Not All Angiotensin-Converting Enzyme Inhibitors
Transcription
Not All Angiotensin-Converting Enzyme Inhibitors
C L I N I C A L F E AT U R E S Not All Angiotensin-Converting Enzyme Inhibitors Are Equal: Focus on Ramipril and Perindopril DOI: James J. DiNicolantonio, PharmD 1,4 Carl J. Lavie, MD 2,3 James H. O’Keefe, MD 4 Wegmans Pharmacy, Ithaca, NY; 2John Ochsner Heart and Vascular Institute, Ochsner Clinical School/University of Queensland School of Medicine, New Orleans, LA; 3Pennington Biomedical Research Center, Baton Rouge, LA; 4 Mid America Heart Institute at Saint Luke’s Hospital, University of Missouri–Kansas City, Kansas City, MO 1 Abstract: Angiotensin-converting enzyme (ACE) inhibitors are a heterogeneous class, varying in pharmacologic properties, which have different therapeutic impacts on patient bradykinin availability. Among the ACE inhibitor class, the agent perindopril, in particular, has pleiotropic effects that are not equally shared by other ACE inhibitors, including bradykinin site selectivity and subsequent enhancement of nitric oxide and inhibition of endothelial cell apoptosis. Moreover, there is a large amount of evidence to suggest that perindopril therapy may reduce cardiovascular event rates in patients, yet perindopril is rarely prescribed in the impressive outcomes data. Our review compares the pharmacologic and trial data among perindopril, ramipril, and other ACE inhibitors. In patients with or at high risk for coronary heart disease who do not have heart failure, or in patients with heart failure with preserved ejection fraction, perindopril should be among the preferred treatment agents in the ACE inhibitor class. Ramipril has an impressive track record of improving cardiovascular outcomes, too, and should be considered a preferred agent among the ACE inhibitor class. Keywords: angiotensin-converting enzyme inhibitor; bradykinin; heart failure; cardiovascular disease; ramipril; perindopril Introduction Angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce morbidity and mortality rates in patients with systolic heart failure (HF) and in those who have recently experienced an acute myocardial infarction (AMI). Additionally, ACE inhibitors are effective agents for treating patients with hypertension, and current data suggest that they are more effective therapeutic agents for reducing rates of morbidity and mortality due to cardiovascular (CV) events compared with the use of angiotensin receptor blockers.1,2 Thus, ACE inhibitors should be prescribed frequently, as there mortality rates.1,2 However, not all ACE inhibitors appear to be equally effective for improving patient CV outcomes. Pharmacokinetic/Pharmacodynamic Data The ACE inhibitors, as a drug class, differ considerably in their clinical properties from Correspondence: James J. DiNicolantonio, PharmD, 500 South Meadow St., Ithaca, NY 14850. Tel: 607-277-5750 Fax: 607-277-5890 E-mail: [email protected] ramipril and perindopril, appear to have superior therapeutic qualities compared with most other currently available ACE inhibitors. Perindopril has been shown to have a longer duration of therapeutic action and thus offers full 24-hour blood pressure (BP) © Postgraduate Medicine, Volume 125, Issue 4, July 2013, ISSN – 0032-5481, e-ISSN – 1941-9260 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] 1 DiNicolantonio_proof2 DiNicolantonio et al and local inhibition of the renin-angiotensin-aldosterone system in tissues such as the heart, brain, kidneys, adrenal glands, and blood vessels, as well as a greater selectivity for bradykinin binding sites compared with other ACE inhibitors (Table 1; Figure 1, 2). Moreover, unlike enalapril, no titration is needed with perindopril treatment to provide the patient with maximal antihypertensive effect.9 Additionally, enalapril,9,10 which can lead to underperfusion of target organs and subsequent negative consequences.10 When initiating a patient on ACE inhibitor therapy, perindopril seems to be the safer choice compared to enalapril, especially in patients relying on hemodynamics to maintain tissue perfusion, such as patients who have HF. The lower risk for hypotension with perindopril versus enalapril in patients with HF may also be clinically relevant in those who are at risk for hypotension, such as individuals who have experienced an AMI, those in circulatory failure or shock, those with chronic kidney disease, or in patients with a propensity for orthostasis/presyncope/syncope (ie,dehydration, Parkinson’s disease, chronic diabetes, those on low-sodium diets, carbohydrate-restricted diets, or those taking medications that can precipitate orthostasis).10 However, further trials are required in these patient populations testing perindopril versus other ACE-inhibitors to know for certain. Treatment with perindopril has been shown to more strongly inhibit endothelial cell apoptosis compared with most other ACE inhibitors (enalapril, quinapril, and trandolapril; P ! 