Safety Profile of Perindopril Luther T. Clark,
MD
Approximately 25% of US adults have high blood pressure (BP). Selection of effective and safe antihypertensive therapy for these individuals is an important health-care priority. High BP can be treated with a wide range of antihypertensive agents from a number of different classes. These drugs may differ in their suitability for administration to different subpopulations of patients. Results from both clinical trials and postmarketing surveillance indicate that the angiotensin-converting enzyme (ACE) inhibitor perindopril erbumine is safe and well tolerated in a wide range of patients with hypertension. Cough, the most common ACE inhibitor–associated side effect, is also the most common clinical adverse event reported for perindopril, but <2% of perindopriltreated patients discontinue therapy because of cough. Other adverse events often associated with ACE inhibi-
tors, first-dose hypotension and hyperkalemia, appear to occur less often with perindopril than with other agents in this class. The favorable safety profile for perindopril extends to a wide range of patients, including the elderly and those with either heart failure or renal disease. Perindopril has no negative effects on lipids in patients with hyperlipidemia or on glycemic control in patients with type 2 diabetes mellitus, and it reduces proteinuria in patients with renal disease. Perindopril has no known clinically significant drug– drug interactions. Thus, perindopril is a safe BP-lowering agent with documented tolerability in a wide range of patients with hypertension. 䊚2001 by Excerpta Medica, Inc. Am J Cardiol 2001;88(suppl):36i– 40i
pproximately 25% of US adults may be hypertensive according to the definition set forth in the A Sixth Report of the Joint National Committee on Pre-
have been used effectively to lower BP in a wide range of patients with hypertension and to reduce cardiovascular risk.9 Perindopril erbumine is a longacting ACE inhibitor that is effective with once-daily administration for the treatment of mild-to-moderate hypertension.10 The effectiveness of perindopril in reducing cardiovascular risk in patients with hypertension and/or other cardiovascular disease is being evaluated in large-scale long-term studies.11,12 This article is a review of the safety profile of perindopril in patients with hypertension and other concurrent diseases.
vention, Detection, Evaluation, and Treatment of High Blood Pressure,1,2 and the prevalence of hypertension may be as high as 50% among adults in some communities.3 Untreated or ineffectively treated high blood pressure (BP) is associated with increased risk for cardiovascular morbidity and mortality,4 and effective treatment of hypertension can significantly lower cardiovascular risk.5 Thus, safe and effective BP-lowering therapy is an important health-care priority. A wide range of agents from a number of different classes are safe and effective for the management of hypertension.2 There is considerable controversy about the safety of calcium antagonists for the treatment of patients with hypertension and the possibility that they may be associated with a higher rate of cardiovascular events than other therapies.6,7 Further, use of the ␣-adrenoceptor antagonist doxazosin was discontinued in the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT), because it was associated with a higher risk for heart failure than chlorthalidone.8 Because there are many classes of antihypertensives and many agents within each class from which to choose, and all of these drugs have been shown to reduce BP effectively, safety and tolerability are primary considerations in selecting ⱖ1 of these drugs for patient therapy. Angiotensin-converting enzyme (ACE) inhibitors
SAFETY AND TOLERABILITY OF PERINDOPRIL IN PATIENTS WITH UNCOMPLICATED HYPERTENSION Brown13 summarized safety data obtained for perindopril in developmental clinical trials for this drug. Analysis included safety data from ⬎2,500 patients who received perindopril, some treated for up to 4 years. Analysis of results from 632 patients who received perindopril in a long-term acceptability study indicated that it was safe and well tolerated— only 6.2% (n ⫽ 39) of patients discontinued therapy with perindopril (Table 1). The most common reason for discontinuation was cough (1.3%). (This persistent dry cough, usually accompanied by an irritating sensation in the throat, is an adverse event common to all ACE inhibitors.14) The safety analysis carried out by Brown also indicated that the incidence of hypotension with perindopril is low (0.2% of patients).
POSTMARKETING SURVEILLANCE From the Department of Medicine, State University of New York Health Science Center at Brooklyn, Brooklyn, New York, USA. Address for reprints: Luther T. Clark, MD, State University of New York Health Science Center at Brooklyn, 450 Clarkson Avenue, B-334, Brooklyn, New York 11203.
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©2001 by Excerpta Medica, Inc. All rights reserved.
