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Treatment with angiotensin-converting enzyme inhibitors: insight into perindopril cardiovascular protection

Roberto Ferrari
DOI: http://dx.doi.org/10.1093/eurheartj/sun025 G13-G20 First published online: 1 September 2008


Angiotensin-converting enzyme (ACE) inhibitors have an established role in the treatment of patients across the cardiovascular disease continuum, from uncomplicated hypertension to established cardiovascular disease. The first data showing the efficacy of ACE inhibitors for the prevention of cardiovascular events came from the Heart Outcomes Prevention Evaluation trial with ramipril. Since then a number of other large, randomized, controlled trials have confirmed the beneficial effects of ACE inhibitors on cardiovascular outcomes in a variety of patient groups. In addition, evidence suggests that these beneficial effects of ACE inhibitors occur independently of their blood pressure (BP)-lowering effects, a phenomenon that has not been observed for angiotensin receptor blockers. Among the ACE inhibitors, perindopril has the greatest body of evidence for cardiovascular preventive efficacy from major morbidity–mortality trials (e.g. ADVANCE, ASCOT-BPLA, EUROPA, PREAMI, PEP-CHF, PROGRESS). In addition, perindopril may be the treatment of choice in stable coronary artery disease because of its unique anti-apoptotic activity and protective effects on the endothelium. A current major trend in cardiovascular medicine is the increased use of combination therapies. The data reviewed here suggest that any combination therapy for secondary prevention across the continuum of cardiovascular disease should contain an ACE inhibitor.

  • ACE inhibitors
  • Perindopril
  • Cardiovascular events


It is more than 25 years since angiotensin-converting enzyme (ACE) inhibitors were first used in clinical practice as antihypertensive agents. Today, these compounds also have an important role in various indications across the continuum of cardiovascular disease beyond chronic blood pressure (BP) reduction (Figure 1).1 While the antihypertensive activity of ACE inhibitors tends to be most prominent in patients with renin-dependent hypertension, the general cardiovascular benefits of ACE inhibitors have manifested even in patients without systemic hyperactivity of the circulating renin-angiotensin-aldosterone system (RAAS), suggesting that the inhibition of tissue ACE is also important, particularly for secondary prevention of cardiovascular disease. Importantly, all ACE inhibitors are not the same in terms of their pharmacological, cardiovascular efficacy, and tolerability profiles (see the section on ‘All ACE inhibitors are not the same’).1 Where combination therapy with an ACE inhibitor is required, the best evidence to date was based on the data from large morbidity–mortality trials available for perindopril (Figure 1). The current review explores the available evidence for considering perindopril as an ideal ACE inhibitor when combination therapy is required.

Figure 1

Major morbidity–mortality studies of angiotensin-converting enzyme inhibitors across the continuum of cardiovascular disease. AIRE, Acute Infarction Ramipril Efficacy; ALLHAT, Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial; ASCOT-BPLA, Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm; CAD, coronary artery disease; CAPPP, CAPtopril Prevention Project; CHF, congestive heart failure; CONSENSUS, COoperative North Scandinavian ENalapril SUrvival Study; CVD, cerebrovascular disease; EUROPA, EUropean trial on Reduction Of cardiac events with Perindopril among patients with stable coronary Artery disease; ESRD/F, end-stage renal disease/failure; HOPE, Heart Outcomes Prevention Evaluation; MI, myocardial infarction; PEACE, Prevention of Events with ACE inhibition; PEP-CHF, Perindopril in Elderly People with Chronic Heart Failure; PREAMI, Perindopril and Remodelling in Elderly with Acute Myocardial Infarction; PROGRESS, PeRindopril prOtection aGainst REcurrent Stroke Study; REIN, Ramipril Efficacy in Nephropathy; SAVE, Survival And Ventricular Enlargement; SOLVD, Studies Of Left Ventricular Dysfunction; STOP-H2, Swedish Trial in Old Patients with Hypertension; TRACE, TRAndolapril Cardiac Evaluation; V-HeFT, Vasodilator-Heart Failure Trial. Reproduced from Borer et al. (2007)1 with modification by permission of Oxford Journals.