0.001), vs ramipril (P = difference in favor of perindopril) (Figure 3).11 Treatment Table 1. Advantages of Perindopril Therapy Compared With Other ACE Inhibitors 3,4 Greater tissue and plasma ACE inhibition3–6 Longer duration of action. Perindopril provides complete 24-hour blood pressure control. Enalapril should be dosed twice daily, whereas perindopril only needs to be dosed once daily.6 No titration needed to achieve maximum effective dose7 Despite greater selectivity for bradykinin binding sites compared with other ACE inhibitors, perindopril has a very low rate of discontinuation due to ACE inhibitor–induced cough (∼2% in EUROPA and PROGRESS)8,21,22 9,10 10 Greater inhibition of endothelial cell apoptosis compared with other ACE inhibitors11 III compared with enalapril12 Associated with lower mortality rates in patients with acute myocardial infarction compared with other ACE inhibitors13 more than trandolapril, quinapril, ramipril, and enalapril; P ! 0.05 vs trandolapril and ramipril; P ! 0.02 vs enalapril, respectively)14 Better reduction in resistin levels in patients with stable coronary artery disease compared with enalapril17 effects compared with enalapril18 Brain ACE inhibition, which was not shown with quinapril56 Abbreviations: ACE, angiotensin-converting enzyme; EUROPA, European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease; PROGRESS, Perindopril Protection Against Recurrent Stroke Study. with trandolapril and quinapril vs baseline; P ! 0.001 with perindopril and ramipril vs baseline) (Figure 4, 5).14 An to improve myocardial tolerance to reperfusion injury15 and transforming growth factor and collagen III compared with enalapril therapy.12 Treatment with perindopril or ramipril have been associated with a lower incidence of mortality in patients with AMI compared with other ACE inhibitor therapies (eg, enalapril, fosinopril, captopril, quinapril, and lisinopril).13 expression in the aorta seen with perindopril treatment (P ! 0.001) compared with other ACE inhibitor therapies (P = P ! 0.05 vs ramipril; P ! 0.01 vs quinapril; P ! in the aorta (P = P ! 0.05 vs trandolapril and ramipril; P ! expression in cardiac myocytes (P ! 0.05 with enalapril and quinapril vs baseline; P ! 0.01 with ramipril vs baseline; P ! 0.001 with perindopril and trandolapril vs baseline); and P ! 0.05 with enalapril vs baseline; P ! 0.01 2 β pic responses, thus providing a cardioprotective effect against excess catecholamine stimulation.16 Moreover, compared with enalapril treatment, perindopril therapy produces greater reductions in resistin levels in patients with stable coronary heart disease (CHD)17 (decreased C-reactive protein), anti-atherosclerotic (reduced monocyte chemo-attractant protein-1), antioxidant (lowered oxidized low-density lipoprotein), antithrombotic (lowered activator inhibitor-1) effects (Table 1). Pleiotropic effects were shown to occur in normotensive patients with stable CHD, and were not related to reductions in BP (either from baseline or compared with BP changes seen in patients treated with enalapril). In summary, treatment with perindopril © Postgraduate Medicine, Volume 125, Issue 4, July 2013, ISSN – 0032-5481, e-ISSN – 1941-9260 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] DiNicolantonio_proof2 ACE Inhibitor Advantage: Focus on Ramipril and Perindopril Figure 1. with treatment with other ACE inhibitors. The greater pleiotropic effects of perindopril therapy may be due to bradykinin sites on angiotensin converting enzyme compared with other ACE inhibitor therapy. to occur by several distinct mechanisms, which include improved patient bradykinin availability (vasodilation, effect, increased anti-remodeling effect, preservation of endothelial function, anti-adhesion of monocytes (anti- 5 atherosclerotic effect), and inhibiting the conversion of angiotensin I to angiotensin II (thereby reducing vasoconstriction, hypertrophy, adhesion of monocytes, plasminogen activator inhibitor-1 and thrombogenesis, free radical oxygen production, and endothelial dysfunction) (Figure 6). However, inhibition of angiotensin II receives more attention than improvement in bradykinin availability as the primary mechanism of action of ACE inhibitors. Despite this, the angiotensin I, suggesting that the ACE pathway primarily functions to degrade bradykinin. To inhibit both angiotensin I conversion to angiotensin II and inhibit the degradation of C-terminals) is required.19 However, angiotensin I can be Figure 2. Relative selectivity of tested ACEIs for bradykinin vs angiotensin I binding sites. P ! 0.001 by ANOVA for repeated measures; **P ! 0.001 vs ramiprilat, quinaprilat, trandolaprilat, and enalaprilat; *P ! 