Meta-Analysis of Randomized Controlled Trials on Risk of Myocardial Infarction from the Use of Oral Direct Thrombin Inhibitors

Dabigatran has been associated with greater risk of myocardial infarction (MI) than warfarin. It is unknown whether the increased risk is unique to dabigatran, an adverse effect shared by other oral direct thrombin inhibitors (DTIs), or the result of a protective effect of warfarin against MI. To address these questions, we systematically searched MEDLINE and performed a meta-analysis on randomized trials that compared oral DTIs with warfarin for any indication with end point of MIs after randomization. We furthermore performed a secondary meta-analysis on atrial fibrillation stroke prevention trials with alternative anticoagulants compared with warfarin with end point of MIs after randomization. A total of 11 trials (39,357 patients) that compared warfarin to DTIs (dabigatran, ximelagatran, and AZD0837) were identified. In these trials, patients treated with oral DTIs were more likely to experience an MI than their counterparts treated with warfarin (285 of 23,333 vs 133 of 16,024, odds ratio 1.35, 95% confidence interval 1.10 to 1.66, p = 0.005). For secondary analysis, 8 studies (69,615 patients) were identified that compared warfarin with alternative anticoagulant including factor Xa inhibitors, DTIs, aspirin, and clopidogrel. There was no significant advantage in the rate of MIs with the use of warfarin versus comparators (odds ratio 1.06, 95% confidence interval 0.85 to 1.34, p = 0.59). In conclusion, our data suggest that oral DTIs were associated with increased risk of MI. This increased risk appears to be a class effect of these agents, not a specific phenomenon unique to dabigatran or protective effect of warfarin. These findings support the need for enhanced postmarket surveillance of oral DTIs and other novel agents. Dabigatran has been associated with greater risk of myocardial infarction (MI) than warfarin. It is unknown whether the increased risk is unique to dabigatran, an adverse effect shared by other oral direct thrombin inhibitors (DTIs), or the result of a protective effect of warfarin against MI. To address these questions, we systematically searched MEDLINE and performed a meta-analysis on randomized trials that compared oral DTIs with warfarin for any indication with end point of MIs after randomization. We furthermore performed a secondary meta-analysis on atrial fibrillation stroke prevention trials with alternative anticoagulants compared with warfarin with end point of MIs after randomization. A total of 11 trials (39,357 patients) that compared warfarin to DTIs (dabigatran, ximelagatran, and AZD0837) were identified. In these trials, patients treated with oral DTIs were more likely to experience an MI than their counterparts treated with warfarin (285 of 23,333 vs 133 of 16,024, odds ratio 1.35, 95% confidence interval 1.10 to 1.66, p = 0.005). For secondary analysis, 8 studies (69,615 patients) were identified that compared warfarin with alternative anticoagulant including factor Xa inhibitors, DTIs, aspirin, and clopidogrel. There was no significant advantage in the rate of MIs with the use of warfarin versus comparators (odds ratio 1.06, 95% confidence interval 0.85 to 1.34, p = 0.59). In conclusion, our data suggest that oral DTIs were associated with increased risk of MI. This increased risk appears to be a class effect of these agents, not a specific phenomenon unique to dabigatran or protective effect of warfarin. These findings support the need for enhanced postmarket surveillance of oral DTIs and other novel agents. The use of the oral direct thrombin inhibitor (DTI), dabigatran, was associated with lower rates of stroke and systemic embolism compared with warfarin demonstrated in the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial.1Connolly S.J. Ezekowitz M.D. Yusuf S. Eikelboom J. Oldgren J. Parekh A. Pogue J. Reilly P.A. Themeles E. Varrone J. Wang S. Alings M. Xavier D. Zhu J. Diaz R. Lewis B.S. Darius H. Diener H.C. Joyner C.D. Wallentin L. N Engl J Med. 2009; 361: 1139-1151Crossref PubMed Scopus (9303) Google Scholar The study also revealed that a higher rate of clinical myocardial infarction (MI) was observed with dabigatran than with warfarin that was found to be statistically not significant in the post hoc analysis.2Hohnloser S.H. Oldgren J. Yang S. Wallentin L. Ezekowitz M. Reilly P. Eikelboom J. Brueckmann M. Yusuf S. Connolly S.J. Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY trial.Circulation. 2012; 125: 669-676Crossref PubMed Scopus (337) Google Scholar A recent meta-analysis revealed that the rate of coronary events was increased with the use of dabigatran compared with various types of controls.3Uchino K. Hernandez A.V. Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials.Arch Intern Med. 2012; 172: 397-402Crossref PubMed Scopus (433) Google Scholar Ximelagatran, another oral thrombin inhibitor no longer available for clinical use, was associated with a significantly increased risk of myocardial ischemia compared with warfarin in patients who had acute deep vein thrombosis.4Fiessinger J.N. Huisman M.V. Davidson B.L. Bounameaux H. Francis C.W. Eriksson H. Lundström T. Berkowitz S.D. Nyström P. Thorsén M. Ginsberg J.S. Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis: a randomized trial.JAMA. 2005; 293: 681-689Crossref PubMed Scopus (329) Google Scholar It has been proposed that warfarin might provide a protective effect against MI compared with non-warfarin anticoagulants in patients with atrial fibrillation who are prescribed anticoagulation for stroke thromboprophylaxis.5Lip G.Y. Lane D.A. Does warfarin for stroke thromboprophylaxis protect against MI in atrial fibrillation patients?.Am J Med. 2010; 23: 785-789Abstract Full Text Full Text PDF Scopus (106) Google Scholar The purpose of this study was twofold. The first objective was to investigate whether the excess rate of MIs with dabigatran compared with warfarin was related to the effect of dabigatran alone or was an effect consistent for the entire class of oral DTIs. The second objective was to evaluate whether the use of warfarin indeed is associated with less incidence of MI in the more recent large-scale atrial fibrillation stroke prevention trials compared with non-warfarin anticoagulants. This meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.6Liberati A. Altman D.G. Tetzlaff J. Mulrow C. Gøtzsche P.C. Ioannidis J.P. Clarke M. Devereaux P.J. Kleijnen J. Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.J Clin Epidemiol. 2009; 62: e1-e34Abstract Full Text Full Text PDF PubMed Scopus (7844) Google Scholar To reduce the signal-to-noise ratio, a deliberate decision was made to include only the data on “myocardial infarction” as compared with “acute coronary syndrome” or other coronary ischemia related terms that are more likely to be influenced by subjective interpretation because detailed description of clinical history at the time of initial presentation or information on electrocardiographic changes, cardiac enzyme levels, and the result of possible coronary ischemia evaluation was not disclosed in the individual published trials. Based on the objectives of the study, we performed 2 separate systematic literature searches. To address the observation of incidence of MI in trials with oral DTIs, we searched MEDLINE, Embase, and the Cochrane Collaboration, up to March 2013 using key words: “oral,” “direct thrombin inhibitor” with the limiting term “clinical trial” without language or publication date restrictions. We then performed a secondary search using the individual agent name: “dabigatran” with the limiting term “clinical trial,” “ximelagatran” with the limiting term “clinical trial,” and lastly “AZD0837” and “sofigatran” with no limitations. Studies were included in meta-analysis if (1) the comparison between an oral DTI and warfarin was made for any indication and (2) the occurrence of MI after randomization was reported by investigators by any definition. Regarding the possible protective effect of warfarin in preventing MI in more recent atrial fibrillation stroke prevention trials, we performed a MEDLINE search using the PubMed medical subject heading database using terms: “atrial fibrillation,” “stroke prevention and control,” “anticoagulants/therapeutic use,” and “warfarin/therapeutic use” with the limiting term of “randomized trials” and time limit of “10 years.” Studies were included in the meta-analysis if (1) comparison between warfarin and any alternative antithrombotic agent was performed and (2) the occurrence of MI after randomization was reported by investigators by any definition. The data were analyzed using Comprehensive Meta-Analysis, version 2 (Biostat, Englewood, New Jersey). The pooled odds ratio (OR) with 95% confidence interval (CI) for MI was calculated using the fixed-effects Mantel-Haenszel model, whereas in the case of significant heterogeneity across studies, the random-effects model was used instead. The likelihood of statistical heterogeneity was assessed using the Cochrane Q test and quantified with the I² statistic. An I² >50% was considered statistically significant heterogeneity. In addition, an influence analysis, in which meta-analysis estimates are computed omitting 1 study at a time, was performed for the primary end point. Publication bias was evaluated with the funnel plot and the Egger regression test. The results of the literature search on oral DTIs versus warfarin are shown in Figure 1. A total of 676 publications were identified and screened. Of those, 14 full-text manuscripts were found eligible for detail review. Eleven randomized controlled trials fulfilled the inclusion criteria and were selected for meta-analysis, with the total number of 39,357 participants. The individual study details are listed in Table 1. The MI definition was prespecified in the trial design in less than half of the studies. None of the studies had prespecified definition of other