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Physicians speak out on implications of dabigatran approval
Experts weigh pros and cons of the first new oral anticoagulant in more than 50 years.
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The market for stroke prevention in patients with nonvalvular atrial fibrillation may soon be heading in a new direction with the recent FDA approval of dabigatran etexilate.
This approval came 1 year after data published in The New England Journal of Medicine from the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial reported a reduction in risk for stroke and systemic embolism in patients given dabigatran (Pradaxa, Boehringer Ingelheim) compared with the current standard of care, warfarin (Coumadin, Bristol-Myers Squibb). The 150-mg dose of the newly approved drug was released to pharmacies nationwide on Nov. 3, with the release of the 75-mg dose following shortly afterward.
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Peter Kowey, MD |
According to Chris Corsico, MD, US medical director, Boehringer Ingelheim Pharmaceuticals Inc., dabigatran was the end result of 14 years of research and development, which culminated with the findings presented in RE-LY.
The RE-LY study, Corsico said, was designed as a noninferiority study that could also be tested for superiority. “Based on the results, we followed our prespecified hypothesis testing plan and were able to demonstrate superiority,” he told Cardiology Today. This superiority for the 150-mg dabigatran dose included a stroke risk reduction of 35% compared with warfarin, as well as a reduction in the risk for intracranial hemorrhage by 59% vs. warfarin.
With no drug being its equal in the market for stroke prevention in AF patients for more than half a century, it is perhaps unsurprising that many of the physicians were not expecting dabigatran to be any different than the other drugs that have attempted to challenge warfarin in the past.
“It was long thought that well-administered warfarin would be unbeatable, and the trials were designed with the idea of showing that a new treatment might be at least as good as warfarin, but we only dreamed that one could be superior,” Jonathan L. Halperin, MD, director of clinical cardiology services, Zena and Michael A. Wiener Cardiovascular Institute, The Mount Sinai Medical Center, New York, said in an interview. “Then along comes the RE-LY trial, and it’s the first time we’ve seen warfarin beaten. That’s very exciting in and of itself.”
Cost considerations
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After the FDA’s approval of dabigatran, questions immediately arose among practicing physicians as to what the end cost of the drug would be. According to Boehringer Ingelheim, the price of dabigatran at the wholesaler acquisition level in the US will be $6.75 per day, with the price applying to both 150-mg twice daily and 75-mg twice daily doses. This pricing, the company said, takes into consideration the cost of research and development, health-economic aspects, the outcomes observed in the clinical trial and the need for no international normalized ratio monitoring as would be required with warfarin usage.
Although the price for dabigatran will be noticeably higher than warfarin, lower price is simply one benefit of a drug that has been around for 50-plus years, Halperin said.
“There is, however, the cost of managing warfarin that goes beyond the cost of the drug,” he said. “You don’t get the benefit just from taking the tablet; patients need frequent blood test monitoring to adjust the intensity of therapy, which can vary because of interactions with foods and other drugs. The typical patient with AF is over 70 years old and taking nearly a dozen concomitantly prescribed medications because of associated CVD. The doses of many of those other drugs are changing all the time, too. It’s a hassle, at best, to manage warfarin anticoagulation for these people.”
Although INR monitoring is one of the cost considerations patients on warfarin must take into account, Larry B. Goldstein, MD, director, Duke Stroke Center, Duke University Medical Center, said patients have the option to check INR at home with a home monitoring kit, which could help patients save from costly visits to an anticoagulation clinic.
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“There is a recent paper in the Oct. 21 issue of The New England Journal of Medicine that found no real difference between getting your INR checked at a high-quality anticoagulation clinic and home monitoring in patients who can do that,” Goldstein said. “That takes away some of the logistic issues related to being on warfarin. The patients who did a home monitoring had somewhat better quality of life and satisfaction, although there are technical issues in interpreting that.”
Another economic factor that must be considered, according to Albert L. Waldo, MD, Walter H. Prichard Professor of Cardiology at Case Western Reserve University/University Hospitals Case Medical Center, Cleveland, and Editorial Board member for Cardiology Today’s Arrhythmia Disorders section, is the expected long-term benefits with dabigatran.
“If this drug is significantly better than warfarin, you would hope that there would be fewer complications than from warfarin. So it would be more economical in the long run by keeping people out of hospitals,” Waldo told Cardiology Today. “However, on an individual basis, there is concern about the expense of the pill. So I think it is going to have to filter through our health care system on how drugs get supported by the different insurance plans and see how costly it is going to be for the patient. The hope is that because the drug is better and safer, there will be a lot of cost savings in the long run associated with fewer strokes and less bleeding than in patients taking warfarin.”
Approval’s effect for clinical practice
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At this early stage in the clinical life of dabigatran, physicians were quick to discuss what they believe will be the effect of implementing dabigatran into practice.
“The obvious thing is that it’s an improvement because we don’t have to monitor the patients, there’s not as many drug interactions and there’s evidence of superiority for the endpoint,” said Peter Kowey, MD, professor of medicine and clinical pharmacology, Jefferson Medical College, Philadelphia, and member of the Cardiology Today Editorial Board. “But it’s like everything else in medicine — there’s good news and bad news. The good news is that this wonderful drug will be available, but there’s a burden. There’s a lot of education that needs to be done for physicians to understand the drug and use it properly: If they are going to transition patients from warfarin to this drug, how to do it; how to monitor patients because even though there is no blood testing, there is still need for clinical monitoring and supervision; and how to determine which patients within the population may not be good candidates for this drug.”
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Waldo said patients on dabigatran must be made aware that they must take the drug twice daily. “With warfarin, if you missed a dose, it didn’t matter quite as much since its half-life is long,” he said. “With this drug, since it has a short half-life, if you don’t take it on a regular basis, you quickly become unprotected. The hope would be that patients understand the risk and take the drug properly.”
And there are additional downsides with dabigatran, Goldstein said. “There are some types of patients who have had hepatic dysfunction that can’t be treated. We don’t know how frequently or how long we need to monitor liver function in patients taking dabigatran because it can affect liver function. The RE-LY data are also a bit complicated, and I think it will take us some time to sort through this in terms of clinical use,” he said.
The bottom line, Goldstein said, “is that although there are clear potential advantages with dabigatran, I don’t think this is a panacea. I also think we are going to need to gain experience in the real world to determine how well it performs.” – by Brian Ellis
For more information:
- Connolly S. N Engl J Med. 2009;361:1139-1151.
- Matchar D. N Engl J Med. 2010;363:1608-1620.
Disclosure: Dr. Goldstein has served as a consultant for Boehringer Ingelheim
Disclosure: Dr. Halperin has acted as an adviser for Boehringer Ingelheim
Disclosure: Dr. Kowey has served as a consultant for Boehringer Ingelheim, Merck, Portola, Daiichi Sankyo, GlaxoSmithKline, Astra Zeneca, Johnson & Johnson and Bristol-Myers Squibb
Disclosure: Dr. Waldo has acted as a consultant to Boehringer Ingelheim, Bristol-Myers Squibb, Ortho-McNeil Janssen, Portola, Daiichi Sankyo and Merck, and the University Hospitals Case Medical Center served as an enrolling site for the RE-LY trial.