Abstract
New oral anticoagulants (NOACs) may represent an alternative to standard therapy with vitamin K antagonists (VKA). However, up to the present, it is unknown whether these drugs are safer than VKA. The aim of this study was to perform a meta-analysis of the interventional trials with NOACs vs VKA in patients with acute venous thromboembolism (VTE) to obtain the balance between clinical efficacy and complications. A meta-analysis of double blind randomized controlled trials (RCTs) was performed. We included RCTs that compared, in acute VTE, the beneficial and harmful effects of NOACs (ximelagatran, apixaban, dabigatran, edoxaban and rivaroxaban) vs VKA (warfarin). Seven studies including 29,482 patients were selected. Compared with warfarin, recurrent VTE and death from any cause were not significantly reduced by NOACs. Myocardial infarction was significantly increased with NOACs compared with warfarin (RR 2.55; 95 % CI 1.1–5.6; p = 0.02). NOACs significantly reduced the major bleedings (RR 0.63; 95 % CI 0.47–0.83; p = 0.001). This meta-analysis suggests that treatment with NOACs in patients with acute VTE is not inferior to conventional therapy with warfarin for recurrent VTE and death from any cause, but there might be an increased incidence of myocardial infarction.
Similar content being viewed by others
References
White RH (2003) The epidemiology of venous thromboembolism. Circulation 107:I4–I8
Goldhaber SZ, Bounameaux H (2012) Pulmonary embolism and deep vein thrombosis. Lancet 379:1835–1846
Kahn SR, Lim W, Dunn AS, Cushman M, Dentali F et al (2012) Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis: American College of Chest Physicians evidence-based clinical practice guidelines, 9th edn. Chest 141:e195S–e226S
Guyatt GH, Eikelboom JW, Gould MK, Garcia DA, Crowther M et al (2012) Approach to outcome measurement in the prevention of thrombosis in surgical and medical patients: antithrombotic therapy and prevention of thrombosis: American College of Chest Physicians evidence-based clinical practice guidelines, 9th edn. Chest 141:e185S–e194S
Violi F, Perri L, Loffredo L (2013) Should all acutely ill medical patients be treated with antithrombotic drugs? A review of the interventional trials. Thromb Haemost 109:589–595
Violi F, Perri L, Loffredo L (2013) Interventional trials with anticoagulants in acutely ill medical patients: a methodological pitfall? Intern Emerg Med 8:461–464
Fareed J, Thethi I, Hoppensteadt D (2012) Old versus new oral anticoagulants: focus on pharmacology. Annu Rev Pharmacol Toxicol 52:79–99
Ferro D, Loffredo L, Polimeni L, Violi F (2007) Underuse of oral anticoagulants in patients with nonvalvular atrial fibrillation in Italy. Intern Emerg Med 2:24–28
Baker WL, Phung OJ (2012) Systematic review and adjusted indirect comparison meta-analysis of oral anticoagulants in atrial fibrillation. Circ Cardiovasc Qual Outcomes 5:711–719
Kwong JS, Lam YY, Yan BP, Yu CM (2013) Bleeding of new oral anticoagulants for stroke prevention in atrial fibrillation: a meta-analysis of randomized controlled trials. Cardiovasc Drugs Ther 27:23–35
Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM et al (2012) Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis: American College of Chest Physicians evidence-based clinical practice guidelines, 9th edn. Chest 141:e44S–e88S
Skanes AC, Healey JS, Cairns JA, Dorian P, Gillis AM et al (2012) Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate/rhythm control. Can J Cardiol 28:125–136
Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ (2012) Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. Am J Cardiol 110:453–460
Wasserlauf G, Grandi SM, Filion KB, Eisenberg MJ (2013) Meta-analysis of rivaroxaban and bleeding risk. Am J Cardiol 112:454–460
Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J et al (2009) Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361:1139–1151
Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N et al (2013) Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 383(9921):955–962
Artang R, Rome E, Nielsen JD, Vidaillet HJ (2013) Meta-analysis of randomized controlled trials on risk of myocardial infarction from the use of oral direct thrombin inhibitors. Am J Cardiol 112:1973–1979
Uchino K, Hernandez AV (2012) Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials. Arch Intern Med 172:397–402
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ et al (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17:1–12
Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6:e1000097
Higgins JGS (2011) Cochrane handbook for systematic reviews of interventions. The Cochrane Collaboration. http://handbook.cochrane.org/
Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22:719–748
Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634
Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS et al (2013) Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 369:799–808
Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S et al (2009) Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 361:2342–2352
Buller HR, Decousus H, Grosso MA, Mercuri M, Middeldorp S et al (2013) Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 369:1406–1415
Fiessinger JN, Huisman MV, Davidson BL, Bounameaux H, Francis CW et al (2005) Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis: a randomized trial. JAMA 293:681–689
Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H et al (2010) Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 363:2499–2510
Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, et al. (2013) Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation
Buller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF et al (2012) Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 366:1287–1297
Fox BD, Kahn SR, Langleben D, Eisenberg MJ, Shimony A (2012) Efficacy and safety of novel oral anticoagulants for treatment of acute venous thromboembolism: direct and adjusted indirect meta-analysis of randomised controlled trials. BMJ 345:e7498
van der Hulle T, Kooiman J, den Exter PL, Dekkers OM, Klok FA et al (2014) Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost 12:320–328
Gomez-Outes A, Terleira-Fernandez AI, Lecumberri R, Suarez-Gea ML, Vargas-Castrillon E (2014) Direct oral anticoagulants in the treatment of acute venous thromboembolism: a systematic review and meta-analysis. Thromb Res 134:774–782
Tomblyn MR, Rizzo JD (2007) Are there circumstances in which phase 2 study results should be practice-changing? Hematol Am Soc Hematol Educ Progr: 489–492
Manly DA, Boles J, Mackman N (2011) Role of tissue factor in venous thrombosis. Annu Rev Physiol 73:515–525
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Loffredo, L., Perri, L., Del Ben, M. et al. New oral anticoagulants for the treatment of acute venous thromboembolism: are they safer than vitamin K antagonists? A meta-analysis of the interventional trials. Intern Emerg Med 10, 499–506 (2015). https://doi.org/10.1007/s11739-014-1171-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11739-014-1171-7