Angiotensin-converting enzyme inhibitors have proven benefits, beyond blood pressure lowering, in various cardiovascular settings

Results of the earlier trials on ACE inhibitors in hypertension (CAPPP,2 STOP-HT2,3 and ALLHAT4) demonstrated that these drugs have the same BP-lowering efficacy as that of β-blockers, diuretics, and calcium-channel blockers. The Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA),5 compared the cardiovascular preventive efficacy of the combination of amlodipine/perindopril with that of atenolol/bendroflumethiazide in >19 000 patients with hypertension and ≥3 other cardiovascular risk factors. The amlodipine/perindopril vs. β-blocker/thiazide diuretic combination was associated with statistically significant relative risk reductions in the following endpoints: all-cause mortality (−11%; P = 0.025), total cardiovascular events and procedures (−16%; P < 0.0001), fatal and non-fatal stroke (−23%; P = 0.0003), and new-onset diabetes mellitus (−30%; P < 0.0001).5 Subsequent multivariate analyses of ASCOT-BPLA data also revealed that amlodipine/perindopril vs. atenolol/thiazide diuretic therapy significantly reduced the relative risk of new-onset diabetes mellitus [hazard ratio (HR) 0.66; P<0.001], such that over a median follow-up of 5.5 years, the number of patients needed to be treated with amlodipine/perindopril to prevent one case of new-onset diabetes was 30.6

The first proof of the efficacy of ACE inhibitors for the prophylaxis of cardiovascular events came from the results of the Heart Outcomes Prevention Evaluation (HOPE) trial, which demonstrated that the ACE inhibitor ramipril significantly reduced the incidence of cardiovascular events in a wide range of high-risk patients, including those with coronary artery disease (CAD).7 The EUropean trial on Reduction Of cardiac events with Perindopril among patients with stable coronary Artery disease (EUROPA)8 evaluated patients with a generally lower level of cardiovascular risk than in the HOPE study. Nevertheless, EUROPA corroborated and extended the findings of the HOPE study: that is, in the EUROPA trial in >12 000 randomized patients, perindopril [added to standard background therapy with antiplatelet agents (92% of patients), β-blockers (62%), and/or lipid-lowering agents (58%)] significantly reduced relative risk of the composite primary endpoint of cardiovascular death, myocardial infarction (MI), or cardiac arrest by 20% vs. placebo (P = 0.0003; Figure 2).8 Moreover, in the PERindopril-Thrombosis, InflammatioN, Endothelial dysfunction and Neurohormonal activation Trial (PERTINENT),9 a sub-study of EUROPA, human umbilical vein endothelial cells (HUVECs) were incubated with serum taken from EUROPA patients both at baseline and after 1-year treatment with either placebo or perindopril. Perindopril upregulated endothelial nitric oxide synthase (eNOS) protein expression by 19% (not significant) and activity by 27% (P < 0.05); these changes were significantly correlated (r = 0.45 and r = 0.43, respectively; both P < 0.05) with increased blood bradykinin levels. In addition, perindopril vs. placebo reduced the rate of HUVEC apoptosis by 31% (P < 0.01).9 Thus, EUROPA data show a reduction of atherosclerosis progression and the results of PERTINENT confirm perindopril protection of the endothelium.

Figure 2

Time to first occurrence of the composite primary endpoint of cardiovascular death, myocardial infarction, or cardiac arrest during administration of perindopril vs. placebo in the EUROPA trial in more than 12 000 randomized patients with stable coronary artery disease. Error bars depict standard error of mean. Reproduced from Fox et al. (2003)8 by permission of Elsevier.

