60 years ago, warfarin, the most widely used anticoagulant in the world, was approved by the FDA for prevention of stroke and other cardiovascular events in at-risk patients. Since then, warfarin has been studied in more than 20,000 patients and relied upon as the consensus-endorsed, long-term treatment for patients with atrial fibrillation (AF)—a condition that affects 2.5 million Americans. The drug has been a boon for patients, because as the evidence shows, warfarin decreases the risk of stroke in those with AF by about 68%.
Weighing benefits, weighing risks
However, as much as physicians rely on it, they resent the fact that warfarin, most often marketed as Coumadin in the U.S., requires constant testing and adjustments. This drug has such a narrow therapeutic window that it can take weeks, or even months, to figure out optimal dosing.
Another problem: The risk of a major bleed while taking warfarin is about 6.5%. Warfarin-treated patients must be careful with their diets and the medications they take, or they could experience a bleeding episode that lands them in the hospital or kills them. Nonetheless, most physicians would argue that warfarin has saved hundreds of thousands of people from early death.
As Eric Malter, Founding Partner and CEO of MDC, a programmatic healthcare advertising and communications agency in New York City, explains, “Warfarin is tried and true. It is inexpensive and the effects of its anticoagulation are quickly and easily reversed with an inexpensive and readily available therapy, namely vitamin K.”
Anticoagulation in the 21st century
While warfarin was a major game-changer in the twentieth century, and continues to be widely used, things have changed in the last five years. The non-vitamin K antagonist oral anticoagulants (NOACs) arrived on the scene and have been positioned as next-generation, equally effective, easier-to-use, safer anticoagulant treatment options for patients with AF and other thromboembolic conditions.
When Boehringer Ingelheim’s (BI) direct thrombin inhibitor Pradaxa (dabigatran) was approved on October 19, 2010 for prevention of stroke in patients with non-valvular AF, the treatment landscape automatically shifted beyond a warfarin-or-nothing decision. At that time, Pradaxa was hailed as a major breakthrough in anticoagulation therapy and an important alternative to warfarin. Physicians and patients alike were excited to have a more convenient treatment option that was as effective as warfarin and presumably much safer.
But was it really safer—or simply dangerous in a different way?
Significantly less bleeding in clinical trials
According to a randomized, non-inferiority study published in the New England Journal of Medicine in 2009, when warfarin-treated patients were compared with patients treated with 110 mg of Pradaxa twice daily, Pradaxa was deemed non-inferior. Likewise, when warfarin-treated patients were compared with patients treated with 150 mg of Pradaxa twice a day, the Pradaxa arm showed superior results. The primary outcomes of this study, which included more than 18,000 patients with AF, were stroke and systemic embolism. It also tracked treatment-associated bleeding risk.
Overall, 1.69% of warfarin-treated patients experienced stroke or embolism during the two-year treatment period, compared with 1.53% of patients treated with 110 mg of Pradaxa and 1.11% of patients treated with 150 mg of Pradaxa. During the study period, major bleeds in the warfarin group occurred at a rate of 3.36% per year, compared with 2.71% per year in the 110-mg Pradaxa treatment group (significantly lower, P=0.003) and 3.11% in the 150-mg Pradaxa treatment group. This evidence, along with other data, was the basis for Pradaxa approval in the U.S., the E.U., Canada and other markets.
Concerns about non-reversibility
Since approval, there has been substantial product uptake of Pradaxa, and many patients have done very well, reaping the benefits of anticoagulation without the day-to-day burden of testing, monitoring and modifying their treatment regimen. In fact, a cross-sectional analysis of 3,415 patients from the GLORIA-AF trial, which is designed to collect data on patients with newly identified AF at risk of stroke, found that during the study period (November 2011 to February 2014), 25% of newly diagnosed patients were treated with Pradaxa, 20.5% were treated with Xarelto, 13.5% were treated with aspirin, 6.6% were treated with Eliquis—and 26.1% were treated with warfarin. Unfortunately, 7.6% of patients remained untreated despite being at high risk for stroke.
Some patients, however, did not do so well. All told, there have been reports of approximately 280 Pradaxa-related deaths and 4,000 lawsuits related to drug-related bleeding. And as reports of fatal bleeds have been publicized, many physicians have thought harder about the risks of the NOACs, including not only Pradaxa, but also Bayer’s Xarelto (rivoroxaban) and Bristol-Myers' Eliquis (apixiban).
The main complaint has been: “There is no reliable way to reverse the anticoagulant effect of these new non-VKA anticoagulants.” According to Sabine Luik, MD, senior vice president, Medicine & Regulatory Affairs at Boehringer Ingelheim, “Our market research indicates that physicians are concerned about the lack of a reversal agent for any of the NOACs.”
The advent of a NOAC antidote
That concern may soon be alleviated, however, assuming BI’s Pradaxa antidote, idarucizumab, an antibody-based treatment, which has already been submitted to the FDA, the EMA, and Health Canada, is approved.
Will this change physicians’ opinions? Luik says, “We cannot speculate if physicians will prescribe Pradaxa differently; however, we understand that some physicians are concerned about the need to reverse the anticoagulant effects of the NOACs in certain clinical situations. If approved, idarucizumab may provide these physicians with more confidence in prescribing Pradaxa.”
Malter thinks that many physicians and patients will want to try Pradaxa. "Of course, there is great appeal to the newer therapies, both in terms of patient lifestyle and the savings that less monitoring afford," he said. "The ability to eat certain green vegetables again and not have to undergo blood draws on a frequent basis makes the newer drugs much more appealing to many patients—especially if this therapy is covered by their health insurance."
The role of marketing and market share
From a marketing perspective, Malter points out that BI and other companies are spending a great deal on advertising and promotion, which he says is “appropriate given the high margins these products enjoy.”
But it’s different for warfarin. According to Malter, “Similar to any generic medication with a cost most likely measured in pennies, and with the thinnest of margins, there is no impetus for any manufacturer to spend a great deal of money to promote it. It would make no sense. So, as with many other therapeutic categories, those patients with good health insurance coverage may or may not switch to the newer therapies, based on their doctor’s evaluation, and those patients with coverage that is less than ideal, and who are currently maintained quite well on warfarin, will stay the course. That being said, I believe there will continue to be a significant population for whom warfarin will be the answer, with or without marketing.”
“Will Coumadin and the warfarin products lose significant market share to the newer therapies. Definitely, and there’s not much that can be done about it. Death knell for Coumadin? Not for many years to come, in my opinion.”