Clinical

How to manage bleeding in patients taking direct oral anticoagulants (DOACs)


 

There are no FDA-approved antidotes for the factor Xa inhibitors. One promising agent is andexanet-alfa, an inactivated form of factor Xa that irreversibly binds Xa inhibitors. The ongoing, open-label ANNEXA-4 trial12 reported a decrease in anti–factor Xa activity of ~90% after bolus administration of the drug followed by 2-hour infusion in 67 patients with life-threatening bleeding, with clinical hemostasis achieved in 79% in patients by 12 hours. However, thrombotic events occurred in 18% of the patients at 1 month. Additional safety and efficacy data, along with plans for postmarket surveillance, will be needed prior to approval for clinical use.

Are there other options to obtain hemostasis?

Clotting factor products, specifically fresh frozen plasma (FFP) and prothrombin complex concentrates (PCCs), are often used to attempt to reverse anticoagulation from DOACs. While FFP alone has no evidence to support its use in reversing the effect of DOACs, PCCs might reverse anticoagulation for both Xa inhibitors and direct thrombin inhibitors.13 Some experts recommend unactivated PCC over activated PCC because of a theoretically increased thrombotic risk of activated PCC.14 For patients taking Xa inhibitors or dabigatran (if idarucizumab is unavailable) with life-threatening bleeding, PCC should be used in an attempt to reverse the bleeding.

Another strategy to promote hemostasis in bleeding patients taking DOACs is to use antifibrinolytics. Effective for control of bleeding in trauma and surgical patients, tranexamic acid has not been widely studied in nonsurgical bleeding, much less DOAC-related nonsurgical bleeding. A 2014 Cochrane review of a small number of trials suggested a possible mortality benefit from its use in upper GI bleeding, but the quality of included trials was poor.15 The ongoing HALT-IT trial, enrolling 8,000 patients with gastrointestinal bleeding, aims to clarify the mortality benefit of tranexamic acid.16 Despite effectively promoting hemostasis in many populations of bleeding patients, tranexamic acid carries no discernible thrombotic risk.17,18 By preventing clot degradation through a downstream mechanism at low cost and risk, antifibrinolytics are a practical adjunctive therapy to control major bleeding in patients on DOACs.

Can charcoal or dialysis reduce the systemic concentration of DOACs?

In addition to discontinuing the DOAC, both charcoal and dialysis can reduce the systemic concentration of DOACs. If the ingestion was recent, oral activated charcoal can reduce the systemic absorption of DOACs. To date there are no data on the efficacy of charcoal in bleeding patients taking DOACs. However, in two recent trials, administration of a single dose of charcoal in healthy patients led to significantly decreased area under concentration-time curves (AUC) when given at 6 and 8 hours after ingestion of a therapeutic dose of apixaban and rivaroxaban, respectively.19,20 While further studies are needed to confirm its clinical benefit, charcoal is recommended for major bleeding when given within 2 hours of ingestion of a DOAC and may be useful within 8 hours.

Unlike charcoal, which can be used for patients on Xa inhibitors or dabigatran, hemodialysis is only effective for reducing serum concentrations of dabigatran because of its low plasma protein binding (~35%). A review of 35 patients (10 with normal renal function) with severe bleeding showed significant reductions in coagulation tests (aPTT, PT, TT) and dabigatran levels after hemodialysis.21 For severe bleeding episodes particularly in patients with impaired renal function, providers should consider the use of continuous renal replacement therapy until clinical hemostasis is achieved.

What is the expert’s opinion?

We asked one of our hematologists with expertise in DOACs for his opinion on this topic. Most patients with DOAC-associated bleeding can be managed with supportive care because of the short half-life of these agents in patients with reasonably preserved renal function. The main scenario for escalating therapy to PCC or idarucizumab is life-threatening bleeding, such as intracranial hemorrhage and gastrointestinal hemorrhage with hemodynamic instability. The threshold for use of idarucizumab for patients taking dabigatran with bleeding should be lower than PCCs because there is better evidence for clinical benefit with less risk.

Developing reversal agents continues to be costly, requiring extensive preclinical work and clinical trials that are difficult to do. Assuming that reversal agents become more affordable in the longer term, and safety profiles are better established, clinicians may eventually have a lower threshold for their use in a wider variety of bleeding episodes. Lastly, adverse outcomes often occur, not during the acute bleeding episode, but several weeks later in patients whose providers delay restarting anticoagulation. Thus, it is important to resume anticoagulant therapy as soon as it is safe to do so.

Back to the case

Our patient was given a 50-g suspension of oral activated charcoal, along with two doses of 1 g intravenous tranexamic acid 8 hours apart. He was typed and crossed for blood, and ultimately received 1 unit of packed red blood cells before stabilizing without other measures. His colonoscopy subsequently revealed a diverticular bleed with a visible vessel that was coagulated. He was discharged 2 days later after remaining clinically stable after colonoscopy.

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