These effects were independent of the antihypertensive action of perindopril. In EUROPA,8 the benefits of perindopril in terms of cardiovascular outcomes were also manifested in CAD patients whose BP was low or high at study entry, or whose BP was not reduced during the trial. Moreover, PERTINENT9 showed that perindopril improved endothelial dysfunction by increasing bradykinin and reducing angiotensin II levels, thereby restoring the angiotensin II/bradykinin balance.10

The benefits of ACE inhibitors in the post-infarct setting are unequivocal.11,12 For instance, a meta-analysis of data from almost 100 000 patients with acute MI revealed that early ACE inhibition (i.e. administered within 36 h of MI) significantly reduced mortality during the first week and first month post-infarct.11 Long-term studies in post-acute MI patients with left ventricular (LV) dysfunction (ejection fraction <40%), such as the Acute Infarction Ramipril Efficacy (AIRE) trial,13 the TRAndolapril Cardiac Evaluation (TRACE),14 and the Survival And Ventricular Enlargement (SAVE) study,15 confirmed that these benefits are maintained over several years. Furthermore, ACE inhibitors prevent or delay the deleterious post-infarct cardiac remodelling. In the Perindopril and Remodeling in Elderly with Acute MI (PREAMI) trial,12 for example, perindopril significantly reduced relative risk of the composite primary endpoint (death, hospitalization for heart failure, or LV remodelling) by 38% (P < 0.001) in 1252 elderly post-infarct patients with preserved LV function. Approximately, 50% fewer perindopril vs. placebo recipients (27.7% vs. 51.2%; P < 0.001) experienced remodelling, defined as an increase of ≥8% in LV end-diastolic volume (Figure 3).12

Figure 3

Effects of angiotensin-converting enzyme inhibitor therapy on post-infarct remodelling and left ventricular end-diastolic volume (LVEDV) over 12 months in the PREAMI study (adapted from Ferrari12). (A) Remodelling was evaluated in 896 patients with baseline, and either month-6 or month-12, echocardiographic values available; data shown are percentages with 95% confidence intervals (error bars). (B) LVEDV values are shown as mean with SE (error bars). Reproduced with modification by permission of the American Medical Association.

Thus, the benefits of ACE inhibitors in patients with systolic heart failure have been widely documented, but the benefits in diastolic heart failure are less well-known.16 Nevertheless, ACE inhibitors may have an important role in the latter setting because they can reduce cardiac remodelling, and myocardial mass, fibrosis, and stiffness. Indeed, among antihypertensive agents, ACE inhibitors have the greatest efficacy in reversing LV hypertrophy: in a meta-analysis of 39 clinical trials in patients with essential hypertension, ACE inhibitors reduced LV mass by 13%, calcium-channel blockers by 9%, diuretics by 7%, and β-blockers by 6%.17

The Perindopril pROtection aGainst REcurrent Stroke Study (PROGRESS) was the first trial to assess ACE inhibitor efficacy in the clinical setting of cerebrovascular disease.18 In a total of 6105 patients with a history of stroke or transient ischaemic attack, with or without hypertension, perindopril-based treatment (±indapamide) compared with placebo reduced, over 3.9 years, the relative risks of stroke (−28%; P < 0.0001) and all major vascular events (−26%). The specific decrease in relative risk of stroke for perindopril plus indapamide combination therapy was 43%.18

ACE inhibitors have widely recognized clinical benefits in both diabetic and non-diabetic renal disease. In the latter setting, for example, in a French end-stage renal failure study in 150 patients,19 those receiving perindopril had an 81% lower risk of total mortality (P = 0.0003) and an 82% lower risk of cardiovascular mortality (P = 0.0003 vs. not receiving perindopril).19 Moreover, ACE inhibitors appear to have direct effects in reducing new-onset diabetes: in a meta-analysis of six clinical trials involving approximately 40 000 patients with hypertension, and CAD and/or heart failure, ACE inhibitor therapy was associated with an odds ratio (OR) of 0.79 for the occurrence of new-onset type 2 diabetes.20 These findings corroborate those from ASCOT-BPLA, in which perindopril-based therapy reduced the relative risk of new-onset diabetes by 34% (P < 0.001).6

