Reed Miller

June 20, 2012

June 20, 2012 (Nice, France) — Here at Cardiostim 2012, two of the experts working on new European guidelines on stroke prevention in atrial-fibrillation patients gave a broad preview of how those guidelines will address the questions created by the introduction of several new anticoagulants [1].

"In the coming years, we won't have to decide who needs anticoagulant therapy--because that's practically all patients with atrial fibrillation--but we will suddenly have to pick which anticoagulant to use," Dr Paulus Kirchhof (University of Birmingham, UK) explained during a presentation entitled, "What should the new guideline revisions on stroke prevention look like?"

For a long time, vitamin-K antagonists, especially warfarin, were the only option for mitigating stroke risk in patients with atrial fibrillation, until the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial showed that dabigatran (Boehringer Ingelheim, Pradaxa) could reduce ischemic and hemorrhagic stroke more effectively than warfarin with the same risk of bleeding. RE-LY was the "game changer," according to Kirchhof, and since then, rivaroxaban (Xarelto, Bayer/Johnson & Johnson) and apixaban (Eliquis, Pfizer/Bristol-Myers Squibb), both direct factor Xa inhibitors, have also emerged as warfarin alternatives.

Kirchhof couldn't reveal exactly how the European guidelines will treat the new agents but indicated that newer agents will be considered preferable to warfarin for most AF patients. "New anticoagulants give us a way to treat those patients who are untreated so far. That is the most prominent benefit. In terms of safety, I would think people would prefer the new anticoagulants over vitamin-K antagonists, because even in patients in RE-LY who were well controlled, the rare fatal bleed is just less likely on the new anticoagulants than on vitamin-K antagonists."

The US multisociety guidelines have made dabigatran a class I recommendation, while the Canadian guidelines state that "most patients should receive dabigatran, rivaroxaban, or apixaban in preference to warfarin."

Different Bleeding Risks Require Different Drugs

Dr Gregory Lip (City Hospital, Birmingham, UK), who is also involved in writing the new guidelines, agreed that the new agents will be better than warfarin for many patients but cautioned that each of them present somewhat different risk/benefit profiles. He told heartwire , "We now have an opportunity for a choice, and I think we're moving toward recognizing that 'one size fits all' does not necessarily hold true, while [there was a time recently when] there was a suggestion or implication that one size might fit all and hold all the answers."

Kirchhof suggested that the treating physician will have to understand each patient's mix of bleeding risk factors to know which anticoagulant agent to choose. "I think these bleeding risk factors may give us some initial guidance, not so much on whether to anticoagulate the patient but on picking the type of anticoagulant," he said. "In patients at a very high stroke risk, we may want to choose one that is more effective, but in patients with a moderate stroke risk but a high bleeding risk, we may choose one that is safer with less bleeding risk."

Although the benefit of stroke reduction outweighs the bleeding risk with these drugs, there may nevertheless emerge a small group of people for whom the risk of stroke, as measured by CHA2DS2-VASc score, is so low that anticoagulation is not cost-effective. In these patients, "yes, you have a net clinical benefit, but the number needed to treat is in the thousands," he said. "Whether we as a society want to treat 10 000 people to prevent one stroke if the treatment costs such and such at a given time point is an interesting question."

He also added that the patient's preference, related to their subjective fears based on their own experience, may determine whether the risk of bleeding is a more important consideration than the risk of stroke.

Lip also stressed that while "the new drugs do offer efficacy, safety, convenience, and cost-effectiveness . . . appropriate use in the correct patient is necessary. Careful and considerate prescribing is crucial--you're not giving chocolates to patients, you are giving powerful anticoagulants. They will work well if you give them correctly and use them appropriately."

The End of Aspirin

Both Lip and Kirchhof mentioned that the AVERROES trial shows the risk of bleeding is as high with aspirin as it was with apixaban, so aspirin is clearly less effective than the new anticoagulants without offering any safety advantage. "Aspirin is not benign, at least with atrial fibrillation," Kirchof said. "From these trials, we can say there is no good role for antiplatelet therapy in antithrombotic management of atrial fibrillation."

Lip agreed. "In patients with stable vascular disease, there is really no good reason to add an antiplatelet drug to an anticoagulant," he said. "You don't make any appreciable impact on cardiovascular events. What you do instead is increase major bleeding and, frighteningly, intracranial bleeds."

Throwing It in Reverse?

An important consideration with any anticoagulant is knowing how to stop or reverse its effects if necessary.

Kirchhof said that in most cases, the effect of the drug will wear off in a few hours or, in the case of severe bleeds, can be treated with coagulant factors. In cases where it appears to be necessary to prevent the drug from becoming active, simple charcoal can be ingested to absorb the drug if it was taken recently, he said, or it may even be necessary to consider dialysis in extreme cases.

However, he added that the optimal way to handle emergencies with patients on these powerful anticoagulants will have to be learned over time from registry data.

Lip told heartwire that the best way to prevent a bleeding crisis in a patient on anticoagulants is to choose the right patients for the drug to begin with. "The problem we have is that physicians sometimes forget that we're still dealing with powerful anticoagulants, so you need to select your patients correctly, and carefully consider prescribing. What gets people into trouble is inappropriate patients being given the drug inappropriately," he said.


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