Risk of myocardial infarction and death in patients with atrial fibrillation treated with dabigatran or vitamin K antagonists

Walid Darwiche; Theodora Bejan-Angoulvant; Denis Angoulvant; Dominique Babuty; Laurent Fauchier

doi:10.1160/TH16-06-0483

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2016; 116(06): 1150-1158
DOI: 10.1160/TH16-06-0483

Stroke, Systemic or Venous Thromboembolism

Schattauer GmbH

Risk of myocardial infarction and death in patients with atrial fibrillation treated with dabigatran or vitamin K antagonists

Meta-analysis of observational analyses

Authors

Walid Darwiche

¹Cardiologie, Pole Cœur Thorax Vasculaire, Centre Hospitalier Universitaire Trousseau et Faculté de Médecine, Université Francois Rabelais, Tours, France
Theodora Bejan-Angoulvant

¹Cardiologie, Pole Cœur Thorax Vasculaire, Centre Hospitalier Universitaire Trousseau et Faculté de Médecine, Université Francois Rabelais, Tours, France
Denis Angoulvant

¹Cardiologie, Pole Cœur Thorax Vasculaire, Centre Hospitalier Universitaire Trousseau et Faculté de Médecine, Université Francois Rabelais, Tours, France
Dominique Babuty

¹Cardiologie, Pole Cœur Thorax Vasculaire, Centre Hospitalier Universitaire Trousseau et Faculté de Médecine, Université Francois Rabelais, Tours, France
Laurent Fauchier

¹Cardiologie, Pole Cœur Thorax Vasculaire, Centre Hospitalier Universitaire Trousseau et Faculté de Médecine, Université Francois Rabelais, Tours, France

Abstract

Summary

The safety of dabigatran versus adjusted-dose vitamin K antagonist (VKA) treatment is the subject of debate. We evaluated the risk of myocardial infarction (MI) or mortality in patients with atrial fibrillation (AF) treated in clinical practice with dabigatran or a VKA. We performed a meta-analysis of observational studies that included an adjusted or matched analysis and reported MI, or death in AF patients treated with dabigatran or a VKA. Ten published analyses met the inclusion criteria. Of the 539,559 patients, 17,365 (3%) patients were on dabigatran 110 mg twice daily (bid), 150,948 (28%) were on dabigatran 150 mg bid, and 371,246 (69%) were on VKA. Adjusted risk for MI versus VKA was 0.71 (0.47–1.07; p=0.10) in patients starting oral anticoagulant (OAC) treatment with dabigatran 110 mg, 0.82 (0.71–0.96; p=0.01) in patients starting dabigatran 150 mg, 1.40 (1.04–1.88; p=0.03) in patients switching OAC treatment to dabigatran 110 mg, and 1.28 (0.88–1.87; p=0.19) in patients switching OAC treatment to dabigatran 150 mg, with statistical homogeneity in each subgroup. Risk of death was consistently lower in patients treated with dabigatran 110 mg (HR 0.79; 0.65–0.96; p=0.02) or 150 mg (HR 0.65; 0.57–0.73; p<0.00001) versus VKA. In conclusion, dabigatran use, as currently prescribed in routine practice for AF patients, was associated with a lower risk of MI in OAC-naïve patients treated with dabigatran 150 mg compared with VKA, and a higher risk of MI in patients switching from VKA to dabigatran 110 mg. Risk of death was lower in AF patients treated with either dose of dabigatran versus VKA.

