Anticoagulant Market Thickens for AF Stroke Prevention

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Approximately 15 percent of strokes occur in people with atrial fibrillation (AF). Warfarin has been the standard of care for more than 50 years in the U.S. and Canada to prevent and treat thromboemboli. However, dabigatran (Pradaxa, Boehringer Ingelheim) was approved in the second half of 2010. Whether this newcomer becomes the gold standard, or if yet-to-be approved therapies will prove more beneficial, remains to be seen.

Insufficient standard of care

Approximately two million Americans initiate warfarin therapy annually, in spite of its association with significant morbidity and mortality. It is the second leading drug-related reason for emergency department visits (JAMA 2006;296:1858-1866) and the most often cited reason for drug-related mortality (Arch Intern Med 2007;167:1414-1419). In October 2006, the FDA issued a black box warning for warfarin due to its hazards.

“While not every patient with AF requires antithrombotic therapy, every AF patients needs to be assessed for their stroke risk due to their increased jeopardy,” says Stuart J. Connolly, MD, director of the division of cardiology at McMaster University in Hamilton, Ontario, Canada.

According to the current U.S. and European guidelines,, the only AF patients at low enough risk to defer warfarin therapy are those less than 65 years old, with no other risk factors for stroke. For all other patients with AF, lifelong anticoagulation at low intensity—international normalized ratio (INR) of 2.0 to 3.0—is indicated (Stroke 2008;39:1647-1652).

The requirement of INR monitoring has relegated millions of individuals to receiving no therapy or ineffective therapy because of a lack of access to monitoring, says Elaine M. Hylek, MD, an associate professor of medicine at Boston University School of Medicine. “These complications have led to an intense search for alternatives to warfarin with a more predictable dose response that obviates the need for monitoring,” she adds.

Promise of dabigatran

Based on the RE-LY trial, dabigatran (110 mg) was associated with similar rates of stroke and systemic embolism as with warfarin in AF patients, as well as lower rates of major hemorrhage (N Engl J Med 2009;361:1139-1151). Also, dabigatran administered at 150 mg was associated with lower rates of stroke and systemic embolism compared with warfarin, but similar rates of major hemorrhage. (In October, the FDA approved dabigatran for doses of 75 mg and 150 mg capsules, and Health Canada approved the dose of 150 mg—not 110 mg.)

The rate of hemorrhagic stroke was 0.38 percent per year in the warfarin group, compared with 0.12 percent per year with 110 mg of dabigatran and 0.1 percent per year with 150 mg of dabigatran, Connolly et al reported from their RE-LY findings. About 20 percent of strokes are hemorrhagic, and the mortality rate is about 50 percent with these types of strokes, Connolly explains.

Translating these results into real-life clinical practice is causing much consternation. Connolly suggests that dabigatran can now be considered for all patients indicated for warfarin. “The higher the risk of the patient, the more benefits from dabigatran,” he says.

Some are debating which patients, if any, should remain on warfarin. One group who may continue taking warfarin are those, as described by Connolly, who “have been taking warfarin for a long time with good results and don’t mind the required blood tests.” Yet, he suggests the risk of bleeding into the brain, which is “markedly reduced” with dabigatran, is one reason to switch these patients.

Brian F. Gage, MD, from Washington University in St. Louis, concurs. “Patients with AF who are doing well on warfarin—including those often achieving the appropriate INR range with no side effects—are likely to continue that anticoagulant.”  

However, RE-LY showed that about 11 percent of participants taking dabigatran developed dyspepsia. Therefore, Gage suggests that some patients who begin dabigatran and have discomfort may switch to warfarin or to apixaban (Bristol-Myers Squibb/Pfizer), if the latter anticoagulant becomes available.

Mintu Turakhia, MD, a cardiac electrophysiologist at Stanford University and the Palo Alto VA Health Care System in Calif., also points to the possible increase in MI event rates with dabigatran, based on the RE-LY results.  

Dollars and sense

As always, cost may enter into the decision-making process. Using a Markov model analysis, which estimated the price of dabigatran at $13 per day, Turakhia and colleagues found that twice-daily dabigatran (110 or 150 mg) may be a cost-effective alternative to warfarin therapy in 10,000 AF patients with stroke risk who are 65 years of age or older. Compared with warfarin, the incremental cost-effectiveness ratios for low-dose and high-dose dabigatran were $51,229 and $45,372 per quality-adjusted life year gained, respectively. “Thus, at our base-case prices, high-dose dabigatran was more cost effective than low-dose dabigatran,” the authors wrote.

In actuality, Boehringer has said the wholesale acquisition price for both doses of dabigatran will be $6.75 a day for two capsules. The retail markups could increase the cost by 15 to 20 percent, making the actual cost approximately $8 per day.  

“If the actual cost is less than $7 per day, there could be a net cost-savings,” says Turakhia.  “However, our cost-effectiveness analysis examines the societal and health policy perspective. It does not take into account the cost consideration to the hospital, which may include infrastructural expenses related to warfarin management or an anticoagulation clinic. We still don’t know if dabigatran is a straightforward enough therapy to be directly managed by physicians, or will require clinic management. These considerations could seriously impact the overhead costs.”

Rivaroxaban: More questions than answers

ROCKET AF investigators randomized 14,269 patients with AF and a history of stroke, or at least two stroke risk factors, at 1,215 participating sites in 45 countries to receive either rivaroxaban (Xarelto, Johnson & Johnson), an oral direct factor Xa inhibitor (20 mg daily), or dose-adjusted warfarin (target INR range 2.5).

Rivaroxaban was found to be non-inferior to warfarin for the prevention of stroke and non-CNS systemic embolism for patients with nonvalvular AF in the primary analysis, and did not achieve superiority by the intention-to-treat analysis.

The intrinsic stroke risk of enrolled patients was “quite high,” with a majority of CHADS2 scores in the three-and-up range, said co-principal investigator Robert M. Califf, MD, from Duke University in Durham, N.C., during his AHA.10 trial presentation in November.

In the primary analysis, those taking rivaroxaban compared with  warfarin had fewer strokes and emboli to other parts of the body. With rivaroxaban, there were 1.71 events per 100 patient-years (188 patients) and with warfarin 2.16 (241 patients). The full intention-to-treat analysis, which counts all events from the time of randomization until study completion, regardless of whether participants were taking medication, found fewer strokes and emboli occurred in participants assigned to rivaroxaban (296 patients) versus warfarin (306 patients). However, this difference fell short of statistical significance for declaring rivaroxaban superior to warfarin.

Califf explained that the trial was uniquely designed because at the time, there was no alternative to warfarin, and “we thought the most critical aspect was to provide a superior alternative for people who couldn’t take warfarin.” Despite the non-inferiority findings, the study authors concluded that rivaroxaban is a “proven alternative to warfarin for moderate or high-risk patients with AF.”

Now that alternatives to warfarin have entered the U.S. and Canadian markets, with potentially more options on the way, only time will tell if warfarin will cease to be used and what challenges the new agents could pose.