Warfarina y anticoagulantes orales directos. Revisión sistemática y metanálisis sobre estudios de no inferioridad en fibrilación auricular y trombosis venosa profunda. / Warfarin and direct oral anticoagulants: a systematic review on non-inferiority studies in atrial fibrillation and deep venous thrombosis.
Abstract
Resumen.
Los anticoagulantes orales directos (ACODs), se han convertido en una alternativa de anticoagulación en fibrilación auricular (FA) y en trombosis venosa profunda (TVP). Los estudios de no inferioridad entre los ACODs y la warfarina, están diseñados para demostrar que los primeros mantienen al menos la misma eficacia y mejor seguridad que la warfarina. Se realizó una revisión sistemática y metanálisis de ensayos aleatorios controlados en FA (4 estudios) y TVP (6 estudios). El evento primario fue el ictus isquémico y embolismo sistémico) en FA y la trombosis venosa recurrente para TVP, y la hemorragia mayor para seguridad en ambas patologías. En FA, el análisis mostró equivalencia entre los ACODs y la warfarina, el resultado combinado evidenció una reducción significativa del riesgo de 24% [RR (IC95%)=0,76 (0,69-0,84), p<0,0001]. En el análisis de seguridad, en todos los estudios no hubo diferencias con warfarina y el resultado combinado mostró una reducción no significativa del riesgo del 14% [RR (IC95%)=0,86 (0,76- 1,01), p=0,058]. Para TVP recurrente, todos los estudios mostraron criterios de no inferioridad respecto a la warfarina pero sin uniformidad; el resultado combinado no obtuvo significación estadística [RR (IC95%)=0,93 (0,79-1,08), p=0,372]. El análisis de seguridad indicó que los ACODs fueron superiores a la warfarina, con una reducción significativa del riesgo de hemorragia (42%) [RR (IC95%)=0,58 (0,42- 0,79), p<0,0001]. En conclusión, estos resultados señalan que los ACODs son una buena alternativa para el uso terapéutico en FA y TVP, con una eficacia similar a la warfarina pero una ligera ventaja en la reducción del riesgo hemorrágico.
Abstract.
New oral anticoagulants (NOACs) have become an alternative for patients receiving long-term anticoagulation in atrial fibrillation (AF) and deep vein thrombosis (DVT). Studies of non-inferiority between NOACs and warfarin are designed to demonstrate that the former maintain at least the same efficacy and better safety in hemorrhagic events than warfarin. A systematic review and meta-analysis of randomized controlled trials was conducted in atrial fibrillation (AF) and deep vein thrombosis (DVT). The primary event was stroke (ischemic stroke and systemic embolism) for AF, recurrent venous thrombosis for DVT and the safety event was major bleeding for both pathologies. In AF, the analysis showed equivalence and significant reduction of NOACs compared to warfarin, with a 24% reduction in the relative risk [RR (IC95%)=0.76 (0.69-0.84), p<0.001]. In the safety analysis, all studies did not reveal differences with warfarin and the overall result showed a non-significant risk reduction of 14% [RR (IC95%)=0.86 (0.76-1.01), p=0.058]. For DVT, all studies showed non-inferiority criteria in comparison with warfarin [RR (IC95%) = 0.93 (0.79-1.08), p=0,372]. The safety analysis indicated superiority of NOACs over warfarin in all studies. The combined result revealed that there was a significant reduction of the risk of bleeding (42%) in favor of NOACs compared to warfarin [RR (IC95%) = 0.58 (0.42-0.79), p<0.0001]. In conclusion, these results showed that NOACs are a good alternative for therapeutic use in AF and DVT, with similar efficacy on warfarin but with a slight advantage in the reduction of hemorrhagic risk.
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References
Pirmohamed M. Warfarin: almost 60 years old and still causing problems. Br J Phama- col 2006;62:509-511.
Quintero González JA. Cincuenta años de uso clínico de la warfarina. Invest Clin 2010;51:269-287.
Pérez Requejo JL, Martínez Gutiérrez E, Castillo González E, Ettedgui de Pérez G. Nuevos paradigmas en anticoagulación oral. http://svcardiologia.org/es/index. php/publicaciones/e-books/463, 2016.
Quintero J, Torres E, Diez-Ewald M, Ar- teaga-Vizcaíno M, Vizcaíno G, León M, Rodríguez Z, Fernández N. Uso de warfa- rina y bajo rango de INR en la prevención de trombosis venosa recurrente. Invest Clin 2011;52:230–238.
