy of beta-blocker or thiazide diuretic. In both trials, there was no significant benefit from the calcium antagonist strategy compared with the reference treatment, although it must be noted that blood pressure control with amlodipine in ALLHAT was substantially less satisfactory than with chlorthalidone, presumably because of the very low doses used at entry. In ALLHAT, amlodipine treatment was associated with a non-significant 4% reduction in all-cause death. In contrast, the CONVINCE trial was stopped prematurely by the sponsor when it appeared that demonstrating the superiority of the verapamil-based strategy was highly unlikely, as a 9% increase in cardiovascular death was observed. A meta-analysis of placebo-controlled trials of antihypertensive agents (BPLTTC, Lancet 2003) concluded that calcium-channel blockers were associated with reductions of 38% in stroke, 22% in coronary heart disease, and 18% in major cardiovascular events. A recent meta-analysis (Verdecchia, Hypertension 2005) has found that calcium-channel blockers may provide a blood pressure-independent reduction in strokes. Bearing in mind a question raised about the safety of calcium-channel blockers in the mid-1990s, it is worth pointing out that both the ALLHAT and ASCOT trials have demonstrated that long-term treatment with amlodipine is safe.
Beyond their antihypertensive role, calcium-channel blockers are potent anti-anginal medications and their role in CAD has been assessed in a number of randomized, controlled trials.
Patients with stable coronary artery disease
Calcium-channel blockers have arterial vasodilatory capacities; they increase coronary blood flow, decrease myocardial oxygen demand, and have additional antispastic properties. Among calcium-channel blockers, there is extensive evidence of amlodipine's anti-anginal properties.15 Compared with atenolol, amlodipine has a similar anti-ischaemic efficacy as assessed by treadmill testing.16 Amlodipine also reduces ambulatory myocardial ischaemia in patients with stable CAD. Finally, the combination of amlodipine and beta-blockers improves ischaemic control, compared with either medication used alone.17
The International Nifedipine Trial on Antiatherosclerotic Therapy was carried out at the end of the 1980s and assessed the progression of CAD, using repeated quantitative coronary angiography 3 years apart, in patients receiving either nifedipine or placebo.18 There was no change in the progression or regression of the existing coronary artery lesions. Fewer new lesions, however, were detected in the nifedipine group. Likewise, in the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT) trial,19 which also used quantitative coronary angiography to assess CAD progression, no difference was found between amlodipine and placebo, after a 36-month observation eriod. In the Coronary AngioPlasty Amlodipine REStenosis study (CAPARES) trial,20 the effect of amlodipine on restenosis following percutaneous coronary angioplasty (mainly balloon angioplasty) was not different from that of placebo.
More recently, a substudy of the CAMELOT trial evaluated progression of CAD in 274 normotensive coronary patients randomized to placebo, enalapril, or amlodipine, using intravascular ultrasound.21 A trend to less progression of CAD was noted in the amlodipine group, compared with placebo; CAD progressed in placebo-treated patients, but not in the amlodipine group.
In an ancillary study of the Intervention as a Goal in Hypertension Treatment trial,22 nifedipine stopped intima-media thickness (IMT) progression in hypertensive patients, while co-amilozide did not. At the end of the 4-year treatment period, a significant difference in the progression of carotid IMT was observed in favour of nifedipine. In the PREVENT trial, amlodipine was also associated with a slower progression of carotid IMT, compared with placebo.19
In the ACTION trial, which included patients with stable angina and no significant LV systolic dysfunction, the long-acting formulation of nifedipine was associated with a reduction in the combined cardiovascular events including myocardial revascularization procedures, coronary angiography, and stroke.23 There was, however, no benefit in terms of mortality or MI. Similar results were found in several randomized, controlled trials testing the effect of amlodipine on progression of atherosclerosis (PREVENT, CAMELOT, CAPARES): no difference in all-cause mortality was observed, but fewer cardiovascular events were noted (Table 2).
