Journal of Neurology

, Volume 262, Issue 3, pp 516–522

Intracranial hemorrhage risk with the new oral anticoagulants: a systematic review and meta-analysis

  • Daniel Caldeira
  • Márcio Barra
  • Fausto J. Pinto
  • Joaquim J. Ferreira
  • João Costa
Review

Abstract

The new oral anticoagulants/non-vitamin K antagonists oral anticoagulants (NOACs) have recently reached the market and less is known about their safety in comparison to their efficacy. Therefore, we aimed to evaluate intracranial hemorrhage (ICH) risk with NOACs, the most feared adverse event of anticoagulation treatment. This is a systematic review and meta-analysis of phase III randomized controlled trials (RCTs) comparing NOACs versus any control and reporting ICH events. Studies were searched through Medline and Cochrane Library (April 2014). Reviews and reference lists were also screened. Random effects’ meta-analysis was performed to derive pooled estimates expressed as relative risk (RR) and 95 % CI. Number needed to treat/harm (NNT/NNH) taking into account the baseline risk was also calculated. Heterogeneity was evaluated with I2 test. 18 RCTs evaluating 148,149 patients were included. NOAC significantly reduced ICH risk compared to vitamin K antagonists (VKA) (RR 0.44; 95 % CI 0.36–0.54; I2 = 37 %; NNT: 137 during 2 years) and to sequential treatment with low molecular weight heparin and VKA (RR 0.28; 95 % CI 0.12–0.65; I2 = 0 %; NNT: 463 patients during 7 months). Compared to placebo, NOACs were associated with an increased ICH risk (RR 3.31; 95 % CI 1.59–6.90; I2 = 0 %; NNH: 433 during 1 year). Results were similar for the different NOAC drugs and across the different clinical conditions. In patients requiring anticoagulation treatment, the risk of ICH is about half with the NOACs in comparison to standard antithrombotic treatment. This safer profile found in RCTs should be confirmed in real-world database studies.

Keywords

Intracranial hemorrhages Anticoagulants Meta-analysis 

Supplementary material

415_2014_7462_MOESM1_ESM.tif (164 kb)
Supplementary Fig. 1: Flowchart of studies selection (TIFF 163 kb)
415_2014_7462_MOESM2_ESM.tif (455 kb)
Supplementary Fig. 2: Risk of bias table (TIFF 454 kb)
415_2014_7462_MOESM3_ESM.tif (85 kb)
Supplementary Fig. 3: Funnel plot of included studies (TIFF 85 kb)
415_2014_7462_MOESM4_ESM.pdf (198 kb)
Supplementary Table 1: Characteristics of included studies (PDF 197 kb)
415_2014_7462_MOESM5_ESM.pdf (124 kb)
Supplementary material 5 (PDF 124 kb)

