ROCKET AF: Stopping Rivaroxaban or Warfarin Equally Harmful in A-fib Patients

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Patients with nonvalvular atrial fibrillation (A-fib) who temporarily or permanently halt anticoagulant therapy suffer high risk of stroke and systemic embolism, irrespective of whether they were originally on warfarin or the oral factor Xa inhibitor rivaroxaban. The findings, from a subanalysis of the pivotal ROCKET AF trial, were published online ahead of print in Circulation and presented in an American Heart Association (AHA) webinar on April 25, 2012.

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), which appeared in the September 8, 2011, issue of the New England Journal of Medicine, randomized 14,264 patients to fixed-dose rivaroxaban (20 mg daily or 15 mg daily) 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.

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. However, concerns had been raised that rivaroxaban patients were at high risk of rebound when taken off their medication.

Both Anticoagulants Affected

For the current substudy, Jonathan P. Piccini, MD, of Duke Clinical Research Institute (Durham, NC), looked at the effect of drug cessation on stroke and non-central nervous system (CNS) embolism as well as thrombotic events. When patients temporarily stopped their assigned study drug (n = 8,245), outcomes were measured from 3 days after interruption until 3 days after restarting. Outcomes also were assessed from 3 to 30 days after permanent discontinuation (n = 4,895).

The main reasons for temporary cessation, which lasted a median of 6 days, included the need to undergo a surgical or invasive procedure (38.2%) and experiencing a non-bleeding adverse event (26.5%). Permanent cessation, meanwhile, mainly resulted from non-bleeding adverse events (28.3%) or withdrawal of consent (27.4%).

The rates of combined stroke and embolism were similar regardless of which drug patients had previously received and regardless of whether the discontinuation was permanent or temporary (table 1).

Table 1. Combined Stroke and Non-CNS Embolism Events per 100 Patient Years

After the blinded phase of ROCKET AF ended and patients were transitioned to open-label therapy—most often warfarin—stroke rates were significantly higher among those originally assigned to rivaroxaban than those already taking warfarin at 6.42 vs. 1.73 events per 100 patient-years, respectively (HR 3.72; 95% CI 1.51-9.16; P < 0.0044). When considering all discontinuations and the effect of transitioning to the open-label phase, stroke rates were higher for rivaroxaban patients (HR 1.50; 95% CI 1.05-2.15; P = 0.003) but the overall risk of thrombotic events—including stroke, embolism, MI, and death—was equivalent (HR 1.08; 95% CI 0.89-1.32; P = 0.44).

While the risk was similar between the 2 drugs after cessation, Dr. Piccini characterized it as “high.”

How to Handle Risk

Asked what clinicians can do to mitigate the risk that occurs in the 30 days after cessation, Dr. Piccini stressed to TCTMD in an e-mail communication that “[p]atients who stop anticoagulation resume their original risk of stroke.”

Therefore, the consequences of interrupting or stopping anticoagulation “need to be considered in every patient following a careful evaluation of the risks and benefits,” he explained, adding that “periods without anticoagulation coverage should be minimized once the decision to treat has been made.”

Panel Explores Clinical Implications

Discussant Jeffrey I. Weitz, MD, of McMaster University (Hamilton, Canada), said in the AHA webinar that the findings of the current analysis dispute the idea of a rebound phenomenon specific to rivaroxaban.

Dr. Piccini agreed, noting that the temporal distribution of events provides additional evidence against this. “Furthermore, the increased incidence of major bleeding in the patients transitioning from rivaroxaban to warfarin would also argue against a prothrombotic state.” Such transitions occurred during the open-label phase.

Patients will rarely be able to seamlessly transition from one oral anticoagulant to another, he acknowledged, because there often is a clinical reason for temporary drug cessation. But in those rare cases, such as those who have a change in prescription drug benefit, physicians can overlap rivaroxaban and warfarin for a short time while monitoring INR values. Low molecular weight heparin might also be used as a bridging therapy. “No matter what strategy is chosen, monitoring is essential,” Dr. Piccini stressed.

Dr. Weitz pointed out that rivaroxaban can affect INR, so it is crucial to measure at the “trough” of rivaroxaban concentrations in order to avoid confounding.

Co-moderator Robert A. Harrington, MD, of Duke Clinical Research Institute, said that since rivaroxaban’s 2011 approval for stroke prevention in A-fib by the US Food and Drug Administration, the potential rebound effect “has been one of the key questions that practitioners want to better understand.” He also expressed concern over the high frequency of interruptions in therapy.

Elliott Antman, MD, of Brigham and Women’s Hospital (Boston, MA), who also co-moderated the panel, commented, “This whole discussion emphasizes to me the conversations we need to be having with our patients.

“The decision to initiate oral anticoagulation therapy is an important one in a patient’s life,” he continued. Transitioning between the 2 drugs is complicated, Dr. Antman said, “and we need to take that time . . . and use each office visit as a teachable moment to remind the patients about all these issues that we’re bringing up today.”

 

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Source:
Patel M, Hellkamp A, Lokhnygina Y, et al. Outcomes of discontinuing rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: Analysis from the ROCKET AF trial. Circulation. 2012;Epub ahead of print.

 

 

Related Stories:

• Rivaroxaban Continues Emergence of New Class of Anticoagulants for A-Fib
• ROCKET AF Published: Rivaroxaban Matches Warfarin in Treating A-Fib Patients
• Dabigatran an Alternative to Warfarin for Stroke Prevention in A-Fib Patients

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