Oral dabigatran etexilate versus enoxaparin for venous thromboembolism prevention after total hip arthroplasty: pooled analysis of two phase 3 randomized trials

Bengt I Eriksson, Ola E Dahl, Nadia Rosencher, Andreas Clemens, Stefan Hantel, Martin Feuring, Jörg Kreuzer, Michael Huo, Richard J Friedman, Bengt I Eriksson, Ola E Dahl, Nadia Rosencher, Andreas Clemens, Stefan Hantel, Martin Feuring, Jörg Kreuzer, Michael Huo, Richard J Friedman

Abstract

Background: Two phase 3 trials compared 28-35 days of treatment with oral dabigatran 220 mg or 150 mg (RE-NOVATE) or 220 mg (RE-NOVATE II) once daily with subcutaneous enoxaparin 40 mg once daily for prevention of venous thromboembolism (VTE) after elective total hip arthroplasty.

Methods: This prespecified pooled analysis compared the outcomes for the dabigatran 220 mg dose with enoxaparin, which included 4,374 patients. Total VTE (venographic and symptomatic) plus all-cause mortality (primary efficacy), major VTE (proximal deep vein thrombosis [DVT] or non-fatal pulmonary embolism) plus VTE-related death, and bleeding events were evaluated. Efficacy analysis was based on the modified intention-to-treat (ITT) population and safety analysis was based on all treated patients. The common risk difference (RD) for dabigatran versus enoxaparin was estimated using a fixed effects model.

Results: Total VTE and all-cause mortality occurred in 6.8 % (114/1,672) and 7.7 % (129/1,682) (RD:-0.8 %, 95 % confidence interval [CI] -2.6 to 0.9) for dabigatran and enoxaparin, respectively. Major VTE plus VTE-related mortality occurred in 2.7 % (46/1,714) and 4.0 % (69/1,711) (RD: -1.4 %, 95 % CI -2.6 to -0.2) of patients receiving dabigatran 220 mg and enoxaparin, respectively. Major bleeding occurred in 1.7 % (37/2,156) and 1.3 % (27/2,157) (RD: 0.5 %, 95 % CI -0.2 to 1.2), for dabigatran and enoxaparin respectively.

Conclusions: Extended prophylaxis with oral dabigatran 220 mg once daily was as effective as enoxaparin 40 mg once daily in reducing the risk of total VTE and all-cause mortality after total hip arthroplasty, with a similar bleeding profile. The clinically relevant outcome of major VTE and VTE-related death was significantly reduced with dabigatran versus enoxaparin.

Trial registration: NCT00657150 and NCT00168818.

Keywords: Arthroplasty; Bleeding; Dabigatran; Deep vein thrombosis; Enoxaparin; Mortality; Prophylaxis; Pulmonary embolism; Venous thromboembolism.

Figures

Fig. 1
Fig. 1
Flow of patients through the study
Fig. 2
Fig. 2
Total VTE and all-cause mortality during treatment period by subgroup (risk differences)

References

    1. Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet. 2007;370:949–56. doi: 10.1016/S0140-6736(07)61445-7.
    1. Eriksson BI, Dahl OE, Huo MH, Kurth AA, Hantel S, Hermansson K, et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A randomised, double-blind, non-inferiority trial. Thromb Haemost. 2011;105:721–9. doi: 10.1160/TH10-10-0679.
    1. Eriksson BI, Dahl OE, Buller HR, Hettiarachchi R, Rosencher N, Bravo ML, et al. 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;3:103–11. doi: 10.1111/j.1538-7836.2004.01100.x.
    1. Friedman RJ, Dahl OE, Rosencher N, Caprini JA, Kurth AA, Francis CW, et al. Dabigatran versus enoxaparin for prevention of venous thromboembolism after hip or knee arthroplasty: a pooled analysis of three trials. Thromb Res. 2010;126:175–82. doi: 10.1016/j.thromres.2010.03.021.
    1. Eriksson BI, Smith JJ, Caprini J, Hantel S, Clemens A, Feuring M, et al. Evaluation of the acute coronary syndrome safety profile of dabigatran etexilate in patients undergoing major orthopedic surgery: findings from four Phase 3 trials. Thromb Res. 2012;130:396–402. doi: 10.1016/j.thromres.2012.05.014.
    1. The European Agency for the Evaluation of Medicinal Products. Guideline on clinical investigation of medicinal products for prophylaxis of high intra- and post-operative venous thromboembolic risk. CPMP/EWP/707/98 Rev. 1. 2007. . Accessed 30 June 2015.
    1. The European Agency for the Evaluation of Medicinal Products. Points to consider on application with 1. meta-analyses; 2. one pivotal study. CPMP/EWP/2330/99. 2001. . Accessed 30 June 2015.
    1. Normand SL. Meta-analysis: formulating, evaluating, combining, and reporting. Stat Med. 1999;18:321–59. doi: 10.1002/(SICI)1097-0258(19990215)18:3<321::AID-SIM28>;2-P.
    1. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60. doi: 10.1136/bmj.327.7414.557.
    1. Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358:2765–75. doi: 10.1056/NEJMoa0800374.
    1. Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010;363:2487–98. doi: 10.1056/NEJMoa1006885.
    1. U.S. Food and Drug Administration. Guidance for Industry. Drug-Induced Liver Injury: Premarketing Clinical Evaluation. . Accessed 30 June, 2015.
    1. Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Chest. 2008;133:381S–453S. doi: 10.1378/chest.08-0656.
    1. Friedman RJ, Gallus AS, Cushner FD, FitzGerald G, Anderson FA., Jr Physician compliance with guidelines for deep-vein thrombosis prevention in total hip and knee arthroplasty. Curr Med Res Opin. 2008;24:87–97. doi: 10.1185/030079907X242746.
    1. Wolowacz SE, Roskell NS, Maciver F, Beard SM, Robinson PA, Plumb JM, et al. Economic evaluation of dabigatran etexilate for the prevention of venous thromboembolism after total knee and hip replacement surgery. Clin Ther. 2009;31:194–212. doi: 10.1016/j.clinthera.2009.01.001.
    1. Fernandes RA, Quintella FF, Teich VD. Cost-effectiveness analysis of dabigatran etexilate versus enoxaparin for the prevention of venous thromboembolism after total hip replacement under the Brazilian public health care system perspective [abstract] Value Health. 2009;12(7):A502.
    1. Boersma C, Kappelhoff BS, Postma MJ. Dabigatran etexilate is cost-saving for the primary prevention of venous thromboembolic events following major orthopaedic surgery in the Netherlands [abstract] Value Health. 2009;12(7):A334. doi: 10.1016/S1098-3015(10)74641-6.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться