BMJ  2005;330:1270-1271 (28 May), doi:10.1136/bmj.330.7502.1270-b

Letter

Angiotensin receptor blockers and myocardial infarction

Authors' reply

Editor—We agree with McMurray et al that angiotensin receptor blockers have not been associated with increased myocardial infarction in all trials, although viewing myocardial infarction in concert with cardiovascular death may be more appropriate. For example, in OPTIMAAL cardiovascular mortality was higher with losartan (relative risk 1.17, 95% confidence interval 1.01-1.34) and myocardial infarction did not change. In RENAAL losartan actually decreased myocardial infarction by 26% and delayed the need for dialysis by 40 days, but once dialysis was required the mortality in the losartan group was 29% higher.¹

The VALIANT rate of myocardial infarction had not been published previously, and we thank the trialists for providing this information. VALIANT lasted only 24.7 months, and 39% of the patients received angiotensin converting enzyme (ACE) inhibitors before randomisation (average day 5). Early administration of these drugs after myocardial infarction reduces 30 day mortality by 7% with 85% of that benefit in the first week,² thereby potentially masking differences between ACE inhibitors and angiotensin receptor blockers. VALIANT proved the "non-inferiority" of valsartan to captopril, but this does not imply equivalence of treatment, rather simply that valsartan is "not substantially worse."³

CHARM-ADDED and OVERALL were not discussed since the rate of myocardial infarction for candesartan without ACE inhibitors in the background could not be ascertained. In LIFE the blocker atenolol does not seem to be anti-ischaemic. A meta-analysis in almost 25 000 hypertensive patients confirmed that atenolol significantly reduces blood pressure, but has no reduction in myocardial infarction, death, or stroke.⁴ According to some experts,⁵ the 19% difference in blood pressure rate (P = 0.02) seen in VALUE cannot be explained by blood pressure difference in favor of amlodipine, nor by "serial median matching."

Results of placebo controlled trials in coronary artery disease with both amlodipine (CAMELOT) and nifedipine (ACTION) confirm that calcium channel blockers improve symptoms of angina, reduce need for angiography or revascularisation, and reduce blood pressure, but they do not decrease myocardial infarction or death, implying that blood pressure differences or vascular benefits of amlodipine were not responsible for the heightened myocardial infarction rate with valsartan.

With respect to Lewis's and Opie's comments, it is important to point out that captopril in reference 5 of Lewis's letter reduced mortality by 40%, whereas irbesartan compared with placebo in the irbesartan diabetic nephropathy trial (IDNT) did not reduce mortality or myocardial infarction despite a reduction of 4/3 mm Hg in blood pressure.^w1 A meta-analysis in diabetic kidney disease confirms that ACE inhibitors and angiotensin receptor blockers are similar and powerful nephroprotective agents.^w2 However, ACE inhibitors significantly reduced all cause mortality (relative risk 0.79, 95% confidence interval 0.63 to 0.99), whereas angiotensin receptor blockers did not (0.99, 0.85 to 1.17). Furthermore, the aetiology of the diabetes did not affect the benefit. In patients with diabetes, the benefit of ACE inhibitors has been well established by MICRO-HOPE and PERSUADE.^w1

The body of evidence supporting both myocardial and mortality benefit of ACE inhibitors greatly exceeds that of angiotensin receptor blockers, which is probably why most worldwide guidelines recommend it first line across the disease spectrum.^w3

Division of Cardiology, North York General Hospital, 4001 Leslie Street, Suite 107, Toronto, ON, Canada M2K 2K9 Dr.marty{at}bellnet.ca

Division of Cardiac Surgery, Toronto General Hospital, Toronto, ON, Canada M5G 2C4

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Competing interests: MHS has received speaking honorariums from Aventis Canada, Novartis Canada, MerckFrosst Canada, Pfizer Canada, and AstraZeneca Canada. SV has received research grants and speaking honorariums from GlaxoSmithKline Canada, Aventis, Pfizer Canada, Actelion Canada, AstraZeneca Canada, and Merck/MerckFrosst Schering Canada.

Additional references w1-w3 and for eight named studies are on bmj.com

References

1. FDA Advisory Briefing NDA 20-386 (S-028) www.fda.gov
2. ACEI Inhibitor Myocardial Infarction Collaborative Group. Indications for ACE inhibitors in the early treatment of acute myocardial infarctions: Systematic overview of individual data from 100,000 patients in randomized trials. Circulation 1998;97: 2202-12.[Abstract/Free Full Text]
3. Siegel JP. Equivalence and noninferiority trials Am Heart J 2000;139: S166-70.[CrossRef][ISI][Medline]
4. Carlberg B, Samuelsson O, Lindholm LH. Atenolol in hypertension: Is it a wise choice? Lancet 2004;364: 1684-9.[CrossRef][ISI][Medline]
5. Staessen JA, Thijis L, Birkenhager WH. VALUE: Analysis of results. Lancet 2004;364: 931 (author's reply 935).[CrossRef][Medline]

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