Rivaroxaban Continues Emergence of New Class of Anticoagulants for A-Fib

In the wake of the US Food and Drug Administration (FDA) advisory panel vote to recommend approval of the novel anticoagulant rivaroxaban, physicians are still debating the merits of the ROCKET AF trial and how the drug should impact clinical practice. But regardless, the vote represents another step forward for a new class of emerging agents that promises to become an effective alternative to warfarin in patients with atrial fibrillation (A-fib).

The FDA panel voted 9 to 2 in favor of the oral factor Xa inhibitor, with 1 abstention, on September 8, 2011.

Last July, rivaroxaban (Xarelto; Johnson & Johnson, New Brunswick, NJ; Bayer HealthCare, Leverkusen, Germany) gained FDA approval for the prevention of deep vein thrombosis in patients undergoing knee or hip replacement surgery. The recent FDA meeting focused on the new indication for prevention of stroke and systemic embolism in patients with nonvalvular atrial A-fib.

But American Heart Association president Gordon Tomaselli, MD, of Johns Hopkins University School of Medicine (Baltimore, MD), stressed that approval is hardly “a forgone conclusion,” given the nuanced debates among members of the FDA advisory panel. Irrespective of whether this particular drug goes on the market, however, the important message is that the array of warfarin alternatives continues to grow, he said in a telephone interview with TCTMD.

“This is not the end of the conga line here. There are a few other drugs still being looked at,” Dr. Tomaselli noted. Not only is the direct thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim, Ridgefield, CT) already on the market, he said, but positive results were reported for the oral factor Xa inhibitor apixaban (Eliquis; Pfizer, New York, NY; Bristol-Myers Squibb, Princeton, NJ) only weeks ago at the European Society of Cardiology Congress 2011 in Paris, France.

In a telephone interview, Mitchell S. Elkind, MD, of Columbia University Medical Center (New York, NY), agreed that most physicians are more excited about the group of novel warfarin alternatives as a whole than 1 particular drug. “There are specific differences here and there, but my impression in general is that they are, more or less, as effective as warfarin. The benefits are really in ease of use and perhaps patient compliance with the medications,” he commented to TCTMD.

ROCKET AF Makes the Case

Support for rivaroxaban’s approval comes from the pivotal 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) trial, first presented in November 2010 at the annual American Heart Association Scientific Sessions in Chicago, IL, and published in August 2011 in the New England Journal of Medicine.

For the study, subjects were randomized to fixed-dose rivaroxaban (20 mg daily, or 15 mg daily in those with creatinine clearance 30-49 mL/min) or dose-adjusted warfarin (target international normalized ratio [INR] 2.0-3.0). Among patients given warfarin, INR values were within the therapeutic range a mean of 55% of the time.

Notably, ROCKET AF included 3 different analyses of outcomes. In the main efficacy analysis of the per-protocol population, rivaroxaban was found to be noninferior to warfarin for the primary endpoint of stroke or systemic embolism. An intention-to-treat analysis also found that the drugs were equivalent. Yet a safety analysis that examined the as-treated population—patients who received at least 1 dose of a study drug and were followed for events during treatment—showed a significant advantage for rivaroxaban (table 1).

Table 1. Annual Risk of Stroke or Systemic Embolism

^aP for noninferiority.

In addition, the study observed no difference in the risk of major and nonmajor clinically relevant bleeding, the primary safety endpoint, between the 2 drugs.

Nothing More Than Noninferior?

Going into the meeting, FDA reviewers questioned how to interpret the complex results for rivaroxaban from ROCKET AF.

“To justify the sponsor’s claim for superiority, rivaroxaban needed to be demonstrated to be superior to warfarin,” panel member Sanjay Kaul, MD, MPH, of Cedars-Sinai Medical Center (Los Angeles, CA), told TCTMD in an e-mail communication. “It clearly did not pass this muster in the ROCKET AF trial, as the [intention-to-treat analysis], which is required for superiority, was not significantly in favor of it.”

The most clinically relevant question, he added, “is whether one is willing to accept a new treatment being ‘acceptably’ worse with regards to the prevention of stroke in exchange for a meaningful safety, cost, or convenience advantage over the standard therapy.”

In the most stringent analysis of ROCKET AF—covering the intent-to-treat population up to the time of data cutoff—rivaroxaban was associated with as much as a 24% increase in stroke risk compared with warfarin (HR 1.03; 95% CI 0.85-1.24), Dr. Kaul pointed out. And while rivaroxaban offers convenience, he said, it failed to decrease major bleeding and is unlikely to be less expensive than warfarin.

Other concerns include whether warfarin management was suboptimal in ROCKET AF as well as hints that rivaroxaban patients may experience a rebound hypercoagulable state after treatment discontinuation, Dr. Kaul noted. Moreover, hemorrhagic strokes factored into both the trial’s efficacy and safety composites. Such “double counting,” he said, may have biased the risk-benefit equation in favor of rivaroxaban because the outcome “constituted a bulk of the critical or fatal bleeding, and because hemorrhagic strokes were the only outcome that were significantly reduced by rivaroxaban.”

Impact on Patient Care

Therefore, rivaroxaban may have limited use in clinical practice, Dr. Kaul explained. “In my opinion, rivaroxaban should only be used in patients who encounter difficulty with warfarin due to substantial diet or drug interaction, inadequate anticoagulation, inconveniences of monitoring, or life-threatening side effects of skin necrosis—or [in those] who are intolerant of dabigatran due to GI side effects,” he advised. “So at this time, I can only envision rivaroxaban as a 3^rd line option.”

According to Dr. Tomaselli, rivaroxaban shares the same virtues as other novel anticoagulants. “They’re easier to take [than warfarin]. There’s not as much monitoring that needs to go on,” he said. On the other hand, there are currently no therapies to reverse the drugs, although some are in the pipeline, he added.

That being said, Dr. Tomaselli does not envision switching every warfarin patient to one of the newer drugs, “particularly [not] those who have taken warfarin for a long time without much problem and are on a relatively infrequent and not terribly inconvenient schedule for getting their blood checked. [As a practitioner,] I’m not switching people over en masse.

“But if [problems arise with warfarin], I’m certainly not hesitating to put people on dabigatran,” he continued, adding that he would feel much the same way about rivaroxaban or apixaban.

Similarly, Dr. Elkind said, “it is too early to know whether any of these are going to be the perfect drug or the sole agent to be used. I suspect that we’ll have many different options, which is good for patients and good for doctors. I think it will become clearer over the next several years what the relative advantages and disadvantages are to the different medicines. It doesn’t seem to me that any one of them is emerging as a clear front runner at this time.”

In describing his experience with dabigatran, Dr. Elkind noted that he has not been using the newer drug exclusively in patients who have difficulty with warfarin. “The biggest problem with dabigatran right now has been cost, and the fact that many insurance companies won’t cover it,” he reported. “There are patients for whom we’d like to start dabigatran, but they can’t get it because they can’t afford it.”

Dr. Kaul said that, for now, a head-to-head trial of rivaroxaban vs. dabigatran is unlikely unless the newer drug’s manufacturer wants to take on the competition. However, he added, the recent news on apixaban “might complicate this equation!”

Sources:

1. US Food and Drug Administration. Questions: Rivaroxaban. Published September 8, 2011. Accessed September 13, 2011.
2. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883-891.

Related Stories:

• ROCKET AF Published: Rivaroxaban Matches Warfarin in Treating A-Fib Patients
• Novel Anticoagulant Increases Bleeding, Reduces Ischemic Outcomes in ACS
• Dabigatran an Alternative to Warfarin for Stroke Prevention in A-Fib Patients