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Non-vitamin K antagonist oral anticoagulants and major bleeding-related fatality in patients with atrial fibrillation and venous thromboembolism: a systematic review and meta-analysis
  1. Daniel Caldeira1,2,3,
  2. Filipe B Rodrigues1,3,
  3. Márcio Barra1,3,
  4. Ana Teresa Santos1,3,
  5. Daisy de Abreu1,3,
  6. Nilza Gonçalves1,3,
  7. Fausto J Pinto4,
  8. Joaquim J Ferreira1,3,
  9. João Costa1,3,5,6
  1. 1Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Medicine, University of Lisbon, Lisbon, Portugal
  2. 2Cardiology Department, Hospital Garcia de Orta, Almada, Portugal
  3. 3Clinical Pharmacology Unit, Instituto de Medicina Molecular, Lisbon, Portugal
  4. 4Cardiology Department, CCUL, CAML, Faculty of Medicine, Lisbon, Portugal
  5. 5Center for Evidence-Based Medicine, Faculty of Medicine, University of Lisbon, Lisbon, Portugal
  6. 6Portuguese Collaborating Center of the IberoAmerican Cochrane Network, Faculty of Medicine, University of Lisbon, Lisbon, Portugal
  1. Correspondence to Dr Daniel Caldeira, Laboratório de Farmacologia Clínica e Terapêutica, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, Lisboa 1649-028, Portugal; dgcaldeira{at}


Objective Non-vitamin K antagonist oral anticoagulants (NOACs) are efficacious and safe antithrombotic drugs but the non-availability of an antidote for potential fatal haemorrhagic events is clinically perceived as a strong limitation. We aimed at evaluating the risk of haemorrhage-related fatalities associated with NOACs in patients requiring long-term anticoagulation.

Methods MEDLINE, Cochrane Library and Web of Science databases were searched in November 2014 for atrial fibrillation (AF) or venous thromboembolism (VTE) phase III randomised controlled trials (RCT) comparing NOACs with vitamin K antagonists (VKAs) or low molecular weight heparin (LMWH) followed by VKAs. Pooled OR and 95% CIs were estimated through meta-analysis. Heterogeneity was assessed with the I2 test.

Results Eleven studies were included: 5 on AF and 6 on VTE. A total of 100 324 patients were evaluated in 4 rivaroxaban, 3 dabigatran, 2 apixaban and 2 edoxaban studies. NOAC-treated patients had a 47% odds reduction compared with VKA (OR 0.53; 95% CI 0.42 to 0.68; I2=0%; 3 events avoided per 1000 patients) and 64% odds reduction compared with LMWH–VKA (OR 0.36; 95% CI 0.15 to 0.84; I2=0%; 1 event avoided per 1000 patients) regarding fatal bleeding risk. Case fatality due to major bleeding was lower in NOAC-treated patients both in AF (OR 0.68; 95% CI 0.48 to 0.96; I2=37%; 1 death avoided per 39 major bleedings) and VTE (OR 0.54; 95% CI 0.22 to 1.32; I2=0%) patients. AF survivors of major bleeding events treated with NOACs had lower mortality compared with patients treated with VKAs (OR 0.57; 95% CI 0.45 to 0.73; I2=0%; 78 events avoided per 1000 survivors to major bleeding).

Conclusions These data suggest that NOACs decrease the risk of fatality cases related to major bleeding events, particularly in AF patients. These results support the safety profile of NOACs even without having a widely available drug-specific antidote.

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