Efficacy and safety of the drugs used to reverse direct oral anticoagulants: a systematic review and meta-analysis.
Direct oral anticoagulants (DOACs) are effective and safe for prophylaxis and treatment of thromboembolic phenomena. However, managing DOACs during bleeding emergencies is challenging. A systematic review and meta-analysis was conducted on studies addressing efficacy and safety of the drugs used for reversal of DOACs.



Medline, Embase, Cochrane Library, and ClinicalTrials.gov were searched up to September 2016. Studies that examined clinical and laboratory effects of drugs used to reverse DOACs were included. Risk of bias was assessed using Newcastle-Ottawa scale and Cochrane Collaboration tool. Primary and secondary outcomes assessed were reversal of clinical bleeding, clotting assays, and safety, respectively. Overall effect estimates were pooled, and clinical and statistical heterogeneity were assessed. Meta-analysis was conducted using random-effects model.



Four cohort studies in bleeding patients (n = 230) and eight randomized controlled trials in healthy volunteers (n = 381) were included, both with moderate risk of bias. Reversal of clotting assays in healthy volunteers was frequently reported, demonstrating that prothrombin complex concentrate (PCC) reversed prothrombin time (PT) and endogenous thrombin potential (ETP) substantially. For PT, pooled mean difference was 1.68 seconds (95% confidence interval [CI], -0.33 to 3.70 sec; p < 0.01; I2= 97%). For ETP, pooled mean difference was 2.16 seconds (95% CI, 0.57 to 3.75 sec; p < 0.01; I2=98%). Andexanet alfa and idarucizumab both reverse clotting assays. No important safety concerns were identified.



Clotting assays are partially reversed by PCC in healthy volunteers. Idarucizumab and andexanet alfa have solid laboratory reversal effect and potential to be clinically efficacious and safe. However, clinical evidence is still lacking for all agents.
Departments of Surgery (Sunnybrook Health Sciences Centre).
Luis Teodoro
LT
da Luz
Department of Surgery, University of Sherbrooke, Sherbrooke, Quebec, Canada.
Mylene
M
Marchand
Departments of Surgery (Sunnybrook Health Sciences Centre).
Bartolomeu
B
Nascimento
Departments of Surgery (Sunnybrook Health Sciences Centre).
Homer
H
Tien
Departments of Surgery (Sunnybrook Health Sciences Centre).
Avery
A
Nathens
Pediatrics (Mount Sinai Hospital), University of Toronto, Toronto, Ontario, Canada.
Prakesh
P
Shah
D000284:Administration, Oral; D000368:Aged; D000925:Anticoagulants / Q000494:pharmacology*; D001779:Blood Coagulation Factors / Q000009:adverse effects / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D011517:Prothrombin Time; D013917:Thrombin / Q000096:biosynthesis
D000925:Anticoagulants; D001779:Blood Coagulation Factors; C025667:prothrombin complex concentrates; D013917:Thrombin