CORRESPONDENCE: LETTER TO THE EDITOR
Reply
Bryan Williams, MD, FRCP, FAHA*
* Department of Cardiovascular Sciences, University of Leicester School of Medicine, Clinical Sciences Building, P.O. Box 65, Leicester, LE2 7LX, United Kingdom (Email: Bw17{at}leicester.ac.uk).
In a previous review, I stated that the data from large-scale clinical trials of the treatment of hypertension suggested that the main driver of benefit from blood-pressure (BP) lowering drugs was the BP lowering per se (1). Dr. Schwartz in his response to this review notes that, although the HOPE (Heart Outcomes Prevention Evaluation) (2) and EUROPA (EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease) (3) studies showed benefits of angiotensin-converting enzyme (ACE) inhibition versus placebo in reducing cardiovascular events in patients with cardiovascular disease, the more recent PEACE (Prevention of Events with Angiotensin Converting Enzyme inhibition) (4) study did not. Dr. Schwartz states that this dichotomy might suggest within-drug-class differences, pointing to the benefit of specific ACE inhibitors "beyond blood pressure." This concept is tenuous at best and could only be proven by testing different ACE inhibitors head-to-head in the same patient population.
The differences in outcomes when comparing the HOPE and EUROPA trials with the PEACE trial reflect different patient populations and differences in comcomitant medications. Compared to the HOPE and EUROPA trials, the the PEACE trial cohort was more aggressively treated with lipid-lowering drugs (70%), antiplatelet drugs (90%), and beta-blockers (60%), and in such an aggressively treated population it was not even possible to show an additional benefit of the ACE inhibitor-induced BP lowering. The message from the PEACE study was admirably summed up by the investigators: "in a population of patients with coronary artery disease and preserved ejection fraction who receive intensive current standard therapy . . . , there appears to be no evidence of cardiovascular benefit from the addition of ACE-inhibitor therapy" (4).
With regard to treating hypertension in an endeavor to prevent the development of fatal or nonfatal myocardial infarction (MI), the ALLHAT (Antihypertensive and Lipid Lowering treatment to prevent Heart Attack Trial) study tested this hypothesis and failed to show an advantage of ACE inhibition (5). Moreover, the more recent CAMELOT (Comparison of Amlodipine vs. Enalapril to Limit Occurrences of Thrombosis) study also failed to show an advantage of ACE inhibition over the comparator, a calcium channel blocker (CCB) in patients with angiographically proven coronary disease (6). Finally, meta-analyses of hypertension trials have consistently failed to show an advantage of ACE inhibitor-based therapy over other classes of BP lowering therapy in the prevention of MI (1).
I concede that on the basis of our recent data from the CAFE (Conduit Artery Function Evaluation) study, it is possible to go beyond brachial BP, depending on the choice of the BP-lowering agent (7). In the CAFE study we showed that beta-blocker ± thiazide-based therapy was less effective at lowering central aortic pressure when compared to a CCB ± ACE inhibitor-based treatment, despite similar effects on brachial BPs. Thus, it is plausible that brachial BP measurements underestimated the beneficial effects of ACE inhibition on central aortic BPs in the HOPE and EUROPA trials. However, even then it is still pressure and hemodynamics and not mysterious biology that explain the benefit of the drugs in these trials.
It is surely beyond dispute that the most effective way to "go beyond blood pressure" to prevent MI in patients with hypertension at high risk of cardiovascular disease is to add a statin to their therapy (1). No amount of ACE inhibition will compete with this, no matter what clothes the emperor wears—indeed, on the basis of evidence alone, with regard to ACE inhibition and the prevention of MI by drug-specific effects, the emperor has no clothes!
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1. Williams B. Recent hypertension trialsimplications and controversies. J Am Coll Cardiol 2005;45:814-827.2. 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.[Abstract/Free Full Text] 3. EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery diseaserandomized, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 2003;362:782-788.[CrossRef][Web of Science][Medline] 4. The PEACE Investigators Angiotensin-converting enzyme inhibitors in stable coronary artery disease N Engl J Med 2004;351:2058-2068.[Abstract/Free Full Text] 5. 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 diureticthe Antihypertensive and Lipid Lowering treatment to prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981-2997.[Abstract/Free Full Text] 6. Nissen S, Tuzcu EM, Libby P, et al. The CAMELOT study: a randomized controlled trial Effect of antihypertensive agents on cardiovascular events in patients with coronary heart disease and normal blood pressure JAMA 2004;292:2217-2226.[Abstract/Free Full Text] 7. Williams B, Lacy PS, Thom S, et al. CAFE Investigators for the ASCOT Investigators Differential impact of blood pressure lowering drugs on central aortic pressure and clinical outcomes—The principal results of the Conduit Artery Function Evaluation (CAFE) study Circulation 2006;113:1213-1225.[Abstract/Free Full Text]
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