Dabigatran Recommended as Alternative to Warfarin in A-fib Patients

Based on the positive results of the RE-LY trial, the newly approved anticoagulant dabigatran may be used as an alternative to warfarin for stroke prevention in patients with atrial fibrillation (A-fib). The new guidelines come in a ‘focused update’ published jointly online February 14, 2011, ahead of print in Circulation, Journal of the American College of Cardiology, and HeartRhythm Journal.

Dabigatran (Pradaxa, Boehringer-Ingelhiem Pharmaceuticals, Ridgefield, CT) was approved by the US Food and Drug Administration (FDA) in October 2010 for the prevention of stroke and systemic embolism in patients with nonvalvular A-fib.

RE-LY Recap

In the randomized RE-LY (Randomized Evaluation of Long-term anticoagulant therapY) trial, researchers led by Stuart J. Connolly, MD, of McMaster University (Hamilton, Canada), compared 2 doses of dabigatran (110 or 150 mg twice daily) with warfarin (adjusted dose) in 18,113 patients who were at risk of stroke from nonvalvular A-fib.

The results, published in 2009 (Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151), showed that the higher dose of dabigatran was superior to warfarin with regard to stroke or systemic embolism (1.11% per year vs. 1.71% per year; P < 0.001) and equivalent with regard to major bleeding (3.32% per year vs. 3.57% per year; P = 0.32).

The lower dose, meanwhile, showed noninferiority compared with warfarin with regard to stroke or systemic embolism (1.54% per year with 110 mg dabigatran; P < 0.001 for noninferiority) and superiority with regard to major bleeding (2.87% per year with dabigatran; P = 0.003). Both doses more than halved the rate of intracranial bleeding compared with warfarin.

Only the higher dose, though, received FDA approval.

What the Guideline Says

The new guideline represents the second update to the 2006 American College of Cardiology/American Heart Association/European Society of Cardiology A-fib guidelines since 2010, when the combination of aspirin and clopidogrel was recommended for patients who had difficulty staying on warfarin. The guideline states that the direct thrombin inhibitor dabigatran is “useful as an alternative to warfarin for the prevention of stroke and systemic thromboembolism in patients with paroxysmal to permanent [A-fib] and risk factors for stroke or systemic embolization who do not have a prosthetic heart valve or . . . significant valve disease, severe renal failure, or advanced liver disease.” The update carries a class B level of evidence.

The authors of the update, led by writing committee chair L. Samuel Wann, MD, of the Wisconsin Heart and Vascular Clinics (Milwaukee, WI), note that patients already on warfarin who experience adequate drug level control may not need to switch to dabigatran. However, those who do experience difficulty staying on warfarin, either because of frequent monitoring or side effects, may wish to switch. Before doing so, however, they should consider the twice-daily dosing regimen of the newer anticoagulant, potential bleeding problems with dabigatran, and cost: Dabigatran is estimated to cost about $13 per day compared with $1 for warfarin.

According to writing committee member Craig T. January, MD, PhD, of the University of Wisconsin (Madison, WI), the new guideline may prove useful in helping to establish practice patterns since it “reflects the current state [of the knowledge base],” he told TCTMD in an e-mail communication.

Just Right, or Not Far Enough?

“People were already aware of dabigatran and beginning to use it,” commented Mitchell S. Elkind, MD, of Columbia University Medical Center (New York, NY), in a telephone interview with TCTMD, “so I don’t know how much effect a guideline statement actually has, but people who may be on the fence about it may be more comfortable using it once they see their colleagues officially endorsing it.”

Dr. Elkind also indicated that the new guideline may spur interest in other promising alternatives to warfarin currently on the horizon, such as rivaroxaban and apixaban.

However, according to Dr. Connolly, principal investigator of the RE-LY trial, the new guideline does not go far enough. “The recommendation is really quite soft,” he told TCTMD in a telephone interview. “In Canada we went a bit further. The guidelines here say both drugs are reasonable, but dabigatran is actually preferred.”

