Similar articles

Abstract: Background: Antithrombotic therapy using new oral anticoagulants (NOACs) in patients with atrial fibrillation (AF) has been generally shown to have a favorable risk-benefit profile. Since there has been dispute about the risks of gastrointestinal bleeding (GIB) and intracranial hemorrhage (ICH), we sought to conduct a systematic review and network meta-analysis using Bayesian inference to analyze the risks of GIB and ICH in AF patients taking NOACs. Methods: We analyzed data from 20 randomized controlled trials of 91 671 AF patients receiving anticoagulants, antiplatelet drugs, or placebo. Bayesian network meta-analysis of two different evidence networks was performed using a binomial likelihood model, based on a network in which different agents (and doses) were treated as separate nodes. Odds ratios (ORs) and 95% confidence intervals (CIs) were modeled using Markov chain Monte Carlo methods. Results: Indirect comparisons with the Bayesian model confirmed that aspirin+clopidogrel significantly increased the risk of GIB in AF patients compared to the placebo (OR 0.33, 95% CI 0.01–0.92). Warfarin was identified as greatly increasing the risk of ICH compared to edoxaban 30 mg (OR 3.42, 95% CI 1.22–7.24) and dabigatran 110 mg (OR 3.56, 95% CI 1.10–8.45). We further ranked the NOACs for the lowest risk of GIB (apixaban 5 mg) and ICH (apixaban 5 mg, dabigatran 110 mg, and edoxaban 30 mg). Conclusions: Bayesian network meta-analysis of treatment of non-valvular AF patients with anticoagulants suggested that NOACs do not increase risks of GIB and/or ICH, compared to each other.

新型口服抗凝血剂在心房颤动患者中胃肠道出血和颅内出血的风险分析：系统回顾和网络meta分析

[1]Alexander, J.H., Lopes, R.D., James, S., et al., 2011. Apixaban with antiplatelet therapy after acute coronary syndrome. N. Engl. J. Med., 365(8):699-708.

[2]Begg, C.B., Mazumdar, M., 1994. Operating characteristics of a rank correlation test for publication bias. Biometrics, 50(4):1088-1101.

[3]Biondi-Zoccai, G., Malavasi, V., D'Ascenzo, F., et al., 2013. Comparative effectiveness of novel oral anticoagulants for atrial fibrillation: evidence from pair-wise and warfarin-controlled network meta-analyses. HSR Proc. Intens. Care Cardiovasc. Anesth., 5(1):40-54.

[4]Camm, A.J., Lip, G.Y., de Caterina, R., et al., 2012. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur. Heart J., 33(21):2719-2747.

[5]Candel, F.J., Matesanz, M., Cogolludo, F., et al., 2004. Prevalence of atrial fibrillation and relationed factors in a population in the centre Madrid. An. Med. Interna (Madrid), 21(10):477-482.

[6]http://doi.org/10.4321/S0212-71992004001000003

[7]Chatterjee, S., Sardar, P., Biondi-Zoccai, G., et al., 2013. New oral anticoagulants and the risk of intracranial hemorrhage: traditional and Bayesian meta-analysis and mixed treatment comparison of randomized trials of new oral anticoagulants in atrial fibrillation. JAMA Neurol., 70(12):1486-1490.

[8]Chen, W.C., Chen, Y.H., Hsu, P.I., et al., 2014. Gastrointestinal hemorrhage in warfarin anticoagulated patients: incidence, risk factor, management, and outcome. BioMed Res. Int., 2014:463767.

[9]Chung, N., Jeon, H.K., Lien, L.M., et al., 2011. Safety of edoxaban, an oral factor Xa inhibitor, in Asian patients with non-valvular atrial fibrillation. Thromb. Haemost., 105(3):535-544.

[10]Connolly, S.J., Pogue, J., Hart, R., et al., 2006. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet, 367(9526):1903-1912.

[11]Connolly, S.J., Laupacis, A., Gent, M., et al., 1991. Canadian atrial fibrillation anticoagulation (CAFA) Study. J. Am. Coll. Cardiol., 18(2):349-355.

