Dabigatran etexilate and risk of myocardial infarction, other cardiovascular events, major bleeding, and all-cause mortality: A systematic review and meta-analysis of randomized controlled trials

Journal of the American Heart Association

Volumn 3, Issue 3, 2014, Pages

  Douxfils, Jonathan ^a   Buckinx, Fanny ^b   Mullier, François ^a,c   Minet, Valentine ^a   Rabenda, Većronique ^b   Reginster, Jean Yves ^b   Hainaut, Philippe ^d   Bruyére, Olivier ^b   Dogné, Jean Michel ^a  

^a University of Namur   (Belgium)

^b UNIVERSITY OF LIÈGE   (Belgium)

^c UNIVERSITY HOSPITAL OF MONT GODINNE   (Belgium)

^d CLINIQUES UNIVERSITAIRES SAINT LUC   (Belgium)

Author keywords

All cause mortality; Dabigatran etexilate; Major bleeding; Myocardial infarction

Indexed keywords

DABIGATRAN ETEXILATE; ENOXAPARIN; PLACEBO; WARFARIN; BENZIMIDAZOLE DERIVATIVE; BLOOD CLOTTING FACTOR 10A INHIBITOR; DABIGATRAN; PYRIDINE DERIVATIVE;

ACUTE CORONARY SYNDROME; ANTICOAGULANT THERAPY; ARTICLE; BLEEDING; CARDIOVASCULAR MORTALITY; CARDIOVASCULAR RISK; DEEP VEIN THROMBOSIS; DOSE RESPONSE; DRUG DOSE COMPARISON; HEART ATRIUM FIBRILLATION; HEART DEATH; HEART INFARCTION; HEART MUSCLE ISCHEMIA; HUMAN; LUNG EMBOLISM; META ANALYSIS; MORTALITY; OUTCOME ASSESSMENT; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); RECURRENT DISEASE; RISK ASSESSMENT; SYSTEMATIC REVIEW; THROMBOSIS PREVENTION; UNSTABLE ANGINA PECTORIS; VENOUS THROMBOEMBOLISM; CARDIOVASCULAR DISEASE; CHEMICALLY INDUCED; RISK FACTOR;

BENZIMIDAZOLES; CARDIOVASCULAR DISEASES; DABIGATRAN; FACTOR XA INHIBITORS; HEMORRHAGE; HUMANS; MORTALITY; MYOCARDIAL INFARCTION; PYRIDINES; RANDOMIZED CONTROLLED TRIALS AS TOPIC; RISK FACTORS; VENOUS THROMBOEMBOLISM;

EID: 84911464122     PISSN: None     EISSN: 20479980     Source Type: Journal    
DOI: 10.1161/JAHA.113.000515     Document Type: Article

References (54)

1. Hohnloser SH, Oldgren J, Yang S, Wallentin L, Ezekowitz M, Reilly P, Eikelboom J, Brueckmann M, Yusuf S, Connolly SJ. 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.
2. Dentali F, Riva N, Crowther M, Turpie AG, Lip GY, 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.
3. 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.
4. Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L; Randomized Evaluation of Long-Term Anticoagulation Therapy I. Newly identified events in the RE-LY trial. N Engl J Med. 2010;363:1875-1876.
5. Committee R-MW, Ginsberg JS, Davidson BL, Comp PC, Francis CW, Friedman RJ, Huo MH, Lieberman JR, Muntz JE, Raskob GE, Clements ML, Hantel S, Schnee JM, Caprini JA. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty. 2009;24:1-9.
6. Mak KH. Coronary and mortality risk of novel oral antithrombotic agents: a meta-analysis of large randomised trials. BMJ Open. 2012;2:e001592.
7. Sam Schulman AKK, Schellong SM, Goldhaber SZ, Henry E, Mismetti P, Christiansen AV, Schnee J, Kearon C. A randomized Trial of Dabigatran Versus Warfarin in the Treatment of Acute Venous Thromboembolism (RE-COVER II). American Society of Hematology 2011 Annual Meeting; December 12, 2011; San Diego, CA. Abstract 205, 2011.
8. Eikelboom JW, Connolly SJ, Brueckmann M, Granger CB, Kappetein AP, Mack MJ, Blatchford J, Devenny K, Friedman J, Guiver K, Harper R, Khder Y, Lobmeyer MT, Maas H, Voigt JU, Simoons ML, Van de Werf F; Investigators R-A. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013;369:1206-1214.
9. Roskell NS, Lip GY, Noack H, Clemens A, Plumb JM. Treatments for stroke prevention in atrial fibrillation: a network meta-analysis and indirect comparisons versus dabigatran etexilate. Thromb Haemost. 2010;104:1106-1115.
10. Oldgren J, Budaj A, Granger CB, Khder Y, Roberts J, Siegbahn A, Tijssen JG, Van de Werf F, Wallentin L; Investigators R-D. 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.
11. Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ; Group R-CS. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361:2342-2352.
12. Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, Kvamme AM, Friedman J, Mismetti P, Goldhaber SZ; Investigators R-MT, Investigators R-ST. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013;368:709-718.
13. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1-12.
14. Sweeting MJ, Sutton AJ, Lambert PC. What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Stat Med. 2004;23:1351-1375.
15. Bradburn MJ, Deeks JJ, Berlin JA, Russell Localio A. Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events. Stat Med. 2007;26:53-77.
16. Stijnen T, Hamza TH, Ozdemir P. Random effects meta-analysis of event outcome in the framework of the generalized linear mixed model with applications in sparse data. Stat Med. 2010;29:3046-3067.
17. Wang L, Wang G, Lu C, Feng B, Kang J. Contribution of the-160C/A polymorphism in the E-cadherin promoter to cancer risk: a meta-analysis of 47 case-control studies. PLoS ONE. 2012;7(7):e40219. doi:10.1371/journal.-pone.0040219.
18. Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, Vedel Christiansen A, Friedman J, Le Maulf F, Peter N, Kearon C; RECIIti. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2013;129:764-772.
19. Eriksson BI, Dahl OE, Buller HR, Hettiarachchi R, Rosencher N, Bravo ML, Ahnfelt L, Piovella F, Stangier J, Kalebo P, Reilly P; Group BIS. A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial. J Thromb Haemost. 2005;3:103-111.
20. Fuji T, Fuijita S, Ujihira T, Sato T. Dabigatran etexilate prevents venous thromboembolism after total knee arthroplasty in Japanese patients with a safety profile comparable to placebo. J Arthroplasty. 2010;25:1267-1274.
21. Eriksson BI, Dahl OE, Ahnfelt L, Kalebo P, Stangier J, Nehmiz G, Hermansson K, Kohlbrenner V. Dose escalating safety study of a new oral direct thrombin inhibitor, dabigatran etexilate, in patients undergoing total hip replacement: BISTRO I. J Thromb Haemost. 2004;2:1573-1580.
22. Ezekowitz MD, Reilly PA, Nehmiz G, Simmers TA, Nagarakanti R, Parcham-Azad K, Pedersen KE, Lionetti DA, Stangier J, Wallentin L. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study). Am J Cardiol. 2007;100:1419-1426.
23. Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, Prins MH, Hettiarachchi R, Hantel S, Schnee J, Buller HR. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet. 2007;370:949-956.
24. Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, Kalebo P, Christiansen AV, Hantel S, Hettiarachchi R, Schnee J, Buller HR; Group RMS. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost. 2007;5:2178-2185.
25. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; Committee R-LS and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151.
26. Eriksson BI, Dahl OE, Huo MH, Kurth AA, Hantel S, Hermansson K, Schnee JM, Friedman RJ; Group R-NIS. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A randomised, double-blind, non-inferiority trial. Thromb Haemost. 2011;105:721-729.
27. Ingelheim B. Clinical Study Results. Available at: http://trials.boehringeringelheim. com/trial_results/clinical_trials_overview/clinical_trial_result.c=n.i= 21.html. Accessed December 8, 2013.
28. Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, Hindricks G, Kirchhof P. Guidelines-CPG ESCCfP and Document R. 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. Europace: European pacing, arrhythmias, and cardiac electrophysiology: journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of. Cardiology. 2012;14:1385-1413.