Furthermore, in the Action in Diabetes and Vascular disease: PreterAx and DiamicroN-MR Controlled Evaluation (ADVANCE) trial in >11 000 patients with type 2 diabetes, a fixed-dose combination of perindopril/indapamide reduced the relative risk of major microvascular or macrovascular events by 9% relative to placebo (P = 0.041) over a mean follow-up period of 4.3 years.21 The benefit of this combination was beyond that of standard background therapy, as was the favourable influence of the combination vs. placebo on various secondary outcomes, including all-cause mortality (HR 0.86, P = 0.025), cardiovascular death (HR 0.82, P = 0.027), and total coronary events (HR 0.86, P = 0.020).21

All of the abovementioned trials highlight that ACE inhibitors reduce cardiovascular morbidity and prevent mortality across a broad spectrum of cardiovascular illness. This evidence suggests that ACE inhibitors should be a mandatory consideration when secondary preventive therapy is required, and in all high-risk patients, except when specific contraindications or potential intolerance exists. Various definitive clinical guidelines are now moving more closely towards full endorsement of this suggestion. For example, 2007 guidelines from the European Society of Cardiology (ESC) and other societies on cardiovascular disease prevention in clinical practice stipulate that besides appropriate treatment for BP, lipids, and diabetes, ACE inhibitors are indicated: to reduce BP to goal levels in patients with hypertension or diabetes; in patients with type 1 (and possibly type 2) diabetic nephropathy; and in the treatment of heart failure and LV dysfunction.22 In addition, Joint British Societies' guidelines (JBS 2) on the prevention of cardiovascular disease in clinical practice recommend ACE inhibitors for patients with heart failure at the time of MI, and for patients with persistent post-infarct LV systolic dysfunction (ejection fraction <40%).23 The latter guidelines also document that ACE inhibitors should be considered for all other patients with CAD, and in combination with a thiazide diuretic in all patients with established stroke, particularly if BP is ≥130/80 mmHg.23

Not all angiotensin-converting enzyme inhibitors are the same

The properties and effects of ACE inhibitors are often attributed solely to a class effect. However, and particularly in CAD, not all ACE inhibitors are necessarily the same: several key pharmacological, efficacy, and tolerability differences exist between compounds in this class.1 Regarding basic pharmacology, some ACE inhibitors are prodrugs that require initial metabolism for activation, whereas others are not. Substantial differences exist between ACE inhibitors in terms of absorption, plasma levels, intermediary metabolism, half-lives, elimination characteristics, durations of action, and trough:peak plasma concentration relationships.

ACE inhibitors modify the balance between the principal deleterious cardiovascular actions of angiotensin II (smooth muscle cell hypertrophy, sodium retention, vasoconstriction) and the favourable cardioprotective actions of bradykinin (natriuresis, vasodilation, anti-remodelling; Table 1). By inhibiting tissue and circulating ACE, ACE inhibitors restrict the conversion of angiotensin I to angiotensin II and limit bradykinin degradation.24,25 Nonetheless, major differences have been reported among ACE inhibitors in terms of affinity for tissue ACE, bradykinin selectivity and potentiation, and effects on endothelial-cell apoptosis.10,2428 For example, perindopril is a prodrug ester that is converted, in the liver and plasma, to perindoprilat, a potent, lipophilic ACE inhibitor with high tissue ACE affinity and a long duration of action.10,27 Perindoprilat has wide-ranging pharmacodynamic properties that include the following: vasodilation; restriction of cardiovascular remodelling; anti-atherogenic, anti-ischaemic, and anti-thrombotic activity; enhanced endothelial function; and improved fibrinolytic balance (Table 2).10,27

View this table:
Table 1

Angiotensin-converting enzyme inhibitors reduce tissue and circulating levels of angiotensin II, and increase the corresponding levels of bradykinin24

Reduced angiotensin II leads to reduced:Increased bradykinin leads to increased:
Endothelial dysfunctionAntioxidant activity
Extracellular matrix degradationAnti-remodelling activity
Monocyte adhesioneNOS expression
Oxygen-free radical productionMonocyte anti-adhesion
PAI-1 and thrombogenesisPreservation of endothelial function
SMC growth, proliferation, and migrationt-PA and fibrinolysis
  • eNOS, endothelial nitric oxide synthase; PAI-1, plasminogen activator inhibitor-1; SMC, smooth muscle cell; t-PA, tissue plasminogen activator.