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Use of calcium antagonists is not recommended in patients with severe LV dysfunction. In the Prospective Randomized Amlodipine Survival Evaluation (PRAISE) trial, however, amlodipine was tested against placebo in patients with chronic congestive heart failure and LV ejection fraction of 30% or less.24 Overall, amlodipine had no impact on mortality. In the ischaemic stratum of the trial, mortality and risk of MI did not differ between amlodipine and placebo, suggesting that no deleterious effect of amlodipine existed, even in patients with severe LV dysfunction. Note, however, that because the trial was carried out in the early 1990s, very few, if any, patients received beta-blocking agents, which are now recommended as first-line therapy in such patients with congestive heart failure.
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Which patients would benefit from the perindopril–amlodipine combination? |
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The specific mode of action of the amlodipine–perindopril strategy: insights from the ASCOT-CAFÉ substudy
In ASCOT-BPLA, the amlodipine–perindopril strategy had a slightly more marked effect on peripheral blood pressure than the atenolol–thiazide strategy (about 2 mmHg), but this difference was unlikely to explain the 11% reduction in mortality and the 16% reduction in all the cardiovascular events and procedures. In contrast, as documented in the Conduit Artery Function Evaluation (CAFÉ) substudy, the reduction in central aortic pressures was much more substantial (4.3 mmHg difference in central aortic systolic blood pressure, 3.0 mmHg difference in central aortic pulse pressure). In a post hoc analysis, central aortic pulse pressure was correlated with a composite endpoint of cardiovascular events and procedures and development of renal impairment. From this substudy, it appears that different antihypertensive strategies leading to roughly similar reductions in brachial artery pressure could have a different impact on central pressures, the role of which appears particularly important in the development of CAD and its complications. In fact, central pulse pressure has been shown to be correlated with the presence and extent of CAD,25–27 and with the occurrence of complications in patients with known CAD.28 Overall, the amlodipine–perindopril strategy had a better capacity than the atenolol–thiazide strategy to reduce central aortic pressures, thereby potentially explaining part or all of the reduction in cardiovascular events noted in the ASCOT-BPLA trial.
The International Verapamil-TrandoLapril Study (INVEST)29 and ASCOT-BPLA1 trials compared a calcium antagonist–ACE inhibitor strategy with an atenolol–thiazide strategy. The INVEST trial included hypertensive patients with CAD and the ‘challenger’ regimen was based on the combination of verapamil and trandolapril.29 The ASCOT-BPLA included hypertensive patients with concomitant risk factors and used the amlodipine–perindopril combination. In INVEST, 32% of the patients had a history of MI, while history of infarction was an exclusive criterion in ASCOT-BPLA. INVEST patients had a worse risk profile than ASCOT-BPLA patients, with annual mortality rates of 2.9 vs. 1.6%, respectively. In spite of this higher risk, INVEST showed no difference in mortality between the two groups (relative risk of death 0.98; relative risk of cardiovascular death: 1.00). In contrast, the ASCOT-BPLA trial was stopped prematurely because a significant reduction in mortality was observed in the amlodipine–perindopril group (8 vs. 9%, hazard ratio, 0.89; 95% confidence interval, 0.81–0.99; P = 0.0247). These findings suggest that a class effect is unlikely for the combination of a calcium antagonist and an ACE inhibitor, as only the amlodipine–perindopril strategy proved superior to the conventional beta-blocker–thiazide strategy.
Bearing in mind these specificities of both amlodipine and perindopril, one may hypothesize that some types of patients would particularly benefit from the use of amlodipine–perindopril combination.
Hypertensive patients
In the recent ESC–ESH guidelines,30 low-dose combination therapy is suggested as the first-line treatment when initial blood pressure is in the range of grade 2 or 3 (i.e. systolic blood pressure 
160 mmHg or diastolic blood pressure 100 mmHg) or when total cardiovascular risk is high or very high. As it has been shown that ACE inhibitors reduce the risk of incident coronary events (cardiac death or MI) while calcium-channel blockers reduce the risk of stroke,31 the combination of these two classes appears to be a logical choice to provide optimal cardiovascular protection.
