Featured Interview: Michael Ezekowitz, MD, PhD, and Lars Wallentin, MD, PhD, on the Underuse of New Anticoagulants

At ESC.12 in Munich, a standing-room only crowd attended the session "Anticoagulation in Atrial Fibrillation in 2012." After the session, CardioSource WorldNews Executive Editor Rick McGuire spoke to Michael D. Ezekowitz, MD, PhD, and Lars Wallentin, MD, PhD, two world-class leaders in the field of antithrombotic therapy in CV disease. Dr. Ezekowitz led the first double-blind study of warfarin for stroke prevention in nonrheumatic atrial fibrillation, and he joined Dr. Wallentin in the RE-LY and ARISTOTLE trials.

Rick McGuire: This was a packed session with more than 100 people sitting out here watching a monitor because there were no seats left inside. It certainly was riveting because none of the attendees gave up their space on the hallway floor. What held their attention for this main session here at ESC?

Dr. Ezekowitz: There is obviously tremendous interest in atrial fibrillation and the novel anticoagulants. The point that both Lars and I made was that the trials far exceeded the expectations from when they were originally designed. But the disappointment at the moment is in patients who have a new diagnosis of atrial fibrillation—and I know the data best from the United States—there is underutilization of anticoagulation and particularly these novel agents. We don't really understand why this is occurring. My talk focused on the emphasis that clinicians seem to be making on the risk of novel anticoagulation, which is bleeding. The point I made to the audience was that these trials, which is a point that Lars also made, were huge in size and none of them was stopped because of adverse events or higher bleeding rates than the gold standard, which was warfarin. This is very important to emphasize.

McGuire: Dr. Wallentin, are you doing any better in Europe in terms of achieving this balance? There seems to be a lot of emphasis on risk but do we really appreciate the benefits?

Dr. Wallentin: No, I think there is under-use and a slow uptake even in Europe. There was very strong evidence, based on 55,000 patients, that all these compounds are at least as or more effective at stroke prevention than warfarin—all of them. They all reduce intracranial hemorrhage and are all safe and for some of them—the dabigatran 110-mg dose, apixaban 5-mg dose—are safer than warfarin, so we have treatments that are more effective, they are safer, they are more convenient, and we are still not using them.

People have been asking for these alternatives for years and there are larger similarities than differences between the trials, which I emphasized. So this goes for all of them. And it’s difficult to understand why we don’t have a very rapid uptake. And the patients’ preferences are, of course, to go with a standard-dose treatment without repeated hospital visits, without affecting their lifestyle, without affecting their eating habits, without affecting them with relation to their other treatments, so it's difficult to understand. And, of course, the elephant in the room is economy.

McGuire: Correct. You want to be efficient and effective with your money, but Dr. Ezekowitz, you and colleagues conducted a survey several years ago asking physicians to estimate the annual rate of warfarin-associated intracerebral hemorrhage and the estimates were more than 10-fold higher than literature-based estimates.1 Physicians were more influenced by events induced (such as bleeding) than those prevented (such as strokes) and the decision to use warfarin in nonvalvular atrial fibrillation was driven by perceived risk rather than perceived benefits. Is that still true?

Dr. Ezekowitz: The over-estimation of risk is driven by the fact that, after approval, there have been sporadic reports of bleeding that have occurred in patients, but there has not been a denominator. The denominator is obviously the number of patients treated. It turns out that the incidence of bleeding, after taking into consideration the denominator, the number of patients who've received the drugs, is actually even lower than the clinical trials.

In the warfarin era, the fear was intracerebral hemorrhage. Intracerebral hemorrhages are a devastating complication. Patients are massively disabled after them. Antidotes do not work and it's a terrible complication. The intracerebral bleed rates with the novel agents are very significantly reduced compared to warfarin. In two of the drugs, that is rivaroxaban and the high dose of dabigatran, there is an excess of gastrointestinal hemorrhages but gastrointestinal hemorrhages are not intracerebral hemorrhages. That doesn't mean to say that we do not need to spend more time and effort trying to determine the nature of these hemorrhages, the mechanism, and so forth. But, overall, the bleeding rates are less with the newer agents than with warfarin and this should not be a reason for hesitation for using these drugs.

McGuire: What do the new ESC guidelines say regarding the use of these new agents?

Dr. Wallentin: The new guidelines emphasize that almost all patients with atrial fibrillation should be treated with anticoagulation and that is the most important message. Warfarin is effective but has obvious downsides and there is a recommendation that if a patient needs an oral anticoagulant, the newer oral anticoagulants are preferable and they are, as a matter of fact, more effective, they are safer, and they are more convenient.

Cardiologists need to accept innovation. We have always been doing that. Why don't we push for the use of innovation? Innovation will stop unless we bring that to our patients and our patients are asking for innovations. They dislike the current treatment with warfarin and what it means to their lifestyle and quality of life. So I think we should go for innovation and the health economy looks very good with an oral anticoagulant versus aspirin or placebo.


  1. Gross CP, Vogel EW, Dhond AJ, et al. Clin Ther. 2003;25:1750-64.

Gregory Y.H. Lip, MD, who co-chaired the session featuring Drs. Ezekowitz and Wallentin, spoke with CSWN about his new paper in JACC on assessing stroke risk. To watch to the interview, visit youtube.cswnews.org.

Keywords: Stroke, Intracranial Hemorrhages, Warfarin, Atrial Fibrillation, Cerebral Hemorrhage

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