Achieving hemostasis vital after major bleeding from direct oral anticoagulants
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In a meta-analysis, researchers observed that severe direct oral anticoagulant-related bleeding death was relatively frequent, despite treatment with reversal agents, and that achieving hemostasis greatly improved survival.
According to data published in the Journal of the American College of Cardiology, failure to achieve effective hemostasis in patients experiencing a major bleeding event was associated with a more than threefold increased risk for mortality.
“Approximately 1% to 2% of the population in Western countries is on long-term anticoagulation. Direct oral anticoagulants (DOACs) have overtaken vitamin K antagonists in market share, currently being prescribed in 68% to 79% of new anticoagulated patients in the European Union and the United States,” Antonio Gómez-Outes, MD, PhD, MSc, of the division of pharmacology and clinical drug evaluation at the Spanish Agency for Medicines and Medical Devices in Madrid, and colleagues wrote. “Despite being safer than vitamin K antagonists, the introduction of DOACs has been paradoxically associated with an increase in the number of urgent admissions for bleeding complications in some countries, probably due to the increase in the number of candidates for anticoagulation.
“We conducted a systematic review and meta-analysis to investigate the clinical outcomes associated with the use of nonspecific reversal of DOAC with 4-factor prothrombin complex concentrates and specific reversal of DOAC with idarucizumab (for dabigatran) or andexanet (for oral direct Factor Xa inhibitors) in patients with severe or uncontrolled major bleeding,” the researchers wrote.
For this meta-analysis, researchers assessed 60 studies including 4,735 patients (mean age, 77 years; 57% men; 55% with intracranial hemorrhage) with severe direct oral anticoagulant-related bleeding treated with the following reversal agents: 4-factor prothrombin complex concentrates for any DOAC, idarucizumab (Praxbind, Boehringer Ingelheim) for dabigatran (Pradaxa, Boehringer Ingelheim) or andexanet (Andexxa, Portola). Outcomes of interest included mortality rates, thromboembolic events and hemostatic efficacy.
Effect on major bleeding
Researchers observed that mortality occurred at a rate of 17.7% (95% CI, 15.1-20.4) among patients who experienced major bleeding. Mortality was higher among patients with intracranial bleedings (20.2%) compared with those with extracranial hemorrhages (15.4%).
According to the study, the rate of thromboembolism was 4.6% (95% CI, 3.3-6) among patients who experienced major bleeding and was especially high among those treated with andexanet (10.7%) compared with 4-factor prothrombin complex concentrates (4.3%) and idarucizumab (3.8%).
According to the study, the rate of effective hemostasis was 78.5% (95% CI, 75.1-81.8) and was similar regardless of the reversal agent administered.
Moreover, risk for death was more than three times greater if effective hemostasis was not achieved (RR = 3.63; 95% CI, 2.56-5.16).
According to the researchers, results of this meta-analysis were robust regardless of the type of study or the hemostatic scale used.
“The arrival of DOAC-specific antidotes meets an unmet need and will increase confidence in the safe use of the DOAC. Some recent guidelines favor the use of specific reversal agents based on expert consensus and surrogate evidence from biomarkers,” the researchers wrote. “However, 4-factor prothrombin complex concentrates may be associated to similar rates of effective hemostasis than specific antidotes and low rates of thromboembolism, and therefore could be a valuable treatment when a specific antidote is not available.”
‘Another tool in our armamentarium’
In a related editorial, Christopher B. Granger, MD, and Sean D. Pokorney, MD, MBA, of the Duke Clinical Research Institute and Duke University Medical Center, addressed the importance of the administration of reversal agents for major bleeding as well as areas for future research.
“The morbidity and mortality from ischemic strokes as a result of undertreatment of stroke prevention in patients with AF continue to dwarf the bleeding-related mortality among patients with AF and on DOACs, and thus the No. 1 priority is to treat nearly all patients with AF with a DOAC,” Granger and Pokorney wrote. “The availability of reversal agents for DOACs should provide reassurance, with another tool in our armamentarium, to providers to prescribe OACs for stroke prevention. The relatively poor outcomes among patients with life-threatening bleeding, even with the use of reversal agents, calls for additional research to refine major bleeding management algorithms and to test them in implementation programs.”
Reference:
Granger CB, et al. J Am Coll Cardiol. 2021;doi:10.1016/j.jacc.2021.04.053.
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