[12]Connolly, S.J., Pogue, J., Hart, R.G., et al., 2009a. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N. Engl. J. Med., 360(20):2066-2078.

[13]Connolly, S.J., Ezekowitz, M.D., Yusuf, S., et al., 2009b. Dabigatran versus warfarin in patients with atrial fibrillation. N. Engl. J. Med., 361(12):1139-1151.

[14]Connolly, S.J., Eikelboom, J., Joyner, C., et al., 2011. Apixaban in patients with atrial fibrillation. N. Engl. J. Med., 364(9):806-817.

[15]Dias, S., Welton, N.J., Sutton, A.J., 2011. NICE DSU technical support document 2: a generalised linear modelling framework for pairwise and network meta-analysis of randomised controlled trials. Technical Support Document in Evidence Synthesis, No. TSD2. National Institute for Health and Clinical Excellence.

[16]http://core.ac.uk/download/pdf/29025987.pdf

[17]Dias, S., Welton, N.J., Sutton, A.J., et al., 2013. Evidence synthesis for decision making 4: inconsistency in networks of evidence based on randomized controlled trials. Med. Decis. Making, 33(5):641-656.

[18]Dogliotti, A., Paolasso, E., Giugliano, R.P., 2014. Current and new oral antithrombotics in non-valvular atrial fibrillation: a network meta-analysis of 79 808 patients. Heart, 100(5):396-405.

[19]Dulli, D.A., Stanko, H., Levine, R.L., 2003. Atrial fibrillation is associated with severe acute ischemic stroke. Neuroepidemiology, 22(2):118-123.

[20]Ezekowitz, M.D., Bridgers, S.L., James, K.E., et al., 1992. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. N. Engl. J. Med., 327(20):1406-1412.

[21]Fuster, V., Ryden, L.E., Cannom, D.S., et al., 2006. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation. Circulation, 114(7):e257-e354.

[22]Gersh, B.J., Tsang, T.S., Seward, J.B., 2004. The changing epidemiology and natural history of nonvalvular atrial fibrillation: clinical implications. Trans. Am. Clin. Climatol. Assoc., 115:149-159.

[23]Gibson, C.M., Mega, J.L., Burton, P., et al., 2011. Rationale and design of the Anti-Xa therapy to lower cardiovascular events in addition to standard therapy in subjects with acute coronary syndrome-thrombolysis in myocardial infarction 51 (ATLAS-ACS 2 TIMI 51) trial: a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of rivaroxaban in subjects with acute coronary syndrome. Am. Heart J., 161(5):815-821.e6.

[24]Giorda, C.B., Nada, E., Tartaglino, B., 2014. Pharmacokinetics, safety, and efficacy of DPP-4 inhibitors and GLP-1 receptor agonists in patients with type 2 diabetes mellitus and renal or hepatic impairment. A systematic review of the literature. Endocrine, 46(3):406-419.

[25]Giugliano, R.P., Ruff, C.T., Braunwald, E., et al., 2013. Edoxaban versus warfarin in patients with atrial fibrillation. N. Engl. J. Med., 369(22):2093-2104.

[26]Gomez-Outes, A., Terleira-Fernandez, A.I., Calvo-Rojas, G., et al., 2013. Dabigatran, rivaroxaban, or apixaban versus warfarin in patients with nonvalvular atrial fibrillation: a systematic review and meta-analysis of subgroups. Thrombosis, 2013:640723.

[27]Granger, C.B., Alexander, J.H., McMurray, J.J., et al., 2011. Apixaban versus warfarin in patients with atrial fibrillation. N. Engl. J. Med., 365(11):981-992.

[28]Gullov, A.L., Koefoed, B.G., Petersen, P., et al., 1998. Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation: Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study. Arch. Intern. Med., 158(14):1513-1521.

[29]Hellemons, B.S., Langenberg, M., Lodder, J., et al., 1999. Primary prevention of arterial thromboembolism in non-rheumatic atrial fibrillation in primary care: randomised controlled trial comparing two intensities of coumarin with aspirin. BMJ, 319(7215):958-964.

[30]Higgins, J., Green, S., 2006. Cochrane Handbook for Systematic Reviews of Interventions. John Wiley & Sons, Ltd., Chichester, UK.

