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Rivaroxaban versus enoxaparin after total knee arthroplasty
Correspondence
Rivaroxaban versus enoxaparin after total knee arthroplasty The RECORD4 study (May 16, p 1673) showed that the new oral selective factor Xa inhibitor, rivaroxaban, given at a dose of 10 mg once daily is superior to enoxaparin given at the NorthAmerican-approved dose of 30 mg twice daily for the prevention of venous thromboembolism (VTE) after total knee arthroplasty. An earlier trial, the RECORD3 study,2 showed that rivaroxaban 10 mg once daily was also superior to enoxaparin given at the European-approved dose of 40 mg once daily for prevention of VTE after total knee arthroplasty.2 To our knowledge, no randomised trials have directly compared the North American and European enoxaparin dosing regimens in patients undergoing knee arthroplasty. Yet, indirect comparisons between the results of the RECORD4 and RECORD3 trials, and between the results of the REMOBILIZE trial3 (which compared the new oral selective factor IIa inhibitor, dabigatran, with enoxaparin 30 mg twice daily) and the REMODEL trial4 (dabigatran vs enoxaparin 40 mg once daily) indicate a more modest treatment effect of the new oral drug when compared against the 1
North American enoxaparin dosing regimen than when compared against the European regimen (p≤0·10 for heterogeneity). These results suggest that enoxaparin 30 mg twice daily is substantially more effective than enoxaparin 40 mg once daily for the prevention of VTE in patients undergoing knee arthroplasty (table). The apparently superior efficacy of the North American enoxaparin dosing regimen over the European one might be related either to differences in the total daily dose of enoxaparin (60 mg vs 40 mg, respectively) or the frequency of enoxaparin administration (twice daily vs once daily) because the drug has a halflife of only 5–7 h. Irrespective of the mechanism, however, these data are consistent with the hypothesis that differences in the efficacy of new oral anticoagulants compared with enoxaparin are primarily determined by a contrast in dose intensity rather than differences between the drugs in their pharmacological target. JWE has received research support and/or honoraria from Bayer, Boehringer-Ingelheim, and SanofiAventis. NCR and SD declare that they have no conflicts of interest.
Nina Chetty Raju, Simon Dimmitt, *John W Eikelboom [email protected] McMaster University, HHSC, Hamilton General Hospital Site, Hamilton, ON L8L 2X2, Canada
North American regimen (enoxaparin 30 mg twice daily)
European regimen (enoxaparin 40 mg once daily)
Trial
RECORD4 (n=3148)
RECORD3 (n=2531)
Comparator
Rivaroxaban 10 mg once daily
Rivaroxaban 10 mg once daily
Relative risk (95% CI)
1·46 (1·08−1·98)
1·97 (1·53−2·53)
Trial
REMOBILIZE (n=2610)
REMODEL (n=2076)
Comparator
Dabigatran 220 mg once daily
Dabigatran 220 mg once daily
Relative risk (95% CI)
0·81 (0·68−0·97)
1·03 (0·88−1·22)
Comparator
Dabigatran 150 mg once daily
Dabigatran 150 mg once daily
Relative risk (95% CI)
0·75 (0·63−0·89)
0·93 (0·80−1·08)
p for heterogeneity*
2
3
4
Turpie A, Lassen MR, Davidson BL, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet 2009; 373: 1673–80. Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008; 358: 2776–86. Ginsberg JS, Davidson BL, Comp PC, et al. The oral thrombin inhibitor dabigatran etexilate vs the North America enoxaparin regimen for the prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty 2009; 24: 1–9. 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 Hemost 2007; 5: 2178–85.
In Alexander Turpie and colleagues’ study on rivaroxaban,1 the control group should have been treated with at least 80 mg enoxaparin instead of only 60 mg per day. The enoxaparin dose should have been adjusted so as to obtain only 10–20% of normal extrinsic thrombin generation.2 To achieve good haemostasis, some patients, especially patients with such a prothrombotic condition as total knee arthroplasty, can require much more enoxaparin than 60 mg/day. If these undertreated patients had been identified and treated with an adequate dose, enoxaparin—as the more physiological anticoagulant— would probably have been superior to rivaroxaban. I declare that I have no conflicts of interests.
T Stief [email protected] Department of Clinical Chemistry, University Hospital, D-35043 Marburg, Germany
0·09
0·06
0·10
*Breslow-Day test for homogeneity.
Table: Primary outcome (any deep-vein thrombosis, pulmonary embolism, or death) of phase 3 randomised controlled trials comparing enoxaparin 40 mg once daily or 30 mg twice daily with rivaroxaban or dabigatran for the prevention of VTE in patients undergoing knee arthroplasty
www.thelancet.com Vol 374 August 29, 2009
1
1
2
Turpie AG, Lassen MR, Davidson BL, et al, for the RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet 2009; 373: 1673–80. Stief TW, Ajib S, Renz H. The sensibility of individual plasma to heparins. Hemostasis Laboratory 2008; 1: 143–57.
