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PRIORITY PRESS - 31st Annual Congress of the European Society of Cardiology

Barcelona, Spain / August 29-September 2, 2009

Better evidence-based strategies to reduce the risk of stroke are emerging from new clinical data presented here during the ESC. The dominant set of data was generated by a study called RE-LY (Randomized Evaluation of Long-term anticoagulation therapY), which compared the oral direct thrombin inhibitor (DTI) dabigatran against the standard of care, warfarin, for stroke prevention. While other data challenged the value of statins and renewed evidence of the benefit of the antiarrhythmia agent dronedarone, the RE-LY study associated the DTI with large relative advantages regarding efficacy and safety. It is the first of a new class of anticoagulant therapies to show efficacy in stroke and its practical advantages over warfarin, independent of the efficacy advantages, are substantial.

RE-LY Findings

“The results of dabigatran in RE-LY exceeded all our expectations. We now have an oral treatment which offers superior protection from stroke with less bleeding and without the need for routine monitoring,” reported Dr. Stuart Connolly, Director, Division of Cardiology, Population Health Research Institute, McMaster University, Hamilton, Ontario. The results of RE-LY, which is the largest atrial fibrillation study ever conducted, were published (Connolly et al. N Engl J Med 2009;361:epub August 31) simultaneously with Dr. Connolly’s presentation.

In RE-LY, over 18,000 atrial fibrillation patients (N=18,133) in 44 countries, including Canada, were randomized to one of two doses of dabigatran or warfarin. The fixed doses of the DTI, 110 mg or 150 mg, were administered in a blinded fashion. Warfarin administration, which required dose adjustments to maintain patients within an international normalized ratio of 2.0 to 3.0 (measured at least monthly), was not blinded. The primary end point was stroke or systemic embolism.

After a median duration of two years, the relative risk reduction in the primary end point was superior on either dose of the DTI relative to warfarin. For the lower dose of 110 mg, the hazard ratio of 9% reduction (RR 0.91; 95% CI, 0.74-1.11) was not statistically significant for superiority but was highly significant for non-inferiority (P<0.001), which was the outcome anticipated by the trial design. However, the higher dose provided a 36% reduction in the primary end point relative to warfarin, which was a highly statistically significant advantage (RR 0.64; 95% CI, 0.53-0.82; P<0.001 for superiority).

In clinical practice, therapies as effective as the vitamin K antagonist warfarin have the potential to establish a new standard of care. “Vitamin K antagonists are cumbersome to use because of their multiple interactions with food and drugs, and they require frequent laboratory monitoring [to be maintained within its therapeutic window],” reported Dr. Connolly and his co-investigators in their published results. “Therefore, they are often not used, and when they are, rates of discontinuation are high.”

It is expected that dabigatran will be strongly considered for approval in the treatment of atrial fibrillation on the basis of this trial. It appeared safer than warfarin in the lower dose and at least as safe in the higher dose. On the major safety end point of major bleeding, the rates of this adverse event were 3.36%/year on warfarin, 2.76%/year (P=0.003 vs. warfarin) on 110 mg dabigatran and 3.11%/year (P=0.31 vs. warfarin) on 150 mg. The rates of hemorrhagic stroke for these three therapies, respectively, were 0.36%, 0.12% and 0.10% (P<0.001 vs. warfarin for both doses of dabigatran). Even more compelling, mortality rates were lower on both doses of the DTI with a strong trend for a significant advantage at the higher dose (Figure 1).

“Both doses of dabigatran offer advantages over warfarin, providing a potential to tailor therapy in regard to the individual patient,” Dr. Connolly told delegates. He noted that in a large array of stratifications, such as those made by weight, gender, previous stroke, hypertension, ASA use at baseline, amiodarone use at baseline or proton pump inhibitor use at baseline, the hazard ratios remained consistently in favour of the 150-mg dose of the DTI relative to warfarin. In the few cases where hazard ratios did not trend toward greater efficacy for the lower dose of the DTI relative to warfarin, the CIs confirmed that the agents were at least comparably effective.

Figure 1.

