The limitations of warfarin for stroke prevention in patients with atrial fibrillation (AF) are well known. For this reason, the recent FDA approval and commercial availability of the new direct thrombin inhibitor, dabigatran (Pradaxa®, Boehringer Ingelheim), as an alternative to warfarin for patients with AF was embraced by many patients and health care providers. Dabigatran appears to offer slightly better protection from stroke when compared to warfarin with a similar bleeding risk, and has the advantages of not requiring frequent drug monitoring and having no drug and food interactions. However, dabigatran is expensive, must be taken twice daily, is not an option for patients with severe kidney disease, and is not reversible.
The findings of a large trial using a new factor Xa inhibitor, rivaroxaban, to prevent stroke in patients with AF were finally published this August in the New England Journal of Medicine.1 Preliminary results were presented last November 2010 during the American Heart Association meeting in Chicago. This direct factor Xa inhibitor has already been approved for use in patients with deep venous thrombosis, and is marketed as Xarelto® by both Bayer and Johnson & Johnson. The study, known as ROCKET-AF (Rivaroxaban once daily Oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation), was a double-blind, double-dummy study in 14,264 patients with AF who were at high risk of stroke. Patients were randomized between December 2006 and June 2009 to 20-mg rivaroxaban once daily (or 15 mg in patients with moderate renal insufficiency) or to warfarin targeting an INR of 2.5. Patients in the trial were at high risk of stroke. Over half had a history of stroke and 90% had hypertension. In addition, 90% of the patients had a CHADS2 score ≥ 3.
The results of the study showed that rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. In the primary analysis, the primary endpoint occurred in 1.7% per year in the rivaroxaban group and in 2.2% per year in the warfarin group (P<0.001 for noninferiority). There was also no significant difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. Major and nonmajor clinically relevant bleeding occurred in 14.9% per year in the rivaroxaban group and in 14.5% per year in the warfarin group (P=0.44), with significant reductions in intracranial hemorrhage (0.5% vs. 0.7%, P=0.02) and fatal bleeding (0.2% vs. 0.5%, P=0.003) in the rivaroxaban group.
It is interesting that both rivaroxaban and dabigatran have each been associated with less intracranial bleeding, but more gastrointestinal bleeding, than warfarin. This suggests a potential local anticoagulant effect in the gut. It is not surprising that the average time that patients assigned to warfarin in ROCKET-AF had a therapeutic INR was only 55%, but it was surprising that the relative efficacy of rivaroxaban was as favorable in centers with the best INR control as in those with poorer control.
Much will be made about the fact that rivaroxaban was only found to be noninferior to warfarin in the ROCKET-AF trial, unlike dabigatran, which at a dose of 150 mg twice daily was found to be superior to warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, and the various types of analysis that were performed to determine relative efficacy of rivaroxaban. However, it is not possible to compare these two new anticoagulants directly without a head-to-head comparison trial. What can be said about this new drug is that its availability would introduce competition into the market and likely make alternatives to warfarin more affordable. It also cannot be disputed that an advantage of rivaroxaban over dabigatran is that it only needs to be taken once daily. The fact that rivaroxaban is already FDA approved for a different indication suggests that it might be easier to get third party payors to cover it within a reasonable time frame if it receives FDA approval.
Rivaroxaban appears to be an important step toward improved options for patients with AF to reduce their risk of stroke. However, more progress is needed. It would be ideal, for example, to have a drug that is as effective as warfarin but has a significantly lower bleeding risk, and a drug that can be easily reversed.
- Patel MR, et al, for the ROCKET AF Investigators. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. N Engl J Med Published online August 10, 2011;10.1056/NEJMoa1009638.