0.01 vs enalaprilat8 © Postgraduate Medicine, Volume 125, Issue 4, July 2013, ISSN – 0032-5481, e-ISSN – 1941-9260 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] 3 DiNicolantonio_proof2 DiNicolantonio et al domains, whereas bradykinin inactivation requires the activity of both terminal sites.19 Moreover, ACE inhibitors generally angiotensin I, which suggests that ACE inhibitors function primarily to inhibit bradykinin degradation and secondarily inhibit the production of angiotensin II. This is further supported by the fact that patient angiotensin II levels generally return to baseline, or are greater than baseline, after prolonged ACE inhibitor use, as angiotensin II can be formed through other non-ACE pathways (eg, cathepsin, tonin).5 The selectivity for bradykinin sites of the ACE inhibitors, in descending order, is perindopril (P ! 0.001 vs the latter 4 named ACE inhibitors), ramipril (P ! 0.01 vs enalapril), quinapril, trandolapril, and enalapril. Perindopril has the greater selectivity for bradykinin sites on ACE (ratio, 1.44), whereas enalapril has the poorest selectivity (ratio, 1.00); binding sites compared with enalapril. Thus, compared to 4 other ACE inhibitors, perindopril has the greatest selectivity for bradykinin sites on ACE. Bradykinin has been shown to exert potent anti-apoptotic actions on both the endothelium and cardiac myocytes, which could account for the greater anti-apoptotic actions of perindopril treatment compared with use of other ACE inhibitors.11 dykinin levels (+ P ! 0.05 vs placebo) and a reduction in angiotensin II levels (− P ! 0.05 vs placebo).20 The increase in bradykinin with perindopril therapy most likely P ! 0.05) increase in protein expresP! activity, as the addition of a bradykinin B2 receptor antagonist P ! 0.05) and P ! 0.05).20 in the rate of apoptosis (P ! 0.05), which was, in part, mediated by the activation of the bradykinin B2 receptors, as the apoptosis rate was increased with the addition of a bradykinin B2 receptor antagonist (P ! decrease in von Willebrand factor was seen in patients after 1 year of treatment with perindopril (P ! 0.001).20 Although increases in patient bradykinin levels with ACE inhibitor treatment have generally been thought to cause the the low rates of cough (∼ in the European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease (EUROPA) and the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), challenge the theory. A " 2-fold higher incidence of cough seen in patients undergoing enalapril dykinin sites vs the 4 other ACE inhibitors) compared with Figure 3. Rate of apoptosis in rats treated for 7 days with ACEI or vehicle only (control) expressed as the percentage of annexin V-positive rat aortic endothelial cells following lipopolysaccharide-induced apoptosis. *P ! 0.001 vs control.11,57 4 © Postgraduate Medicine, Volume 125, Issue 4, July 2013, ISSN – 0032-5481, e-ISSN – 1941-9260 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] DiNicolantonio_proof2 ACE Inhibitor Advantage: Focus on Ramipril and Perindopril Figure 4. Endothelial nitric oxide synthase (eNOS) protein expression (A) and activity (B) in the descending aorta of rats treated with different ACEIs. (**) P ! 0.001 vs vehicle, (°) P ! 0.001, (*)P ! 0.01 and (ˆ)P ! 0.05 each ACEI vs others. In each group of treatment, 5 animals were employed.14 study that used a de-challenge and re-challenge method (a strict criteria to attribute cough not yet used in previous reports), as well as cough incidences seen with enalapril in a retrospective study of 1113 patients with arterial hypertension, highlight the need for more research into other increased bradykinin availability. therapy restored patient bradykinin levels to those seen explain the low rates of cough seen in subjects taking perindopril in multiple clinical trials (ie, increased bradykinin cough). The inhibition of bradykinin degradation seems cardioprotection (although more research is required), and CV endpoints and account for the low incidence of cough in patients undergoing perindopril therapy. A large meta-analysis of randomized placebo-controlled trials echoed the data, with the included trials indicating that for patients with or at risk for atherosclerotic vascular disease with a systolic BP (SBP) ! 130 mm Hg, ACE inhibitor therapy provided a substantial and sustained mary outcome of CV mortality, nonfatal AMI, or nonfatal © Postgraduate Medicine, Volume 125, Issue 4, July 2013, ISSN – 0032-5481, e-ISSN – 1941-9260 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] 5 DiNicolantonio_proof2 DiNicolantonio et al Figure 5. eNOS synthase (eNOS) protein expression (A) and activity (B) in isolated cardiac myocytes from rats treated with different ACEIs. (**) P ! 0.001, (*) P ! 0.01, (ˆ) P ! 0.05 vs vehicle. In each group of treatment, 5 animals were employed.14 25 In clinical practice, many physicians tend to think of ACE inhibitors as antihypertensive medications, and, if a patient has an SBP ! 140 mm Hg (and certainly if ! 130 mm Hg), the patient is presumed to be “at goal,” and treatment with an ACE inhibitor would generally not be prescribed. However, even in patients with an SBP ! 