Published online before print August 7, 2006, doi: 10.1161/01.HYP.0000238045.76905.94
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(Hypertension. 2006;48:359.)
© 2006 American Heart Association, Inc.
Editorial Commentaries |
Amlodipine Better Than Lisinopril?
How One Randomized Clinical Trial Ended Fallacies From Observational Studies
From the Hypertension Program (F.H.M.), Division of Cardiology, St Luke’s-Roosevelt Hospital, New York, NY; and the Studies Coordinating Centre (J.A.S.), Division of Hypertension and Cardiovascular Rehabilitation, Department of Cardiovascular Disease, University of Leuven, Leuven, Belgium.
Correspondence to Franz H. Messerli, Division of Cardiology, St Luke’s-Roosevelt Hospital, 1000 Tenth Ave, Suite 3b-30, New York, NY 10019. E-mail fmesserli{at}aol.com
The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) compared in >30 000 high-risk hypertensive patients the effects on coronary heart disease of 3 treatment strategies: (1) based on the diuretic chlorthalidone, (2) the calcium-channel blocker (CCB) amlodipine, and (3) the angiotensin converting-enzyme (ACE) inhibitor lisinopril, respectively.1 Sponsored by the National Heart, Lung, and Blood Institute, ALLHAT stands out because no differences occurred in the incidence of the primary end point that consisted of the combination of fatal coronary heart disease and acute myocardial infarction.1 Not surprisingly, the attention of the ALLHAT consortium shifted to secondary end points, such as stroke, or to loosely defined2 components of secondary end points, such as heart failure. At the end of the line, the ALLHAT investigators based their main conclusions on events that, at the initiation of the trial, they regarded as "soft data that will at best confirm or supplement the primary endpoint."3 More importantly, what was not identical in the 3 treatment groups was the on-treatment blood pressure despite vigorous attempts to titrate and combine the study medications to achieve a blood pressure of <140 mm Hg systolic and 90 mm Hg diastolic.1 These salient features of ALLHAT should be kept in mind whenever one attempts to interpret the findings of this landmark trial.
In this issue of Hypertension, Leenen et al4 published a post hoc analysis, in which they made a direct comparison of cardiovascular and other outcomes among the 18 102 ALLHAT participants randomly assigned to amlodipine or lisinopril. In line with previous reports,1 the incidence of the primary coronary end point and total and cardiovascular mortality were similar in both groups. However, the patients randomly assigned to lisinopril experienced higher risks of stroke, combined cardiovascular disease, gastrointestinal bleeding, and angioedema, whereas the risk of heart failure was higher in the amlodipine group.4 The excess cardiovascular risk was particularly apparent in women and black patients. Leenen et al4 concluded that "considering the totality of outcome measures in ALLHAT, amlodipine appeared to have advantages over lisinopril." This is a provocative statement that is in line with the published literature (Table) and that is prone to at least dent, if not shatter, the halo surrounding the ACE inhibitors. The conclusions of Leenen et al4 underscore the difficulty in bridging the gap between scientifically attractive pathogenetic concepts based on experimental models5 and the clinical reality that matters to patients, that is, event-free survival.
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The ALLHAT investigators attributed at least part of the better cardiovascular outcome on amlodipine compared with lisinopril to the more pronounced blood pressure reduction on the CCB, particularly in women and black patients.4 The Heart Outcomes Prevention Evaluation study (HOPE)6 and the Losartan Intervention For Endpoint reduction in hypertension study (LIFE)7 launched the notion of benefit beyond blood pressure lowering, although in both trials the baseline-adjusted systolic blood pressure at the last visit was significantly lower in the patients randomly assigned to the ACE inhibitor (3.0 mm Hg; P<0.001)6 or the angiotensin II receptor blocker (1.3 mm Hg; P=0.017)7 than in those allocated placebo6 or atenolol,7 respectively. Stroke is the complication of hypertension that is most directly linked to the blood pressure level.8 Not surprisingly, metaregression analyses published by us9,10 and other researchers11 demonstrated that, in keeping with large-scale prospective observational studies12 and also in randomized clinical trials, small gradients in the achieved systolic blood pressure explain most of the differences in the cardiovascular outcomes. An updated metaregression analysis13 accounted not only for the differences in the achieved systolic blood pressure between groups randomly assigned in clinical trials but also for drug class, the interaction between on-treatment systolic pressure and drug class, age at randomization, year of publication, and duration of follow-up. The updated results corroborated that blood pressure reduction was by far the most important determinant of cardiovascular outcome.13 In keeping with the current ALLHAT findings, CCBs compared with ACE inhibitors provided a small blood pressure–independent benefit (&14%; P=0.042) in the prevention of stroke, and the same was true for ACE inhibitors compared with CCBs in relation to coronary heart disease (&10%; P=0.028).13 The observation that the incidence of the primary end point was similar in the 2 treatment groups in the study of Leenen et al4 might be interpreted as indirect evidence suggesting that lisinopril-based therapy conferred greater cardiac benefit than treatment initiated with amlodipine.
