The angiotensin-receptor blocker irbesartan lowered blood pressure modestly but did not reduce cardiovascular events in a study of patients with atrial fibrillation, in the randomized, controlled ACTIVE-I trial reported in the March 10 issue of the New England Journal of Medicine.
Contrary to the study hypothesis, "Among patients with atrial fibrillation, most of whom had well-controlled hypertension and 60% of whom were receiving an ACE inhibitor, the addition of irbesartan did not reduce the risk of death from cardiovascular causes, stroke, or myocardial infarction, or this composite outcome plus hospitalization for heart failure," said Dr. Salim Yusuf of McMaster University and the David Braley Cardiac, Vascular, and Stroke Research Institute at Hamilton (Ont.) Health Sciences, and his associates.
Previous research showed that lowering blood pressure cuts the risk of stroke and heart failure in patients without atrial fibrillation, but no such effect has yet been demonstrated in AF. "We hypothesized that an ARB may prevent cardiovascular events and enhance the maintenance of sinus rhythm in patients with intermittent AF by reducing BP and by special effects related to blockade of the renin-angiotensin-aldosterone system," wrote Dr. Yusuf and his associates in the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE I).
The trial, funded by Bristol-Myers Squibb and Sanofi-Aventis, involved 9,016 AF patients (mean age 70 years) who were randomly assigned to receive once-daily oral irbesartan (4,518 subjects) or a matching placebo (4,498 subjects) and were followed for a mean of 4 years.
Mean blood pressure declined by 6.8/4.5 mm Hg in subjects who received irbesartan, compared with 3.9/2.6 mm Hg, respectively, in the placebo group.
Despite this modest effect, the rate of the first coprimary outcome – a composite of stroke, MI, or death from vascular causes – was identical in both groups, at 5.4% per 100 patient-years. The rate of the second coprimary outcome – the first composite plus hospitalization for heart failure – also was not significantly different, at 7.3% and 7.7% per 100 patient-years with irbesartan and placebo, respectively.
"The only component of the coprimary outcome that showed a nominally significant reduction with irbesartan was a first hospitalization for heart failure," the investigators noted (N. Engl. J. Med. 2011;364:928-38).
There was a nonsignificant numerical trend toward fewer strokes, transient ischemic attacks, and cases of systemic emboli with active treatment.
A subgroup of 1,730 patients who had been in sinus rhythm at baseline were followed for recurrence of AF. Irbesartan had no effect on recurrence in these patients.
"An important observation in ACTIVE I was that hospitalizations for heart failure were more common than stroke in this population of patients with AF, and both increased the risk of death by a factor of 4. This finding suggests that preventing heart failure is as important as preventing strokes in this population," Dr. Yusuf and his colleagues said.
More subjects in the irbesartan group (127 patients) than in the placebo group (64 patients) discontinued their medication because of hypotension. Renal dysfunction leading to drug discontinuation also was more common with irbesartan (43 patients) than placebo (24 patients). In addition, four patients taking irbesartan required dialysis, while none of those taking placebo did.
ACTIVE-I was funded by Bristol-Myers Squibb and Sanofi-Aventis, which in partnership distribute irbesartan (Avapro). Dr. Yusuf is a consultant to those companies and to AstraZeneca and Boehringer-Ingelheim. Other investigators also reported ties to pharmaceutical companies.