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Alcubilla P.AuthorCalvo-Rojas G.Author
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Meta-Analysis of Reversal Agents for Severe Bleeding Associated With Direct Oral Anticoagulants

Publicated to:Journal Of The American College Of Cardiology. 77 (24): 2987-3001 - 2021-06-22 77(24), DOI: 10.1016/j.jacc.2021.04.061

Authors: Gómez-Outes, A; Alcubilla, P; Calvo-Rojas, G; Terleira-Fernández, AI; Suárez-Gea, L; Lecumberri, R; Vargas-Castrillón, E

Affiliations

Clínica Universitaria de Navarra - Author
Hosp Clin Barcelona, Dept Clin Pharmacol, Barcelona, Spain - Author
Hosp Clinico San Carlos, Dept Clin Pharmacol, IdISSC, Madrid, Spain - Author
Hospital Clinic Barcelona - Author
Hospital Clinico San Carlos de Madrid - Author
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Cardiovasc CIB, Madrid, Spain - Author
Spanish Agcy Med & Med Devices AEMPS, Div Pharmacol & Clin Drug Evaluat, Madrid, Spain - Author
Spanish Agency for Medicines and Medical Devices (AEMPS) - Author
Univ Barcelona, Barcelona, Spain - Author
Univ Clin Navarra, Hematol Serv, Pamplona, Spain - Author
Univ Complutense, Dept Pharmacol, IdISSC, Madrid, Spain - Author
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Abstract

BACKGROUND: Direct oral anticoagulants (DOACs) have shown a positive benefit-risk balance in both clinical trials and real-world data, but approximately 2% to 3.5% of patients experience major bleeding annually. Many of these patients require hospitalization, and the administration of reversal agents may be required to control bleeding. OBJECTIVES: The aim of this study was to investigate clinical outcomes associated with the use of 4-factor prothrombin complex concentrates, idarucizumab, or andexanet for reversal of severe DOAC-associated bleeding. METHODS: The investigators systematically searched for studies of reversal agents for the treatment of severe bleeding associated with DOAC. Mortality rates, thromboembolic events, and hemostatic efficacy were meta-analyzed using a random effects model. RESULTS: The investigators evaluated 60 studies in 4,735 patients with severe DOAC-related bleeding who were treated with 4-factor prothrombin complex concentrates (n = 2,688), idarucizumab (n = 1,111), or andexanet (n = 936). The mortality rate was 17.7% (95% confidence interval [CI]: 15.1% to 20.4%), and it was higher in patients with intracranial bleedings (20.2%) than in patients with extracranial hemorrhages (15.4%). The thromboembolism rate was 4.6% (95% CI: 3.3% to 6.0%), being particularly high with andexanet (10.7%; 95% CI: 6.5% to 15.7%). The effective hemostasis rate was 78.5% (95% CI: 75.1% to 81.8%) and was similar regardless of the reversal agent considered. The rebleeding rate was 13.2% (95% CI: 5.5% to 23.1%) and 78% of rebleeds occurred after resumption of anticoagulation. The risk of death was markedly and significantly associated with failure to achieve effective hemostasis (relative risk: 3.63; 95% CI: 2.56 to 5.16). The results were robust regardless of the type of study or the hemostatic scale used. CONCLUSIONS: The risk of death after severe DOAC-related bleeding remains significant despite a high rate of effective hemostasis with reversal agents. Failure to achieve effective hemostasis strongly correlated with a fatal outcome. Thromboembolism rates are particularly high with andexanet. Comparative clinical trials are needed.

Keywords
andexanet alphaandexanet alfaatrial-fibrillationbleedingclinical-practicedabigatran reversaldirect oral anticoagulantsemergent reversalfactor xa inhibitorsidarucizumabintracranial hemorrhagemanagementAndexanet alfaBleedingDirect oral anticoagulantsIdarucizumabProthrombin complex concentrateReversal agents

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Journal Of The American College Of Cardiology due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2021, it was in position 5/143, thus managing to position itself as a Q1 (Primer Cuartil), in the category Cardiac & Cardiovascular Systems. Notably, the journal is positioned above the 90th percentile.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 5.33. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Weighted Average of Normalized Impact by the Scopus agency: 7.73 (source consulted: FECYT Feb 2024)
  • Field Citation Ratio (FCR) from Dimensions: 36.3 (source consulted: Dimensions May 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-05-15, the following number of citations:

  • WoS: 69
  • Scopus: 102
  • OpenCitations: 85
Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-05-15:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 110.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 109 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 69.65.
  • The number of mentions on the social network Facebook: 1 (Altmetric).
  • The number of mentions on the social network X (formerly Twitter): 40 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.