ischemic coronary terms such as “acute coronary syndrome,” “ischemic coronary event,” or “unstable angina.” Overall, the entire cohort of oral DTIs was associated with a significantly higher rate of MI compared with warfarin. MI was reported in 285 of 23,333 subjects treated with oral DTIs versus 133 of 16,024 subjects treated with warfarin, with an OR of 1.35 (95% CI 1.10 to 1.66), p = 0.005 using the fixed-effects model. There was no significant heterogeneity among the studies (Q = 15.3, degree of freedom [DF] = 9, I2 = 41.1% and P = 0.084 for heterogeneity; Figure 2). Among the 4 trials that compared dabigatran to warfarin, there were significantly higher rates of MI among those randomized to dabigatran. These included 212 out of 14,954 subjects treated with dabigatran versus 78 out of 8,803 subjects treated with warfarin (OR 1.41, 95% CI 1.09 to 1.83, p = 0.009, Q = 4.5, DF = 3, I2 = 33.2% and P = 0.21 for heterogeneity).Table 1Characteristics of the included randomized controlled trials of oral direct thrombin inhibitor compared with warfarinStudy NamePopulationDesignPrimary End PointNumber of SubjectsPrespecified MI Definition∗The original study publication and additional publications including supplementary appendices and trial design publications were screened for prespecified definition of MI or any related terms as any type of end point or an adverse event after randomization.Thrombin Inhibitor†Comparison in this table was against adjusted dose warfarin to an international normalized ratio of 2.0-3.0.Duration (Mo)RE-LY2Hohnloser S.H. Oldgren J. Yang S. Wallentin L. Ezekowitz M. Reilly P. Eikelboom J. Brueckmann M. Yusuf S. Connolly S.J. Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY trial.Circulation. 2012; 125: 669-676Crossref PubMed Scopus (337) Google and and S. C. P. S. Eriksson H. D. J. Engl J Med. 2009; 361: PubMed Scopus Google or related S. C. S. Eriksson H. D. J. P. use of dabigatran, warfarin, or in Engl J Med. PubMed Scopus Google or related study acute coronary were evaluated and by The details be available as a separate This is not available in the or The study had end point that also included dabigatran and was The study was was for the of MI among other end and of the prevention with the oral direct thrombin inhibitor compared with warfarin in patients with atrial fibrillation controlled Full Text Full Text PDF PubMed Scopus Google and Diener H.C. L. M. M. S. J. P. A. Ximelagatran vs warfarin for stroke prevention in patients with atrial a randomized trial.JAMA. 2005; 293: PubMed Scopus Google and J.N. Huisman M.V. Davidson B.L. Bounameaux H. Francis C.W. Eriksson H. Lundström T. Berkowitz S.D. Nyström P. Thorsén M. Ginsberg J.S. Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis: a randomized trial.JAMA. 2005; 293: 681-689Crossref PubMed Scopus (329) Google A and C.W. Berkowitz S.D. P.C. Ginsberg J.S. J. C.W. of with warfarin for the prevention of after total Engl J Med. PubMed Scopus Google C.W. Berkowitz S.D. P.C. Ginsberg J.S. J. Francis C.W. direct thrombin inhibitor compared with warfarin for the prevention of after total 2005; PubMed Scopus Google The of and the Clin Full Text Full Text PDF PubMed Scopus Google and and G.Y. Eriksson direct thrombin inhibitor for the prevention of stroke and systemic embolism in patients with atrial a randomized and study of of J. 2009; PubMed Scopus Google and dose and adverse to and A. E. P. S. 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The study was by the number of studies the comparison between thrombin inhibitors and warfarin, there were only 11 studies the RE-LY trial had a of the influence revealed that the result of the meta-analysis was consistent without the RE-LY The study was by information MI events in individual trials that were screened including time to In the to trials, the MI data were not disclosed in the original publications and were a published and The of and the Clin Full Text Full Text PDF PubMed Scopus Google Scholar The Dabigatran or compared with alone in patients with not included in this analysis, reported of of 2 were as acute coronary in the with various of dabigatran compared with no ischemic events in the warfarin the definition of or acute coronary was not prespecified in the trial M.D. Reilly P.A. R. K. D.A. J. Wallentin L. Dabigatran with or without compared with warfarin alone in patients with atrial fibrillation J Full Text Full Text PDF PubMed Scopus Google Scholar It is for the studies on any class of to and data on types of adverse events including MI at of We to for in the The no of to of Myocardial Based on of direct thrombin inhibitors been to the risk of myocardial infarction The meta-analysis by has this by 2 separate (1) there an excess rate of MI that be to (2) Does warfarin reduce the incidence of MI to a greater than Based on 2 separate data of randomized controlled trials, their findings by that DTIs are associated with an increased risk of MI and that warfarin not the other anticoagulants in the risk of MI. PDF