Keywords

Atrial fibrillation - dabigatran - myocardial infarction - vitamin K antagonist

Full Text

References

References
1 Ruff CT, Giugliano RP, Braunwald E. et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a metaanalysis of randomised trials. Lancet 2014; 383: 955-962.
2 Davidson BL. The association of direct thrombin inhibitor anticoagulants with cardiac thromboses. Chest 2015; 147: 21-24.
3 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
4 Southworth MR, Reichman ME, Unger EF. Dabigatran and postmarketing reports of bleeding. N Engl J Med 2013; 368: 1272-1274.
5 Sørensen R, Gislason G, Torp-Pedersen C. et al. Dabigatran use in Danish atrial fibrillation patients in 2011: a nationwide study. BMJ Open 2013 03.
6 Stroup DF, Berlin JA, Morton SC. et al. Metaanalysis of observational studies in epidemiology: a proposal for reporting. Metaanalysis Of Observational Studies in Epidemiology (MOOSE) group. J Am Med Assoc 2000; 283: 2008-2012.
7 Wells GA, Shea B, O’Connell D. et al. Newcastle–Ottawa Scale. Available at: http://www.lrica.programsceuoxford.htm
8 Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959; 22: 719-748.
9 DerSimonian R, Laird N. Metaanalysis in clinical trials. Control Clin Trials 1986; 07: 177-188.
10 Higgins JPT, Thompson SG, Deeks JJ. et al. Measuring inconsistency in metaanalyses. Br Med J 2003; 327: 557-560.
11 Larsen TB, Rasmussen LH, Skjøth F. et al. Efficacy and safety of dabigatran etexilate and warfarin in ‘real-world’ patients with atrial fibrillation: a prospective nationwide cohort study. J Am Coll Cardiol 2013; 61: 2264-2273.
12 Larsen TB, Rasmussen LH, Gorst-Rasmussen A. et al. Myocardial ischemic events in ‘real world’ patients with atrial fibrillation treated with dabigatran or warfarin. Am J Med 2014; 127: 329-336. e4.
13 Larsen TB, Skjøth F, Nielsen PB. et al. Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study. Br Med J 2016; 353: 3189.
14 Vaughan Sarrazin MS, Jones M, Mazur A. et al. Bleeding rates in Veterans Affairs patients with atrial fibrillation who switch from warfarin to dabigatran. Am J Med 2014; 127: 1179-1185.
15 Graham DJ, Reichman ME, Wernecke M. et al. Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation. Circulation 2015; 131: 157-164.
16 Bouillon K, Bertrand M, Maura G. et al. Risk of bleeding and arterial thromboembolism in patients with nonvalvular atrial fibrillation either maintained on a vitamin K antagonist or switched to a nonvitamin K-antagonist oral anticoagulant: a retrospective, matchedcohort study. Lancet Haematol 2015; 02: e150-159.
17 Lauffenburger JC, Farley JF, Gehi AK. et al. Effectiveness and safety of dabigatran and warfarin in real-world US patients with nonvalvular atrial fibrillation: a retrospective cohort study. J Am Heart Assoc 2015; 04: e001798.
18 Villines TC, Schnee J, Fraeman K. et al. A comparison of the safety and effectiveness of dabigatran and warfarin in nonvalvular atrial fibrillation patients in a large healthcare system. Thromb Haemost 2015; 114: 1290-1298.
19 Avgil Tsadok M, Jackevicius CA, Rahme E. et al. Sex Differences in Dabigatran Use, Safety, And Effectiveness In a Population-Based Cohort of Patients With Atrial Fibrillation. Circ Cardiovasc Qual Outcomes 2015; 08: 593-599.
20 Seeger JD, Bykov K, Bartels DB. et al. Safety and effectiveness of dabigatran and warfarin in routine care of patients with atrial fibrillation. Thromb Haemost 2015; 114: 1277-1289.
21 Ezekowitz MD, Wallentin L, Connolly SJ. et al. Dabigatran and Warfarin in Vitamin K Antagonist-Naive and -Experienced Cohorts With Atrial Fibrillation. Circulation 2010; 122: 2246-2253.
22 Uchino K, Hernandez AV. Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials. Arch Intern Med 2012; 172: 397-402.
23 Hohnloser SH, Oldgren J, Yang S. et al. Myocardial Ischemic Events in Patients With Atrial Fibrillation Treated With Dabigatran or Warfarin in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) Trial. Circulation 2012; 125: 669-676.
24 Anand SS, Yusuf S. Oral anticoagulant therapy in patients with coronary artery disease: a meta-analysis. J Am Med Assoc 1999; 282: 2058-2067.
25 Heidbuchel H, Verhamme P, Alings M. et al. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace 2015; 17: 1467-1507.
26 Oldgren J, Budaj A, Granger CB. et al. Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial. Eur Heart J 2011; 32: 2781-2789.
27 Artang R, Rome E, Nielsen JD. et al. Meta-analysis of randomized controlled trials on risk of myocardial infarction from the use of oral direct thrombin inhibitors. Am J Cardiol 2013; 112: 1973-1979.
28 Lip GYH, Lane DA. Does warfarin for stroke thromboprophylaxis protect against MI in atrial fibrillation patients?. Am J Med 2010; 123: 785-789.
29 Hohnloser SH, Lip GYH. Dabigatran and myocardial infarction. Chest 2015; 147: e70-71.
30 Frère C, Laine M, Paganelli F. et al. Antiplatelet properties of oral anticoagulants. Int J Cardiol 2015; 181: 413-414.
31 Lip GYH, Windecker S, Huber K. et al. Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary or valve interventions: a joint consensus document of the European Society of Cardiology Working Group on Thrombosis, European Heart Rhythm Association (EHRA), European Association of Percutaneous Cardiovascular Interventions (EAPCI) and European Association of Acute Cardiac Care (ACCA) endorsed by the Heart Rhythm Society (HRS) and Asia-Pacific Heart Rhythm Society (APHRS). Eur Heart J 2014; 35: 3155-3179.
32 Erkens PMG, ten Cate H, Büller HR. et al. Benchmark for time in therapeutic range in venous thromboembolism: a systematic review and meta-analysis. PloS One 2012; 07: e42269.
33 Dickersin K, Chan S, Chalmers TC. et al. Publication bias and clinical trials. Control Clin Trials 1987; 08: 343-353.
34 Pastori D, Pignatelli P, Saliola M. et al. Inadequate anticoagulation by Vitamin K Antagonists is associated with Major Adverse Cardiovascular Events in patients with atrial fibrillation. Int J Cardiol 2015; 201: 513-516.