Editor—Verma and Strauss say that, compared with angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers do not reduce (and may increase) the risk of myocardial infarction.1 Their claim represents an incomplete, inaccurate, and misleading “analysis” of the evidence.
They did not cite the two largest studies that randomised patients to an ACE inhibitor or angiotensin receptor blockers and had the statistical power to evaluate cardiovascular outcomes.2,3 These had twice as many myocardial infarctions as their trials combined (table). As none of their trials randomised these two treatments, their conclusions depend on indirect comparisons, small numbers of events and are unreliable. OPTIMAAL (379 patients with MI in the captopril group and 384 losartan) and VALIANT (798 total myocardial infarctions in captopril group, 796 valsartan) strongly refute the authors' hypothesis.
Other data were selectively and incorrectly cited—for example, mentioning the only CHARM trial with an excess of myocardial infarctions in the candesartan group (the other two trials had fewer) and inaccurate citation of the risk increase (table).4 That the losartan group in RENAAL had fewer myocardial infarctions was not mentioned. It is no surprise that angiotensin receptor blockers failed to reduce mortality in trials underpowered to test for this.5 The interpretation of trials using an active control is confounded when these can reduce myocardial infarction (for example, a β blocker) or lower blood pressure more (for example, amlodipine).w1 w2
Table 1.
Trial | Patients' condition | Treatments | No of patients | Follow-up in years | No of patients with myocardial infarction* |
---|---|---|---|---|---|
IDNT | Diabetic nephropathy | Placebo | 569 | 2.6 | 51 |
Irbesartan | 579 | 48 | |||
Amlodipine | 567 | 29 | |||
RENAAL | Diabetic | Placebo | 762 | 3.4 | 68 |
nephropathy | Losartan | 751 | 50 | ||
SCOPE | Elderly | Placebo | 2460 | 3.7 | 63 |
hypertension | Candesartan | 2477 | 70 | ||
LIFE | Hypertension | Atenolol | 4588 | 4.8 | 188 |
Left ventricular | Losartan | 4605 | 198 | ||
hypertrophy | |||||
VALUE | Hypertension risk factors | Amlodipine | 7596 | 4.2 | 313 |
Valsartan | 7649 | 369 | |||
CHARM | Heart failure | Placebo | 3796 | 3.1 | 190 |
Candesartan | 3803 | 176 | |||
OPTIMAAL | Myocardial infarction | Captopril | 2733 | 2.7 | 379 |
Losartan | 2744 | 384 | |||
VALIANT | Myocardial infarction | Captopril | 4909 | 2.1 | 559 |
Valsartan | 4909 | 587 | |||
Captopril and valsartan | 4885 | 554 |
CHARM: candesartan cilexitil in heart failure: assessment of reduction mortality and morbidity. IDNT: irbesartan in diabetic nephropathy trial. LIFE: losartan intervention for endpoint reduction in hypertension. OPTIMAAL: optimal trial in myocardial infarction with the angiotensin II antagonist losartan. RENAAL: reduction in endpoints in patients with non—insulin-dependent diabetes mellitus with the angiotensin II antagonist losartan. SCOPE: study of cognition and prognosis in the elderly. VALIANT: valsartan in acute myocardial infarction trial. VALUE: valsartan antihypertensive long-term use evaluation.
Fatal or non-fatal.
A correct analysis would have considered all relevant data, appropriately weighted, and composite non-fatal and fatal outcomes, to take account of competing risks.
We endorse the need to obtain (and disclose) evidence from randomised trials to support the use of new drugs. Seeing such a misleading opinion in the BMJ does a disservice to the proper evaluation of drug efficacy and safety, as well causing unnecessary anxiety for patients.
Supplementary Material
Competing interests: All authors have been or are involved in clinical trials with angiotensin receptor blockers in cardiovascular disease and have received honorariums for speaking, consultancy fees, and research grants from pharmaceutical companies that market angiotensin receptor blockers.
Details of the eight coauthors and additional references w1 and w2 are on bmj.com
References
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