View this table:
Table 2

Overview of the key pharmacodynamic properties of perindoprilat43

Inhibits angiotensin-converting enzyme in plasma and tissue, including blood vessels
Reduces plasma aldosterone levels in hypertensive patients
 ↓ SBP and DBP
 ↓ aortic carotid-femoral PWV
 ↓ systemic vascular resistance
 ↑ arterial diameter, compliance, and blood flow
Normalizes arterial media-lumen ratio in hypertensive patients
 ↓ LVMI, diastolic wall and intraventricular septal thickness
Does not affect heart rate or cardiac output
 ↓ albuminuria in hypertensive patients with nephropathy, diabetes mellitus, or after renal transplantation
 ↓ plasma uric acid levels in hypertensive patients
Normalises hypofibrinolysis in hypertensive patients
 ↓ plasma kallikrein activity
Does not adversely influence plasma glucose, fructosamine, and glycosylated haemoglobin levels in diabetic patients
Does not adversely influence plasma lipid profiles
  • ACE, angiotensin-converting enzyme; DBP, diastolic blood pressure; LVMI, left ventricular mass index; PWV, pulse-wave velocity; SBP, systolic blood pressure.↓and↑represent significant (P < 0.05) decreases and increases, respectively, vs. baseline or placebo.

Perindoprilat in vitro has demonstrated greater relative tissue affinity than other ACE inhibitors (Figure 4), and such affinity has been correlated with anti-atherosclerotic activity.10,27,29 Moreover, perindoprilat has a particularly marked effect on bradykinin potentiation.10 In in vitro double-displacement binding experiments, various ACE inhibitors displayed different affinity for bradykinin than angiotensin I binding sites on ACE, thus suggesting that ACE inhibitors are, primarily, inhibitors of bradykinin degradation and, secondarily, inhibitors of angiotensin II formation.24 Importantly, in vitro, perindoprilat demonstrated a markedly greater bradykinin/angiotensin I selectivity ratio than other ACE inhibitors (Figure 5),24 and in a different experimental model, restoration of bradykinin levels has been reported at perindopril dosages much lower than those needed to decrease angiotensin II levels.28 These findings of bradykinin potentiation with perindoprilat are supported by clinical data from the PERTINENT trial;9 showing that marked bradykinin/angiotensin I binding site selectivity may, to some extent, explain the substantial efficacy of perindopril in reducing cardiovascular events, which has been widely observed in clinical trials.24

Figure 4

Relative tissue affinity of various angiotensin-converting enzyme inhibitors.29 DD50, ACE inhibitor concentration required for 50% displacement of bound radioligand. Adapted from Ferrari (2004)29 by permission of LLS.

Figure 5

Relative selectivity of perindoprilat and other angiotensin-converting enzyme (ACE) inhibitors for bradykinin vs. angiotensin I binding sites on ACE: results from double-displacement binding studies. Statistical significance: P < 0.001 by analysis of variance for repeated measures; **P < 0.001 vs. the other four ACE inhibitors; *P < 0.01 vs. enalaprilat. Adapted from Ceconi et al. (2007)24 by permission of Elsevier.