In 2003, the Blood Pressure Lowering Trialists’ Collaboration noticed that for every outcome other than heart failure, the differences between randomized groups in cardiovascular outcomes were directly related to the achieved systolic blood pressure.11 However, the lack of association among 34 reviewed trails was mainly because of the noise of 4 that compared CCBs to placebo. The summary statistic breaking the relationship included results from a primary prevention trial in older patients and from 3 secondary prevention studies in diabetic patients with renal dysfunction or in high-risk patients with coronary heart disease.11 Substantial differences in the pathogenetic mechanisms causing left ventricular failure in such heterogeneous conditions cast doubt on the proposed conclusion of no association between the prevention of heart failure and the level of achieved systolic blood pressure.11 In the Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm (ASCOT-BPLA)14 and in A Coronary disease Trial Investigating Outcome with Nifedipine gastrointestinal therapeutic system (ACTION),15 the relative risks of heart failure were slightly (hazard ratio: 0.84; 95% CI: 0.66 to 1.05; P=0.13)14 or significantly (hazard ratio: 0.71; 95% CI: 0.54 to 0.94; P=0.015)15 lower for the CCB compared with atenolol14 or placebo15 and followed the gradients in systolic blood pressure, amounting to 2.7 mm Hg14 and 6.0 mm Hg,15 respectively. In line with the epidemiological evidence linking heart failure to hypertension, these observations14,15 suggest that blood pressure lowering by a CCB or any other class of antihypertensive agents contributes to the prevention of left ventricular dysfunction.
Remarkably, in ALLHAT,1,4 as well as in the Valsartan Antihypertensive Long-term Use Evaluation trial (VALUE),16 heart failure, against the blood pressure gradient, occurred more frequently on amlodipine than on lisinopril1,4 or valsartan.16 This could either indicate that, for a given fall in blood pressure, blockers of the renin–angiotensin system are more powerful in preventing heart failure than are CCBs or that blood pressure is a less important predictor of congestive heart failure than of heart attack and stroke. However, in both trials,1,4,16 the Kaplan–Meier estimates for heart failure only started to diverge after 2 to 3 years, when, compared with the amlodipine arm, a greater proportion of patients randomly assigned to the ACE inhibitor1,4 or the angiotensin II receptor blocker16 had stopped the alternative first-line treatment, had crossed over, and/or were receiving combination therapy, including second-line antihypertensive medications.
Most clinicians regard ACE inhibitors as being well-tolerated antihypertensive drugs. Unexpectedly, in the current ALLHAT report, adherence to randomized treatment was significantly lower in the lisinopril than in the amlodipine arm (at 5 years, 72.6% versus 80.4%). Persistence was lowest in women and blacks. The reason for this difference is unclear but is likely to be because of adverse effects, frequently dry cough on ACE inhibitors and ankle edema on CCBs. For drugs that are used by hypertensive patients over decades, long-term safety is of paramount concern. Angioedema is a well-documented but rare adverse event in patients taking ACE inhibitors. It can appear from a few hours to 8 years after an ACE inhibitor is first taken. Unfortunately, a median of 10 months may elapse before onset of angioedema and withdrawal of the ACE inhibitor.17 This potentially fatal adverse event was observed in 38 patients in the lisinopril group but only in 3 randomly assigned to amlodipine. In the lisinopril arm, the rates were 0.72% in blacks and 0.26% in nonblacks. Although fatalities of angioedema are exceedingly rare, one should consider that as worldwide 30 to 40 million patients are exposed to ACE inhibitors, this drug class might account for several hundred fatalities per year.18 That these are not just hypothetical numbers is underscored by instances of fatal angioedema in both ALLHAT1,4 and HOPE6 and also by a recent report from a single coroner’s office describing 7 cases of asphyxiation associated with ACE inhibitors within a mere 3-year period of time.19
Finally, how should clinicians translate the new ALLHAT findings in their day-to-day practice? Foremost, they should be aware that high blood pressure is a reversible risk factor with lower levels leading to fewer strokes and heart attacks. Furthermore, several landmark trials, over and above those listed in the Table (for review, see Reference 10), proved in no uncertain terms that CCBs are powerful, efficacious, and safe antihypertensive drugs and that they can be prescribed to high-risk patients as first-line drugs for indications that were until now dominated by inhibitors of the renin–angiotensin system. Finally, observational studies, which are prone to observer bias, should never be taken at face value, even if they make headlines in the medical and lay media and even if, in some instances, they might be hypothesis generating. The analysis of Leenen et al4 puts a definite end to what was called the CCB controversy, which flourished for more than a decade. Only randomized trials provide evidence strong enough to be useful in the management of hypertensive patients, which currently already represent 20% to 30% of the world’s population, a proportion likely to steadily increase over the next decades.
