Interpretation of endpoints in a network meta-analysis of new oral anticoagulants following total hip or total knee replacement surgery

Summary

New oral anticoagulant (NOAC) regimens [dabigatran 150 mg (D150) and 220 mg (D220), rivaroxaban 10 mg (R20), and apixaban 2.5 mg bid (A5)] were effective and safe compared to enoxaparin for the prevention of venous thromboembolism (VTE) following elective total knee (TKR) or hip replacement (THR) surgery. First a cluster analysis was used to identify homogeneous studies for the trial programs of each NOAC. Second, only studies reporting VTE and VTE-related death, major bleeding, and mortality were included. The odds ratio (OR) and 95% confidence interval (CI) were calculated for each NOAC regimen versus the comparator. Third, these data were used for the indirect comparison between NOACs. Cluster analysis identified duration of treatment (10 ± 5 and 34 ± 5 days) as the only homogeneous parameter across all NOAC programs (p>0.05) except for A5 and VTE over 10 ± 5 days (analysis not performed). The results of the calculated OR and 95% CI of the four NOAC regimens over 10 ± 5 and 34 ± 5 days showed inferiority of D150 and D220 compared to R10 for VTE (p<0.01, p<0.001). Comparisons of major bleeding and mortality were not different for all indirect comparisons. Despite the lack of standard definitions for VTE and bleeding outcomes, cluster analysis seems to be an appropriate tool to identify homogeneity across trial programs and to perform an indirect comparison for NOACs for prevention of VTE following TKR and THR surgery.

Keywords

Apixaban - dabigatran - rivaroxaban - knee replacement - hip replacement - network meta-analysis

• References

• 1 Tasker A, Harbord R, Bannister GC. Meta-analysis of low molecular weight heparin versus placebo in patients undergoing total hip replacement and post-operative morbidity and mortality since their introduction. Hip Int 2010; 20: 64-74.
• 2 Falck-Ytter Y, Francis CW, Johanson NA. et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (Suppl. 02) e278S-e325S.
• 3 Linkins LA, Dans AL, Moores LK. et al. Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (Suppl. 02) e495S-e530S.
• 4 Harenberg J, Wehling M. Future of anticoagulant therapy. Cardiovasc Ther 2011; 29: 291-300.
• 5 Turpie AG, Lassen MR, Eriksson BI. et al. Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty. Pooled analysis of four studies. Thromb Haemost 2011; 105: 444-453.
• 6 Lereun C, Wells P, Diamantopoulos A. et al. An indirect comparison, via enoxaparin, of rivaroxaban with dabigatran in the prevention of venous thromboembolism after hip or knee replacement. J Med Econ 2011; 14: 238-244.
• 7 Loke YK, Kwok CS. Dabigatran and rivaroxaban for prevention of venous thromboembolism--systematic review and adjusted indirect comparison. J Clin Pharm Ther 2011; 36: 111-124.
• 8 Trkulja V, Kolundzic R. Rivaroxaban vs dabigatran for thromboprophylaxis after joint-replacement surgery: exploratory indirect comparison based on meta-analysis of pivotal clinical trials. Croat Med J 2010; 51: 113-123.
• 9 Bochenek T, Nizankowski R. The treatment of venous thromboembolism with low-molecular-weight heparins. A meta-analysis. Thromb Haemost 2012; 107: 699-716.
• 10 Cohen A, Drost P, Marchant N. et al. The Efficacy and Safety of Pharmacological Prophylaxis of Venous Thromboembolism Following Elective Knee or Hip Replacement: Systematic Review and Network Meta-Analysis. Clin Appl Thromb Hemost. 2012 epub ahead of print.
• 11 Dahl OE, Quinlan DJ, Bergqvist D. et al. A critical appraisal of bleeding events reported in venous thromboembolism prevention trials of patients undergoing hip and knee arthroplasty. J Thromb Haemost 2010; 8: 1966-1975.
• 12 Schwarzer G, Antes G, Schumacher M. A test for publication bias in meta-analysis with sparse binary data. Stat Med 2007; 26: 721-733.
• 13 Glenny AM, Altman DG, Song F. et al. Indirect comparisons of competing interventions. Health Technol Assess 2005; 9: 1-134.
• 14 Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 2009; 151: 264-269.
• 15 Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3: 692-694.
• 16 Frades I, Matthiesen R. Overview on techniques in cluster analysis. Methods Mol Biol 2010; 593: 81-107.
• 17 Whitehead A, Whitehead J. A general parametric approach to the meta-analysis of randomized clinical trials. Stat Med 1991; 10: 1665-1677.
• 18 Lucka TC, Pathirana D, Sammain A. et al. Efficacy of systemic therapies for moderate-to-severe psoriasis: a systematic review and meta-analysis of long-term treatment. J Eur Acad Dermatol Venereol. 2012 epub ahead of print.
• 19 Fadda V, Maratea D, Trippoli S. et al. Network meta-analysis. Results can be summarised in a simple figure. Br Med J 2011; 342: d1555.
• 20 Kakkar AK, Brenner B, Dahl OE. et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet 2008; 372: 31-39.
• 21 Eriksson BI, Borris LC, Dahl OE. et al. Dose-escalation study of rivaroxaban (BAY 59–7939) – an oral, direct Factor Xa inhibitor--for the prevention of venous thromboembolism in patients undergoing total hip replacement. Thromb Res 2007; 120: 685-693.
• 22 Eriksson BI, Dahl OE, Rosencher N. 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: 949-956.
• 23 Eriksson BI, Dahl OE, Rosencher N. et al. 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.
• 24 Ginsberg JS, Davidson BL, Comp PC. et al. 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.
• 25 Eriksson BI, Dahl OE, Huo MH. 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: 721-729.
• 26 Turpie AG, Fisher WD, Bauer KA, Kwong LM, Irwin MW, Kalebo P. et al. BAY 59–7939: an oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study. J Thromb Haemost 2005; 3: 2479-2486.
• 27 Eriksson BI, Borris L, Dahl OE. et al. Oral, direct Factor Xa inhibition with BAY 59–7939 for the prevention of venous thromboembolism after total hip replacement. J Thromb Haemost 2006; 4: 121-128.
• 28 Eriksson BI, Borris LC, Dahl OE. et al. A once-daily, oral, direct Factor Xa inhibitor, rivaroxaban (BAY 59–7939), for thromboprophylaxis after total hip replacement. Circulation 2006; 114: 2374-2381.
• 29 Eriksson BI, Borris LC, Friedman RJ. et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008; 358: 2765-2775.
• 30 Geerts WH, Bergqvist D, Pineo GF. et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 (Suppl. 06) 381S-453S.
• 31 Turpie AG, Lassen MR, Davidson BL. et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet 2009; 373: 1673-1680.
• 32 Lassen MR, Davidson BL, Gallus A. et al. The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement. J Thromb Haemost 2007; 5: 2368-2375.
• 33 Lassen MR, Raskob GE, Gallus A. et al. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med 2009; 361: 594-604.
• 34 Lassen MR, Raskob GE, Gallus A. et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet 2010; 375: 807-815.
• 35 Lassen MR, Gallus A, Raskob GE. et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010; 363: 2487-2498.