The Pharmaceutical Journal
Vol 270 No 7247 p607
3 May 2003

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Aborted heart disease trial hints at the comparative effectiveness of therapies

The effectiveness of calcium channel blockers in reducing cardiovascular disease is probably similar to but not better than that of diuretic or beta-blocker treatment, say researchers (JAMA 2003;289:2073).

The CONVINCE trial The CONVINCE trial was a double-blind randomised trial involving 16,602 patients with hypertension who had one or more additional risk factors for cardiovascular disease. Initially, 8,241 participants received 180mg COER verapamil at bedtime and 8,361 received either 50mg atenolol or 12.5mg hydrochlorothiazide in the morning. Other antihypertensive drugs could be added if needed. Participants were followed for a mean of three years. The CONVINCE trial was sponsored by the manufacturer of COER verapamil.

Their conclusion comes with publication of data from the CONVINCE trial (see Panel) which was designed to assess the equivalence of controlled-onset extended-release (COER) verapamil and standard therapy in preventing cardiovascular disease-related events. However, the trial was stopped early for commercial reasons and so failed to follow patients for long enough to show equivalence.

Data collected before termination of the trial showed that a similar number of cardiovascular events occurred in the COER verapamil group as the atenolol or hydrochlorothiazide group (364 vs 365, hazard ratio 1.02, 95 per cent confidence interval, 0.88–1.18, P=0.77). The incidence of acute myocardial infarction was about 18 per cent lower for COER verapamil than for atenolol or hydrochlorothiazide but this benefit was offset by a 15 per cent higher risk of stroke. "Although quite possibly due to chance, these trends are consistent with COER verapamil's ability to inhibit platelet aggregation," the researchers say.

The researchers also examined the time of day cardiovascular events occurred. In each treatment group, more participants had events between 6am and noon than any other six-hour period (99 out of 277 in the COER verapamil group vs 88 out of 274 in the atenolol or hydrochlorothiazide group).

COER verapamil (Chronovera), which was granted a marketing authorisation by the Medicines Control Agency in 2001 but is not marketed in the United Kingdom, exerts its major antihypertensive effect six to 12 hours after administration. However, the researchers say that the findings "do not support the concept of chronotherapeutics".

In an accompanying editorial, Dr Bruce Psaty, University of Washington, Seattle, and Dr Drummond Rennie, University of California, San Francisco, are critical of trial sponsors who terminate clinical investigations early. "The participants in CONVINCE were not only deprived of personal benefit from the completed trial, but also the social benefit of genuine scientific contributions from an adequately powered study," they say. They also speculate that if the trial had been allowed to run to completion the primary results might have shown that verapamil was slightly better than beta-blockers and that diuretics were better than verapamil. "Such a finding ... would have been an important scientific contribution," they conclude (ibid p2128).