130 mm Hg, from the prescription of an ACE inhibitor, which may be related to ACE-inhibitor effects on lowering the throm(especially in patients treated with perindopril compared with enalapril). Despite ACE inhibitors having been prescribed for decades, there is still uncertainty as to the precise mechanism(s) under- 6 produce a reduction in patient serum ACE levels? Tissue ACE levels? Endothelial ACE levels? Does treatment with an ACE inhibitor produce an increase in patient bradykinin levels? At which point is the mechanism of action exerted? At the prodrug or drug stage (ie, perindoprilat vs perindopril)? Angiotensin-converting enzyme is present in many body tissues (eg, heart, brain, kidneys, adrenal glands, blood vessels) and is, for the most part, a tissue-based enzyme, with ! of ACE found in plasma.26 The ability of ACE inhibitors to bind to tissue ACE seems to be clinically relevant, especially in patients with acute coronary syndromes, in whom ACE activity in the coronary vessels is 5-times higher than that seen in the serum.27 activity has been shown in several patient models of cardiac injury, including volume overload, the hypertrophied heart, HF, AMI, and post-AMI remodeling, where elevated wall © Postgraduate Medicine, Volume 125, Issue 4, July 2013, ISSN – 0032-5481, e-ISSN – 1941-9260 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] DiNicolantonio_proof2 ACE Inhibitor Advantage: Focus on Ramipril and Perindopril Figure 6. The effects of angiotensin II inhibition and improvement in bradykinin availability.8 stretch and subsequent sarcolemmal stretching are believed to be crucial factors for increased patient cardiac ACE activity (Figure 7). In the injured heart, recruited fibroblasts and macrophages also carry high ACE activity,26,30,31 with tissue ACE amassing in human atherosclerotic plaque, preferentially (Figure 7). Localized ACE activity within atherosclerotic plaque may contribute to the progression of advanced coronary lesions and subsequent atherothrombotic events. The anti-atherosclerotic effects of the ACE inhibitors have 26,32 prostacyclin (through increased bradykinin availability and inhibition of angiotensin II formation), leading to subsequent decreased migration and proliferation of vascular smooth and activation, decreased oxidative stress, and improved endothelial function.5,33 Bradykinin B2 receptor antagonists have been shown ; thus, ACE inhibitors may preferentially work through the inhibition of bradykinin degradation. This premise is supported by the fact that perindopril therapy increases patient bradykinin levels at dosages that are lower than those required to reduce angiotensin II levels.34 Perindopril treatment has shown the greatest reductions in 15 other ACE inhibitors,14 - levels.15 Additionally, bradykinin levels have been related to the endothelial-dependent vasodilation seen in patients taking quinapril.35 Considering that treatment with perindopril has shown consistent pleiotropic effects (that are not equally produced by treatment with other ACE inhibitors), and consistent reductions in rates of patient morbidity and mortality in multiple trials, it may be that a high selectivity binding, are at the cornerstone of ACE inhibitor therapeutic In summary, not all ACE inhibitors are equal; of the - matory, antioxidant, anti-atherosclerotic, antithrombotic, Perindopril therapy has consistently been shown to have the when compared with other ACE-inhibitor treatment. The pleiotropic properties of perindopril may translate into improved clinical, hemodynamic, and CV endpoint reductions for patients compared with other ACE inhibitor therapy. In fact, there is a plethora of evidence showing that treatment with perindopril results in reductions in CV event rates. In a 4-year follow-up of 29 463 patients, a perindopril- P= P= P ! P= P = 0.015).36 Results were consistent among all subgroups. The authors concluded that there was strong evidence to indicate that a perindopril-based regimen improved survival and reduced major CV event rates across a broad spectrum of patients with vascular disease. Other ACE inhibitors cannot © Postgraduate Medicine, Volume 125, Issue 4, July 2013, ISSN – 0032-5481, e-ISSN – 1941-9260 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] 7 DiNicolantonio_proof2 DiNicolantonio et al Figure 7. Myocardial tissue ACE.26 Trandolapril as those of perindopril. In the PEACE trial, treatment of patients with trandolapril Patients With or at High Risk of CHD Perindopril and Ramipril (AMI, or coronary revascularization in patients with stable CHD without a history of HF or LV systolic dysfunction).39 Perindopril, in the EUROPA study, and ramipril, in the Heart Outcomes Prevention Evaluation (HOPE) trial, are the only ACE inhibitors that have data showing their therapeutic association with the prevention of CV events and lower CV mortality rates in patients with or at high risk for CHD, who have normal left ventricular (LV) function.21,37 Additionally, treatment with ramipril in a randomized placebo-controlled trial of 2000 patients, post-AMI, with HF, reduced the all-cause P = 0.002) and the adverse CV event 37 P= In patients with or at high risk for CHD, the only evidence-based preventive ACE inhibitor therapeutic