Introduction: The standard length of hospital stay after total hip arthroplasty (THA) can be as short as 4 days. However, the risk of venous thromboembolism (VTE) extends beyond this period of hospitalization. A pooled analysis of the RECORD1 and RECORD2 studies evaluated the efficacy, safety, and timing of events with rivaroxaban compared with enoxaparin for the prevention of VTE after THA.

Methods: Patients (N=7,050) were randomized to receive oral rivaroxaban 10 mg once daily starting postoperatively (for 31–39 days) or subcutaneous enoxaparin 40 mg once daily starting preoperatively (for 31–39 days in RECORD1, and 10–14 days followed by placebo in RECORD2). The primary efficacy endpoint was the composite of symptomatic VTE and all-cause mortality. The safety endpoints were treatment-emergent major bleeding, major bleeding including surgical-site bleeding, major bleeding plus clinically relevant non-major (CRNM) bleeding, and any bleeding. The primary efficacy endpoint was assessed during treatment. The incidence and timing of the safety endpoints were assessed after the first dose of study medication and up to 2 days after the last dose.

Results: Rivaroxaban significantly reduced the incidence of symptomatic VTE and all-cause mortality compared with enoxaparin regimens (0.44% vs 1.01%, respectively; p=0.006), with no significant differences in major bleeding (0.2% vs 0.09%; p=0.219) or the composite of major plus CRNM bleeding (3.23% vs 2.61%; p=0.141). Of the symptomatic VTE and all-cause mortality events, 73% and 86% occurred after day 4 with the rivaroxaban and enoxaparin regimens, respectively. For the composite of major plus CRNM bleeding, 48% and 33% of events occurred after day 4 with the rivaroxaban and enoxaparin regimens, respectively.

Conclusion: Rivaroxaban significantly reduced symptomatic VTE and all-cause mortality after THA compared with the enoxaparin regimens, with no significant difference in bleeding events. Major plus CRNM bleeding was more likely to occur earlier than day 4, whereas the majority of symptomatic venous thromboembolic events occurred after day 4. These results highlight the relevance of extended duration of thromboprophylaxis after THA as most VTE events occur post-discharge.

Introduction: The risk of venous thromboembolism (VTE) remains a major concern beyond the standard period of hospitalization of about 4 days after total knee arthroplasty (TKA). A pooled analysis of the RECORD3 and RECORD4 studies evaluated the efficacy, safety, and timing of events with rivaroxaban compared with enoxaparin for the prevention of VTE after TKA.

Methods: Patients (N=5,679) were randomized to receive oral rivaroxaban 10 mg once daily starting postoperatively or subcutaneous enoxaparin 40 mg once daily starting preoperatively (European Union regimen; RECORD3) or enoxaparin 30 mg every 12 hours starting postoperatively (North American regimen; RECORD4) for 10–14 days. The primary efficacy endpoint was the composite of symptomatic VTE and all-cause mortality, and this was analyzed over the treatment period. The safety endpoints were treatment-emergent major bleeding, major bleeding including surgical-site bleeding, major bleeding plus clinically relevant non-major (CRNM) bleeding, and any bleeding. The incidence and timing of the safety endpoints were assessed after the first dose of study medication and up to 2 days after the last dose.

Results: Rivaroxaban significantly reduced symptomatic VTE and all-cause mortality compared with enoxaparin regimens (0.73% vs 1.71%, respectively; p=0.001) with no significant differences in major bleeding (0.62% vs 0.36%, p=0.185) or composite of major plus CRNM bleeding (3.13% vs 2.48%, p=0.145). The majority of venous thromboembolic events occurred after day 4 for both regimens (rivaroxaban: 70%; enoxaparin: 68%). For the composite of major plus CRNM bleeding events, 44% occurred after day 4 with rivaroxaban regimens and 38% occurred after day 4 with enoxaparin regimens.

