CHICAGO – Rivaroxaban, the first in class, oral factor Xa inhibitor, showed noninferiority to warfarin for preventing stroke and other embolic events in a pivotal trial with more than 14,000 atrial fibrillation patients.
But with the report of these results at the annual scientific sessions of the American Heart Association coming less than 2 weeks after the release of dabigatran, the rival, new anticoagulant that came onto the U.S. market on Nov. 3, the question by many people who heard the results was not just how rivaroxaban compared with warfarin but how to weigh its clinical role versus dabigatran.
Cardiologists had no firm answer, and expect none until rivaroxaban and dabigatran go head to head in a trial. But talk at the meeting about both drugs made it clear that warfarin’s time as the go-to anticoagulant for atrial fibrillation patients had passed. Both of the new drugs eliminate the regular dose monitoring and adjustment required for patients on warfarin.
How rivaroxaban compares with dabigatran "is the inevitable question," said Dr. Kenneth W. Mahaffey, a cardiologist at Duke University in Durham, N.C., who reported the results from Rivaroxaban Once-Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). He noted the pitfalls in comparing the outcomes of ROCKET AF with results from the pivotal trial for dabigatran, the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial (N. Engl. J Med.2009;361:1139-51). ROCKET AF enrolled substantially sicker patients, with an average CHADS score of 3.5 compared with an average 2.1 score in RE-LY, and ROCKET AF was run in a double-blind, double-dummy fashion while in RE-LY patients and physicians knew who received dabigatran or warfarin.
Dr. Robert M. Califf
Dr. Mahaffey’s coinvestigator in ROCKET AF, Dr. Robert M. Califf, agreed. The researchers who ran ROCKET AF "have been discussing [the comparison of rivaroxaban and dabigatran] incessantly, but there is no scientifically valid way to compare the two, so we’ll be left with our feelings." Dr. Califf cited his 84-year-old mother, on warfarin and in remission from multiple myeloma, who has been unhappy with her monitoring regimen. "I can assure you that she will go on one of these two new drugs just because of convenience, but she can afford it," said Dr. Califf, professor of cardiology at Duke. "Cost will ultimately have to be a factor that we need to be sensitive about."
Price will likely be a major factor in deciding the role for both alternatives to warfarin, and the cost calculation is not simple. No price yet exists for rivaroxaban, an agent not yet approved for sale in any country. But on Nov. 3, Boehringer-Ingelheim, the company that markets dabigatran (Pradaxa), announced that the direct thrombin inhibitor was available for U.S. sale at a wholesale price of $6.75/day for either two 150-mg pills or two 75-mg pills, the two dosages approved for U.S. use by the Food and Drug Administration. A recent, informal survey of several large, U.S. retail pharmacies found the 150-mg dose often selling for just under $8 per day. That compares with a drug cost for generic warfarin of usually less than $1 a day. But the price of warfarin therapy also includes the substantial cost for laboratory monitoring of patients on warfarin and the cost of the complications patients have when they are either over- or under-anticoagulated with warfarin.
An analysis published online Nov. 1 presented a cost-effectiveness analysis of dabigatran compared with warfarin (Ann. Intern. Med. 2010, Nov. 1 [epub ahead of print 0003-4819-154-1-201101040-00289v2]). According to the analysis, at a daily cost of $8, treatment of patients with atrial fibrillation with dabigatran had an incremental cost-effectiveness ratio of about $12,500 per quality adjusted life year compared with warfarin, said Dr. James V. Freeman, a cardiologist at Stanford (Calif.) University and lead author of the cost-effectiveness analysis. Although this figure is still subject to adjustment based on newly updated clinical-event data in RE-LY, an incremental cost-effectiveness ratio of "roughly $10,000-$20,000 is likely in the ballpark" based on current dabigatran pricing, Dr. Freeman said in an interview.
"This is in a range generally considered very cost effective. By comparison, implantable cardioverter defibrillators have been estimated to have an incremental cost-effectiveness ratio of $34,000-$70,000 per quality adjusted life year, compared with control therapy," he said.
Dr. Peter Kowey
Even if calculations show that dabigatran is cost effective, a monthly prescription could still deliver a patient an unexpectedly high drug bill. "We’ve been very careful, in this early phase, that patients don’t get whacked with a $200 bill they can’t pay," said Dr. Peter R. Kowey, a cardiologist and professor of medicine at Thomas Jefferson University in Philadelphia. "We call each insurance company to make sure the patient will have some kind of compensation. That’s our biggest concern with dabigatran."