agents are perindopril and ramipril.21,37 Unfortunately, many clinicians prescribe other ACE inhibitors (eg, lisinopril, enalapril, or benazepril) in this setting. However, the belief in a “class effect” is not supported by randomized controlled trials using ACE inhibitor treatments. For example, use of trandolapril in the Prevention of Events With Angiotensin-Converting Enzyme Inhibition (PEACE) trial, and quinapril in the Quinapril Ischemic Event Trial (QUIET) did not show reductions in the primary outcome, whereas ramipril and perindopril, used 8 as being caused by the high use of optimal medical therapy. However, in the EUROPA, HOPE, and PEACE trials, rates of use of antiplatelet agents, statins, and β-blockers were Thus, the background medical therapy was similar between EUROPA and PEACE, whereas HOPE had lower percentages of all 3 background 21,37,39 clinical CV practice in treating patients. Perindopril is the only ACE inhibitor that was powered to show therapeutic reductions in CV endpoints in patients with or at high risk for CHD (in patients without HF) on optimal background medical therapy.21,37 Additionally, Dagenais et al41 group analysis evaluating patients on lipid-lowering agents, β-blockers, and antiplatelet drugs (alone or in combination). Therefore, even patients on optimal background medical Dagenais et al41 also conducted a subgroup analysis of lowrisk patients in the HOPE and EUROPA trials, who also showed large reductions in the composite endpoint of CV © Postgraduate Medicine, Volume 125, Issue 4, July 2013, ISSN – 0032-5481, e-ISSN – 1941-9260 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] DiNicolantonio_proof2 ACE Inhibitor Advantage: Focus on Ramipril and Perindopril Figure 8. Primary outcomes from the four major ACEI trials.38 mortality, nonfatal AMI, or stroke, when patients were treated with either perindopril or ramipril therapy.41 The high percentage of patients on optimal medical background therapy and/or the low-risk patient populations in the PEACE trial do not explain the therapeutic failure of trandolapril to prevent or reduce patient vascular events, as opposed to the success with perindopril and ramipril treatment in similar trials. While a head-to-head comparison trial is required to determine with certainty the inferiority of trandolapril treatment and other ACE inhibitor therapy compared with perindopril and ramipril, a class effect should not be assumed to be true. For example, in the cases of pioglitazone compared with rosiglitazone, or hydrochlorothiazide compared with chlorthalidone, therapeutic agents within the same class have been shown to have markedly different clinical and CV effects. Considering that no trial data exist for trandolapril treatment demonstrating a reduction in CV endpoints in patients with or at risk for CHD (without HF), we believe that trandolapril should not be prescribed preferentially over ramipril or perindopril. If we are to practice evidence-based medicine, ramipril or perindopril should be the preferred ACE inhibitor for treating this high-risk patient population.21,37,39 Quinapril The QUIET study was a randomized, blinded, multicenter, 36-month trial (mean duration of follow-up, 27 months) that compared treatment with quinapril 20 mg with placebo in 1750 patients with CHD without systolic LV dysfunction.40 There was no difference in rates of ischemic events between patients taking quinapril therapy compared with those P = 0.60), or in the incidence of patients who experienced angiographic progression of coronary disease (P = 0.71). The rates of CV mortality, overall mortality, and nonfatal AMI were similar between patients treated with quinapril P= Furthermore, the development of new coronary lesions was similar in incidence for both patient groups (P = 0.35). However, treatment with quinapril did reduce patient incidence of angioplasty for new (previously un-intervened) vessels (P = of coronary atherosclerosis. However, the study authors did note that the absence of a demonstrable effect with quinapril therapy may have been due to several limitations in study design, including: 1) the QUIET study would have needed potentially underpowered to show a reduction in major CV endpoints; 2) the subjectivity in the decision to proceed with management increased the number of non-major outcomes, which may have masked detection of the effect of quinapril therapy on major CV outcomes; and 3) the dose of quinapril may have been low (20 mg) compared with 40 mg daily, endothelial reactivity in the Trial on Reversing Endothelial 42 Despite these limitations, there was less reduction in patient BP with perindopril treatment in the EUROPA trial and ramipril therapy in the HOPE study compared with quinapril use in QUIET and trandolapril therapy © Postgraduate Medicine, Volume 125, Issue 4, July 2013, ISSN – 0032-5481, e-ISSN – 1941-9260 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] 9 DiNicolantonio_proof2 DiNicolantonio et al Table 2. Comparing Patient Population Characteristics