Although data from controlled clinical trials are a key element in establishing the safety profile for any drug, such information may not be definitive. This view is supported by recent withdrawals of several drugs (eg, fenfluramine, terfenadine, mibefradil, 0002-9149/01/$ – see front matter PII S0002-9149(01)01920-8
TABLE 1 Reasons for Discontinuation of Perindopril in a Longterm Safety and Acceptability Study
Nature of Event Cough GI disturbance Cutaneous signs Sexual disorder Taste disturbance Dizziness Hypotension Orthostatic hypotension Sweating Hot flushes Thrombocytopenic purpura Proteinuria Facial edema Tachycardia Fatigue Myocardial infarction Multiple symptoms Death Total
Cases N (Possibly/Probably Related)
% Incidence
8 (6) 6 (3) 3 (2) 3 2 (2) 2 (1) 2 (1) 1 (1) 1 (1) 1 (1) 1
1.27 0.95 0.47 0.47 0.32 0.32 0.32 0.16 0.16 0.16 0.16
1 1 1 1 1 1 (1) 3 39 (19)
0.16 0.16 0.16 0.16 0.16 0.16 0.48 6.2
TABLE 2 Adverse Events Reported in Postmarketing Surveillance of 47,351 Hypertensive Patients Over 12 Months of Perindopril Treatment N (%) Type of Reaction Cough GI upset/dyspepsia Asthenia Headache Dizziness/vertigo Insomnia Hypotension/malaise Dry mouth Cramps Rash Palpitations/tachycardia Loss of libido Lower-limb edema Taste disturbance Renal dysfunction Angioneurotic edema Hemotological disturbance Serious allergic reaction Other
Men 1,705 389 409 291 251 84 64 67 75 45 26 51 13 19 31 1 4
(7.8) (1.8) (1.9) (1.3) (1.1) (0.38) (0.29) (0.31) (0.34) (0.21) (0.12) (0.23) (0.06) (0.09) (0.14) (0.004) (0.02)
5 (0.02) 164 (0.75)
Women 2,841 532 454 367 384 114 99 89 84 76 41 4 28 18 38 2 1
(11) (2.1) (1.8) (1.5) (1.5) (0.46) (0.40) (0.36) (0.34) (0.30) (0.19) (0.02) (0.11) (0.07) (0.17) (0.02) (0.004)
6 (0.01) 238 (0.95)
GI ⫽ gastrointestinal. Reprinted with permission from Br J Clin Pharmacol.17
GI ⫽ gastrointestinal. Reprinted with permission from J Hum Hypertens.13
bromfenac) from the US market because of unexpected adverse events revealed during postmarketing surveillance.15 Although spontaneous reporting of adverse events may be insufficient for assignment of causality, the large number of patients sampled can make such surveillance effective for detection of rare, but potentially serious side effects of drugs.16 Speirs et al17 reported safety results for perindopril from 47,351 patients who participated in a 12-month postmarketing study. Withdrawals because of adverse events occurred in 6.1% of women and 3.2% of men, an overall rate lower than that reported in clinical trials. The most common adverse event for perindopril in this very large patient population was cough (11.3% of women and 7.8% of men, Table 2). Serious adverse events were rare. Thus, postmarketing data for perindopril yield results remarkably consistent with those in controlled clinical studies.
HYPOTENSIVE EVENTS Although cough is the side effect most commonly associated with ACE inhibitors, a potentially more serious adverse event reported for patients taking these drugs, particularly those with heart failure, is first-dose hypotension.18 Perindopril has a relatively slow onset of action, which reduces its potential for this adverse event. Navookarasu et al19 reported that perindopril results in less substantial first-dose reductions in BP than other ACE inhibitors. Their study of 80 patients with congestive heart failure (CHF) indicated that a 2-mg dose of perindopril resulted in a maximum reduction in mean arterial pressure of 5.3 mm Hg versus 13.3 mm Hg for a 2.5-mg dose of
enalapril, 16.8 mm Hg for a 6.25-mg dose of captopril, and 15.0 mm Hg for 2.5 mg of lisinopril (Figure 1). Vitovec and Spinar20 reported similar findings in a comparison of first-dose responses to perindopril (2 mg) versus enalapril (2.5 mg) in 298 patients with stable symptomatic New York Heart Association (NYHA) class II to IV CHF. Patients in the enalapril group had a significantly higher incidence of asymptomatic hypotension than those who received perindopril. No patient in either group had symptoms of hypotension. The results of Brown et al13 are consistent with the view that perindopril has a low risk for hypotensive events. Their review of safety data indicated that only 0.16% of patients withdrew from perindopril therapy because of orthostatic hypotension.
