Abstract
Four multinational, randomized, double-blind, double-dummy phase III studies (RECORD1, 2, 3 and 4) investigated the oral, direct Factor Xa inhibitor rivaroxaban for the prevention of venous thromboembolism (VTE) in patients undergoing major orthopaedic surgery. A total of 12,729 patients were randomized to receive oral rivaroxaban 10 mg once daily (od) starting 6–8 hours after surgery, or subcutaneous enoxaparin 40 mg od starting the evening before surgery (RECORD1–3), or 30 mg bid starting 12–24 hours after wound closure or adequate hemostasis (RECORD4). In both RECORD1 and 2, patients undergoing total hip replacement (THR) were given rivaroxaban for 31–39 days. Enoxaparin was given for 31–39 days in RECORD1 or 10–14 days in RECORD2. In RECORD3 and 4, patients undergoing total knee replacement (TKR) received prophylaxis for 10–14 days. All patients were followed up for 30–35 days after the last dose of study medication. All outcomes, including symptomatic outcomes, were adjudicated by the same independent, blinded committees for all four studies. In each of the studies, the rivaroxaban regimens tested significantly reduced the incidence of the primary efficacy outcome (total VTE; the composite of any deep vein thrombosis [DVT], non-fatal pulmonary embolism [PE], and all-cause mortality) compared with enoxaparin regimens tested, with similar rates of bleeding in both groups. The rivaroxaban regimens also consistently reduced the incidence of major VTE (the composite of proximal DVT, non-fatal PE, and VTE-related death) in all four trials compared with the enoxaparin regimens tested. This pre-specified pooled analysis was performed on all randomized patients who received at least one dose of double-blind study medication to evaluate the effect of rivaroxaban on the composite of symptomatic VTE (comprising DVT or PE) and death, and bleeding. These primary outcomes were analyzed at day 12±2 in the active treatment pool (i.e. during the enoxaparin-controlled period common to all studies, to allow for unbiased comparison with enoxaparin), and for the total study duration pool (planned treatment period and 30–35 days follow-up). The results are shown in the table. Rivaroxaban significantly reduced the incidence of symptomatic VTE and death compared with enoxaparin regimens at day 12±2 (0.47% vs 0.97%; p=0.001) and for the total study duration (0.81% vs 1.63%; p<0.001). Rivaroxaban was not associated with a statistically significant increased risk of major bleeding (Table). These data demonstrate that in the regimens tested, rivaroxaban reduced the composite of major clinical outcomes compared with enoxaparin regimens, with no significant increase in the risk of major bleeding in patients undergoing major orthopaedic surgery.
Rivaroxaban n=6183 n (%) Enoxaparin n=6200 n (%) p-value *Total study duration pool: active study drug period and 30–35 days follow-up including the placebo phase in RECORD2. †Bleeding after initiation of study medication, regardless of onset after last dose of study medication. ‡Post hoc analysis. p-values refer to Cox regression with treatment and study as covariates (two-sided Wald-test). Symptomatic VTE and death (primary outcome) 29 (0.5) 60 (1.0) 0.001 Day 12±2 active treatment pool 50 (0.8) 101 (1.6) <0.001 Total study duration pool* Death 6 (0.1) 10 (0.2) 0.320 Day 12±2 active treatment pool 13 (0.2) 25 (0.4) 0.055 Total study duration pool* PE or death 12 (0.2) 24 (0.4) 0.049 Day 12±2 active treatment pool 29 (0.5) 47 (0.8) 0.039 Total study duration pool* Major bleeding 21 (0.3) 13 (0.2) 0.175 Day 12±2 active treatment pool 27 (0.4) 17 (0.3) 0.135 Total study duration pool† Any bleeding 409 (6.6) 384 (6.2) 0.376 Day 12±2 active treatment pool 452 (7.3) 415 (6.7) 0.207 Total study duration pool† Composite of major clinical outcomes (death, myocardial infarction, stroke, symptomatic VTE, and major bleeding)*‡ 96 (1.6) 139 (2.2) 0.004
Incidence and risk factors of major bleeding following major orthopaedic surgery with fondaparinux thromboprophylaxis. A time-to-event analysis