of the HOPE, EUROPA, and PEACE Trials21,37,39 Parameter HOPE N = 9,297 EUROPA N = 12,218 PEACE N = 8,290 Age, y, mean Diabetes, % Prior CABG surgery/PCI, % SBP/DBP, mm Hg, mean Prior MI, % On antiplatelet therapy, % On β-blocker therapy, % On statin therapy, % 66 38 40 139/79 53 76 40 29 60 12 55 137/82 65 92 62 58 64 17 72 133/78 55 90 60 70 Abbreviations: CABG, coronary artery bypass graft; EUROPA, European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease; HOPE, Heart Outcomes Prevention Evaluation; MI, myocardial infarction; PEACE, Prevention of Events with Angiotensin Converting Enzyme Inhibition; PCI, percutaneous coronary intervention. in the PEACE study (Figure 9). Suggesting that quinapril’s being too low is unlikely, despite the fact that there are no reports, to our knowledge, comparing rates of central BP P = 0.16). However, there was ment compared with placebo, which just missed statistical P = 0.11).43 There are a few explanations that may explain the results of the CAMELOT trial. For example, the placebo group was actually treated with ACE inhibitors and calcium channel 43 ; thus, active therapy drop-ins into the placebo group could have muted is not fully apparent when these patient drop-ins occurred or whether they were clinically meaningful (ie, if most occurred late in the trial, it may not have caused a clinically meaningful effect); however, this limitation should not be overlooked nor over-interpreted. Another possible explanation for the placebo could be due to a higher rate of patients discontinuing 3-year follow-up in QUIET may have been too short a time reaching a maximum target dose in the enalapril group duration of 5 years, requiring 1 to 2 years of treatment with ramipril before the AMI/stroke/death Kaplan-Meier curves began to separate compared with placebo.37 The Comparison of Amlodipine Versus Enalapril to Limit Occurrences of Thrombosis (CAMELOT) study was a randomized, double-blind, multicenter, 24-month trial that compared amlodipine or enalapril with placebo in approximately 2000 patients with angiographically documented CHD (" stolic BP ! 100 mm Hg (Table 3).43 Patients were randomized to receive amlodipine 10 mg, enalapril 20 mg, or placebo. Compared with placebo, amlodipine therapy reduced nonfatal 43 Although enalapril treatment failed to reduce CV event rates in patients with CHD, some explanations could potentially clarify this failure. Despite these limitations, treatment with enalapril was not shown to reduce CV event rates in patients with CHD who did not have HF, and thus should not be readily prescribed in this patient population, especially considering that treatment with ramipril and perindopril have proven to be therapeutically effective ACE inhibitors in this setting.21,37,43 Although differences in patient populations and duration of follow-up among trials may explain why treatment with trandolapril, quinapril, and enalapril failed to show a compared with placebo, it is also plausible that these 3 ACE P= reduced the rate of resuscitated cardiac arrests compared with P = 0.04). Moreover, amlodipine treatment reduced the primary endpoint compared with enalapril P = 0.10). However, this was mainly driven by a reduction in patient hospitalizations for episodes of angina P = 0.003), and a trend toward fewer episodes of revascularization in patients undergoing perindopril and ramipril treatment. Patients With HF and Systolic Dysfunction an ACE inhibitor within 30 days after hospital discharge, enalapril and captopril therapy were associated with higher patient mortality rates compared with ramipril treatment P = 0.09). While there was a trend for a reduction in CV event 10 © Postgraduate Medicine, Volume 125, Issue 4, July 2013, ISSN – 0032-5481, e-ISSN – 1941-9260 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] DiNicolantonio_proof2 ACE Inhibitor Advantage: Focus on Ramipril and Perindopril Figure 9. Blood pressure reduction from baseline values in four major ACEI trials.38 perindopril was associated with an equivalent reduction In patients with HF, treatment with enalapril or captopril has been associated with a higher rate of patient mortality compared with ramipril or perindopril therapy. A limitation does exist for the aforementioned data, as it was observational, and thus cannot prove causality, although it is vs 2.12 ± 0.07; P = ± ± P = 0.395) compared with baseline values. 44 inhibitor therapies. Masuelli et al45 indicated that patients switched from functional class (P ! LV end-diastolic diameter (P = 0.001) and LV mass index (P ! P ! 0.001). While these improvements may, in part, be explained by not be explained by reductions in patient BP measurements (111 ± ± 1.3 mm Hg vs 112 ± ± 1.0 mm Hg; P value not reported), norepinephrine levels (414 ± 30 pg/mL vs 361 ± 35 pg/mL; P = ± 17 ± 12 pg/mL; P = 0.53), or endothelin-1 levels (2.5 ± 0.4 pg/mL vs 2.2 ± 0.9 pg/mL; P = 0.39), as treatments.46 A study by Kasama et al47 showed that patients with HF ments in total defect score (39 ± 10 to 34 ± 9; P ! 