Conclusion: Rivaroxaban significantly reduced symptomatic VTE and all-cause mortality compared with enoxaparin regimens after TKA, with no significant difference in bleeding events between regimens. Major plus CRNM bleeding was more likely to occur before day 4, whereas the majority of symptomatic venous thromboembolic events occurred after day 4. These results highlight the importance of continuing thromboprophylaxis beyond the normal time of hospital discharge for TKA.

Rivaroxaban is a novel, oral, once-daily, direct Factor Xa inhibitor in advanced clinical development. RECORD1 was a multinational, randomized, double-blind, double-dummy, phase III study investigating the efficacy and safety of extended thromboprophylaxis with rivaroxaban compared with subcutaneous enoxaparin following THR.

Patients (N=4541) were randomized to receive oral rivaroxaban 10 mg (6–8 hours after surgery and once daily thereafter) or subcutaneous enoxaparin 40 mg (administered the evening before surgery, 6–8 hours after surgery, and once daily thereafter) for 35±4 days. The primary efficacy outcome was the composite of deep vein thrombosis (DVT: symptomatic or detected by mandatory, bilateral venography if asymptomatic), non-fatal pulmonary embolism (PE), and all-cause mortality up to day 36±6. Major venous thromboembolism (VTE), the composite of any DVT, non-fatal PE and VTE-related death, was a secondary outcome. Safety endpoints included major and non-major bleeding while receiving study medication.

Rivaroxaban significantly reduced the incidence of the primary efficacy outcome compared with enoxaparin (1.1% vs 3.7%, respectively; p< 0.001; relative risk reduction [RRR] 70%). Rivaroxaban also significantly reduced the incidence of major VTE compared with enoxaparin (0.2% vs 2.0%, respectively; p< 0.001; RRR 88%). There were no significant differences in the incidence of major bleeding (0.3% vs 0.1%; p=0.178) or non-major bleeding (5.8% vs 5.8%; p=1.000) between rivaroxaban and enoxaparin, respectively. There was no evidence of liver safety issues associated with rivaroxaban.

Thromboprophylaxis with once-daily, oral rivaroxaban was significantly more effective than subcutaneous enoxaparin following THR without an increased risk of bleeding. This trial demonstrates the efficacy and safety of a fixed, unmonitored, once-daily dose of oral rivaroxaban for extended thromboprophylaxis after THR.

Introduction: Four randomized, double-blind, phase III studies (RECORD1–4) investigated the oral, direct Factor Xa inhibitor rivaroxaban for the prevention of venous thromboembolism (VTE) after major orthopaedic surgery. Patients (N=12,729) were randomized to receive oral rivaroxaban 10 mg once daily or subcutaneous enoxaparin 40 mg once daily (RECORD1–3), or 30 mg twice daily (RECORD4). In RECORD1 and 2, patients undergoing total hip arthroplasty received rivaroxaban for 31–39 days. Enoxaparin was given for 31–39 days in RECORD1, 10–14 days followed by placebo in RECORD2. In RECORD3 and 4, patients undergoing total knee arthroplasty received prophylaxis for 10–14 days. After prophylaxis, all patients were followed up for a further 30–35 days. Rivaroxaban significantly reduced the incidence of the primary efficacy outcome for the individual studies (total VTE; composite of any deep vein thrombosis, non-fatal pulmonary embolism [PE] and all-cause mortality) compared with the enoxaparin regimens, with similar rates of major bleeding.

Methods: A pre-specified pooled analysis of all four trials 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 and all-cause mortality (primary outcome for pooled analysis), and bleeding. This outcome was analysed at day 12±2 in the active treatment pool (enoxaparin-controlled in all studies) and in the total study duration pool (including follow-up after treatment).

