Rivaroxaban vs Warfarin and a Fishy Story -- A Focus on Afib From AHA 2010

Melissa Walton-Shirley, MD


November 16, 2010

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Welcome to the Day in Review. I'm reporting to you from Chicago on the second day of the 2010 American Heart Association meeting. Today we'll discuss the all-important ROCKET [Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in atrial fibrillation] trial in which the new once-daily direct thrombin inhibitor, rivaroxaban, was pitted against warfarin for atrial fibrillation. We also heard this morning from the very first randomized controlled trial in medical history for percutaneous PFO [patent foramen ovale] closure in cryptogenic stroke. Then we'll look at fish oil for secondary prevention of paroxysmal atrial fibrillation. Finally, the SMART AV DELAY [A Comparison to Other AV Delay Methods Used in Cardiac Resynchronization Therapy] trial will tell us whether we need to continue with clinics for optimal programming in CRT [cardiac resynchronization therapy] patients, or should we just stick with those nominal, out-of-box settings?

Let's start with SMART AV DELAY.[1] We've known for some time that women with left bundle branch block, increased QRS duration, and nonischemic cardiomyopathy respond best to CRT therapy. As the popularity of CRT grew, a 30%-45% "no responder rate" was noted. Hoping to optimize device therapy, several different methods have been utilized, including AV [atrioventricular] delay optimization with ECHO guidance or the SD (smart delay) algorithm.

The smart delay algorithm utilizes information from intrinsic AV delay, lead placement, and intraventricular timing. Since the American Society of Echocardiography proposed the mitral inflow method, coupled with the fact that several trials established the efficacy of CRT using varying methods, the need for an adequate randomized controlled trial was obvious. The 3-group trial design was simple. At postimplant visit on day 1-14, a 1:1:1 random assignment of 980 patients occurred between the smart delay, ECHO-directed, or the nominal setting group.

The devices were programmed to DDD [dual chamber pacing] at a rate of 60. The primary endpoint of this study was left ventricular end systolic volume. The secondary structural endpoints of end diastolic volume and ejection fraction were also assessed, as well as the secondary functional endpoints of the 6-minute walk, quality-of-life scores, and New York Heart Classification. The conclusion was that there were no differences between the groups, except in a post hoc analysis in which women optimized with smart delay and ECHO responded more favorably than women assigned to the nominal arm. The final assessment here was that the routine use of AV optimization techniques, as seen in this trial, is not warranted.

There are many questions today about the prescription of omega-3 acid esters for the prevention of recurrent symptomatic atrial fibrillation during the PALM 3 trial.[2] This trial's hypothesis was that fish oil at a dose of 4 g/day should deter the underlying inflammation that leads to atrial scarring. Investigators also hoped for some benefit from its proposed electrical stabilization properties.

Despite these theories, prescription omega-3 fatty acids in this prospective, randomized, placebo-controlled study of 633 patients did not affect the time to first recurrence of symptomatic atrial fibrillation. It was speculated that a potential increase in parasympathetic tone might be the mechanism that offsets any beneficial antiarrhythmic effects. Despite this negative trial, we must await the outcome of 2 other large-scale, randomized trials on N-3 fatty acids in atrial fibrillation, which include the FORomegaARD [Fish Oil Research with Omega-3 for Atrial Fibrillation Recurrence Delay] trial and the OPERA [Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation] trial, looking at prevention in the postoperative population.

The CLOSURE 1 [Safety and Efficacy of the STARflex® Septal Closure System Versus Best Medical Therapy in Patients with Stroke or Transient Ischemic Attack due to a Presumed Paradoxical Embolism Through a Patent Foramen Ovale][3] patent trial is an important trial in the treatment of cryptogenic stroke and definite TIA [transient ischemic attack]. Many young patients around the world have a PFO closure device implanted due to an off-label indication. Dr. Anthony Furlan, Chairman of the Department of Neurology at Case Western reported on 910 patients randomly assigned either to medical therapy with aspirin or warfarin, or device closure. The device utilized was the STARFlex®, a double-umbrella, clamshell closure unit, which, for 6 months, was coupled with aspirin and Coumadin® [warfarin], followed by 18 months of aspirin only. The best medical therapy group was 24 months of either aspirin, warfarin, or a combination.

The composite primary endpoint of stroke and TIA recurrence with slightly more transient ischemic attacks in the medical arm was not statistically significant over time in any group. Vascular complications of the device implant occurred in 3.2% of patients. Atrial fibrillation was also noted more frequently in the device arm, 60% of which was periprocedural. This trial was not powered to determine best medical therapy, but there was no difference between aspirin and warfarin utilization with respect to the primary or secondary outcomes.

For the 1.8 million patients around the world who suffer from cryptogenic stroke annually, there are 2 more ongoing trials that might shed further light on this issue. The discussion included the opinion that PFO closure must be assessed on a case-by-case basis, with an intense baseline evaluation for hypercoagulable states; plaque rupture; and vertebral, carotid, and other intracranial pathology.

This brings us to the trial of the day, ROCKET AF.[4] This long-awaited study included much more complicated and sicker patients with atrial fibrillation, 80% of whom had a CHADS 2 [Congestive Heart Failure, Hypertension, Age, Diabetes Mellitus, and Stroke] score of 3 or higher, and > 50% had suffered a previous stroke or TIA. The new factor 10A inhibitor, rivaroxaban, at a 20-mg once-daily dose, was pitted against the old school therapy of warfarin at a target INR [international normalized ratio] of 2.5-3.0. The time in therapeutic range for warfarin in this trial was only 57.8%.

This study included 1200 sites and more than 14,000 patients from 45 countries. Although there was a slight increase in the incidence of nose bleeding (10% rivaroxaban vs. 8.6% warfarin), overall similar rates of bleeding and adverse events were noted with the exception of less intracranial bleeding and fatal bleeding with rivaroxaban. Soon it appears we will have another new, viable alternative to warfarin.

That's a wrap for the second day of the 2010 American Heart Association meeting here in the "Windy City." Join us here tomorrow for more exciting and practice-changing news in the world of cardiovascular science and practice.


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