Reversal agents for the direct oral anticoagulants

New class more likely to be used for reassurance than treatment, experts say.

A new drug class—reversal agents for direct oral anticoagulants—may turn out to provide the most benefit for patients who never take the medications.

Idarucizumab (Praxbind), which the FDA approved last October, is indicated for patients taking dabigatran who develop an emergency need to reverse its blood-thinning effects, such as urgent surgery or a life-threatening bleeding episode. Similar antidotes are in the works for other direct oral anticoagulants.

Photo by Thinkstock
Photo by Thinkstock

Only a small number of patients will meet that indication, however, and it's not certain how much impact the drug will have on those who do, according to experts. “I'm not sure that it's going to be easy to demonstrate that these antidotes necessarily save anybody's life,” said Peter Kowey, MD, FACP, a cardiologist and professor of medicine and clinical pharmacology at Jefferson Medical College in Philadelphia.

Instead, the new medications may have more of an impact on patients who haven't yet been prescribed a direct oral anticoagulant.

“There might be as many as 35% of atrial fibrillation patients who would be in a category that would seem to benefit from anticoagulation and who are not getting anticoagulation, and some fraction of that may be due to . . . not wanting to try the novel anticoagulant because of the notion that it can't be reversed,” said Daniel E. Singer, MD, a professor of medicine at Harvard Medical School in Boston who has researched direct oral anticoagulants. “It's an awkward discussion. The patient says, ‘I looked on the Web and I talked to people and they said if you bleed, you can't stop it.’”

Primary care physicians will likely handle most of those now less-awkward conversations, experts said, but the decisions about when to use reversal agents will occur in the hospital. Hospitalists will play a role in ensuring appropriate application of the new drug (or drugs, in the near future), experts said.

Drug effects

Even experts who doubt idarucizumab's life-saving potential are convinced of its effectiveness. FDA approval was based on a study of 123 patients who had uncontrolled bleeding or required emergency surgery, and lab tests showed that the anticoagulant effect of dabigatran was fully reversed in 89% of patients within 4 hours of receiving the reversal agent.

“It certainly reverses the anticoagulant effect of dabigatran promptly, as measured by various coagulation tests,” said Tracy Minichiello, MD, a professor of medicine at University of California San Francisco and chief of the anticoagulation and thrombosis services at the San Francisco VA Hospital. “But we don't have a good sense of the clinical impact of this intervention yet.”

One fact limiting the potential impact of reversal agents is the safety of direct oral anticoagulants themselves, which from trial data appears to be greater than warfarin. “The bleeding outcomes in terms of fatal events and intracranial events were better on the novel agents, even though they don't have a reversal agent,” said Dr. Singer.

Among patients who do have bleeding on the drugs, it might be hard for idarucizumab to show a dramatic effect because life-or-death outcomes are hard to change in such cases, experts said. “Probably we can anticipate it might shorten the GI bleed, but people generally don't die of GI bleeds,” said Dr. Singer.

At the other end of the severity spectrum, “when patients come in with intracranial hemorrhage, their mortality is very high no matter what you do,” said Dr. Kowey. The drug could help some patients with extracranial bleeding, “the very rare case where they're on dabigatran and you're almost at the edge of dialyzing them, which is kind of the last-ditch thing that you can do,” said Dr. Singer.

The drug could prove most beneficial for surgery patients, experts predicted. “For example, somebody comes in with a life-threatening problem that needs to go to surgery and the surgeon is hesitating because of the use of the anticoagulant. These agents will certainly make that easier and lower the time that it takes to get into the operating room, and maybe that will save some lives,” Dr. Kowey said.

However, surgery also offers the most likely area for overuse of the reversal agents. “Define ‘life-threatening,’ define ‘emergency.’ There is always going to be a kind of gray area, where folks might use the agents without that kind of very restricted indication,” said Dr. Singer.

Gray area expertise

Dr. Minichiello can already imagine the consults that will arise from uncertainty about the drug's indication. “They present for their planned surgery and they're in the preop holding area and they say, ‘Oh, you know what, I forgot, I took my dabigatran yesterday or last night.’ I would imagine I'm going to get the call, ‘Can I just give this guy idarucizumab and take him to the OR?’”

If there's no medical risk to delaying surgery, the answer to that question should be no, experts advised. “In most cases, simply waiting for the drug to wear off would be the recommended procedure,” said Jack Ansell, MD, MACP, a hematologist and professor of medicine at New York University.

In addition to deciding which conditions merit reversal, physicians may also face difficulty knowing which patients will actually benefit. “It's not like a warfarin patient where you get an INR, and then you know where you are,” said Dr. Singer. “In the absence of good, widespread measures of how much drug is on board, you're not going to know necessarily when somebody is bleeding that they have a lot of drug on board.”

A good history will be necessary to know exactly how long it's been since a patient took the last dose of anticoagulant and estimate how much effect it might still be having. Another challenge may be finding out which drug a patient is on, if, for example, he offers only, “I'm on that new agent,” Dr. Singer said.

Idarucizumab is specific to dabigatran, and although another reversal agent under development is expected to work for both rivaroxaban and apixaban, it is likely to be used at different doses to reverse the drugs, according to Dr. Singer.

Obviously, clinicians will want to avoid using a reversal agent in patients without the relevant anticoagulant in their bloodstream, but there are reasons to be cautious in use of the reversal agents generally, the experts said.

Not a lot of data exist yet on the risks of idarucizumab, but 1 obvious side effect is clots. “Any reversal of anticoagulation is going to be associated with an increased risk of thromboembolism, so use of this agent will need to be limited to those patients in whom the benefit is thought to exceed the potential risk,” said Dr. Minichiello.

Another is the cost. The wholesale price has been reported to be $3,500. Of course, given that it's a single dose, the drug still might seem cost-effective in situations where it's not appropriate to use it, such as a non-urgent, scheduled surgery.

Hospitals will probably take steps to ensure appropriate use, the experts predicted. “What's going to be very, very important at individual institutions is that there needs to be oversight. Just putting this stuff in the pharmacy and letting people use it willy-nilly is not a really good idea for a lot of reasons,” said Dr. Kowey.

Regulators will also be keeping an eye on this issue. “The FDA is imposing registries on these drugs, because they're being approved on a fast-track approval process,” Dr. Kowey said. “The FDA would like to continue to collect information postapproval to help them understand how the drugs are being used and how well they're being used and what's happening with the patients.”

Chances are what happens to patients treated with reversal agents won't be dramatic, but the availability of idarucizumab and similar drugs could improve care, both directly and indirectly, the experts concluded. “I think it's going to be a small number of instances where it's really going to be crucial and really make a difference in outcomes, but it's very reassuring to know that it's there,” said Dr. Singer.