Results: Rivaroxaban significantly reduced the incidence vs enoxaparin of the composite of symptomatic VTE and death (day 12±2: 0.47% vs 0.97%, respectively, p=0.001; total study duration: 0.81% vs 1.6%, respectively, p< 0.001) and the composite of PE and death (day 12±2: 0.19% vs 0.39%, respectively, p=0.049; total study duration: 0.47% vs 0.76%, respectively, p=0.039). The rates of major bleeding with the rivaroxaban and enoxaparin regimens were 0.34% and 0.21%, respectively, p=0.175 at day 12±2 and at total study duration were 0.44% and 0.27%, respectively, p=0.135. Rivaroxaban also reduced the composite of death, infarction, stroke, symptomatic VTE and major bleeding vs enoxaparin (total study duration: 1.6% vs 2.2%, respectively, p=0.006).

Conclusion: Rivaroxaban reduced the composites of major clinical outcomes compared with enoxaparin regimens, with similar rates of major bleeding, in patients undergoing major orthopaedic surgery.

Dabigatran etexilate (Pradaxa^®) is an oral anticoagulant licensed in multiple countries, Europe and Canada, for the prevention of venous thromboembolic events (VTE) in patients undergoing total hip replacement surgery (THR) or total knee replacement surgery (TKR). The label recommendation for therapy initiation of dabigatran etexilate is a half dose given 1–4 hours after surgery. If this is not possible, then dabigatran etexilate should be started the day following surgery with the full dose. In the European pivotal Phase III clinical trials, this initial dosing was delayed until the day after surgery in 14% of the cases. This prompted a post hoc study to analyze if these patients received adequate thromboprophylaxis. Pooled efficacy data of major VTE events (composite of proximal DVT, symptomatic DVT, pulmonary embolism and VTE-related death) from the two European pivotal trials (RE-MODEL; Eriksson BI et al. J Thromb Haemost2007;5:2178–2185, and RENOVATE; Eriksson BI et al. Lancet2007;370:949–956) where analyzed. The group with delayed dosing was compared to the group that received therapy initiation on the day of surgery to determine if there was any significant effect on clinical outcome. The final decision on the timing of the administration of the first dose required sometimes clinical judgment, and in particular good haemostasis had to be present. Therefore, the bleeding rate and the timing of the first dose are confounded and an analysis of bleeding events was not performed. The major VTE rate in the group with delayed treatment initiation compared with the 1–4 hour post surgery treatment initiation group were 2.2% (95% CI: 0.1–4.4) vs. 3.0% (95% CI: 2.0–3.9) for 220 mg dabigatran etexilate, 8.3% (95% CI: 4.3–12.4) vs. 3.5% (95% CI 2.5–4.5) for 150 mg dabigatran etexilate, and 4.3% (95% CI 1.2–7.4) vs. 3.7% (95% CI 2.7–4.8) for 40 mg enoxaparin. As the confidence intervals overlap markedly, no statistically significant differences where found. In conclusion, no difference in the rates of major VTE and VTE related mortality was seen when the doses of dabigatran etexilate were postponed to the first postoperative day. These data need to be interpreted carefully due to the low number of patients in the delayed treatment group. As recommended in the current labelling of dabigatran etexilate, treatment should be initiated 1–4 hours post-surgery.

