Reverse Course: NOAC Antidotes Poised to Allay Bleeding Concerns

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[11]: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 concentration4 h0.5–2 h3–4 h2–4 h.5 h
Half-life20–60 h2–14 h12 h5–9 h in young, 11–13 h in elderly10–14 h
Renal clearance0%85%27%30%33%
Protein binding99%35%87%92%–95%40%–59%
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 rivaroxaban and the other involving apixaban. A third reversal agent, Perosphere’s PER977, uses a small, synthetic molecule that may bind to both dabigatran and the factor Xa inhibitors. A phase III study is expected to test PER977’s neutralizing ability with edoxaban.

The FDA waved these drugs to the front of the line in the approval pathway, giving idarucizumab and andexanet alfa breakthrough designation as well as fast-tracking PER977. Need is critical for sure as the FDA on October 16th granted accelerated approval to idarucizumab (Praxbind  Injection, Boehringer Ingelheim Pharmaceuticals, Inc.) for the treatment of patients treated with dabigatran (Pradaxa) when reversal of the anticoagulant effects of dabigatran is needed for emergency surgery/urgent procedures, or in life-threatening or uncontrolled bleeding.

Making reversal agents commercially available not only will give emergency physicians a much-needed therapy but it also might appease patients and physicians who are on the fence about taking NOACs. “To the FDA’s credit, a good deal of what they said in terms of prioritization has to do with this perception thing,” notes Peter R. Kowey, MD, a cardiologist at the Lankenau Heart Institute in Philadelphia and a member of the Cardiac Safety Research Consortium’s executive committee. In 2014, the FDA and the consortium co-sponsored a think tank on NOAC antidotes. “They understand very well that more optimal uptake of the new anticoagulants, which they perceive to be a good thing, will occur if we get these reversal agents available.”

The potential availability of reversal agents also raises flags about overutilization of what likely will be an expensive drug. Payers who attended the consortium aired concerns about overutilization, Kowey says. In an editorial that accompanied RE-VERSE AD, Kenneth A. Bauer, MD, a hematologist at Beth Israel Deaconess Medical Center in Boston, pointed out that about 20 percent of patients in the study had only trace amounts of dabigatran in their systems at baseline. They received but ultimately did not need an antidote.

“There is a potential enormous opportunity to overuse these products,” Bauer says. He questions whether the logistic challenges of treating patients with urgent intracranial bleeding, for instance, can be overcome. “You need to get them to the facility, diagnosed with their head bleed, recognize they are on an anticoagulant, have the antidote available and get it to them quickly. If time is lost with someone who has a head bleed, whether or not you can make a difference in their outcomes, it becomes a very tall order.”

Pollack counters that physicians in RE-VERSE AD provided swift care under the trial protocol, which called for an extra blood draw that wouldn’t be required in real-world practice. He added that in an emergency setting, a physician makes reversal of an anticoagulated patient a priority, which then allows him or her to focus on the injury. 

“That is not unusual behavior,” Pollack says. “I don’t wait for an [international normalized ratio] in a patient with a head bleed on warfarin. I reverse it. Many situations are so dire. It is great to say, with the benefit of retrospect, that maybe we could have waited or maybe we didn’t need it, but that is not the way we have to work in the emergency department.”

Thinking ahead

Emergency physicians most likely will need to turn to reversal agents only occasionally. In the RE-LY trial (Randomized Evaluation of Long-term Anticoagulation Therapy), patients on lower- and higher-dose dabigatran had an annual rate of major bleeding of 2.71 percent and 3.11 percent vs. 3.36 percent with warfarin. That in itself poses a quandary, Kowey notes.

“Is every single little, tiny hospital in the country going to have to have these [reversal agents] around?” he asks. “They are very expensive and they will have a shelf life.”

His hospital already has begun thinking about the best pathway for use, trying to balance the need for speed with gate-keeping to ensure reversal agents go to only appropriate patients. Once physicians become familiar with antidotes’ use, they may be inclined to stretch the boundaries.

“Our surgeons have already begun to chatter about this issue of ‘I want to do a gallbladder and it is semi-urgent but not really urgent,’” he says. ‘This person is on a NOAC but I am going to have to wait 24 to 48 hours. Could I use the reversal agent?’ When it first comes out, the answer probably will be no, not if it is not urgent. But as time goes by, you could easily see there could be indication creep.”

Unless the pool of approved patients expands to other indications, the pharmaceutical companies behind the antidotes likely won’t make profits. Instead, physicians observe, alleviating patients’ and physicians’ worries about life-threatening bleeds with NOACs may lead to an increase in prescriptions and more market share for NOAC makers.

Whether profits or philanthropy or both drive the push to get reversal agents in the hands of physicians may not matter to cardiologists if it helps to increase the use of stroke preventive therapies. One registry analysis found that 30 percent of patients with atrial fibrillation who were discharged from a hospital after an ischemic stroke were not prescribed an oral anticoagulant (Stroke online Nov. 6, 2014). Another claims-based study reported that overall, between 19 percent and 51 percent of patients with atrial fibrillation who were at high risk of stroke received anticoagulation therapy (BMC Health Service Research 2014;14:329).  

“I tell people all the time, ‘I don’t care what kind of anticoagulant you use,’” Kowey says. “If people like to use warfarin, then that is perfectly fine with me. The priority is to get people properly anticoagulated.”