The stars appear to be aligned for drugs that reverse the effect of novel oral anticoagulants (NOACs). Regulators in the U.S. have moved them forward, anxious to provide emergency physicians an antidote in cases of life-threatening bleeding. But the ultimate beneficiaries may be patients who need but don’t take anticoagulants because of bleeding fears.
An Achilles heel
NOACs aren’t that novel anymore, which has prompted a campaign to rebrand them as direct oral anticoagulants, or DOACs. Pharmaceutical companies developed this class of drugs as an alternative to warfarin to reduce the risk of stroke in patients with nonvalvular atrial fibrillation and as a treatment for venous thromboembolism. The vitamin K antagonist warfarin, which was the only act in town for decades, requires frequent monitoring and interacts with other medications and foods.
Dabigatran (Pradaxa, Boehringer Ingelheim), a direct thrombin inhibitor, received FDA approval in 2010. Within its first year, dabigatran captured 8.1 percent of oral anticoagulant sales in the U.S. (Circ Cardiovasc Qual Outcomes 2012;5:615-621). Its rivals rivaroxaban (Xarelto, Janssen) and apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) are factor Xa inhibitors approved between 2011 and 2012. By June 2013, the three NOACs accounted for 62 percent of new prescriptions for anticoagulants (J Am Med 2014;127:1075-1082). Edoxaban (Savaysa, Daiichi Sankyo), another factor Xa inhibitor, was FDA approved in early 2015.
In clinical trials, the drugs proved to be as effective and safe (sometimes safer) as warfarin without its unwanted baggage. But warfarin offers one key advantage over NOACs: It can be reversed if a warfarin-treated patient experiences uncontrolled bleeding or needs urgent surgery. The initial rapid uptake of NOACs raised concerns about the lack of an antidote; some of those concerns spilled over into litigation, with Boehringer earmarking about $650 million in 2014 to settle 4,000 claims that it allegedly failed to properly inform patients of dabigatran’s bleeding risk.
“When you survey physicians who treat a lot of atrial fibrillation, there has been some misgiving about NOACs as a class despite their record against warfarin in clinical trials,” says Charles V. Pollack Jr., MD, medical director of emergency medicine at Pennsylvania Hospital in Philadelphia. “There is still some hesitancy because they are not sure what to do if the patient does have a bleeding episode.”
This year, Pollack and other researchers in the phase III RE-VERSE AD trial (Reversal Effects of Idarucizumb on Active Dabigatran) published results on the first 90 of 300 patients to receive idarucizumab, a monoclonal antibody fragment that binds to dabigatran to neutralize its anticoagulant effect (N Eng J Med online June 22, 2015). Boehringer developed the drug and sponsored the prospective study.
To be eligible for the trial, patients had to be on dabigatran and present to the emergency department with serious bleeding or in need of urgent surgery. Idarucizumab quickly and effectively reversed the anticoagulant effect in 88 percent to 98 percent of the patients, with normal hemostasis occurring in 92 percent. A total of 18 patients died, five with fatal bleeding events.
“It is very important that clinicians have reasonable expectations about these reversal agents,” Pollack emphasizes. “They don’t necessarily stop bleeding.” He cited a hypothetical car crash victim on dabigatran who is admitted with severe trauma to the head and pelvis with retroperitoneal bleeding. Idarucizumab may reverse the anticoagulant effect and help stabilize the patient but “his mortality is still quite high even when I take the dabigatran away.”
|Pharmacokinetic Properties of the New Anticoagulants Compared With Warfarin|
|Maximum concentration||4 h||0.5–2 h||3–4 h||2–4 h||.5 h|
|Half-life||20–60 h||2–14 h||12 h||5–9 h in young, 11–13 h in elderly||10–14 h|
|Data sourced from Summary of Product Characteristics. Arterioscler Thromb Vasc Biol 2015;35:1736-1745|
The reversal race
Idarucizumab is one of three NOAC antidotes under development. Portola’s andexanet alfa, which works as a factor Xa decoy to deactivate factor Xa inhibitors, appeared safe and effective in healthy volunteers. It is being evaluated in two phase III clinical trials, one enrolling older patients treated with