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Dabigatran: An alternative to warfarin for reduction of stroke in AF?
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The direct thrombin inhibitor dabigatran, representing what some see as a potential alternative to warfarin, has caused a stir in the atrial fibrillation community.
Warfarin, a vitamin K antagonist, is currently regarded by practitioners as one of the standard anticoagulants administered to appropriate patients with AF to reduce stroke risk and has remained so for several decades. Although not yet approved for use in the United States by the FDA, dabigatran (Boehringer Ingelheim) has been approved in Europe and Canada. With recently published results from the RE-LY study suggesting that dabigatran at minimum demonstrated noninferiority to warfarin for the reduction of stroke in AF patients, the trial has been of keen interest to many practitioners since they were released. The phase-3 trial was designed to compare two fixed doses of dabigatran with open-label warfarin in patients with AF and with increased stroke risk. The researchers included 18,113 patients who were followed up for a median of two years.
According to Andrew E. Epstein, MD, a professor of medicine at the Hospital of the University of Pennsylvania and chief of cardiology at the VA Medical Center in Philadelphia, the question of whether dabigatran could replace warfarin is now a common point of discussion following RE-LY.
“A reasonable question that many practitioners will have is: If a patient is doing well taking warfarin — which is less expensive — why change it?” Epstein asked in an interview with Cardiology Today.
Some of the RE-LY study findings suggested that dabigatran may bestow a modestly greater benefit on certain patients and for certain endpoints when compared with warfarin.
Both the 110-mg and 150-mg doses of dabigatran were efficacious in treating the primary RE-LY endpoint, according to study data. The 110-mg, twice-daily dose of dabigatran was noninferior to adjusted-dose warfarin for the reduction of stroke or systemic embolism (RR=0.91; 95% CI, 0.74-1.11), and the 150-mg dose was superior to the adjusted-dose warfarin (RR=0.66; 95% CI, 0.53-0.82).
One important potential advantage for dabigatran was a reduction in intracerebral hemorrhage, according to the researchers. The complication rates for hemorrhagic stroke observed with both the 110-mg dose (0.12% vs. 0.38%; P<.001) and the 150-mg dose (0.10% vs. 0.38%; P<.001) were less than one-third of those observed with warfarin, although there was an increased risk for gastrointestinal bleeding in the dabigatran 150-mg group (1.51% vs. 1.02%; P<.001).
Choosing what dose of dabigatran to use, according to Epstein, will be one of the challenges of using the drug.
“Assuming the drug is approved, how we choose the 110-mg dose or the 150-mg dose is going to be part of the educational process and learning curve when using dabigatran,” Epstein said. “Conventional wisdom would suggest that for patients at higher risk for bleeding, the lower dose should be used.”
Challenges with warfarin
The use of warfarin carries difficulties that have been well documented. Correspondence published in The New England Journal of Medicine indicated that along with its vitamin K antagonism, warfarin also “inhibits the synthesis of sequential enzymes in the coagulation cascade, which imparts a drastically steep dose-response relationship,” and that the “binding of warfarin to plasma proteins and its metabolism by cytochrome P450 enzymes facilitates drug interactions.” The resulting variability in anticoagulation control can lead to increased bleeding, thrombosis and risk for death.
“Even though we have had warfarin for 50 or 60 years and have pretty well learned how to use it and how to understand its issues, using it remains difficult,” Albert L. Waldo, MD, the Walter H. Prichard Professor of Cardiology at Case Western Reserve University/University Hospitals Case Medical Center in Cleveland, told Cardiology Today. “It is extremely difficult to keep patient INRs within the therapeutic range, which is critical for both safety and efficacy. This problem does not occur with dabigatran.”
Waldo said one of the most significant problems with the administration and management of patients assigned to warfarin is the number of what he called “landmines” that can potentially take a patient out of therapeutic range for effective anticoagulation. The continuous monitoring of interactions between warfarin and a multitude of substances (foods and drugs) the patient may come into contact with remains one of the great challenges for physicians administering the drug. Some foods can affect a patient’s INR, lowering it below the therapeutic range (for example, kiwi or licorice), or raising it above the therapeutic range (eg, mangoes or cranberries).
“Patients often do not realize that what they are eating can knock them out of therapeutic range, and that is worrisome,” Waldo said. “I put together a slide with a partial list of things that could take a patient out of the therapeutic range — foods and lots of drugs (including most diuretics, influenza vaccine, some antiarrhythmic drugs, antibiotics). The size of that list is really overwhelming.”
Significant alterations in diet and medication use are often made when a patient is assigned to warfarin, Waldo said. The magnitude of lifestyle adjustments a typical patient has to make to get and maintain the benefits of warfarin are also associated with a self-reported decrease in the quality of life in those patients.
“There are many quality of life studies suggesting that patients hate warfarin because of what it does to their lifestyles and because they have to be checked so often when using it,” Waldo said. “With dabigatran, we do not have this.” – by Eric Raible
For more information:
- Connolly S. N Engl J Med. 2009;361:1139-1151.
- Houston D. N Engl J Med. 2009;361:2671.