[31]Holster, I.L., Valkhoff, V.E., Kuipers, E.J., et al., 2013. New oral anticoagulants increase risk for gastrointestinal bleeding: a systematic review and meta-analysis. Gastroenterology, 145(1):105-112.e15.

[32]Hori, M., Matsumoto, M., Tanahashi, N., et al., 2012. Rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation. Circ. J., 76(9):2104-2111.

[33]Hu, D.Y., Zhang, H.P., Sun, Y.H., et al., 2006. The randomized study of efficiency and safety of antithrombotic therapy in nonvalvular atrial fibrillation: warfarin compared with aspirin. Chin. J. Cardiol., 34(4):295-298 (in Chinese).

[34]Jansen, J.P., Naci, H., 2013. Is network meta-analysis as valid as standard pairwise meta-analysis? It all depends on the distribution of effect modifiers. BMC Med., 11:159.

[35]January, C.T., Wann, L.S., Alpert, J.S., et al., 2014. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary. Circulation, 130(23):2071-2104.

[36]Levi, M., Eerenberg, E., Kamphuisen, P.W., 2011. Bleeding risk and reversal strategies for old and new anticoagulants and antiplatelet agents. J. Thromb. Haemost., 9(9):1705-1712.

[37]Luengo-Fernandez, R., Gray, A.M., Rothwell, P.M., 2006. Population-based study of determinants of initial secondary care costs of acute stroke in the United Kingdom. Stroke, 37(10):2579-2587.

[38]Lumley, T., 2002. Network meta-analysis for indirect treatment comparisons. Stat. Med., 21(16):2313-2324.

[39]Mant, J., Hobbs, F.D., Fletcher, K., et al., 2007. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet, 370(9586):493-503.

[40]Mega, J.L., Braunwald, E., Wiviott, S.D., et al., 2012. Rivaroxaban in patients with a recent acute coronary syndrome. N. Engl. J. Med., 366(1):9-19.

[41]Ogawa, S., Shinohara, Y., Kanmuri, K., 2011. Safety and efficacy of the oral direct factor Xa inhibitor apixaban in Japanese patients with non-valvular atrial fibrillation. Circ. J., 75(8):1852-1859.

[42]Patel, M.R., Mahaffey, K.W., Garg, J., et al., 2011. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N. Engl. J. Med., 365(10):883-891.

[43]Petersen, P., Boysen, G., Godtfredsen, J., et al., 1989. Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation: the Copenhagen AFASAK Study. Lancet, 333(8631):175-179.

[44]Ruff, C.T., Giugliano, R.P., Braunwald, E., et al., 2014. 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.

[45]Sacco, R.L., Adams, R., Albers, G., et al., 2006. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack. Stroke, 37(2):577-617.

[46]Sato, H., Ishikawa, K., Kitabatake, A., et al., 2006. Low-dose aspirin for prevention of stroke in low-risk patients with atrial fibrillation: Japan Atrial Fibrillation Stroke Trial. Stroke, 37(2):447-451.

[47]Slot, K.B., Berge, E., Dorman, P., et al., 2008. Impact of functional status at six months on long term survival in patients with ischaemic stroke: prospective cohort studies. BMJ, 336(7640):376-379.

[48]Spiegelhalter, D., Thomas, A., Best, N., 2004. WinBUGS User Manual. MRC Biostatistics Unit, Cambridge.

[49]Sweeting, M.J., Sutton, A.J., Lambert, P.C., 2004. What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Stat. Med., 23(9):1351-1375.

[50]The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators, 1990. The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. N. Engl. J. Med., 323(22):1505-1511.

[51]Yamashita, T., Koretsune, Y., Yasaka, M., et al., 2012. Randomized, multicenter, warfarin-controlled phase II study of edoxaban in Japanese patients with non-valvular atrial fibrillation. Circ. J., 76(8):1840-1847.

[52]Zhang, S., 2012. Clinical considerations of anticoagulation therapy for patients with atrial fibrillation. J. Zhejiang Univ.-Sci. B (Biomed. & Biotechnol.), 13(4):609-615.