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Acknowledgments |
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Disclosures
F.H.M. and J.A.S. are ad-hoc consultants for pharmaceutical companies with commercial interests in CCBs and ACE inhibitors and have received funding for studies, seminars, and travel from such companies.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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 Top References |
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1. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002; 288: 2981–2997.
2. Messerli FH. ALLHAT, or the soft science of the secondary end point. Ann Intern Med. 2003; 139: 777–780.
3. Davis BR, Cutler JA, Gordon DJ, Furberg CD, Wright JT Jr, Cushman WC, Grimm RH, LaRosa J, Whelton PK, Perry HM, Alderman MH, Ford CE, Oparil S, Francis C, Proschan M, Pressel S, Black H, Hawkins CM, for the ALLHAT Research Group. Rationale and design for the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Am J Hypertens. 1996; 9: 342–360.[CrossRef][Medline] [Order article via Infotrieve]
4. Leenen FHH, Nwachuku CE, Black HR, Cushman WC, Davis BR, Simpson LM, Alderman MH, Atlas SA, Basile JN, Cuyjet AB, Dart R, Felicetta JV, Grimm RH, Haywood LJ, Jafri SZA, Proschan MA, Thadani U, Whelton PK, Wright JT, for the ALLHAT Collaborative Research Group. Clinical events in high-risk hypertensive patients randomily assigned to calcium channel blocker versus angiotensin-converting enzyme inhibitor in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Hypertension. 2006; 48: 374–384.
5. Kim S, Iwao H. Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev. 2000; 52: 11–34.
6. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000; 342: 145–153.
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8. Zhang H, Thijs L, Staessen JA. Blood pressure lowering for the primary and secondary prevention of stroke. Hypertension. 2006; 48: 187–195.
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11. Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet. 2003; 362: 1527–1535.[CrossRef][Medline] [Order article via Infotrieve]
12. Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002; 360: 1903–1913.[CrossRef][Medline] [Order article via Infotrieve]
13. Verdecchia P, Reboldi G, Angeli A, Gattobigio R, Bentivoglio M, Thijs L, Staessen JA, Porcellati C. Angiotensin-converting enzyme inhibitors and calcium channel blockers for coronary heart disease and stroke prevention. Hypertension. 2005; 46: 386–392.
14. Dahlöf B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O’Brien E, Östergren J, for the ASCOT Investigators. Prevention of cardiovascular events with an amlodipine±perindopril strategy compared with an atenolol±thiazide strategy. The Anglo-Scandinavian Cardiac Outcomes Trial - Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005; 366: 895–906.[CrossRef][Medline] [Order article via Infotrieve]
15. Poole-Wilson PA, Lubsen J, Kirwan BA, van Dalen FJ, Wagener G, Danchin N, Just H, Fox KAA, Pocock SJ, Clayton TC, Motro M, Parker JD, Bourassa MG, Dart AM, Hildebrandt P, Hjalmarson Å, Kragten JA, Molhoek GP, Otterstad JE, Seabra-Gomes R, Soler-Soler J, Weber S, on behalf of the Action (A Coronary disease Trial Investigating Outcome with Nifedipine gastrointestinal therapeutic system) investigators. Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial. Lancet. 2004; 364: 849–857.[CrossRef][Medline] [Order article via Infotrieve]
16. Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, Hua T, Laragh J, McInnes GT, Mitchell L, Platt F, Schork A, Smith B, Zanchetti A, for the VALUE Trial Group. Outcomes in hypertensive patients at high cardiovascular risk treated with valsartan- or amlodipine-based regimens: VALUE, a randomised trial. Lancet. 2004; 363: 2022–2031.[CrossRef][Medline] [Order article via Infotrieve]
17. Agostini A, Cicardi M, Cugno M, Zingale LC, Gioffrè D, Nussberger J. Angioedema due to angiotensin-converting enzyme inhibitors. Immunopharmacology. 1999; 44: 21–25.[CrossRef][Medline] [Order article via Infotrieve]
18. Messerli FH, Nussberger J. Vasopeptidase inhibition and angio-oedema. Lancet. 2000; 356: 608–609.[CrossRef][Medline] [Order article via Infotrieve]
19. Dean DE, Schultz DL, Powers RH. Asphyxia due to angiotensin converting enzyme (ACE) inhibitor mediated angioedema of the tongue during the treatment of hypertensive heart disease. J Forensic Sci. 2001; 46: 1239–1243.[Medline] [Order article via Infotrieve]
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