Patients at risk of diabetes
Patients with impaired fasting glucose and diabetic patients are also likely to benefit greatly from the combination of both medications. Compared with beta-blockers or diuretics, calcium-channel blockers reduce the risk of developing new-onset diabetes.10 ACE inhibitors also have the capacity to delay onset of diabetes in patients with CAD5 and in hypertensive patients.10 In addition, ACE inhibitors have a beneficial effect in diabetic patients. Therefore, and in accordance with the ESC–ESH recommendations,30 the amlodipine–perindopril combination is likely to be of particular interest in hypertensive diabetic patients or in hypertensive patients with impaired fasting glucose. This has been confirmed by the ASCOT-BPLA trial: an analysis in the 14 120 patients at risk of developing diabetes at baseline showed that the use of the combined amlodipine–perindopril strategy, in comparison with the atenolol–thiazide strategy, was associated with a significant reduction in the risk of developing new-onset diabetes (odds ratio, 0.66; 95% confidence interval, 0.59–0.74).32
Elderly hypertensive patients
Because of the potential prognostic importance of central aortic pulse pressure, the amlodipine–perindopril strategy should be of benefit in all clinical circumstances associated with high aortic pulse pressure. In particular, this strategy should prove particularly beneficial in patients with chronic renal impairment33 and in elderly patients. In keeping with this hypothesis, in the ASCOT- BPLA trial, the reduction in cardiovascular events and procedures was slightly more marked in patients aged 60 or more than in younger patients.1
Patients with coronary artery disease
One of the most obvious target populations is that of patients with known CAD, either when anginal symptoms are present or in the case of concomitant hypertension. In this population, combining amlodipine and perindopril is likely to provide both anti-atherosclerotic and secondary preventive effects of perindopril, as documented in the EUROPA trial,6 and to improve symptoms, because of the potent anti-anginal action and stroke-preventing effect of amlodipine. In the ASCOT-BPLA trial,1 and in keeping with the present hypothesis, the reduction in cardiovascular events and procedures was slightly more marked in patients with previous vascular disease (odds ratio 0.80 vs. 0.85).
However, patients with a previous MI were excluded from the ASCOT-BPLA trial. As amlodipine had no deleterious effects in patients with severe LV dysfunction of ischaemic origin in the PRAISE trial,24 and as ACE inhibitors are required in patients with CAD and LV dysfunction, the combination of amlodipine and perindopril is a valuable strategy in hypertensive coronary artery patients or those with angina pectoris, even when they have a history of MI. However, amlodipine should be used with care in patients with severe LV dysfunction and should in no case prevent the use of beta-blockers.
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It is now recognized that most hypertensive patients require combination therapy in order to get the most from their antihypertensive treatment, and combination therapy is now recommended as first-line in grade 2 or 3 hypertension or in hypertensive patients at high cardiovascular risk. Among the numerous combinations that a clinician can choose, that of an ACE inhibitor and a long-acting dihydropyridine appears to be of particular relevance. ACE inhibitors, beyond their antihypertensive efficacy, have a documented secondary preventive effect on cardiovascular events in patients with known CAD, and have been shown to reduce the risk of ischaemic heart disease events in hypertensive patients, in comparison with other classes of antihypertensive agents. Calcium-channel blockers have a potent anti-anginal efficacy, and are associated with a reduced risk of stroke, compared with other antihypertensive regimens. Finally, both classes of medications have a favourable metabolic profile, and their combination has a marked impact on the reduction of central blood pressure, which is a strong determinant of cardiovascular events. The combination of amlodipine and perindopril therefore appears to be a logical choice for many patients presenting with hypertension or CAD or both.
Conflict of interest: none declared.
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