0.01), H/M ratio (1.62 ± 0.27 to 1.76 ± 0.29; P ! ± ± P! ± 155 pg/ mL to 141 ± 90 pg/mL; P ! 0.0005 vs baseline; P ! 0.05 ± 30 mL to 161 ± 30 mL; P ! 0.05), and LV end-systolic volume (122 ± 35 mL to 105 ± 36 mL; P ! 0.05). Patients random- trials that enrolled patients with systolic HF indicated greater were not explained by enhanced BP-lowering effects.46,47 In a study by Tsutamoto et al,46 patients with ischemic HF P value not reported), P = 0.013), plasma brain natri± ± pg/mL; P = 0.042), heart-to-mediastinum (H/M) ratio (2.0 ± 0.07 vs 2.15 ± 0.07; P = 0.013), and washout rate (WR) ± ± P = 0.030) with perindopril therapy compared with baseline values. Patients who received tional class (P ± ± P= ± 26 pg/ mL vs 169.3 ± 33 pg/mL; P = 0.36), H/M ratio (2.09 ± 0.07 P value not reported), LV end-systolic volume (120 vs 111 mL; P P value P (P ! enalapril therapy was less robust (P ! 0.05).47 Perindopril is a unique ACE inhibitor that offers therapeutic improvements for patients with systolic dysfunction in hemodynamic, functional, and neurohumoral parameters dopril therapy cannot be explained by reductions in patient reduction (P = © Postgraduate Medicine, Volume 125, Issue 4, July 2013, ISSN – 0032-5481, e-ISSN – 1941-9260 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] 11 DiNicolantonio_proof2 DiNicolantonio et al Table 3. Clinical Trials of ACE Inhibitors in Patients With CHD ACE Inhibitor Trial Results Perindopril Positive 20% relative risk reduction on the primary endpoint (CV death, MI, or cardiac arrest) (95% CI 9–29, P = 0.0003) with perindopril versus placebo. Positive 22% reduction in the primary outcome (MI, stroke or CV death) (relative risk 0.78: 95% CI: 0.70–0.86, P ! 0.001). Negative No difference in the primary endpoint (CV death, nonfatal MI, CABG, PCI) between trandolapril (21.9%) and placebo (22.5%) (HR 0.96, 95% CI: 0.88–1.08, P = 0.43). Negative The rates of CV mortality, overall mortality, and nonfatal AMI were similar between patients treated with quinapril and those given placebo (1.4% vs 1.5%; 3.1% vs 3.2%; and 4.1% vs 4.6%, respectively; P = NS for each endpoint). Negative Ramipril EUROPA21 HOPE37 Trandolapril PEACE39 Quinapril QUIET40 Enalapril CAMELOT43 enalapril versus placebo (20.2% vs 23.1%), (HR, 0.85; 95% CI, 0.67–1.07; P = 0.16). Abbreviations: ACE, angiotensin-converting enzyme; CHD, coronary heart disease; CAMELOT, Comparison of Amlodipine Versus Enalapril to Limit Occurrences of Thrombosis; EUROPEAN, European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease; HOPE, Heart Outcomes Prevention Evaluation; PEACE, Prevention of Events with Angiotensin Converting Enzyme Inhibition; QUIET, Quinapril Ischemic Event Trial. experienced hypotension that required withdrawal of enalapril. mal medical therapy, especially if patients with less severe HF were studied. While there have been no studies, to our knowledge, of the effect of perindopril therapy on morbidity and mortality rates in patients with systolic HF, it could be hypothesized that treatment with perindopril would provide equivalent if not superior reductions in major CV endpoints compared with enalapril treatment based on the 3 aforementioned trials in this setting. Patients With HF and Preserved EF EF.49 In the Perindopril in Elderly People With Chronic HF (PEP-HF) trial, perindopril treatment was associated with at 1 year, a reduction in composite of all-cause mortality and unplanned HF hospitalization rates (relative risk P = 0.055), P= (P ! 0.030) and 6-minute walking distance (P = 0.011).49 After 1 year trial duration, “drop-in” perindopril treatment was allowed into the placebo-treated group, which resulted tion for all-cause mortality and hospitalization rates in patients with HF and preserved EF,49 which has not been shown with treatment other ACE inhibitors. Patient Outcomes Post-AMI inhibitor within 30 days of hospital discharge after an AMI, enalapril, fosinopril, captopril, quinapril, and lisinopril treatment were associated with higher patient mortality rate perindopril had a mortality rate similar to that of patients 13 The study year after an AMI were less with enalapril, fosinopril, captopril, quinapril, or lisinopril treatment compared with ramipril therapy, and that treatment with perindopril was 13 Limitations to be noted about the study include the fact that it was observational and retrospective in design, and, thus, could not prove causality; however, the results offer real-world evidence consistent with data from trials using ramipril and perindopril to treat patients with and at high risk for CHD. ST-segment elevation AMI in a prospective multicenter registry from Germany to compare the effect of ramipril Perindopril is the only ACE inhibitor with evidence-based patient in-hospital mortality rate. In a multivariate analysis, 12 © Postgraduate Medicine, Volume 125, Issue 4, July 2013, ISSN – 0032-5481, e-ISSN – 1941-9260 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] DiNicolantonio_proof2 ACE Inhibitor Advantage: Focus on Ramipril and Perindopril treatment with ACE inhibitors was associated with lower patient in-hospital mortality and major CV event rates, but treatment with other ACE inhibitors. However, patient HF assessed in this study).50 Perindopril The Perindopril and Remodeling in Elderly With Acute Myocardial Infarction (PREAMI) trial was a 12-month, double-blind, randomized, parallel-group, multicenter trial that enrolled 1252 patients (aged # 65 years) with preserved 51 The primary endpoint (patient mortality, hospitalization for P ! 