How Do Newer Anticoagulants Compare with Warfarin?

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The MD Magazine Peer Exchange “Novel Anticoagulation Options: Target-Specific Oral Agents and Their Antidotes” features leading physician specialists discussing key topics in anticoagulation therapy, including the clinical characteristics of current and emerging agents and criteria for use in specific patient populations.

This Peer Exchange is moderated by Peter Salgo, MD, professor of medicine and anesthesiology at Columbia University and an associate director of surgical intensive care at the New York-Presbyterian Hospital in New York City.

The panelists are:

• Scott Kaatz, DO, MSc, Chief Quality Officer at Hurley Medical Center in Flint, Michigan, and clinical associate professor at Michigan State University
• Seth Bilazarian, MD, clinical and interventional cardiologist at Pentucket Medical and instructor of medicine at Harvard Medical School
• Gerald Naccarelli, MD, Bernard Trabin Chair in Cardiology, professor of medicine and chief of the Division of Cardiology at Penn State University School of Medicine, and associate clinical director at Penn State Heart and Vascular Institute in Hershey, Pennsylvania
• Christian T. Ruff, MD, associate physician in the cardiovascular medicine division at Brigham and Women’s Hospital, and assistant professor of medicine at Harvard Medical School in Boston

In this segment of the Peer Exchange, the panelists discuss the clinical evidence comparing the newer oral anticoagulants to warfarin in terms of reducing stroke and systemic embolism.

Naccarelli noted that the data on the new drugs comes from large trials (involving 14,000-22,000 patients) that assessed their performance against warfarin to see if their performance was “noninferior” to the standard treatment. All of the new drugs were shown to be noninferior to warfarin in these patient populations. The idea was if it could be demonstrated that the new drugs were going to be easier to use—“you’re not going to have to measure anything. You don’t have to worry about dietary interactions”‑‑and if they were as good as warfarin without causing more bleeding, people would use them, he said.

If the trial outcomes were measured by “intention to treat,” some of the new drugs not only were as good as (ie, noninferior to) warfarin but were actually better at reducing stroke. “Dabigatran at 150 mg/twice a day actually was superior and resulted in 35% fewer strokes and systemic embolism. Not only that, those patients had 25% less ischemic strokes than with warfarin,” said Naccarelli. Apixaban actually reduced stroke by an additional 21%, and the other drugs by intention to treat were noninferior.

When it came to bleeding, Naccarelli noted that all the new drugs were basically noninferior to warfarin, with both edoxaban and apixaban statistically having lower bleeding rates.

Another major finding in the trials was that all of the new drugs also reduced hemorrhagic stroke by at least 50%. “This is a bleed that you can’t put a Band-aid on,” said Naccarelli.

Salgo noted that now only 10% of strokes in patients on the new medications are hemorrhagic strokes and asked why this is the case. The short answer from the panelists was: nobody knows the answer to that for sure yet.

Ruff said that regardless of which agent is used, they all reduce life-threatening bleeding (in particular, intracranial hemorrhage) by half, but nobody knows why this occurs.

“There is some thought that the brain is bathed in tissue factor, and so if you have a small bleed or a tear in a vessel, your tissue factor will become very active and help you clot. The way warfarin works, it basically prevents tissue factor from forming hemostasis and a clot,” said Ruff. None of the new agents interact at that part of the coagulation cascade,” so there’s some thought that if you have bleeding in your brain, it’s limited because you can have tissue factor help stanch that bleeding with the new agents. Whether or not that’s the main mechanism, I’m not sure anyone can say. The one thing is it’s consistent.”

Dabigatran, which is a direct thrombin inhibitor, and the factor Xa inhibitors all have the same effect on hemorrhagic stroke risk. “I think the European Society guidelines got it right. They said all this other stuff is wonderful, that you don’t have to get your blood drawn and all. But they said that you could reduce the risk of hemorrhagic stroke by 50% or more if you use these drugs instead of warfarin. And that’s the reason to use them,” said Naccarelli.