29. Skanes AC, Healey JS, Cairns JA, Dorian P, Gillis AM, McMurtry MS, Mitchell LB, Verma A, Nattel S; Canadian Cardiovascular Society Atrial Fibrillation Guidelines C. Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate/rhythm control. Can J Cardiol. 2012;28:125-136
30. You JJ, Singer DE, Howard PA, Lane DA, Eckman MH, Fang MC, Hylek EM, Schulman S, Go AS, Hughes M, Spencer FA, Manning WJ, Halperin JL, Lip GY; American College of Chest P. Antithrombotic therapy for atrial fibrillation: antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e531S-e575S.
31. 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, Gersh 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; Committees A and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-992.
32. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Spinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM; Investigators EA-T. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369:2093-2104.
33. Cairns JA, Connolly S, McMurtry S, Stephenson M, Talajic M. Canadian Cardiovascular Society atrial fibrillation guidelines 2010: prevention of stroke and systemic thromboembolism in atrial fibrillation and flutter. Can J Cardiol. 2011;27:74-90.
34. Wann LS, Curtis AB, Ellenbogen KA, Estes NA III, Ezekowitz MD, Jackman WM, January CT, Lowe JE, Page RL, Slotwiner DJ, Stevenson WG, Tracy CM. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on dabigatran): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol. 2011;57:1330-1337.
35. Furie KL, Goldstein LB, Albers GW, Khatri P, Neyens R, Turakhia MP, Turan TN, Wood KA. Oral antithrombotic agents for the prevention of stroke in nonvalvular atrial fibrillation: a science advisory for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2012;43:3442-3453.
36. Larsen TB, Rasmussen LH, Skjoth F, Due KM, Callreus T, Rosenzweig M, Lip GY. 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.
37. Sipahi I, Celik S, Akyol A. Letter to the editor for ''Efficacy and safety of dabigatran etexilate and warfarin in 'real world' patients with atrial fibrillation'' by Larsen et al. J Am Coll Cardiol. 2013.
38. Effect of long-term oral anticoagulant treatment on mortality and cardiovascular morbidity after myocardial infarction. Anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis (ASPECT) Research Group. Lancet. 1994;343:499-503.
39. Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2002;347:969-974.
40. Lip GY, Lane DA. Does warfarin for stroke thromboprophylaxis protect against MI in atrial fibrillation patients? Am J Med. 2010;123:785-789.
41. American College of Emergency P, Society for Cardiovascular A, Interventions, O'Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, de Lemos JA, Ettinger SM, Fang JC, Fesmire FM, Franklin BA, Granger CB, Krumholz HM, Linderbaum JA, Morrow DA, Newby LK, Ornato JP, Ou N, Radford MJ, Tamis-Holland JE, Tommaso CL, Tracy CM, Woo YJ, Zhao DX, Anderson JL, Jacobs AK, Halperin JL, Albert NM, Brindis RG, Creager MA, DeMets D, Guyton RA, Hochman JS, Kovacs RJ, Kushner FG, Ohman EM, Stevenson WG, Yancy CW. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61:e78-e140.
42. Diener HC. Stroke prevention using the oral direct thrombin inhibitor ximelagatran in patients with non-valvular atrial fibrillation. Pooled analysis from the SPORTIF III and V studies. Cerebrovasc Dis. 2006;21:279-293.
43. Olsson SB. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet. 2003;362:1691-1698.
44. Eikelboom JW, Weitz JI. Anticoagulation therapy. Dabigatran and risk of myocardial infarction. Nat Rev Cardiol. 2012;9:260-262.
45. Wienen W, Stassen JM, Priepke H, Ries UJ, Hauel N. In-vitro profile and ex-vivo anticoagulant activity of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate. Thromb Haemost. 2007;98:155-162.
46. Wong PC, Jiang X. Apixaban, a direct factor Xa inhibitor, inhibits tissue-factor induced human platelet aggregation in vitro: comparison with direct inhibitors of factor VIIa, XIa and thrombin. Thromb Haemost. 2010;104:302-310.
47. Direct Thrombin Inhibitor Trialists' Collaborative G. Direct thrombin inhibitors in acute coronary syndromes: principal results of a meta-analysis based on individual patients' data. Lancet. 2002;359:294-302.
48. Wallentin L, Wilcox RG, Weaver WD, Emanuelsson H, Goodvin A, Nystrom P, Bylock A; Investigators E. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial. Lancet. 2003;362:789-797.
49. Eikelboom JW, Wallentin L, Connolly SJ, Ezekowitz M, Healey JS, Oldgren J, Yang S, Alings M, Kaatz S, Hohnloser SH, Diener HC, Franzosi MG, Huber K, Reilly P, Varrone J, Yusuf S. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RELY) trial. Circulation. 2011;123:2363-2372.
50. Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, Burton P, Cohen M, Cook-Bruns N, Fox KA, Goto S, Murphy SA, Plotnikov AN, Schneider D, Sun X, Verheugt FW, Gibson CM; Investigators AAT. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012;366:9-19.
51. Rasmussen LH, Larsen TB, Graungaard T, Skjoth F, Lip GY. Primary and secondary prevention with new oral anticoagulant drugs for stroke prevention in atrial fibrillation: indirect comparison analysis. BMJ. 2012;345:e7097.
52. Fox BD, Kahn SR, Langleben D, Eisenberg MJ, Shimony A. Efficacy and safety of novel oral anticoagulants for treatment of acute venous thromboembolism: direct and adjusted indirect meta-analysis of randomised controlled trials. BMJ. 2012;345:e7498.
53. Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI; Investigators A. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369:799-808.
54. Hokusai VTEI, Buller HR, Decousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369:1406-1415.