Ridker PM, Goldhaber SZ, Danielson E, Rosenberg Y, Eby CS, Deitcher SR, Cus- hman M, Moll S, Kessler CM, Elliott CG, Paulson R, Wong T, Bauer KA, Schwartz BA, Miletich JP, Bounameaux H, Glynn RJ; PREVENT Investigators. Long-term, low-intensity warfarin therapy for the pre- vention of recurrent venous thromboembo- lism. N Engl J Med 2003;348:1425-1434.
Kearon C, Ginsberg JS, Kovacs MJ, An- derson DR, Wells P, Julian JA, MacKin- non B, Weitz JI, Crowther MA, Dolan S, Turpie AG, Geerts W, Solymoss S, van Nguyen P, Demers C, Kahn SR, Kassis J, Rodger M, Hambleton J, Gent M; Exten- ded Low-Intensity Anticoagulation for Thrombo-Embolism Investigators. Com- parison of low-intensity warfarin therapy with conventional-intensity warfarin the- rapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med 2003;349:631-639.
Pengo V. Management of oral anticoagu- lant treatment in patients with venous thromboembolism. Semin Thromb Hemost 2006;32:781-786.
Van Spall HGC, Salim Yusuf LW, Eikel- boom JW, Nieuwlaat R, Yang S, Kabali C, Reilly PA, Ezekowitz MD, Connolly SJ. Va- riation in warfarin dose adjustment practice is responsible for differences in the quality of anticoagulation control between centers and countries. An analysis of patients recei- ving warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE- LY) Trial. Circulation 2012;126:2309-2316.
Vestergaard AS, Skjøth F, Larsen TB, Ehlers LH. The importance of mean time in therapeutic range for complication ra- tes in warfarin therapy of patients with atrial fibrillation: A systematic review and meta-regression analysis. PLoS One 2017;12(11):e0188482. doi: 10.1371/journal.pone.0188482.
Xiong Q, La YC, Lip GY. Pharmacodyna- mic profile and drug interactions with non- vitamin K antagonist oral anticoagulants: implications for patients with atrial fibri- llation. Expert Opin Drug Metab Toxicol 2015;11:937-948.
Hellwig T, Gulseth M. Pharmacokinetic and pharmacodynamic drug interactions with new oral anticoagulants: what do they mean for patients with atrial fibrillation? Ann Pharmacother 2013;47:1478-1487.
Hylek EM. Anticoagulation therapy for atrial fibrillation. Semin Thromb Hemost 2013;39:147-152.
Ahrens I, Lip GY, Peter K. New oral anti- coagulant drugs in cardiovascular disease. Thromb Haemost 2010;104:49–60.
Ferreira-González I. Bases para la inter- pretación de los estudios de no inferiori- dad: a propósito de los estudios ROCKET– AF, RE-LY y ARISTOTLE. Rev Esp Cardiol 2014;67(6):432–435.
ICH Expert Working Group (1998) Statisti- cal principles for clinical trials E9.Available from www.ich.org.
Committee for Medicinal Products for Hu- man Use (CHMP). Guideline on the choi- ce of the non-inferiority margin. Stat Med 2006;25(10):1628-1638.
Committee for Proprietary Medicinal Pro- ducts (CPMP). Points to consider on swit- ching between superiority and non-inferio- rity. (2000). Available from https://www. ema.europa.eu. CPMP/EWP/482/99.
Hylek EM, Go AS, Chang Y, Jensvold NG, Henault LE, Selby JV, Singer DE. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003;349:1019–1026.
Kearon C, Akl EA, Comerota AJ, Pran- doni P, Bounameaux H, Goldhaber SZ, Nelson ME, Wells PS, Gould MK, Dentali F, Crowther M, Kahn SR. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians, Evidence-Based Clinical Practice Guide- lines. Chest 2012;141(2 Suppl):e419S- e496S. doi: 10.1378/chest.11-2301.
Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G. Oral anticoagulant therapy: antithrombotic the- rapy and prevention of thrombosis, 9th ed: American College of Chest Physicians, Evi- dence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e44S-e88S. doi: 10.1378/chest.11-2292.
Dentali F, Riva N, Crowther M, Turpie AGG, Lip GYH, Ageno W. Efficacy and safety of the novel oral anticoagulants in atrial fibrillation. A systematic review and meta-analysis of the literature. Circulation 2012;126:2381-2391.
Gómez-Outes A, Terleira-Fernández AI, Calvo-Rojas G, Suárez-Gea MA, Vargas- Castrillón E. Dabigatran, rivaroxaban, or apixaban versus warfarin in patients with nonvalvular atrial fibrillation: a systema- tic review and meta-analysis of subgroups. Thrombosis 2013;2013:640723. doi: 10.1 155/2013/640723.