In fact, for patients already on warfarin and doing well, he would still recommend switching them. “Just because you’ve done well on warfarin doesn’t necessarily guarantee you’ll do well in the future,” Dr. Connolly said. “From data we’ve published, we know that even well-controlled patients on warfarin still have a substantially higher risk of intracranial hemorrhage, so that’s still a serious reason to say that even patients doing well on warfarin should be switched.”

‘We’re Not Just Automatons’

Dr. Elkind understands that argument but takes a more cautious approach. “If one only looks at the result of a clinical trial, you might be tempted to say that every patient should be switched, but we have to weigh that with our knowledge that often what’s found in a clinical trial turns out to be not exactly the case in clinical practice,” he said. “And there are also all the psychological factors that go along with changing to a new drug. There are [existing] comfort levels among both patients and doctors when a new drug is introduced. We’re not just automatons that react to a study in that way. It is more complicated than that.”

Dr. January called the decision whether or not to switch from warfarin to dabigatran one best left between doctors and patients. “In my view, there is not a mandate to switch,” he said. “I think our guidelines are sufficient for the data currently available. He added that even for a new patient, either drug is acceptable. “When full anticoagulation is indicated for nonvalvular A-fib in a person who meets renal function guidelines, either warfarin or dabigatran is a reasonable alternative,” Dr. January said.

Dr. Connolly’s enthusiasm, though, would not be dampened. “For a new patient, it’s the preferred therapy, easily,” he said. “It’s very clear to me that if we ran history in reverse and we had [dabigatran and the other new anticoagulants] first and then warfarin came along, warfarin would never have been approved and people would’ve said it’s nowhere near as good and why use it?”

Bowing to the Inevitable

Dr. Connolly went further, calling the new guideline a step in an “inevitable shift” away from warfarin and toward the newer anticoagulants. “Two of the drugs [dabigatran and rivaroxaban] now coming out are showing excellent results, clearly better than warfarin, not just easier to use, but superior,” he said. “There’s going to be a very large move away from warfarin that’s obviously not going to happen overnight. These changes take time, people need to get used to new things, and this is a very important and indeed scary part of medicine.”

With this, Dr. Elkind agreed. “I think that’s true, that we’ll see an evolution,” he said. “But it will be gradual, over a few years, not an immediate shift.”

Warfarin will remain an important drug, maintained Dr. January. Still, “having said that, I anticipate that dabigatran will gain favor vs. warfarin,” he said.

Cost an Issue

That is not to say that dabigatran does not have any potential downside. Perhaps the most important one is cost. “We can’t forget these drugs aren’t inexpensive,” Dr. Elkind said. “Quite honestly, many of the patients I take care of here in Northern Manhattan and Washington Heights can’t afford to take these new designer drugs, and so warfarin is actually very good for them. They may even be able to get their blood tests paid for through insurance, but not necessarily newer expensive drugs.”

Dr. Connolly acknowledged that “dabigatran is a lot more expensive. You can’t ignore cost and prescribe things willy-nilly and expect people to just pay for it.”

“Some insurance plans have initially placed it as second tier,” noted Dr. January.

Nevertheless, Dr. January stressed that dabigatran represents the first new anticoagulant in 50 years, and Dr. Elkin related that in his practice, he has recently started using the drug. “I can’t say I have much experience with it, but I haven’t encountered any problems yet,” he said.

Dr. Connolly, meanwhile, admitted that “I’m a pretty strong proponent of dabigatran. I’ve been prescribing it in my practice. Patients go on it, and that’s it.”

 

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Source:
Wann LS, Curtis AB, Ellenbogen KA, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on dabigatran): A report of the American College of Cardiology Foundation/American Heart Association task force practice guidelines. Circulation; HeartRhythm; J Am Coll Cardiol. 2011;Epub ahead of print.

 

 

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