SAFETY IN SPECIAL PATIENT POPULATIONS Patients with hypertension have a wide range of concurrent medical conditions that can compromise the safety of antihypertensive therapy. For example, diuretics may exacerbate serum lipid elevations in a patient with hypertension and hypercholesterolemia,21 and short-acting calcium antagonists may increase the risk for cardiovascular events and mortality in patients with previous myocardial infarction.22 Results obtained for perindopril indicate that it is safe in a wide range of special patient populations with hypertension. The elderly: Results from the third National Health and Nutrition Examination Survey (NHANES III) indicate that approximately half of white men and women and ⬎70% of black men and women in the
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FIGURE 1. Reductions in mean arterial pressure (MAP) in patients with congestive heart failure who received single doses of perindopril, enalapril, captopril, or lisinopril. (Reprinted with permission from Int J Clin Pract.19)
United States between 60 and 74 years of age are hypertensive.1 Antihypertensive therapy, including perindopril, is generally well tolerated in older patients.23 Suraniti et al24 evaluated the safety and acceptability of perindopril in 2,927 elderly (ⱖ70 years of age) hypertensive patients who were being treated in a general practice setting. These patients were participating in an open 6-month trial that included 23,460 patients with mild-to-moderate hypertension. Perindopril was started at 2 or 4 mg once daily, and if supine diastolic BP remained ⬎90 mm Hg, the daily dose could be doubled after 1 or 3 months (or a diuretic added if perindopril titration reached 8 mg). The withdrawal rate for adverse events among these elderly patients was 6.1%. This discontinuation rate is remarkably similar to that reported for perindopril in a long-term study that included patients of all ages.13 The adverse event reported most often for the elderly patients in this study was cough (8.9%). No other adverse event was reported by ⬎2.5% of patients (Table 3). Patients with heart failure: Clinical trial results reviewed by Sonnenblick25 in this supplement show that ACE-inhibitor therapy is effective in reducing mortality in patients with heart failure. ACE inhibitors are now recommended as treatment for patients with heart failure.2 Lechat et al26 conducted a 3-month double-blind, placebo-controlled trial to evaluate the safety and efficacy of perindopril (2 mg/day) versus placebo in 125 patients with NYHA class II or III CHF. Perindopril was safe in patients with heart failure. Only 2 of 61 patients (3.3%) who received perindopril withdrew because of adverse events (a cerebrovascular accident in 1 patient and elevated ␥-glutamyl transferase in a 38i THE AMERICAN JOURNAL OF CARDIOLOGY姞
second patient). Overall, 5 of 64 patients (7.8%) treated with placebo withdrew because of adverse events. Adverse events were similar in the patients who received perindopril or placebo (Table 4). None of the patients in either treatment group had orthostatic hypotension. Patients with renal dysfunction: ACE inhibitors are preferred antihypertensive therapy in patients with renal dysfunction and in those with diabetes (and thus increased risk for kidney disease) because they reduce proteinuria and the progression of renal dysfunction.2 Dratwa et al27 assessed the safety of perindopril (initial dose 2 to 4 mg/day) in a study that included 36 hypertensive patients with impaired renal function. Results showed that 1 year of perindopril therapy produced a significant reduction in proteinuria. Plasma creatinine and creatinine clearance remained stable over the treatment period. Altogether, 6 patients (16.7%) withdrew from treatment because of adverse
TABLE 3 Adverse Events Reported Most Often for Elderly Hypertensive Patients Being Treated with Perindopril Symptoms Occurring in 0.4% of Patients
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Cough Digestive disorders Dizziness Asthenia Headache Dry mouth Cutaneous signs Insomnia Muscular cramps Other symptoms Reprinted with permission from Am J Cardiol.24
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N (%) 260 70 64 58 53 15 15 12 12 53
(8.9) (2.4) (2.2) (2.0) (1.8) (0.5) (0.5) (0.4) (0.4) (1.8)
TABLE 4 Adverse Events Experienced by Patients with Congestive Heart Failure Treated with Perindopril Perindopril (n ⫽ 61)
Placebo (n ⫽ 64)
% Spontaneous
% Elicited
% Spontaneous
% Elicited
7 5 5 3 3 3 2 2 2 1 0
10 7 10 10 13 15 8 5 16 7 5
3 0 2 3 0 5 2 2 0 0 2
17 8 2 9 14 14 9 5 17 8 9
Fatigue Muscular cramps Diarrhea Headache Cough Dizziness Mood or sleep disturbances Cutaneous signs Dryness of mouth Nausea Taste disturbances
Reprinted with permission from Am Heart J.25
events. No adverse event was reported by ⬎4 patients, and the most common events were dizziness (4 patients), cough, headache, skin rash, and asthenia (3 patients each). Bonner et al28 evaluated the safety of perindopril in a 6-week study that included 56 patients with nephropathy and mild hypertension. Perindopril therapy had no significant effect on parameters reflective of renal function, including serum creatinine, creatinine clearance, urinary albumin excretion, and ␣1-microglobulin. In a subgroup of patients with albuminuria, perindopril significantly reduced urinary albumin excretion.