Fox BD, Kahn SR, Langleben D, Eisen- berg MJ, Shimony A. Efficacy and safety of novel oral anticoagulants for treatment of acute venous thromboembolism: direct and adjusted indirect meta-analysis of randomi- sed controlled trials. BMJ 2012;345:e7498, doi:10.1136/bmj.e7498.
Connolly, SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L. Newly identified events in the RE-LY Trial. N Engl J Med 2010;363(19):1875–1876.
Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al- Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Ger- sh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-992.
Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Hal- perin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM; ROCKET AF Investi- gators. Rivaroxaban versus warfarin in non- valvular atrial fibrillation. N Engl J Med 2011;365:883-891.
Giugliano RP, Ruff CT, Braunwald E, Mur- phy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Špinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I, Han- yok JJ, Mercuri M, Antman EM; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093-2104.
Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboem- bolism. N Engl J Med 2013;369:799-808
The EINSTEIN Investigators. Oral rivaro- xaban for symptomatic venous thromboem- bolism. N Engl J Med 2010;363:2499-2510.
The EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of sympto- matic pulmonary embolism. N Engl J Med 2012;366:1287–1297.
Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, Christiansen AV, Friedman J, Le Maulf F, Peter N, Kearon C; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2013;129:764–772.
The Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symp- tomatic venous thromboembolism. N Engl J Med 2013;369:1406–1415.
Schulman S, Kearon C, Kakkar AK, Sche- llong S, Eriksson H, Baanstra D, Kvamme AM, Friedman J, Mismetti P, Goldhaber SZ; RE-MEDY Trial Investigators; RE- SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013;368:709–718.
Schulman S, Kearon C. Subcommittee on Control of Anticoagulation of the Scienti- fic and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemosta- tic medicinal products in non-surgical pa- tients. J Thromb Haemost 2005;3:692–694.
Vizcaíno G. La Estadística al alcance del Médico. Análisis crítico de ensayos clínicos. Capítulo III. Los estudios de no inferioridad en clínica médica. Ediciones Astro Data, ISBN 978-980-402-254-5, Maracaibo, pp 153.
Hung HM, Wang SJ, Tsong Y, Lawrence J, O’neil RT. Some fundamental issues with non-inferiority testing in active controlled trials. Stat Med 2003;22:213-225.
Pluchino S. Estudios clínicos de no infe- rioridad y de equivalencia: metodología, análisis e interpretación de los resultados. Avances Cardiol 2009; 29:76-81.
Hart RG, Benavente O, McBride R, Pear- ce LA. Antithrombotic therapy to pre- vent stroke in patients with atrial fibri- llation: a meta-analysis. Ann Intern Med 1999;131:492-501.
Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta- analyses: the PRISMA statement. PLoS Med 2009;6(7):e1000097. doi: 10.1371/journal.pmed.1000097.
Higgins JPT, Thompson SG, Deeks JJ, Alt- man DG. Measuring inconsistency in meta- analyses. BMJ 2003;327:557-560.
Sjögren V, Byström B, Renlund H, Svens- son PJ, Oldgren J, Norrving B, Själander Non-vitamin K oral anticoagulants are non-inferior for stroke prevention but cause fewer major bleedings than well-managed warfarin: A retrospective register study. PLoS One 2017;12(7): e0181000. Published online 2017 Jul 10. doi: 10.1371/jour- nal.pone.018100.
Almutairi AR, Zhou L, Gellad WF, Lee JK, Slack MK, Martin JR, Lo-Ciganic WH. Effectiveness and safety of non-vitamin K antagonist oral anticoagulants for atrial fi- brillation and venous thromboembolism: a systematic review and meta-analyses. Clin Ther 2017;39(7):1456-1478.
Yao X, Abraham NS, Sangaralingham LR, Bellolio F, McBane RD, Shah ND, Nosewor- thy PA. Effectiveness and safety of dabiga- tran, rivaroxaban, and apixaban versus war- farin in non-valvular atrial fibrillation. J Am Heart Assoc 2016;5:e003725 doi: 10.1161/ JAHA.116.003725.
Banerjee A, Lane DA, Torp-Pedersen C, Lip GY. Net clinical benefit of new oral anti- coagulants (dabigatran, rivaroxaban, apixa- ban) versus no treatment in a ‘real world’ atrial fibrillation population: A modelling analysis based on a nationwide cohort stu- dy. Thromb Haemost 2012;107:584-589.
Escobar C, Martí-Almor J, Pérez Cabeza A, Martínez-Zapata MJ. Direct oral anticoagu- lants versus vitamin K antagonists in real-life patients with atrial fibrillation. A systematic review and meta-analysis. Rev Esp Cardiol (Engl Ed). 2019;72(4):305-316.