The dabigatran data provide needed promise for new approaches to stroke management in the context of less encouraging results with statins. Although several studies and meta-analyses have associated statin therapy with a reduction in the risk of stroke among patients with atrial fibrillation, an effort to pool all data generated inconsistent results. Although a large database is available for interpretation, different methods of analysis do not consistently support a statin benefit.

“The proposed benefit of statin therapy on atrial fibrillation suggested by previous meta-analyses that examined just part of the randomized evidence is not supported by a more complete review of statin trials,” stated Dr. Kazem Rahimi, Clinical Trial Service Unit, Oxford, UK. Representing a collaboration between the Oxford research group, the Royal Infirmary of Glasgow, UK, the University of Groningen in The Netherlands, and the Medical University of Würzburg, Germany, Dr. Rahimi reported that the new data “cast doubt over whether statins have any direct effects on atrial fibrillation.”

Several analyses were undertaken. In one, data from seven randomized and controlled trials published between 1966 and 2008 with a collective total of 3609 atrial fibrillation patients were pooled. These associated statins with a 30% reduction in the risk of stroke (RR 0.70; 95% CI, 0.56-0.88; P=0.002), but the individual studies were heterogeneous, with the largest study finding no advantage for the statin evaluated. When a separate pool of 15 hypothesis-testing trials with 68,504 patients were evaluated, statin therapy was not associated with any significant protection against atrial fibrillation (RR 0.96; 95% CI, 0.87-1.07; P=0.49). In a third pool of studies comparing statins that included 109,242 atrial fibrillation patients, there was also no statistical benefit (RR 0.99; 95% CI, 0.92-1.06; P=0.73).

“This is a much larger set of trials than have been analyzed previously,” remarked Dr. Rahimi, who noted that the authors of all studies included in these analyses were contacted for unpublished data. The “striking” heterogeneity suggests that the efficacy of statins for protection against vascular events in patients with atrial fibrillation is not yet proven.

Encouraging Results with Anti-arrhythmia Strategies

In contrast, more support has been generated for the anti-arrhythmia agent dronedarone in post-hoc analyses of the ATHENA (A placebo-controlled, double-blind Trial to assess the efficacy of dronedarone 400 mg for the prevention of cardiovascular Hospitalization or dEath from aNy cause in patients with Atrial fibrillation/atrial flutter). In this study, published earlier this year (Hohnloser et al. N Engl J Med 2009;360:68-78), 4628 atrial fibrillation patients were randomized to 400 mg dronedarone (a compound chemically related to amiodarone but with fewer toxic effects) or placebo. The drug was associated with a 24% reduction (RR 0.76; 95% CI, 0.69-0.84; P<0.001) in the primary end point of first hospitalization due to cardiovascular causes or death.

A new analysis of the frequency and characteristics of atrial fibrillation/atrial flutter-related hospitalizations has shown that dronedarone not only reduced atrial fibrillation-related hospitalizations but produced a 37% reduction (RR 0.63; P<0.001) in hospitalizations of any kind. Surprisingly, the likelihood of cardioversion during hospitalization was identical in the dronedarone and placebo groups (27% in each), suggesting that the active compound offers a more fundamental protection against cardiovascular pathology induced by atrial fibrillation.

“Only about a quarter of the hospitalizations included electrical cardioversion in either of the randomized groups, suggesting that the reduction in atrial fibrillation-related hospitalizations in ATHENA was not simply the result of reduced admission for cardioversion but rather was related to other clinical factors,” reported Dr. Richard L. Page, Head, Division of Cardiology, University of Washington, Seattle.

Summary

Substantial progress has been reported in the effort to improve management of atrial fibrillation. Although new data have raised concerns about the protective effect of statins for stroke prevention, the oral DTI dabigatran has demonstrated predictable stroke prevention at 150 mg that was superior to warfarin. Perhaps most impressive, the higher of the two tested dosages of the DTI, which does not require dose adjustments or laboratory monitoring, was associated with a mortality benefit relative to warfarin. Further support for dronedarone, an antiarrhythmia agent showing promise in atrial fibrillation, also appears to have broadened treatment options for this disease.