SAN FRANCISCO--Will we ever be free of INR checks is the question Marianne T. Cosentino, APN, MS, of the Yale New Haven Hospital in New Haven, Conn., attempted to answer during a May 4 presentation at the 32nd annual scientific session of the Heart Rhythm Society (HRS). Her answer? Not yet.
Because atrial fibrillation (AF) is so prevalent in the current population and because it increases a patient’s risk of stroke five-fold, recent research has centered on the development of newer, safer anticoagulants to provide alternatives to the commonly used warfarin.
Currently, drug therapy to prevent stroke in non-valvular AF patients fixates on aspirin and oral anticoagulants (mainly warfarin for the past 60 years), said Cosentino, but now the “new kid on the block,” dabigatran, could provide an alternative to the often limiting warfarin.
“Despite its shortcomings, warfarin works” and has shown a 62 percent reduction in stroke compared to placebo in many studies, Cosentino said. However, she also called the drug’s limitations “very real.”
While warfarin has a peak plasma level that is 72 to 96 hours and a half-life of 40 hours, dabigatran, in contrast, has a half-life equal to 12 to 17 hours. Additional limitations of warfarin include a narrow therapeutic window and numerous food and drug interactions.
The therapeutic window you must reach is between 2 to 3 on warfarin, which Cosentino called "difficult." In fact, she said that this is only reached 60 percent of the time.
Cosentino offered that the desirable qualities of newer anticoagulants would be “the opposite of warfarin” and be:
- More effective than current agents;
- Safer than current agents;
- Minimal food and drug interactions; and
- Have predicable anticoagulation.
Based off promising results of the RE-LY trial, the FDA has approved dabigatran (Pradaxa, Boehringer Ingelheim) earlier this year. And, in comparison to warfarin, dabigatran has a half-life equal to 12 to 17 hours, is 80 percent renally excreted, has a rapid onset of actions and provides conistant anticoagulation. “The drug has no peaks or troughs like warfarin.”
The RE-LY trial randomized patients to receive either warfarin or dabigatran in 110 mg or 150 mg doses. The results showed that the drug was not inferior to warfarin and in fact, at the 150 mg dose, dabigatran was superior to warfarin. The 110 mg dose was equal, but the risk reduction for the 150 mg dose was 35 percent. Additionally, intracranial bleeds were significantly reduced by dabigatran.
And while the results were mostly positive, patients on dabigatran did have significantly higher rates of GI bleeds with the 150 mg doseage compared with warfarin. Rates of discontinuation for dabigatran were higher than warfarin, 21 percent vs. 16 percent.
Earlier in this year, HRS, ACCF and AHA put forth Class I recommendations that supported dabigatran as an alternative to warfarin in AF patients to prevent stroke.
However, Cosentino said that the “FDA threw us for a loop with its approval because it approved the 150 mg and the 75 mg dose, which has no safety or efficacy data as of yet.” However, she said that the 75 mg dose is somewhat equivalent to the outcomes of the 150 mg dose of dabigatran, so that could be the reason why.
Additionally, Cosentino said that dabigatran may gain more traction in the field because the overall costs may be less. She said that this may be due to the fact that dabigatran use will eliminate the need for anticoagulation monitoring, the cost of managing warfarin/manpower in the clinic and additional hospital admissions.
Cosentino outlined other anticoagulants that may soon be approved based off positive clinical results. These include:
- Rivaroxaban (Bayer Healthcare): currently, the ROCKET AF trial is evaluating rivaroxban compared to warfarin and the results showed that the drug was non-inferior to warfarin for the prevention of stroke and non-CNS embolism, but had similar rates of bleeding and adverse events. Constantino said the drug is a “proven alternative to warfarin”;
- Apixaban (Bristol-Myers Squibb/Pfizer): currently being studied in the ARISTOTLE trial. Additionally, the AVERROES trial was stopped last June when apixaban when investigators realized a 54 percent reduction in stroke when apixaban was administered; and
- Edoxaban (Daiichi Sankyo): Is being studied in the ENGAGE AF-TIMI 48 trial that will enroll 20,500 patients. The trial is expected to be completed next year.
While Cosentino offered