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Death was often the result of severe bleeding due to direct oral anticoagulant (DOAC) use despite the use of a reversal agent, according to a meta-analysis.

The incidence of mortality reached 17.7% across 60 studies of people who had been treated with 4-factor prothrombin complex concentrates (4PCC; n=2,688), idarucizumab (Praxbind; n=1,111), or andexanet (Andexxa; n=936) for reversal of severe DOAC-associated bleeding.

Death rates were heterogeneous across studies, yet not substantially different by reversal agent, reported a group led by Antonio Gómez-Outes, MD, PhD, of Agencia Española de Medicamentos y Productos Sanitarios in Madrid.

DOAC reversal agents were associated with an effective hemostasis rate of 78.5%. Failure to achieve effective hemostasis with a reversal agent emerged as a predictor of mortality after severe DOAC-relating bleeds (RR 3.63, 95% CI 2.56-5.16), the authors reported in their paper online in the .

"Therefore, a plausible conclusion is that, in the event of insufficient response, additional attempts and/or combination with other treatment modalities aimed at achieving effective hemostasis should be considered," the group suggested.

Andexanet, the antidote for oral direct factor Xa inhibitors, was notable for a numerical excess in thromboembolism (10.7%) compared with 4PCC (4.3%) and the dabigatran (Pradaxa) neutralizer idarucizumab (3.8%).

"A prothrombotic rebound effect cannot be ruled out with andexanet within the first days after reversal since andexanet has shown to transiently increase thrombin generation," Gómez-Outes and colleagues noted.

"In the absence of prospective comparative trials, it cannot be determined whether specific reversal agents are more effective and/or safer than nonspecific reversal with 4PCC. Comparative studies are needed," the investigators concluded.

Writing in an , Christopher Granger, MD, and Sean Pokorney, MD, MBA, both of the Duke Clinical Research Institute in Durham, North Carolina, stressed that DOACs are still a safer alternative to warfarin for people with an indication for anticoagulation.

"The best way to deal with bleeding is to prevent it. The DOACs as a class have a 52% statistically significant relative risk reduction in ICH [intracranial hemorrhage] and a 14% trend toward a relative risk reduction in major bleeding relative to warfarin, with a 31% relative reduction in major bleeding with apixaban versus warfarin," Granger and Pokorney said.

Safety is the reason why DOACs are recommended over warfarin in atrial fibrillation (Afib) guidelines, according to the duo.

"The morbidity and mortality from ischemic strokes as a result of undertreatment of stroke prevention in patients with Afib continue to dwarf the bleeding-related mortality among patients with Afib and on DOACs, and thus the number one priority is to treat nearly all patients with Afib with a DOAC," the editorialists urged. "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."

Gómez-Outes and co-authors included mostly retrospective studies in the meta-analysis, with only two clinical trials. The more than 4,700 study participants included averaged 77 years of age, and 57% were men.

DOAC users had been split between rivaroxaban (Xarelto; 36%), apixaban (Eliquis; 32%), dabigatran (31%), and edoxaban (Savaysa; 1%). The indication for anticoagulation with a DOAC was most commonly Afib (82%), followed by venous thromboembolism (14%).

More than half the cohort had had an ICH as the index event prompting DOAC reversal.

Mortality was numerically higher in people with intracranial bleeds (20.2%) instead of extracranial hemorrhages (15.4%).

After DOAC reversal, 57% of people resumed anticoagulation approximately 11 days later.

The rebleeding rate was 13.2%, with most rebleeds being ICH. Over three-quarters of rebleeds occurred after resuming anticoagulation, prompting the study authors to advise caution when doing so.

They acknowledged that 45 of the 60 studies in their meta-analysis had a high risk of bias.

Other limitations include the analysis of mortality by hemostasis status not accounting for people who died early, and poor reporting of important variables (e.g., time from last DOAC dose to reversal, post-bleeding anticoagulation management) in many studies.

"This meta-analysis on reversal agents highlights several ongoing gaps in our knowledge. How should one manage OACs [oral anticoagulants] after a major bleeding event, especially given that 13% of patients did have rebleeding in the meta-analysis?" asked Granger and Pokorney.

Understanding the implications of mortality and thromboembolism in DOAC reversal is another challenge.

"Thrombosis is expected to occur with discontinuing anticoagulation, and death will occur in the setting of life-threatening bleeding from the bleeding itself (especially intracranial), from comorbid conditions, and from thrombosis," the editorialists wrote. "The fact that failure to achieve hemostasis was associated with death is both expected and may be related to the way hemostasis was defined, rather than the actual failure of the hemostatic treatments."

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