DOACs: Clear benefits, yet questions remain

July 12, 2019

Though direct oral anticoagulants (DOACs) offer advantages to patients as well as medical professionals, they also present challenges at the time of a traumatic injury due to the potential need for reversal. In addition, uncertainties remain for their use in some patient groups.

Advancements over medications such as warfarin, the standard anticoagulant for many years, with factor Xa inhibitors such as apixaban, rivaroxaban or edoxaban or with direct thrombin inhibitor dabigatran include a similar-to-reduced risk of bleeding overall and no routine monitoring requirement.

"Patients may live out where they don't have access to health care or a lab, so these therapies can be life changing for these patients," says Andrea M. Nei, Pharm.D., R.Ph., a pharmacist at Mayo Clinic's campus in Rochester, Minnesota, noting that with warfarin, patients have needed to make multiple visits at first to get the right dosage.

Concerns with direct oral anticoagulants

Despite the benefits, Nei says medical professionals have some concerns with use of DOACs, such as appropriate dosing and uncertainties with DOAC reversal agents and protocols.

Appropriate dosing

For certain populations, such as patients who are morbidly obese or have undergone gastric bypass, optimal DOAC dosing is still somewhat unclear. It remains uncertain whether these patients need higher doses, whether Food and Drug Administration (FDA)-approved dosing can be extrapolated to them and how to monitor these patients.

Uncertainties with DOAC reversal agents and protocols

Unlike warfarin that has reversal agents available, including vitamin K, prothrombin complex concentrates or fresh frozen plasma, no such agents existed at first for the newer anticoagulants. Now, new reversal agents have been introduced, but with some controversy, says Nei.

The FDA has approved coagulation factor Xa (recombinant), inactivated-zhzo as well as idarucizumab injection under expedited review, thus supported by data from prospective cohort studies rather than randomized clinical trials. A longer term clinical trial with inactivated-zhzo is now underway, but results from the study will not be available until 2020. Debate also has arisen regarding the cost of coagulation factor Xa (recombinant), inactivated-zhzo, which can run $25 to $50,000 for a single dose.

Though reversal is indicated for some patients prescribed DOACs who face traumatic injury, the approach remains unclear due to lack of significant evidence in this patient population, says Nei, especially in the following aspects of reversal agent usage:

  • Whether these agents cause an increase in thrombotic events after administration
  • How some of the few existing studies addressing DOAC reversal apply to the trauma population, such as a coagulation factor Xa (recombinant), inactivated-zhzo study excluding patients undergoing surgery within twelve hours, as many trauma patients are sent to the operating room in this time frame
  • If clinical benefit warrants the significant cost of some reversal agents

Nei points out that many Mayo Clinic staff members have questions about DOAC reversal therapy for trauma patients and hesitate to routinely use some of the new reversal agents. In order to make the best possible decisions for patients while further studies are ongoing, she says that Mayo Clinic Trauma Center hosts regular journal clubs at which a multidisciplinary group discusses new publications.

Examples of literature that could be discussed at these meetings include "Full Study Report of Andexanet Alfa for Bleeding Associated With Factor Xa Inhibitors," published in April 2019 in the New England Journal of Medicine, and "Reversal of Direct Oral Anticoagulants: Guidance From the Anticoagulation Forum," a critical review article published in the American Journal of Hematology in March 2019.

What trauma professionals can do prior to transfer

At low-volume trauma centers and critical access hospitals, there are a number of measures trauma personnel can take to prepare for patients taking DOACs who present with traumatic injury, says Nei. She recommends these steps:

Know your stock.

Hospital staff members treating trauma patients should be keenly aware of their reversal stock, whether that is prothrombin complex concentrate human injection or fresh frozen plasma.

"The biggest thing is what's available for you at your center for DOAC reversal," says Nei. "Unfortunately, there have been shortages in the last couple of years, so it's important to know what you have on hand."

Determine your reversal plan.

Beyond the initial resuscitation of the patient, starting in July 2019, The Joint Commission is requiring all hospitals, including critical access hospitals, to have anticoagulant therapy safety measures in place, including a number of requirements for reversal management. Bearing in mind what is feasible at your facility and what medications are available, a multidisciplinary team, including pharmacy, needs to create a plan, even if your facility does not frequently see patients requiring such reversals.

Awareness of The Joint Commission consensus guidelines pertaining to anticoagulant reversal in patients undergoing trauma also is important in formulating a plan, says Nei, as the guidelines do not suggest routine reversal in all patients, particularly those who aren't bleeding. Rather, consensus guidelines encourage providers to carefully consider whether reversal is needed on an individual basis.

Additionally, knowing what labs your facility can draw upon — those that would be rapidly available to conduct such as thromboelastogram, anti-Xa level or prothrombin time — is crucial, as prolongation of coagulopathy testing may assist in identifying resuscitative agents.

Establish communication with your receiving hospital.

Ensuring the accepting physician is aware of the injured patient's DOAC prescription and the status of reversal agent administration is critical upon transfer. If the medical center where the patient initially presents does not stock the necessary reversal agent to treat immediately, alert the physician at the receiving hospital. As some of these medications can take time to prepare, such as bringing them to room temperature before administration, advance notice helps give the pharmacy at the receiving facility sufficient time to be ready for the patient's needs.

"These are challenging products to get to the bedside," says Nei. "It's really challenging for institutions trying to come up with a plan. But achievement of hemostasis is critical. I'm hoping as more studies are done, we will have more of an idea of how to manage these patients."

For more information

Connolly SJ, et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. New England Journal of Medicine. 2016;375:1131.

Connolly SJ, et al. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. New England Journal of Medicine. 2019;380:1326.

Cuker A, et al. Reversal of direct oral anticoagulants: Guidance from the Anticoagulation Forum. American Journal of Hematology. 2019;94:697.

R3 report issue 19: National patient safety goal for anticoagulant therapy. The Joint Commission.