Recently, it seems like more and more of our patients are on anticoagulation, with direct acting oral anticoagulants (DOACs) being used more often. DOACs have significant advantages over the older anticoagulants, and they are associated with lower risks of bleeding. However, bleeding episodes do occur, and clinicians need to have tools to deal with them. Fortunately, new reversal agents are available for DOACs.

Tadd Hellwig, PharmD, BCPS, from South Dakota State University, College of Pharmacy and Allied Health Professions, presented a session at the 2019 Directions in Pharmacy conference. Dr. Hellwig reported that approximately 70% of all new prescriptions for anticoagulants are DOACs, making this topic timely and important.

Although bleeding rates are low among patients treated with DOACs, they do occur. Approximately 3.3% of patients who have atrial fibrillation experience a DOAC-related major bleeding episode. Every hospitalization averages 5.3 days in length at a cost of more than ,000 each.

Dr. Hellwig covered risk factors for DOAC-associated bleeding, which include conditions covered by the acronym HEMORR2 HAGES (hepatic or renal disease, ethanol abuse, malignancy, older age, reduced platelets, re-bleeding, hypertension, anemia, genetic factors, excessive fall risk, stroke). He emphasized that one of the best ways to prevent inadvertent bleeding is to ensure that the DOAC dose prescribed matches the patient’s indication.

If bleeding occurs, discontinuing a DOAC can sometimes be sufficient to stop the bleeding. All DOAC-associated bleeds need local management, either surgical or mechanical in nature. Some patients will need volume resuscitation, red blood cell or platelet transfusions, and other supportive measures. If the DOAC that causes the bleed is dabigatran, hemodialysis may be indicated.

Dr. Hellwig covered various assays that can help interpret a patient’s condition. Two assays provide the most assistance: ecarin clotting time (ECT) and anti-Xa (calibrated to the specific DOAC agent).

Fortunately, researchers have been able to develop 2 reversal agents for DOAC-induced bleeding. Idarucizumab is a monoclonal antibody fragment that binds to dabigatran with 350 times the affinity of dabigatran to thrombin. Pivotal studies supported its approval, and found that the medium maximum reversal occurred within 4 hours of administering idarucizumab in patients who had experienced bleeds. A full 67.7% of patients stopped bleeding at 24 hours. Some patients may require an additional dose.

Pharmacists need to pay special attention to coagulation assays and suggest re-dosing idarucizumab, if necessary. Pharmacists should also monitor renal function because acute kidney insufficiency extends dabigatran’s half-life. Pharmacists must ensure that prescribers have stopped all other antiplatelet drugs, nonsteroidal anti-inflammatory drugs, and anticoagulants.

Andexanet alfa is a recombinant modified FXa protein that acts as a decoy protein. DOACs then bind to andexanet alfa instead of natural FXa. Andexanet alfa received accelerated approval for patients treated with rivaroxaban or apixaban when anticoagulation reversal is needed due to life-threatening or uncontrolled bleeding. Its labeling includes a boxed warning for life-threatening adverse effects, including arterial and venous thromboembolic events, ischemic events (including myocardial infarction and ischemic stroke), cardiac arrest, and sudden death. It is important to monitor for thromboembolic events and reinitiate anticoagulation as soon as medically appropriate. Pharmacists should also note that multiple vials of the biologic will be needed, and they should alert the treatment team that reconstitution takes time.

Dr. Hellwig mentioned ciraparantag, a water-soluble molecule designed as a specific reversal agent targeting DOACs and heparins. This agent, currently awaiting phase 3 trials, creates a strong physical, noncovalent bond.

Anticoagulation has advanced tremendously in the past decade, and we look forward to great strides in the upcoming years.