Alexander Turpie and colleagues1 show that rivaroxaban, an orally active, highly selective, direct inhibitor of activated factor X, given at a fixed dose of 10 mg daily, holds the promise of greatly simplifying
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
681
Rivaroxaban versus enoxaparin after total knee arthroplasty The RECORD4 study (May 16, p 1673) showed that the new oral selective factor Xa inhibitor, rivaroxaban, given at a dose of 10 mg once daily is superior to enoxaparin given at the NorthAmerican-approved dose of 30 mg twice daily for the prevention of venous thromboembolism (VTE) after total knee arthroplasty. An earlier trial, the RECORD3 study,2 showed that rivaroxaban 10 mg once daily was also superior to enoxaparin given at the European-approved dose of 40 mg once daily for prevention of VTE after total knee arthroplasty.2 To our knowledge, no randomised trials have directly compared the North American and European enoxaparin dosing regimens in patients undergoing knee arthroplasty. Yet, indirect comparisons between the results of the RECORD4 and RECORD3 trials, and between the results of the REMOBILIZE trial3 (which compared the new oral selective factor IIa inhibitor, dabigatran, with enoxaparin 30 mg twice daily) and the REMODEL trial4 (dabigatran vs enoxaparin 40 mg once daily) indicate a more modest treatment effect of the new oral drug when compared against the 1
North American enoxaparin dosing regimen than when compared against the European regimen (p≤0·10 for heterogeneity). These results suggest that enoxaparin 30 mg twice daily is substantially more effective than enoxaparin 40 mg once daily for the prevention of VTE in patients undergoing knee arthroplasty (table). The apparently superior efficacy of the North American enoxaparin dosing regimen over the European one might be related either to differences in the total daily dose of enoxaparin (60 mg vs 40 mg, respectively) or the frequency of enoxaparin administration (twice daily vs once daily) because the drug has a halflife of only 5–7 h. Irrespective of the mechanism, however, these data are consistent with the hypothesis that differences in the efficacy of new oral anticoagulants compared with enoxaparin are primarily determined by a contrast in dose intensity rather than differences between the drugs in their pharmacological target. JWE has received research support and/or honoraria from Bayer, Boehringer-Ingelheim, and SanofiAventis. NCR and SD declare that they have no conflicts of interest.
Nina Chetty Raju, Simon Dimmitt, *John W Eikelboom [email protected] McMaster University, HHSC, Hamilton General Hospital Site, Hamilton, ON L8L 2X2, Canada
North American regimen (enoxaparin 30 mg twice daily)
European regimen (enoxaparin 40 mg once daily)
Trial
RECORD4 (n=3148)
RECORD3 (n=2531)
Comparator
Rivaroxaban 10 mg once daily
Rivaroxaban 10 mg once daily
Relative risk (95% CI)
1·46 (1·08−1·98)
1·97 (1·53−2·53)
Trial
REMOBILIZE (n=2610)
REMODEL (n=2076)
Comparator
Dabigatran 220 mg once daily
Dabigatran 220 mg once daily
Relative risk (95% CI)
0·81 (0·68−0·97)
1·03 (0·88−1·22)
Comparator
Dabigatran 150 mg once daily
Dabigatran 150 mg once daily
Relative risk (95% CI)
0·75 (0·63−0·89)
0·93 (0·80−1·08)
p for heterogeneity*
2
3
4
Turpie A, Lassen MR, Davidson BL, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet 2009; 373: 1673–80. Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008; 358: 2776–86. Ginsberg JS, Davidson BL, Comp PC, et al. The oral thrombin inhibitor dabigatran etexilate vs the North America enoxaparin regimen for the prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty 2009; 24: 1–9. 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 Hemost 2007; 5: 2178–85.
In Alexander Turpie and colleagues’ study on rivaroxaban,1 the control group should have been treated with at least 80 mg enoxaparin instead of only 60 mg per day. The enoxaparin dose should have been adjusted so as to obtain only 10–20% of normal extrinsic thrombin generation.2 To achieve good haemostasis, some patients, especially patients with such a prothrombotic condition as total knee arthroplasty, can require much more enoxaparin than 60 mg/day. If these undertreated patients had been identified and treated with an adequate dose, enoxaparin—as the more physiological anticoagulant— would probably have been superior to rivaroxaban. I declare that I have no conflicts of interests.
T Stief [email protected] Department of Clinical Chemistry, University Hospital, D-35043 Marburg, Germany
0·09
0·06
0·10
*Breslow-Day test for homogeneity.
Table: Primary outcome (any deep-vein thrombosis, pulmonary embolism, or death) of phase 3 randomised controlled trials comparing enoxaparin 40 mg once daily or 30 mg twice daily with rivaroxaban or dabigatran for the prevention of VTE in patients undergoing knee arthroplasty
www.thelancet.com Vol 374 August 29, 2009
1
1
2
Turpie AG, Lassen MR, Davidson BL, et al, for the RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet 2009; 373: 1673–80. Stief TW, Ajib S, Renz H. The sensibility of individual plasma to heparins. Hemostasis Laboratory 2008; 1: 143–57.
Alexander Turpie and colleagues1 show that rivaroxaban, an orally active, highly selective, direct inhibitor of activated factor X, given at a fixed dose of 10 mg daily, holds the promise of greatly simplifying
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
681