OTHER AT-RISK POPULATIONS Stumpe and Overlack29 assessed the safety of perindopril in a double-blind, randomized, placebo-controlled study that included 480 men and women (30 to 70 years of age) with mild hypertension and concurrent conditions, including hyperlipidemia, type 2 diabetes, ischemic heart disease, cardiac arrhythmia, peripheral arterial occlusive disease, nephropathy with proteinuria, chronic obstructive lung disease, or treatment with nonsteroidal anti-inflammatory drugs. Adverse events reported by perindopril-treated patients in this study (Table 5) did not differ significantly from those noted in patients without concomitant conditions. Perindopril had no negative impact on lipid and lipoprotein profiles in patients with hyperlipidemia, did not adversely affect glycemic control in patients with type 2 diabetes, had antianginal and anti-ischemic effects in patients with ischemic heart disease, reduced urinary albumin excretion in patients with kidney disease, and stimulated production of prostaglandin E2 in the patients who were taking nonsteroidal anti-inflammatory drugs. These investigators concluded that perindopril was a safe and suitable therapeutic option for hypertensive patients with concomitant diseases and/or therapies,29 as has been shown in other studies as well.30,31 Clinical laboratory abnormalities: The clinical laboratory abnormality most often associated with ACE inhibitors is hyperkalemia, which is thought to result
from reduced aldosterone secretion associated with decreased levels of angiotensin II.13,32 Increased levels of serum potassium have been observed in hypertensive patients after 1 month of perindopril therapy, but not thereafter.13 Perindopril has no significant effect on serum potassium or urinary potassium excretion in patients with renal dysfunction.27,28 Drug– drug interactions: Antihypertensive drugs vary markedly in their potential for pharmacokinetic drug– drug interactions.33 Such interactions are particularly important in elderly patients, who are likely to be taking multiple medications for various chronic conditions.34 Perindopril is relatively free of clinically important drug– drug interactions. No deleterious interactions have been noted when perindopril was administered with benzodiazepines, organic nitrates, anTABLE 5 Adverse Events Experienced by Perindopril-treated Patients with Concurrent Medical Conditions Perindopril (n ⫽ 137) Patients reporting spontaneous symptoms (n) Cough Tinnitus Dyspnea Cutaneous signs Palpitations Sexual disturbances Dizziness Abdominal pain Thrombosis Fatigue Cold extremities Sleep disturbances Total Patients withdrawn (n) Poor compliance Dyspnea Blood pressure increase Cough Patient request Intercurrent illness Total
Placebo (n ⫽ 132)
2 2 2 1 1 1 1 1
11 1 1 1 1 1 5
1 2 1 1 5
1
1 2
Reprinted with permission from Am J Cardiol.28
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ticoagulants, nonsteroidal anti-inflammatory drugs, or digitalis.10 Coadministration with hydrochlorothiazide reduces the maximum plasma concentration of perindoprilat, the active metabolite formed by hydrolysis from perindopril, but this interaction does not appear to be clinically significant.10
CONCLUSION Results from both clinical trials and postmarketing surveillance indicate that perindopril is safe and well tolerated in a wide range of patients with hypertension. The clinical adverse event reported most often for perindopril is the nonproductive dry cough observed in patients treated with any member of the ACE-inhibitor class. Other adverse events most often associated with ACE inhibitors, first-dose hypotension and hyperkalemia, appear to occur less frequently with perindopril than with other agents in this class. The favorable safety profile for perindopril extends to a wide range of patients, including the elderly, those with either CHF or renal disease, and those with hypertension and concurrent conditions. Perindopril has no unfavorable effects on lipid levels in patients with hyperlipidemia or glycemic control in patients with type 2 diabetes, and it reduces proteinuria in patients with kidney disease. Finally, perindopril has no known clinically significant drug– drug interactions. Perindopril is thus a safe BP-lowering agent with documented tolerability in a wide range of patients with hypertension.
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Roccella EJ. Trends in the prevalence, awareness, treatment, and control of hypertension in the adult US population: data from the Health Examination Surveys, 1960-1991. Hypertension 1995;26:60 – 69. 2. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1997;157:2413–2446. 3. Meissner I, Whisnant JP, Sheps SG, Schwartz GL, O’Fallon WM, Covalt JL, Sicks JD, Bailey KR, Wiebers DO. Detection and control of high blood pressure in the community: do we need a wake-up call? Hypertension 1999;34:466 – 471. 4. Kannel WB. Risk stratification in hypertension: new insights from the Framingham Study. Am J Hypertens 2000;13:3S–10S. 5. Hansson L, Lindholm LH, Ekbom T, Dahlo¨ f B, Lanke J, Schersten B, Wester P-O, Hedner T, de Faire U, for the STOP-Hypertension 2 Study Group. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish trial in old patients with hypertension-2 study. Lancet 1999;354:1751–1756. 6. Furberg CD, Psaty BM. Should calcium antagonists be first line drugs in hypertension? Herz 1995;20:365–369. 7. Zanchetti A. The calcium channel blocker controversy in perspective. Cardiology 1997;88(suppl 1):66 –70. 8. ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). JAMA 2000;283:1967–1975.
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