Anticoagulation Reversal for DOAC-related Intracranial Hemorrhage

Volume 4, Issue 4

Direct-acting oral anticoagulants (DOAC) have emerged as the standard of care for patients requiring long-term anticoagulation. While these agents all have commercially available antidotes, hesitation about the cost of these agents has led clinicians to prescribe nonspecific therapies (ie, PCCs) in the setting of life-threatening DOAC-related hemorrhage (ie, intracranial hemorrhage). In this week’s issue of Talking Therapeutics, we discuss the findings of a recently published meta-analysis that explored outcomes of patients with intracranial hemorrhage (ICH) managed with various DOAC reversal agents. 

Point 1: Mortality remains high with ICH on DOAC therapy

Investigators of the meta-analysis evaluated 4735 patients from 60 studies with severe DOAC-related bleeding who were treated with 4-factor prothrombin complex concentrates (n=2688), idarucizumab (n=1111), or andexanet (n=936). Mortality rate was 17.7% (95% confidence interval [CI]: 15.1% to 20.4%). While this is better than the 50% mortality rate reported in clinical trials a decade ago, it still signals that room for improvement exists. 

Effective hemostasis was achieved in 78.5% of patients regardless of the reversal agent considered, whereas failure to achieve hemostasis was associated with more than a threefold higher relative risk for death (RR, 3.63; 95% CI, 2.56 to 5.16). Rates of thromboembolism were 4.6% overall, highest among those who received andexanet alpha (although this finding was driven entirely by the ANNEXA-4 trial). Lastly, the rebleeding rate was 13.2% (95% CI: 5.5% to 23.1%) and 78% of rebleeds occurred after resumption of anticoagulation.

Point 2: More questions than answers remain

This meta-analysis confirms that patients with severe DOAC-associated bleeding are at high risk for complications (including death) even when anticoagulant reversal and hemostasis are achieved. Although the size of the meta-analysis the largest study to data to tackle this topic, the findings are limited in that 47 of the 60 studies were retrospective, only 2 had control groups, and 45 had a high risk for bias. 

Furthermore, there was also poor reporting of key clinical data, such as post-bleeding anticoagulation management, and a limitation of the mortality analysis is that it was based in selected patients with effective hemostasis assessed within 48 hours, which may not capture early deaths. 

The bottom line is that head-to-head trials of DOAC reversal agents are needed. And fortunately, an ongoing randomized trial of andexanet alpha vs usual care in patients with intracranial bleeding will provide important safety and efficacy data (NCT03661528).

Dr Jennings is currently an Associate Professor of Pharmacy at Long Island University and the clinical pharmacist for the Heart Transplant and LVAD teams at New York- Presbyterian Hospital Columbia University Irving Medical Center.  He is an active researcher in his field, and he has published over 120 peer-reviewed abstracts and manuscripts, primarily focusing on the pharmacotherapy of patients under mechanical circulatory support. As a recognized expert in this area, he has been invited to speak at numerous national and international venues, including meetings in France, Saudia Arabia, and India. Finally, Dr Jennings has been active in professional organizations throughout his career. He is a fellow of the American College of Clinical Pharmacy, the American College of Cardiology, the Heart Failure Society of America, and the American Heart Association.  

Reference:
Gómez-Outes A, Alcubilla P, Calvo-Rojas G, et al. Meta-Analysis of Reversal Agents for Severe Bleeding Associated With Direct Oral Anticoagulants. J Am Coll Cardiol. 2021;77(24):2987-3001. doi:10.1016/j.jacc.2021.04.061

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