NEJM: ACTIVE I published; irbesartan doesn't reduce CV events in AF patients

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Irbesartan (Avapro, Bristol-Myers Squibb/Sanofi-Aventis) did not reduce cardiovascular events in patients with atrial fibrillation (AF), according to the ACTIVE I trial, published March 9 in the New England Journal of Medicine. Yet, the study authors questioned whether more aggressive blood pressure control would result in more positive outcomes.

Salim Yusuf, MB, from the Population Health Research Institute and Vascular and Stroke Research Institute at the Hamilton Health Sciences and McMaster University in Hamilton, Ontario, and colleagues hypothesized that an ARB may prevent cardiovascular events and enhance the maintenance of sinus rhythm in patients with intermittent AF by reducing blood pressure and by specific effects related to blockade of the renin-angiotensin-aldosterone system.

In ACTIVE I (Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events), patients with AF who were already enrolled into two large parallel trials evaluating clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) plus aspirin underwent a second randomization, to irbesartan or placebo.

“The risk of cardiovascular events among patients with atrial fibrillation is high. We evaluated whether irbesartan, an ARB, would reduce this risk,” the study authors wrote.

The researchers randomly assigned patients with a history of risk factors for stroke and a systolic blood pressure of at least 110 mmHg to receive either irbesartan at a target dose of 300 mg once daily or double-blind placebo. These patients were already enrolled in one of two trials (of clopidogrel plus aspirin versus aspirin alone or versus oral anticoagulants).

The first co-primary outcome was stroke, MI or death from vascular causes; and the second was the composite outcome plus hospitalization for heart failure.

Yusuf and colleagues enrolled a total of 9,016 patients and followed them for a mean of 4.1 years. The mean reduction in systolic blood pressure was 2.9 mmHg greater in the irbesartan group than in the placebo group, and the mean reduction in diastolic blood pressure was 1.9 mmHg greater.

The first co-primary outcome occurred at a rate of 5.4 percent per 100 person-years in both groups. The second co-primary outcome occurred at a rate of 7.3 percent per 100 person-years among patients receiving irbesartan and 7.7 percent per 100 person-years among patients receiving placebo.

“We hypothesized that the key mechanisms of benefit would be due to renin–angiotensin blockade, as well as lowering of blood pressure,” the authors wrote. “The lack of a significant reduction in the co-primary outcomes weakens these hypotheses but may be attributable to several other factors.”

The rates of first hospitalization for heart failure (a pre-specified secondary outcome) were 2.7 percent per 100 person-years among patients receiving irbesartan and 3.2 percent per 100 person-years among patients receiving placebo, the researchers reported.

“In ACTIVE I, we observed a reduction in hospitalizations for heart failure among patients who received irbesartan as compared with those who received placebo, even though 60 percent of all the patients were receiving an ACE inhibitor,” the authors wrote. “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 four. This finding suggests that preventing heart failure is as important as preventing strokes in this population.”

Among patients who were in sinus rhythm at baseline, there was no benefit of irbesartan in preventing hospitalization for AF or AF recorded on 12-lead electrocardiography, nor was there a benefit in a subgroup that underwent transtelephonic monitoring. More patients in the irbesartan group than in the placebo group had symptomatic hypotension (127 vs. 64) and renal dysfunction (43 vs. 24).

In AF patients, Yusuf and colleagues concluded that irbesartan was associated with a modest reduction in blood pressure but did not significantly reduce cardiovascular events. “It was associated with a reduction in heart failure and hospitalizations for cardiovascular causes,” the authors noted. “It is not known whether more aggressive lowering of blood pressure would be effective in patients with AF.”

Bristol-Myers Squibb and Sanofi-Aventis funded the study.