Replacing Warfarin for Atrial Fibrillation Treatment — A Foregone Conclusion!

Abstract & Commentary

By Rahul Gupta, MD, MPH, FACP, Clinical Assistant Professor, West Virginia University School of Medicine, Charleston, WV. Dr. Gupta reports no financial relationships relevant to this field of study.

Synopsis: In nonvalvular atrial fibrillation patients, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. However, an intention-to-treat analysis did not show superiority of rivaroxaban over warfarin.

Source: Patel MR, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-891.

Rivaroxaban (Xarelto) is a direct factor xa inhibitor that may be a potentially attractive alternative to vitamin K antagonists. For the outpatient treatment and prevention of venous and arterial thromboembolic conditions, oral vitamin K antagonists such as warfarin are commonly recommended by clinicians. Atrial fibrillation (AF) is a common but serious cardiac rhythm disturbance and is responsible for substantial morbidity and mortality in the general population. AF is an independent risk factor for mortality and is associated with a doubling of mortality in both sexes. The most serious complication of AF is stroke, the risk of which is increased 4-5 fold in people with existing AF.1 In patients with AF, the estimated risk of stroke without anticoagulation therapy is 5% per year. However, pooled data from five randomized, controlled trials demonstrated that warfarin use reduces the risk of stroke by approximately 68%.2 Due to its narrow therapeutic range, warfarin poses significant challenges as well as the need for frequent monitoring, multiple drug and food interactions, and the risk of bleeding. In patients with AF, for the prevention of stroke, warfarin dosage is typically adjusted to achieve a target International Normalized Ratio (INR) of 2 to 3. An INR less than 1.8 doubles the risk of stroke, whereas an INR greater than 3.5 does not further benefit patients but increases the risk of bleeding. Rivaroxaban can potentially provide more consistent and predictable anticoagulation as a once-daily dosing option, which requires no therapeutic monitoring, and has a lower potential for drug interactions. In previous trials, rivaroxaban has been shown to be superior to enoxaparin in prevention of total deep venous thrombosis, and noninferior to enoxaparin followed by warfarin in a study of patients with deep venous thrombosis.3

In the study referred commonly to as the ROCKET AF trial (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation), the researchers used a double-blind design to randomly assign 14,264 patients with nonvalvular AF who were at moderate-to-high risk for stroke to either once-daily oral rivaroxaban or dose-adjusted warfarin (INR = 2.5). This multicenter, randomized, double-dummy, multinational trial was conducted at 1178 sites from December 2006 through May 2010 and supported by Johnson & Johnson and Bayer. The primary hypothesis was that rivaroxaban would be noninferior to warfarin for the prevention of stroke or systemic embolism. An analysis termed "per-protocol, as treated" was designed to determine this noninferiority. The primary efficacy endpoint was the composite of stroke (ischemic or hemorrhagic) and systemic embolism. Approximately 23.7% in the rivaroxaban group and 22.2% in the warfarin group permanently stopped their assigned therapy before an endpoint event and before the termination date. The median duration of treatment exposure was 590 days; the median follow-up period was 707 days, and only 32 patients were lost to follow-up. In patients included in the primary efficacy analysis, the primary endpoint (stroke or systemic embolism) occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 in the warfarin group (2.2% per year) (hazard ratio in the rivaroxaban group, 0.79; 95% confidence interval [CI], 0.66 to 0.96; P < 0.001 for noninferiority). In the intention-to-treat analysis, the primary endpoint occurred in 269 patients in the rivaroxaban group (2.1% per year) and in 306 patients in the warfarin group (2.4% per year; hazard ratio, 0.88; 95% CI, 0.74 to 1.03; P < 0.001 for noninferiority; P = 0.12 for superiority). In essence, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism in patients with AF. However, an intention-to-treat analysis did not show the superiority of rivaroxaban over warfarin. Additionally, there was no significant difference in the risk of major bleeding between the two groups, although intracranial and fatal bleeding was statistically less in the rivaroxaban group.

Commentary

Whether rivaroxaban (Xarelto) is at least as good as (noninferior) warfarin for preventing stroke or systemic embolism in patients with AF could depend on how one interprets these data. Noninferiority trials are intended to demonstrate that the effect of a new treatment is not worse than that of an active control by more than a specified margin. In noninferiority trials, the "constancy assumption" must be satisfied: the new trial must be designed in a way similar to the past trials so that the control treatment, as administered in the new trial, must have the same magnitude of benefit relative to placebo as it had in the reference trials. There are significant concerns about the above study meeting this constancy assumption, and therefore it has led many to doubt the authors' claim of meeting the noninferiority assessment in ROCKET-AF. Furthermore, in the intention-to-treat superiority analysis, investigators failed to show that rivaroxaban had an advantage, statistically, over warfarin for the prevention of thromboembolic events in patients with nonvalvular AF. A striking increase in death rates after the discontinuation of randomized treatment further complicates the noninferiority assessment in ROCKET-AF. Recently, the FDA's Cardiovascular and Renal Drug Committee recommended approving rivaroxaban for the prevention of stroke and systemic embolism in nonvalvular AF patients. Due to its simplicity of use, rivaroxaban may become a useful alternative in patients who have an inadequate response to or cannot be prescribed dabigatran or warfarin. However, we will still need a significant amount of postmarketing data to demonstrate efficacy and safety, including methods on rapidly reversing the anticoagulation in patients with life-threatening hemorrhages.

References

1. Kannel WB, et al. Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: Population-based estimates. Am J Cardiol 1998;82:2N-9N.

2. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994;154:1449-1457. [Published correction appears in Arch Intern Med 1994;154:2254].

3. DeLoughery TG. Practical aspects of the oral new anticoagulants. Am J Hematol 2011;86:586-590.