In an in vivo model, perindopril increased eNOS protein expression and activity in rat aortic endothelial cells to a greater extent than trandolapril, quinapril, ramipril, and enalapril administered at equi-hypotensive dosages.25 Regarding eNOS protein expression, perindopril was significantly more effective than enalapril (P < 0.001), ramipril (P < 0.05), and quinapril (P < 0.01); and regarding eNOS activity, perindopril was significantly more effective than enalapril (P < 0.01), ramipril (P < 0.05), and trandolapril (P < 0.05). Favourable effects of perindopril on eNOS were attributed to increased bradykinin bioavailability.25 In a similar in vivo rat model, in which endotoxic shock induced by bacterial lipopolysaccharide was shown to significantly increase the rate of apoptosis in aortic endothelial cells, perindopril and ramipril were the only ACE inhibitors tested to significantly reduce the apoptotic rate (Figure 6), with the effects of perindopril being superior to those of ramipril.26 A cautious explanation provided by the authors for this favourable perindopril effect was greater bradykinin/angiotensin I binding-site selectivity for perindopril relative to the other ACE inhibitors.26 This is important because bradykinin has a strong anti-apoptotic action, whereas angiotensin is pro-apoptotic.

Figure 6

Effects of 7 days' ACE inhibitor administration on the rate of lipopolysaccharide (LPS)-induced endothelial apoptosis in rat aorta.26 *P < 0.001 vs. vehicle plus LPS-treated animals. Reproduced from Ceconi et al. (2007)26 by permission of Springer.

Regarding clinical differences among ACE inhibitors, perindopril [in the EUROPA study (Fox 2003)] and ramipril (in the HOPE study),7 reduced cardiovascular morbidity and mortality in CAD patients, whereas no such reduction was evident with trandolapril in the Prevention of Events with Angiotensin Converting Enzyme inhibition (PEACE) trial30 or with quinapril in QUinapril Ischemic Event Trial (QUIET).31 Interestingly, in the subpopulation analyses of patients who had undergone previous revascularization procedures, perindopril (in EUROPA) was still associated with a 17.3% relative risk reduction (P = 0.035) in cardiovascular events, although the overall event rate in this subpopulation was lower than in the total study population.32 Conversely, in the PEACE study,30 in which almost three-quarters of patients had undergone revascularization, trandolapril did not reduce the risk of cardiovascular events in the revascularization subpopulation. In QUIET,31 in which previous revascularization was an inclusion criterion, no significant difference in cardiovascular event rate was noted between the quinapril 20 mg/day and placebo groups.32 Thus, the EUROPA and HOPE trials clearly endorse the importance of ACE inhibitor therapy in patients with stable CAD, which has been widely recognized.23,33,34 More importantly, the disparate results from EUROPA and HOPE on the one hand, and PEACE and QUIET on the other, highlight the fact that an ACE inhibitor such as perindopril or ramipril is likely to be a better therapeutic option than certain other ACE inhibitors in the setting of stable CAD.

Angiotensin-converting enzyme inhibitors: the unquestionable choice for cardiovascular protection

ACE inhibitors have had the most extensive clinical impact of any drug class in cardiovascular medicine, and they remain the vanguard of treatments targeting the RAAS.10 Nonetheless, a common misconception among some physicians may be that angiotensin receptor blockers (ARBs) have similar therapeutic profiles to ACE inhibitors, such that ARBs may rather simply be regarded as ACE inhibitors without associated cough. This is a superficial over-simplification. It has been suggested from retrospective meta-analyses that ACE inhibitors provide considerably greater protection against MI than ARBs.3537 The Blood Pressure Lowering Treatment Trialists’ Collaboration—meta-regression analyses of 26 large-scale trials involving a total of almost 150 000 patients with hypertension or increased cardiovascular risk—revealed that ACE inhibitors and ARBs produced similar BP-dependent decreases in the risks of major coronary heart disease (CHD) events, such as stroke and heart failure.35 However, ACE inhibitors, but not ARBs, had effects beyond BP lowering: a substantial portion (9%) of ACE inhibitor efficacy in reducing CHD risk was attributed to BP-independent effects, and the ACE inhibitor–ARB difference in this respect was statistically significant (P = 0.002).35