References

  1. 1.
    Harder S, Graff J (2013) Novel oral anticoagulants: clinical pharmacology, indications and practical considerations. Eur J Clin Pharmacol 69:1617–1633CrossRefPubMedGoogle Scholar
  2. 2.
    Landefeld CS, Beyth RJ (1993) Anticoagulant-related bleeding: clinical epidemiology, prediction, and prevention. Am J Med 95:315–328CrossRefPubMedGoogle Scholar
  3. 3.
    Linkins L, O’Donnell M, Julian JA, Kearon C (2010) Intracranial and fatal bleeding according to indication for long-term oral anticoagulant therapy. J Thromb Haemost 8:2201–2207CrossRefPubMedGoogle Scholar
  4. 4.
    Fang MC, Go AS, Chang Y, Hylek EM, Henault LE, Jensvold NG et al (2007) Death and disability from warfarin-associated intracranial and extracranial hemorrhages. Am J Med 120:700–705PubMedCentralCrossRefPubMedGoogle Scholar
  5. 5.
    Bloom BJ, Filion KB, Atallah R, Eisenberg MJ (2014) Meta-analysis of randomized controlled trials on the risk of bleeding with dabigatran. Am J Cardiol 113:1066–1074CrossRefPubMedGoogle Scholar
  6. 6.
    Wasserlauf G, Grandi SM, Filion KB, Eisenberg MJ (2013) Meta-analysis of rivaroxaban and bleeding risk. Am J Cardiol 112:454–460CrossRefPubMedGoogle Scholar
  7. 7.
    Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 339:b2700PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Lane PW (2013) Meta-analysis of incidence of rare events. Stat Methods Med Res 22:117–132CrossRefPubMedGoogle Scholar
  9. 9.
    Turner RM, Bird SM, Higgins JP (2013) The impact of study size on meta-analyses: examination of underpowered studies in Cochrane reviews. PLoS One 8:e59202PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Kjaergard LL, Villumsen J, Gluud C (2001) Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Ann Intern Med 135:982–989CrossRefPubMedGoogle Scholar
  11. 11.
    Zhang Z, Xu X, Ni H (2013) Small studies may overestimate the effect sizes in critical care meta-analyses: a meta-epidemiological study. Crit Care 17:R2PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Higgins JPT, Altman DG, Sterne JAC (2011). Chapter 8: assessing risk of bias in included studies. In: Higgins JPT, Green S (eds) Cochrane handbook for systematic reviews of interventions version 5.1.0. The Cochrane Collaboration. http://www.cochrane-handbook.org
  13. 13.
    Deeks JJ (2002) Issues in the selection of a summary statistic for meta-analysis of clinical trials with binary outcomes. Stat Med 21:1575–1600CrossRefPubMedGoogle Scholar
  14. 14.
    Smeeth L, Haines A, Ebrahim S (1999) Numbers needed to treat derived from meta-analyses—sometimes informative, usually misleading. BMJ 318:1548–1551PubMedCentralCrossRefPubMedGoogle Scholar
  15. 15.
    DiCenso A (2001) Clinically useful measures of the effects of treatment. Evid Based Nurs. 4:36–39CrossRefPubMedGoogle Scholar
  16. 16.
    Deeks JJ, Higgins JPT, Altman DG (2011) Chapter 9: analysing data and undertaking meta-analyses. In: Higgins JPT, Green S (eds). Cochrane handbook for systematic reviews of interventions version 5.1.0. The Cochrane Collaboration. http://www.cochrane-handbook.org
  17. 17.
    Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L (2006) Comparison of two methods to detect publication bias in meta-analysis. JAMA 295:676–680CrossRefPubMedGoogle Scholar
  19. 19.
    Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ (2009) Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med 361:594–604CrossRefPubMedGoogle Scholar
  20. 20.
    Alexander JH, Lopes RD, James S, Kilaru R, He Y, Mohan P et al (2011) Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 365:699–708CrossRefPubMedGoogle Scholar
  21. 21.
    Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S et al (2011) Apixaban in patients with atrial fibrillation. N Engl J Med 364:806–817CrossRefPubMedGoogle Scholar
  22. 22.
    Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M et al (2011) Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 365:981–992CrossRefPubMedGoogle Scholar
  23. 23.
    Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M et al (2013) Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 369:799–808CrossRefPubMedGoogle Scholar
  24. 24.
    Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M et al (2013) Apixaban for extended treatment of venous thromboembolism. N Engl J Med 368:699–708CrossRefPubMedGoogle Scholar
  25. 25.
    Goldhaber SZ, Leizorovicz A, Kakkar AK, Haas SK, Merli G, Knabb RM et al (2011) Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med 365:2167–2177CrossRefPubMedGoogle Scholar
  26. 26.
    Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A et al (2009) Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361:1139–1151CrossRefPubMedGoogle Scholar
  27. 27.
    Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H et al (2009) Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 361:2342–2352CrossRefPubMedGoogle Scholar
  28. 28.
    Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D et al (2013) Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 368:709–718CrossRefPubMedGoogle Scholar
  29. 29.
    Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Hokusai-VTE Investigators et al (2013) Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 369:1406–1415CrossRefPubMedGoogle Scholar
  30. 30.
    Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL et al (2013) Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 369:2093–2104CrossRefPubMedGoogle Scholar
  31. 31.
    Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM et al (2009) Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet 373:1673–1680CrossRefPubMedGoogle Scholar
  32. 32.
    Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W et al (2011) Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 365:883–891CrossRefPubMedGoogle Scholar
  33. 33.
    Hori M, Matsumoto M, Tanahashi N, Momomura S, Uchiyama S, Goto S et al (2012) Rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation—the J-ROCKET AF study. Circ J 76(2104):11Google Scholar
  34. 34.
    Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C et al (2012) Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 366:9–19CrossRefPubMedGoogle Scholar
  35. 35.
    Büller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, EINSTEIN–PE Investigators et al (2012) Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 366:1287–1297CrossRefPubMedGoogle Scholar
  36. 36.
    Cohen AT, Spiro TE, Büller HR, Haskell L, Hu D, Hull R et al (2013) Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med 368:513–523CrossRefPubMedGoogle Scholar
  37. 37.
    Lovelock CE, Molyneux AJ, Rothwell PM, Oxford Vascular Study (2007) Change in incidence and aetiology of intracerebral haemorrhage in Oxfordshire, UK, between 1981 and 2006: a population-based study. Lancet Neurol 6:487–493CrossRefPubMedGoogle Scholar
  38. 38.
    Thrift AG, McNeil JJ, Forbes A, Donnan GA (1999) Risk of primary intracerebral haemorrhage associated with aspirin and non-steroidal anti-inflammatory drugs: case–control study. BMJ 318:759–764PubMedCentralCrossRefPubMedGoogle Scholar
  39. 39.
    Linkins L, O’Donnell M, Julian JA, Kearon C (2010) Intracranial and fatal bleeding according to indication for long-term oral anticoagulant therapy. J Thromb Haemost 8:2201–2207CrossRefPubMedGoogle Scholar
  40. 40.
    Hart RG, Diener HC, Yang S, Connolly SJ, Wallentin L, Reilly PA et al (2012) Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: the RE-LY trial. Stroke 43:1511–1517CrossRefPubMedGoogle Scholar
  41. 41.
    Hankey GJ, Stevens SR, Piccini JP, Lokhnygina Y, Mahaffey KW, Halperin JL et al (2014) Intracranial hemorrhage among patients with atrial fibrillation anticoagulated with warfarin or rivaroxaban: the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation. Stroke 45:1304–1312CrossRefPubMedGoogle Scholar
  42. 42.
    Deitelzweig S, Amin A, Jing Y, Makenbaeva D, Wiederkehr D, Lin J et al (2012) Medical cost reductions associated with the usage of novel oral anticoagulants vs warfarin among atrial fibrillation patients, based on the RE-LY, ROCKET-AF, and ARISTOTLE trials. J Med Econ 15:776–785CrossRefPubMedGoogle Scholar
  43. 43.
    Canestaro WJ, Patrick AR, Avorn J, Ito K, Matlin OS, Brennan TA et al (2013) Cost-effectiveness of oral anticoagulants for treatment of atrial fibrillation. Circ Cardiovasc Qual Outcomes 6:724–731CrossRefPubMedGoogle Scholar
  44. 44.
    Mahmoudi M, Sobieraj DM (2013) The cost-effectiveness of oral direct factor Xa inhibitors compared with low-molecular-weight heparin for the prevention of venous thromboembolism prophylaxis in total hip or knee replacement surgery. Pharmacotherapy 33:1333–1340CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Daniel Caldeira
    • 1
    • 2
    • 3
  • Márcio Barra
    • 2
  • Fausto J. Pinto
    • 4
  • Joaquim J. Ferreira
    • 1
    • 2
  • João Costa
    • 1
    • 2
    • 5
    • 6
  1. 1.Clinical Pharmacology UnitInstituto de Medicina MolecularLisbonPortugal
  2. 2.Laboratory of Clinical Pharmacology and Therapeutics, Faculty of MedicineUniversity of LisbonLisbonPortugal
  3. 3.Cardiology DepartmentHospital Garcia de OrtaAlmadaPortugal
  4. 4.Cardiology Department, CCUL, CAML, Faculty of MedicineLisbonPortugal
  5. 5.Evidence Based Medicine Centre, Faculty of MedicineUniversity of LisbonLisbonPortugal
  6. 6.Portuguese Collaborating Centre of the Cochrane Iberoamerican Network, Faculty of MedicineUniversity of LisbonLisbonPortugal

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