Ivabradine Beneficial in Reducing Cardiovascular Events for CAD/LVSD Patients: Presented at ESC

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Title: Ivabradine Beneficial in Reducing Cardiovascular Events for CAD/LVSD Patients: Presented at ESC
URL: http://www.pslgroup.com/dg/22A5FE.htm
Doctor's Guide
September 1, 2008

By Chris Berrie

MUNICH, Germany -- September 1, 2008 -- A heart rate >=70 bpm predicts adverse outcome for patients with coronary artery disease and left ventricular systolic dysfunction (CAD/LVSD). Furthermore, in these patients, the heart-rate lowering drug ivabradine is efficacious and safe for reducing fatal and nonfatal myocardial infarction (MI) and the need for revascularisation.

Kim Fox, MD, Royal Brompton Hospital, London, United Kingdom, presented this study on behalf of the BEAUTIFUL investigators, here on August 31 at the European Society of Cardiology 2008 Congress (ESC).

Increased heart rate is a negative independent predictor for survival in patients with CAD/LVSD. However, current therapies of beta-blockers and calcium-channel blockers have effects beyond heart-rate reduction.

In contrast, Dr. Fox said, "Ivabradine is an I_f current inhibitor that slows the heart rate by inhibiting the sinus node, and unlike a beta-blocker, it causes pure heart-rate reduction." It therefore has potential to benefit such patients when added to optimal treatment.

The objectives were 2-fold: to determine the potential of ivabradine for prevention of cardiovascular events in CAD/LVSD patients and to take the opportunity to examine the effects of elevated heart rate (>=70 bpm) on cardiovascular events.

The inclusion criteria were CAD, LVSD (ejection volume <40%), and sinus rhythm and resting heart rate >=60 bpm.

The primary composite endpoint was cardiovascular death and hospitalisation for acute MI (fatal or nonfatal) or new onset or worsening heart failure. All endpoints were prespecified for the total patient population (heart rate >=60 bpm) as well as for those with a heart rate >=70 bpm.

While receiving their regular cardiovascular medications, 10,917 patients were randomised to placebo (n = 5,438) or ivabradine 5 mg BID (n = 5,479) uptitrated to 7.5 mg BID.

With the same baseline characteristics across the 2 treatment groups, Dr. Fox said, "Importantly, they had normal blood pressures, with a mean resting heart rate of 71 bpm and a mean ejection fraction of 32%." Patient medication was also optimal, with 94% on antithrombotic agents, 90% on renin-angiotensin blockers, 87% on beta-blockers, and 74% on statins.

At median study duration of 19 months, in the placebo group, a heart rate >=70 bpm was a significant predictor of cardiovascular death (hazard ratio [HR], 1.34; 95% confidence interval [CI], 1.10-1.63; P = .0041), hospitalisation for heart failure (HR, 1.53; 95% CI, 1.25-1.88; P < .0001) and MI (HR, 1.46; 95% CI, 1.11-1.91; P = .0066), and coronary revascularisation (HR, 1.38; 95% CI, 1.20-1.86; P = .037).

In the full patient population, after 2 years, ivabradine provided a 5-bpm reduction in mean heart rate over placebo; however, for the primary endpoint, there was no significant effect of ivabradine over placebo.

In patients with a heart rate >=70 bpm, there was a slightly higher, 7-bpm, reduction in mean heart rate at 2 years, with again no significant effect over placebo on the primary composite endpoint and hospitalisation for heart failure.

Dr. Fox said that surprisingly, ivabradine showed significant benefit for these patients regarding hospitalisation for fatal and nonfatal MI (HR, 0.64; 95% CI, 0.49-0.84; P = .001), and for coronary revascularisation (HR, 0.70; 95% CI, 0.52-0.93; P = .016).

"Also, we found that the incidence of serious adverse effects, and indeed adverse effects, was equal between ivabradine and placebo," he added.

In concluding, Dr. Fox noted, "This study has raised a number of very important thoughts in terms of pathophysiology of heart failure and coronary disease and management of these conditions, and it has important implications on how we manage our patients with coronary disease."

This study was sponsored by Servier.

[Presentation title: The BEAUTIFUL Study: Efficacy of Ivabradine in Reduction of Cardiovascular Events Among Patients With Stable Coronary Artery Disease and Left Ventricular Dysfunction. Hot Line I. Abstract 232]

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