In addition, when taken together, data from nine of the 11 principal ARB clinical trials conducted to date suggest that ARBs could increase the risk of MI.37 Similarly, there was a trend in hypertension, for example, the Losartan Intervention For Endpoint (LIFE) reduction trial reported a 5% increase in MI;5 a 10% increase in the risk of fatal plus non-fatal MI was also reported for candesartan in the Study on COgnition and Prognosis in the Elderly (SCOPE).38 The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial documented a 19% increase (P = 0.02) in MI risk for valsartan vs. amlodipine.39 Furthermore, the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Alternative study revealed a 52% increase (P = 0.025) in MI risk for candesartan vs. placebo,40 and the Irbesartan Diabetic Nephropathy Trial (IDNT) in patients with type 2 diabetes and overt nephropathy documented a 54% increase in MI risk for irbesartan vs. amlodipine.41 These findings, although identified retrospectively, have caused some clinicians to suggest that ACE inhibitors prevent more MIs and vascular deaths than ARBs, and consequently, that ACE inhibitors rather than ARBs should be the first choice for cardiometabolic risk reduction across the cardiovascular disease continuum.37

Recently, direct comparative data about the effects of ACE inhibitors and ARBs on morbidity and mortality in patients with high levels of cardiovascular risk have become available. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) was an international prospective, multicentre comparison of telmisartan vs. ramipril and telmisartan+ramipril combination therapy vs. ramipril alone in 25 620 high-risk patients aged ≥55 years with vascular disease or diabetes and end-organ damage.42 There was no increase of the incidence of fatal plus non-fatal infarction in the telmisartan arm vs. ramipril, which contradicts data from the previously discussed retrospective observations. The reduction in BP in patients treated with an ARB alone or an ARB plus an ACE inhibitor was more pronounced than that observed in patients treated with an ACE inhibitor alone, throughout the study. However, there was no difference in the incidence of the primary composite endpoint of cardiovascular death, MI, stroke, or hospitalization for heart failure between treatment groups. Fewer patients treated with the ARB experienced cough, but there was lower incidence of hypotensive symptoms in ramipril recipients. Thus, in patients with vascular disease or diabetes mellitus, adding an ARB to a full dose of a proven ACE inhibitor does not lead to any additional clinical benefit, despite further BP reduction, indicating that BP reduction is not the only mechanism for the cardioprotective effects. With regard to monotherapy, ACE inhibitors remain the first-choice RAAS inhibitors in patients with high cardiovascular risk, while ARBs should be considered as a valid alternative for patients who cannot tolerate ACE inhibitors.


Among cardiovascular medications, ACE inhibitors have the greatest level of evidence for cardiovascular prevention across the entire spectrum of cardiovascular disease (Figure 1). Compared with other agents targeting the RAAS, ACE inhibitors remain the drug of choice. It is important to emphasize that not all ACE inhibitors are the same in terms of their pharmacological, efficacy, and tolerability profiles. Perindopril and ramipril, for example, have markedly reduced cardiovascular risk in patients with stable CAD, whereas quinapril and trandolapril have had no such effects.

Importantly, a current major trend in cardiovascular disease and other areas of medicine is a move towards increased use of combination therapies. Such therapies are associated with simplification of treatment regimens, greater convenience for patients, improved patient adherence to medication schedules and, potentially, with improved clinical efficacy and tolerability. The data presented in this review underline that, in the arena of cardiovascular therapeutics, any combination therapy designed to provide secondary prevention should contain an ACE inhibitor as one of the constituents. Perindopril has the largest body of evidence for any ACE inhibitor, with data from the ASCOT-BPLA, ADVANCE, and PROGRESS studies confirming the major cardiovascular risk-reducing benefits obtained with perindopril-containing combination schedules.


Received unrestricted grant from Servier International.


Technical editing assistance for the preparation of this manuscript was provided by Wolters Kluwer Health. This assistance was funded by Servier.

Conflict of interest: R.F. has received consulting fees from Servier International.


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