Reversal Agents Have Quieted Concerns, Increased Usage

Direct acting oral anticoagulants have a lower risk of major bleeding than warfarin and clinicians have had options for controlling major bleeds for several years. That’s not the message patients have heard, though.

“Patients have been pretty strongly affected by negative direct-to-consumer advertising about bleeding and that’s created a barrier for many veterans who would be good candidates for DOACs,” said Tracy Minichiello, MD, chief of the anticoagulation and thrombosis services in the division of hematology at the San Francisco VAMC and clinical professor of medicine at the University of California San Francisco.

“There were concerns also for physicians. They had a reversal agent for warfarin. It’s comforting knowing that there’s something available in the small chance that you need to reverse” the action of an anticoagulant, she told U.S. Medicine.

Now, physicians and patients have specific reversal agents for several DOACs. Idarucizumab, a reversal agent for dabigatran, received U.S. Food and Drug approval in 2015. Derived from humanized monoclonal antibody segments, the drug has a 350 times stronger affinity for dabigatran than dabigatran has for thrombin, allowing it to rapidly neutralize the anticoagulant without interrupting platelet aggregation by linking with other thrombin-associated factors or proteins.

Andexanet alfa, a novel modified recombinant human factor Xa, gained approval as a reversal agent for apixaban and rivaroxaban in 2018. Studies are evaluating andexanet alfa in the other direct factor Xa inhibitors on the market, edoxaban and betrixaban, as well as for indirect Xa inhibitors such as low molecular weight heparin and fondaparinux.

A third agent, ciraparantag acetate, is in development. A small synthetic water-soluble molecule designed to bind to both direct factor Xa and IIa inhibitors as well as indirect factor Xa inhibitors and unfractionated heparins, ciraparantag has demonstrated effective reversal of edoxaban, LMWH, apixaban and rivaroxaban in small studies of healthy volunteers.

“Availability of reversal agents has made a difference for patients with concerns raised by ‘call us if you’ve had a bleed’ advertisements soliciting patients for legal cases,” Minichiello said. “We’ve literally had patients say, ‘We’re waiting for approval of that medication,’” before they would start on a DOAC.

Access to Idarucizumab may have had some effect already. “People think differently about dabigatran, but I don’t know if there’s been a big swing nationally,” she added. “Other agents have a strong hold for atrial fibrillation in particular as they have a better safety profile for select patients. Having the next reversal agent will have an impact because so many patients are on the anti-Xa agents.”

While andexanet alfa gained approval in May 2018, its distribution was initially limited to 40 hospitals. The FDA permitted broad distribution in January.

Both reversal agents are available in the VA, which has created new national criteria for use for idarucizumab and andexanet alfa to guide individual hospitals. “If you’re standing next to a patient with a life-threatening bleed and know the reversal agent works, it provides more confidence. Guidance provides expert opinion or extrapolation when you don’t the data or randomized clinical trials to help you and you really need to know how to move forward,” Minichiello said.

Before the reversal agents became available, guidelines recommended reversing life-threatening bleeds in patients on factor Xa inhibitors with non-specific prohemostatic agents such as prothrombin complex concentrate and activated PCC. “We don’t have studies yet comparing andexanet alfa to aPCC or four-factor PCC, so we don’t know whether it is as safe or is associated with more thrombosis,” Minichiello cautioned.

Still, a tested, approved reversal agent is reassuring. “These agents have a much lower bleeding risk and much lower intracranial hemorrhage risk, so we have to worry about bleeds less often than with warfarin, but having a specific reversal agent does provide comfort,” she said.

That increased comfort may translate into greater use of the DOACs. “We—everyone in the country—do still undertreat atrial fibrillation. They fear the bleed more than the clot. I do hope that use increases as these medications have a better safety profile than warfarin,” Minichiello explained.

Greater use could lead to better care, she added. “At the VA, we don’t have the hurdle of price, so I hope we will use DOACs appropriately to reduce risk in more patients,” with concerns about reversal addressed. Prior to the agents coming on the market, “many physicians have chosen to use aspirin, but it is not particularly effective in preventing stroke in patients with atrial fibrillation.”

The AVERROES trial demonstrated apixaban’s superiority to aspirin in reducing the risk of stroke in patients with atrial fibrillation without increasing the risk of bleeding. The ARISTOTLE trial found apixaban was better than warfarin for stroke prevention and had a lower risk of bleeding and all-cause mortality.1,2

Some DOACs still do not have specific reversal agents. “Andexanet alfa received approval for only apixaban and rivaroxaban, but all four anti-Xa anticoagulants work the same way,” Minichiello noted. “The Anticoagulation Forum published reversal guidance suggesting that off label use of andexanet alfa for edoxaban and betrixaban, but that’s just one guideline, not the standard of care or a treatment that’s FDA approved.”

When to Use?

DOACs have a much shorter half-life than warfarin’s 35 hours, so clinicians can manage many bleeds with supportive measures. Elimination half-life for the DOACs ranges from about six hours to 17 hours in patients with normal renal function.3

In an emergency situation, though, it may be difficult to tell whether a patient is still experiencing an anticoagulation effect from the drugs as conventional coagulation testing lacks the sensitivity and specificity necessary and thresholds have not been established for all DOACs below which an effect could be excluded. Thrombin time, prothrombin time or activated partial thromboplastin time may provide a general estimate of altered hemostasis when time is of the essence.4

The Anticoagulation Forum recommends “administration of a reversal agent only if bleeding is life-threatening, into a critical organ or is not controlled with maximal supportive measures and there is demonstration or reasonable expectation that the patient has clinically relevant plasma DOAC levels.”

“You don’t want to use a reversal agent if you don’t have to because it may have adverse effects, but if a patient is bleeding into the spine or pericardium or not stable, you may need to consider using one,” Minichiello advised.

For elective surgery, stopping anticoagulant therapy for two or three days will usually suffice, though patients with impaired kidney function may need longer to clear the medication. For unplanned procedures, “if you can wait, that’s ideal because the anticoagulation effect will go away. If you can’t wait and there is a clinically significant amount of anticoagulant there, you may want to use a reversal agent,” Minichiello said.

Idarucizumab is approved for presurgical use, but andexanet alfa is not, she noted. While the Anticoagulation Forum suggests that andexanet alfa could be used prior to urgent surgery, Minichiello clarified that the Forum is providing “guidance where there is no data or FDA indication. Some may opt for four-factor PCC in that situation.”

  1. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in Patients with Atrial Fibrillation. N Engl J Med. 2011 Mar 3; 364(9):806-17.
  2. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med. 2011 Sept 15; 365:981-992.
  3. Piran S, Schulman S. Treatment of bleeding complications in patients on anticoagulant therapy. Blood. 2019; 133(5):425–35.
  4. Kuramatsu JB, Sembill JA, Huttner HB. Reversal of oral anticoagulation in patients with acute intracerebral hemorrhage. Crit Care. 2019 June 6; 23:206.