Rivaroxaban versus enoxaparin after total knee arthroplasty

Abstract

Alexander Turpie and colleagues1Turpie AGG Lassen M Davidson B et al.Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial.Lancet. 2009; 373: 1673-1680Summary Full Text Full Text PDF PubMed Scopus (870) Google Scholar report the fourth comparative study of rivaroxaban and enoxaparin in major orthopaedic surgery (RECORD4), and conclude that there was no significant difference between treatment groups in the risk of major bleeding. However, major bleeding rates in the RECORD4 study were three to six times lower than expected from the ODIXa dose-finding studies with rivaroxaban,2Fisher WD Eriksson BI Bauer KA et al.Rivaroxaban for thromboprophylaxis after orthopaedic surgery: pooled analysis of two studies.Thromb Haemost. 2007; 97: 931-937PubMed Google Scholar and about five times lower than those from contemporary studies in orthopaedic surgery.3Wolowacz SE Roskell NS Plumb JM Caprini JA Eriksson BI Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty. A meta-analysis.Thromb Haemost. 2009; 101: 77-85PubMed Google Scholar This fact could be explained by the exclusion of most wound bleedings from major bleeding assessment in the RECORD studies. With the low rate of major bleeding events seen in RECORD4 (0·66% vs 0·27%), the probability of a type II error is 73% (probability of concluding that no difference between treatment groups exists when, in fact, there is a difference). We have done sensitivity analyses to test what would have occurred in the RECORD4 study if overall major bleeding rates were similar to those in the ODIXa dose-finding studies2Fisher WD Eriksson BI Bauer KA et al.Rivaroxaban for thromboprophylaxis after orthopaedic surgery: pooled analysis of two studies.Thromb Haemost. 2007; 97: 931-937PubMed Google Scholar or other contemporary studies.3Wolowacz SE Roskell NS Plumb JM Caprini JA Eriksson BI Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty. A meta-analysis.Thromb Haemost. 2009; 101: 77-85PubMed Google Scholar Such analyses suggest that an increase in major bleeding of 147% (relative risk 2·47) with rivaroxaban would have been significant in all the scenarios tested (table). Ancillary analyses by the US Food and Drug Administration4FDA Cardiovascular & Renal Drugs Advisory CommitteeMeeting ID: 2009-4418.http://www.fda.govGoogle Scholar have also shown a consistent increased bleeding risk with rivaroxaban compared with enoxaparin in the RECORD programme.TableSensitivity analyses of major bleeding rates in RECORD4 study (safety population)Rivaroxaban (n=1526)Enoxaparin (n=1508)Relative risk (95% CI)p§χ2 test.Major bleeding rates in RECORD4 (base case)10 (0·66%)4 (0·27%)2·47 (0·82–7·46)0·11Major bleeding rates×6*Based on major bleeding rates reported in the enoxaparin control group of the ODIXa studies.260 (3·93%)24 (1·59%)2·47 (1·56–3·93)<0·0001Major bleeding rates×5†Based on major bleeding rates reported in the enoxaparin control group of the dabigatran studies.350 (3·28%)20 (1·33%)2·47 (1·49–4·11)0·0003Major bleeding rates×3‡Based on major bleeding rates reported in the rivaroxaban 10 mg/day dosing groups of the ODIXa studies.230 (1·97%)12 (0·80%)2·47 (1·29–4·76)0·006Major bleeding rates×220 (1·31%)8 (0·53%)2·47 (1·12–5·48)0·025Events occurring during treatment period.* Based on major bleeding rates reported in the enoxaparin control group of the ODIXa studies.2Fisher WD Eriksson BI Bauer KA et al.Rivaroxaban for thromboprophylaxis after orthopaedic surgery: pooled analysis of two studies.Thromb Haemost. 2007; 97: 931-937PubMed Google Scholar† Based on major bleeding rates reported in the enoxaparin control group of the dabigatran studies.3Wolowacz SE Roskell NS Plumb JM Caprini JA Eriksson BI Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty. A meta-analysis.Thromb Haemost. 2009; 101: 77-85PubMed Google Scholar‡ Based on major bleeding rates reported in the rivaroxaban 10 mg/day dosing groups of the ODIXa studies.2Fisher WD Eriksson BI Bauer KA et al.Rivaroxaban for thromboprophylaxis after orthopaedic surgery: pooled analysis of two studies.Thromb Haemost. 2007; 97: 931-937PubMed Google Scholar§ χ2 test. Open table in a new tab Events occurring during treatment period. Differences in the definition of major bleeding have important implications when assessing the relative safety of anticoagulants, making between-study comparisons difficult. Further experience is needed to assess whether the very low major bleeding rates reported in the RECORD programme are representative of what we would expect in unselected populations in clinical practice. We declare that we have no conflicts of interest. The opinions expressed in this letter are of the authors alone and do not necessarily reflect the position or opinion of their institution or any other party. Rivaroxaban versus enoxaparin after total knee arthroplasty – Authors' replyThe RECORD programme compared rivaroxaban 10 mg once daily with either the EU or North American approved regimens of enoxaparin (40 mg once daily or 30 mg twice daily). As Nina Raju and colleagues note, factors such as pharmacological target and differences in dose and frequency, as well as timing of initial postoperative drug administration, can affect the safety or efficacy of anticoagulants. However, RECORD4 and the RECORD programme as a whole were not designed to compare different enoxaparin regimens or to provide indirect comparisons on the efficacy of new anticoagulants. Full-Text PDF