0.001), which was mainly driven by a reduction in LV remodeling on placebo; P ! 0.001). Moreover, the mean increase in with perindopril treatment compared with placebo treatment (0.7 mL vs 4.0 mL; P ! 0.001, respectively). A subanalysis of EUROPA in the PREAMI-like population (# 65 years, LVEF # P = 0.03) for the primary EUROPA endpoint after 3 years of perindopril treatment. In summary, with a recent AMI, despite patients having a normal EF 51 Enalapril ized, double-blind, placebo-controlled, parallel-group trial that compared treatment with enalapril with placebo in 6090 patients with AMI. Enalapril therapy, started within 24 hours of AMI, increased patient mortality risk compared P = 0.26). The increase in mortality with enalapril treatment versus placebo could be argued as being caused by the use of an intravenous dosage form of enalapril, causing hypotension, which would not have been seen with oral enalapril treatment. However, enalapril and perindopril treatment have been shown to produce similar reductions in patient BP when administered intravenously,52 whereas enalapril, given orally, has caused severe hypotension, an effect that has not been seen with orally administered perindopril.10,53 Enalapril, as an individual compound (not the intravenous formulation) was the likely cause of the 4-fold increase in the rate of patient hypotension when compared with placebo P ! 0.001, respectively). The disparate effects of enalapril treatment compared with perindopril therapy on patients with hypotension are further elucidated when evaluating tolerability data of these 2 ACE inhibitors from previous trials in patients with HF, in which indopril. Orally administered enalapril can cause severe hypotension at a much higher rate than treatment with oral perindopril. If a clinician is selecting an ACE inhibitor for a patient with AMI, perindopril and ramipril seem to be the safer therapeutic choices. 54,55 Conclusion Perindopril has been shown to have a longer duration of action, higher lipophilicity, and stronger tissue ACEinhibiting properties compared with other ACE inhibitors. Moreover, there are several clinical trials supporting the CV patients with AMI, those with HF and preserved EF, patients with or at high risk for CHD without HF). Thus, perindopril for treatment of patients with HF and preserved EF and in patients with or at high risk for CHD without HF. Perindopril and ramipril are the only ACE inhibitors to show a reduction in CV event rates in patients with or at high risk for CHD with normal LV function.21,37 Therefore, in ACE inhibitor therapy. Although ramipril has demonstrated excellent ability to improve patient clinical outcomes, most of the trials were completed decades ago, prior to the current era of optimal medical therapies. Only use of the ACE inhibitor perindopril has demonstrated clear reductions in CV endpoints in patients who have been treated in ways that are medical therapy and at a lower baseline risk of CV events compared with patients receiving ramipril in HOPE). Moreover, perindopril is the only ACE inhibitor with evidence for improving morbidity and mortality rates in patients with HF who have a preserved EF.49 Therefore, in patients with or at high risk for CHD (without HF) and HF with preserved EF, © Postgraduate Medicine, Volume 125, Issue 4, July 2013, ISSN – 0032-5481, e-ISSN – 1941-9260 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] 13 DiNicolantonio_proof2 DiNicolantonio et al inhibitor, perhaps even prior to ramipril use. In the future, we are hopeful that perindopril will become more widely prescribed and used, as it possesses an impressive amount of evidence supporting its ability to reduce CV endpoints in a wide range of patient populations. Clinicians should be aware that a clear and complete class effect does not seem to exist with the ACE inhibitors. If we are to practice evidence-based medicine, we should be preferentially prescribing medications that have the strongest evidence (perindopril and ramipril) for improving long-term clinical CV outcomes. 14. Comini L, Bachetti T, Cargnoni A, et al. Therapeutic modulation of the nitric oxide: all ace inhibitors are not equivalent. Pharmacological Res. in the anti-ischaemic effect of trandolapril. British J Pharm. 2001; 16. du Toit EF, Genade S, Carlini S, Moolman JA, Brunner F, Lochner A. ing mouse heart model. Euro J Pharma 17. Krysiak R, Sierant M, Marek B, Okopien B. 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