Irbesartan in Atrial Fibrillation: No Overall Benefit, But It May Prevent Later Heart Failure

September 01, 2009

September 1, 2009 (Barcelona, Spain) — New data suggest there might be a role for the angiotensin-receptor blocker (ARB) irbesartan (Avapro, Sanofi-Aventis/Bristol-Myers Squibb) to prevent the development of atrial-fibrillation–related heart failure. Although irbesartan failed to reduce the primary composite end point of stroke, myocardial infarction (MI), and vascular death in atrial-fibrillation patients randomized to treatment, it did reduce the secondary end point of heart-failure hospitalizations.

"Conventional wisdom is that if a trial misses its primary end point, you stop there, go home, and learn nothing from it," said lead investigator Dr Salim Yusuf (McMaster University, Hamilton, ON). "That's a bit limited. What you need to do is look at the coherence of the data. Clearly, if the primary end point were positive, then the secondary end point would have greater meaning. But when you have clear results on a secondary end point--it's plausible that ARBs and blood-pressure lowering will reduce heart failure, this is not from the moon, we've seen it in other situations--the issue then becomes whether the results are believable. And the answer is that the results are believable."

The results of the study, a rerandomization of patients included in the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE) trial program, were presented here today during the hotline session at the European Society of Cardiology (ESC) 2009 Congress. Speaking to the media, Yusuf said that most clinicians treating atrial fibrillation worry about stroke, but elevated blood pressure is the most common cause of the rhythm disorder, and that in addition to a later stroke risk, heart failure is also a concern.

Still, despite the possible silver lining in the negative study, Dr Josep Brugada Terredellas (Unidad de Arritmias, Barcelona, Spain), the scheduled discussant during the hotline session, remains unconvinced of the benefit of ARBs in this patient population. He told ESC audience members that investigators enrolled patients with systolic blood pressures >110 mm Hg and that patients were well treated, many with three or more medications. In these patients, it is difficult to lower blood pressure further, and even when doctors do, ACTIVE AF showed "it does not add to the treatment" of patients with different forms of atrial fibrillation already treated with multiple hypertension drugs.

ACTIVE With Warfarin and Not

As reported by heartwire , the ACTIVE program included two studies of patients with atrial fibrillation and one or more additional risk factors for stroke. If they were considered suitable candidates for warfarin therapy, they were enrolled in ACTIVE-W, a comparison of warfarin with the combination of clopidogrel and aspirin. The results of ACTIVE-W were reported previously and showed that use of warfarin reduced the risk for stroke by 42% over clopidogrel and aspirin. In the ACTIVE-A study, which included patients unsuitable for warfarin, clopidogrel plus aspirin reduced the risk of major vascular events or death from vascular causes by 11% when compared with aspirin plus placebo.

The ACTIVE Clinical-Trial Program

For this ACTIVE AF study, 9016 of the patients were rerandomized to placebo or irbesartan 300 mg once daily. Treatment with the ARB reduced systolic and diastolic blood pressure 6.84 mm Hg and 4.51 mm Hg, respectively, whereas those treated with placebo had systolic and diastolic reductions of 3.93 mm Hg and 2.63 mm Hg, respectively, an absolute reduction of 2.91 mm Hg systolic and 1.88 mm Hg diastolic.

Regarding the primary end point, Yusuf reported no effect on the primary composite end point of stroke, MI, and vascular death. When hospitalization for heart failure was added to the composite end point, there was a small, nonsignificant benefit observed with irbesartan. In examining heart-failure hospitalizations alone, a secondary end point, researchers found that there was statistically significant 14% reduction in risk with irbesartan.

During a morning press conference announcing the results, Yusuf said that blood-pressure lowering and heart-failure events are typically not on the radar of doctors treating patients for atrial fibrillation. He said the findings are "consciousness-shifting" and "clinically useful" in that the results should get more physicians thinking about preventing future heart-failure events in the atrial-fibrillation setting.

"So many atrial-fibrillation patients have hypertension," Yusuf told heartwire . "You might as well use a drug where there is some clinical benefit. What this is really saying is that there is a part of atrial fibrillation that's being ignored, and we need to pay attention to it."

Dr Heinz Drexel (Academic Teaching Hospital, Feldkirch, Austria), a spokesperson for the ESC who was not part of the trial, told heartwire that the reduction in heart-failure hospitalizations is plausible given that many patients with atrial fibrillation have elevated blood pressure. "The natural course of the disease is high blood pressure, atrial fibrillation, and then heart failure," said Drexel. "Most patients are going to be treated with various blood-pressure medications on top of drugs to prevent stroke risk, so using an ARB in this setting makes sense."

In addition to the reduction in heart-failure hospitalizations, the ACTIVE investigators also observed trends in the reduction of stroke, transient ischemic attack (TIA), and non–central-nervous-system (CNS) systemic embolism but were cautious in overinterpreting the results. Similarly, they also observed trends in the different types of stroke, including hemorrhagic stroke, a potential benefit given that many patients were taking warfarin and dual antiplatelet therapy.

To access complete presentation slides (pdfs), click here.