Cha MJ, Choi EK, Han KD, Lee SR,Lim WH, Oh S, Lip GY. Effectiveness and safety of non-vitamin K antagonist oral anticoagu- lants in Asian patients with atrial fibrilla- tion. Stroke 2017;48:00-00. Doi: 10.1161/ STROKEAHA.117.018773.
Coleman CI, Antz M, Bowrin K, Evers T, Simard EP, Bonnemeier H, Cappato R. Real-world evidence of stroke prevention in patients with non valvular atrial fibrillation in the United States: the REVISIT-US Study. Curr Med Res Opin 2016;32:2047-2053.
Mantha S, Ansell J. An indirect compari- son of dabigatran, rivaroxaban and apixa- ban for atrial fibrillation. Thromb Haemost 2012;108:476-484.
Lip GY, Larsen TB, Skjøth F, Rasmussen LH. Indirect comparisons of new oral anti- coagulant drugs for efficacy and safety when used for stroke Prevention in Atrial Fibrilla- tion. J Am Coll Cardiol 2012;60:738–746.
Skjøth F, Larsen TB, Rasmussen LH, Lip GY. Efficacy and safety of edoxaban in comparison with dabigatran, rivaroxaban and apixaban for stroke prevention in atrial fibrillation. Thromb Haemost 2014;111: 981-998.
Mantha S, Ansell J. Indirect comparison of dabigatran, rivaroxaban, apixaban and edoxaban for the treatment of acute venous thromboembolism. J Thromb Thrombolysis 2015;39:155-165.
Ansell J. New oral anticoagulants should not be used as first-line agents to prevent thromboembolism in patients with atrial fibrillation. Circulation 2012;125:165–170.
Granger CB, Armaganijan LV. Newer oral anticoagulants should be used as first-line agents to prevent thromboembolism in pa- tients with atrial fibrillation and risk fac- tors for stroke or thromboembolism. Circu- lation 2012;125:159–164.
Goldhaber SZ. What’s the “go to” anticoagu- lant for stroke prevention in atrial fibrillation? Thromb Haemost 2012;107(03):397-398.
Adam SS, McDuffie JR, Ortel TL, Williams Jr JW. Comparative effectiveness of warfa- rin and new oral anticoagulants for the ma- nagement of atrial fibrillation and venous thromboembolism. A systematic review. Ann Intern Med 2012;157:796-807.
Wallentin L, Yusuf S, Ezekowitz MD, Alings M, Flather M, Franzosi MG, Pais P, Dans A, Eikelboom J, Oldgren J, Pogue J, Reilly PA, Yang S, Connolly SJ; RE-LY investigators. Efficacy and safety of dabi- gatran compared with warfarin at different levels of international normalised ratio con- trol for stroke prevention in atrial fibrilla- tion: an analysis of the RE-LY trial. Lancet 2010;376: 975–983.
Nedeltche K. Critique of apixaban versus warfarin in patients with atrial fibrillation. Stroke 2012;43:922-923, doi: 10.1161/ STROKEAHA.111.640961.
Goette A, Merino JL, Ezekowitz MD, Za- moryakhin D, Melino M, Jin J, Mercuri MF, Grosso MA, Fernandez V, Al-Saady N, Pelekh N, Merkely B, Zenin S, Kush- nir M, Spinar J, Batushkin V, de Groot JR, Lip GY; ENSURE-AF investigators. Edoxaban versus enoxaparin–warfarin in patients undergoing cardioversion of atrial fibrillation (ENSURE-AF): A rando- mised, open-label, phase 3b trial. Lancet 2016;388(10055):1995-2003.
Witt DM, Nieuwlaat R, Clark NP, Ansell J, Holbrook A, Skov J, Shehab N, Mock J, Myers T, Dentali F, Crowther MA, Agarwal A, Bhatt M, Khatib R, Riva JJ, Zhang Y, Guyatt G. American Society of Hematolo- gy 2018 guidelines for management of ve- nous thromboembolism: optimal manage- ment of anticoagulation therapy. Blood Adv 2018;2(22):3257–3291.
Hohnloser SH, Fudim M, Alexander JH, Wojdyla DM, Ezekowitz JA, Hanna M, Atar D, Hijazi Z, Bahit MC, Al-Khatib SM, Lopez-Sendon J, Wallentin L, Granger CB, Lopes RD. Efficacy and safety of apixa- ban versus warfarin in patients with atrial fibrillation and extremes in body weight: insights from the ARISTOTLE Trial. Circu- lation. 2019;139:2292–2300.
Forslund T, Wettermark B, Andersen M, Hjemdahl P. Stroke and bleeding with non-vitamin K antagonist oral anticoa- gulant or warfarin treatment in patients with non-valvular atrial fibrillation: a po- pulation-based cohort study. Europace 2018;20(3):420-428.
