Rivaroxaban significantly reduces risk of stroke

In Bayer’s double-blind phase 3, ROCKET AF trial, rivaroxaban demonstrated superiority to warfarin in reducing the risk of stroke and non-CNS systemic embolism in patients with atrial fibrillation (AF).

Importantly, rates of bleeding were similar to warfarin, and bleeding events most concerning to physicians and patients, including intracranial hemorrhage, critical organ bleed, and bleeding-related death, were significantly lower in the rivaroxaban group. The results were presented as a late-breaker at the American Heart Association Scientific Sessions 2010 in Chicago, US.

"Atrial fibrillation and stroke devastate the lives of millions of patients and their families worldwide every year. Anticoagulation with warfarin is effective in preventing strokes in patients with atrial fibrillation and has been the standard of care for more than half a century. However, its use in clinical practice is associated with many limitations," said Professor Werner Hacke, chair of the department of neurology at the University of Heidelberg, Germany, and member of the ROCKET AF executive steering committee.

"The ROCKET AF study has shown that once-daily rivaroxaban promises patients improved protection from stroke, with good safety and added convenience."

With 14,264 patients randomized, ROCKET AF is the largest double-blind study undertaken in the prevention of stroke in patients with AF, comparing once-daily rivaroxaban to dose-adjusted warfarin.

For the primary efficacy endpoint, rivaroxaban was superior to warfarin, delivering a 21 percent relative risk reduction in stroke and non-CNS systemic embolism in the pre-specified on treatment population (1.70 percent vs 2.15 percent, p=0.015).

Additionally, in the intent to treat (ITT) population which followed all patients randomised in the trial until its completion, whether or not they completed the full course of therapy or switched to other options, rivaroxaban showed comparable benefits to warfarin (2.12 percent vs 2.42 percent, p<0.001 for non-inferiority). This result indicates that the treatment benefits compared to warfarin were sustained as long as the patients received rivaroxaban.

In addition, significantly fewer cases of hemorrhagic stroke, one of the most severe types of stroke, were observed in patients on rivaroxaban (0.26 percent vs 0.44 percent p=0.024). Compared to warfarin, rivaroxaban also showed numerically fewer cases of myocardial infarction (0.91 percent vs 1.12 percent, p=0.121), and an observed reduction in rates of all-cause mortality (1.87 percent vs 2.21 percent, p=0.073).

The improved protection of patients provided by rivaroxaban in ROCKET AF was not associated with an increase in bleeding. On the principal safety measure of major and non-major clinically relevant bleeding events, rivaroxaban was similar compared with warfarin (14.91 percent vs 14.52 percent, p=0.442). Rates of major bleeding were also comparable between rivaroxaban and warfarin (3.60 percent vs 3.45 percent, p=0.576).

Importantly, patients treated with rivaroxaban had fewer intracranial hemorrhages (0.49 percent vs 0.74 percent, p=0.019), fewer critical organ bleeds (0.82 percent vs 1.18 percent, p=0.007) and lower bleeding-related deaths (0.24 percent vs 0.48 percent, p=0.003) than those on warfarin. Rates of hemoglobin drop (2.77 percent vs 2.26 percent, p=0.019) and transfusion requirements (1.65 percent vs 1.32 percent, p=0.044) were increased when compared to patients who received warfarin.

The frequency of abnormal laboratory values of liver function was balanced between the treatment groups and there was no signal for serious liver damage attributable to rivaroxaban observed in the trial.

Rivaroxaban was well tolerated in the study, and rates of discontinuation due to adverse events were similar to those seen for patients on warfarin. Rivaroxaban, administered once daily, without the need for routine laboratory coagulation monitoring delivered improved protection, simplified dosing and good tolerability.

"Given the prevalence and morbidity associated with atrial fibrillation, and the well-known difficulties with warfarin use, it is exciting to have an alternative which was documented in this study to be effective with no increase in significant bleeding," said Robert M Califf, MD, study co-chairman and vice chancellor for clinical research from Duke University.

ROCKET AF is the seventh consecutive phase 3 trial in the ongoing rivaroxaban global development program that has demonstrated either superiority (RECORD1, 2, 3, 4, EINSTEIN-EXTENSION and ROCKET AF), or non-inferiority (EINSTEIN-DVT). The RECORD trial program compared rivaroxaban to enoxaparin in the prevention of venous thromboembolism in more than 12,500 patients undergoing elective hip or knee replacement surgery.

The multinational phase 3 EINSTEIN-DVT study investigated a new single-drug approach with rivaroxaban compared with initial enoxaparin treatment, followed by a vitamin K antagonist in a randomized, open-label non-inferiority study involving more than 3,400 patients with acute symptomatic DVT, but without any symptoms of PE. EINSTEIN-Extension evaluated the efficacy and safety of rivaroxaban compared to placebo in the secondary prevention of recurrent symptomatic venous blood clots, by extending preventative treatment by six or 12 months beyond a previously completed regimen of six or 12 months of therapy, and enrolled approximately 1,200 patients with symptomatic DVT or PE.