Will Rivaroxaban ROCKET Into The Atrial Fibrillation World?… Or Sputter Out?

The wait for alternatives to warfarin for stroke prevention in atrial fibrillation has been a long one. Patients and clinicians have long noted the limitations of warfarin, with dietary restrictions, drug-interactions and frequent monitoring.  Last year, dabigatran became available as an alternative based on the results of the RE-LY trial.¹ Recently, the results of the ROCKET-AF trial provide us with insight into another potential alternative, the oral factor Xa inhibitor rivaroxaban.²  Rivaroxaban is currently FDA-approved for prevention of thromboembolism in hip and knee replacement surgery.³

The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) was a multi-center, randomized, double-blind, double-dummy study comparing oral rivaroxaban to dose-adjusted warfarin in moderate-to-high risk patients with nonvalvular AFib. The ROCKET-AF trial included over 14,000 patients assigned to either rivaroxaban, dosed as a 20 mg daily or adjusted to 15 mg daily for patients with a creatinine clearance of 30-49 ml/min, or warfarin titrated to a goal INR of 2.0-3.0. Moderate-to-high risk was defined by a history of stroke or transient ischemic attack or a CHADS₂ score of at least 2 (i.e. two or more of the following: heart failure, ejection fraction ≤35%, hypertension,age ≥75, diabetes). To limit the number of patients on the lower end of the stroke risk cut off, the protocol only allowed up to 10% of patients in each region to meet the minimum criteria of CHADS₂ score of 2 and the remainder of the patients must have had a score of 3 or higher. Investigators hypothesized that rivaroxaban would be noninferior to warfarin in the composite primary outcome of stroke (ischemic and hemorrhagic) and systemic embolism.  The pre-specified primary analysis was a per-protocol analysis including patients with data regarding event rates who took at least one dose of study medication and without major protocol violations. Authors pre-specified that they would conduct a superiority analysis if noninferiority was met.  A post hoc intention-to-treat analysis was also performed.

The inclusion criteria resulted in a patient population that was 40% women with a median age of 73. Approximately 80% of patients had persistent AFib and 62-63% of subjects were previously on vitamin K antagonists before enrollment. The mean CHADS₂ score was 3.5 with 13.0% of the population with a score of 2, 86.9% with a score of 3 or higher and 43.4% with a score of 4 or higher. INR mean time in therapeutic range was 55%.

After median follow-up of almost two years, the results regarding the event rates per patient-year for the primary outcome measure (stroke and systemic embolism) were:

The rate of major and non-major clinically relevant bleeding was not statistically significantly different in the rivaroxaban and warfarin groups however intracranial hemorrhage and fatal bleeding were significantly lower in the rivaroxaban group. Major GI bleeding was more common in the rivaroxaban group when compared to warfarin.

So, what do these numbers mean? We can conclude that rivaroxaban is noninferior to warfarin, but how do we make decisions in individual patients? To a clinician, it would be nice to know how outcomes varied based on individual time in therapeutic range (iTTR).  In other words, how do patients on warfarin with poor INR control fare and how do those with good INR control fare in comparison to rivaroxaban? While authors reported that there was no difference in the effect of rivaroxaban when the time in therapeutic range by center (TTRc) were placed in into quartiles (centers with poor anticoagulation control versus centers with better anticoagulation control), no data on iTTR is available. Good INR control by center does not necessarily mean good INR control for most patients at that center as a few well controlled patients can skew the data. Studies confirm that thromboembolic and bleeding event rates are lower for patients with stable INRs within the therapeutic range for 6 months or 12 months versus those who are not stable.^4,5 Data on outcomes by iTTR quartiles would help the clinician weigh clinical decisions of switching patients either currently well-controlled or poorly controlled on warfarin to rivaroxaban. We may also consider the time in therapeutic range in this trial (55%) is lower than other studies in atrial fibrillation. How does this compare to patients in your anticoagulation clinic or patients in other trials? Other considerations may be individual patient risk factors. Patients in ROCKET-AF and RE-LY on rivaroxaban and dabigatran, respectively had higher rates of GI bleeding than those on warfarin.^1,2  Therefore, careful consideration of an individual patient’s GI risk might lead to a continuation of warfarin.

As clinicians, we often encounter patients who will not (or perhaps cannot) take warfarin. We may soon have two alternatives to warfarin for stroke prevention in atrial fibrillation. Reflecting on the lack of head-to-head studies comparing rivaroxaban to dabigatran, how can we approach making a decision between the two agents? A big consideration will be the stroke risk of the individual patient. The patient population in ROCKET-AF (rivaroxaban) had a higher stroke risk overall than the RE-LY trial (dabigatran).^1,2 Almost one-third of patients in the RE-LY trial had a CHADS₂ score of 0 or 1, where current ACCP guidelines recommend aspirin or warfarin as appropriate treatment options.⁴ In patients who have a higher stroke risk, we might favor rivaroxaban based on the study population. Others may argue that dabigatran at the 150 mg twice daily dose was superior to warfarin in the superiority analysis, while rivaroxaban was not superior to warfarin; however, without a head-to-head trial it is difficult to make any conclusions about superiority – especially given the differences in patient populations. Another consideration is cost. Given that both rivaroxaban and dabigatran were noninferior to warfarin, our best bet is sticking with warfarin and doing our best to keep the INR well-controlled. But, what would you do if a patient can’t or won’t take warfarin? If I were forced to make a decision today, I would go with rivaroxaban (over dabigatran) because the patient population studied had a higher stroke risk than the populations in the dabigatran studies. What would you do and why? What other factors would you consider?