The oral direct thrombin inhibitor dabigatran etexilate (Pradaxa^®) was recently approved in Europe for the prevention of venous thromboembolism (VTE) in patients undergoing elective total knee or total hip replacement surgery. In the Phase III RE-MODEL (Eriksson BI et al. J Thromb Haemost2007; 5: 2178–2185) and RENOVATE (Eriksson BI et al. Lancet2007; 370: 949–956) clinical trials the safety and efficacy of 220 mg and 150 mg dabigatran etexilate once daily were studied. In both trials these doses were compared with 40 mg subcutaneous enoxaparin. A post hoc pooled analysis was performed in patients with moderate renal impairment (glomerular filtration rate ≥ 30 and < 50 ml/min) who participated in these two trials. The primary efficacy endpoint in both studies and the post hoc analysis was total VTE and all cause mortality; the key pre-specified secondary efficacy endpoint was major VTE and VTE-related mortality. Bleeding events (the primary safety endpoint) were blindly adjudicated and categorised as major bleeding events (MBE), which includes surgical site bleedings. A total of 1825 patients were treated with 220 mg dabigatran etexilate, 1866 with 150 mg dabigatran etexilate and 1848 with 40 mg enoxaparin. Of these, 337 patients had moderate renal impairment. 68% of these patients could be evaluated for the primary efficacy endpoint, 72% for the secondary efficacy endpoint, and all patients were included in the safety and bleeding analyses. The incidence of total VTE and all cause mortality was 17.7% (14/79), 23.5% (16/68) and 27.8% (25/90) in the 220 mg dabigatran etexilate, 150 mg dabigatran etexilate and enoxaparin groups, respectively. When the secondary efficacy endpoint was analysed a similar trend was seen, with a descriptive statistical significance for a lower event rate in the 220 mg group: 1.2% (1/83; p=0.04 vs enoxaparin using Fisher’s exact test), 4.3% (3/70) with 150 mg dabigatran etexilate; and 9.0% (8/89) in the enoxaparin group. MBE occurred in 6/113 patients (5.3%) in the 220 mg dabigatran etexilate-treated group, in none of the patients in the 150 mg dabigatran etexilate-treated group (0/96; p=0.04 vs enoxaparin using Fisher’s exact test), and in 6/128 patients (4.7%) receiving enoxaparin. Of note, 3/6 MBE in the 220 mg group started before oral dabigatran etexilate treatment was initiated. In conclusion, oral 150 mg dabigatran etexilate showed similar efficacy compared with subcutaneous enoxaparin in patients with moderate renal impairment undergoing hip or knee replacement surgery, with an apparently lower rate of major bleeding. As bleeding is a major concern, especially in this population, the 150 mg once daily dose of dabigatran etexilate is currently recommended by EMEA for this group.

Dabigatran etexilate (Pradaxa^®) is an oral direct thrombin inhibitor that was recently approved in Europe and Canada for the prevention of venous thromboembolism (VTE) in patients undergoing elective total knee replacement or total hip replacement surgery. Two pivotal clinical trials, RE-MODEL (Eriksson BI et al. J Thromb Haemost2007; 5: 2178–2185) and RENOVATE (Eriksson BI et al. Lancet2007; 370: 949–956), studied the efficacy and safety of 220 mg and 150 mg dabigatran etexilate once daily compared with 40 mg subcutaneous enoxaparin. A post hoc pooled analysis was performed in elderly patients (> 75 years) since renal function gradually declines with age. The primary efficacy endpoint was total VTE and all cause mortality and the secondary efficacy endpoint was major VTE and VTE-related mortality. The primary safety endpoint was major bleeding events (MBE), including those occurring at the surgical site. All bleeding events were blindly adjudicated. Of the patients treated with 220 mg dabigatran etexilate (n=1825), 150 mg dabigatran etexilate (n=1866) and enoxaparin (n=1848), 883 patients (16%) were over 75 years. 73% of these elderly patients were evaluable for the primary efficacy endpoint and 75% were evaluable for the secondary efficacy endpoint. All patients > 75 years were evaluable for safety outcomes, including bleeding. The incidence of total VTE and all cause mortality was 20.8% (44/212), 22.6% (49/217), and 27.2% (58/213), respectively, in the three groups. A similar trend was observed for major VTE and VTE-related mortality: 220 mg dabigatran etexilate, 1.9% (4/216, p=0.045 vs enoxaparin using Fisher’s exact test); 150 mg dabigatran etexilate, 4.5% (10/221); enoxaparin, 6.0% (13/218). MBE occurred in 11 of the 295 elderly patients receiving 220 mg dabigatran etexilate (3.7%), 4 of the 282 elderly patients receiving 150 mg dabigatran etexilate (1.4%) and in 9 of the 306 elderly patients taking enoxaparin (2.9%). Notably, 6/11 MBE in the dabigatran 220 mg group and 2/4 MBE in the 150 mg group started before the first dose of treatment. We conclude that in elderly patients (> 75 years) undergoing hip or knee replacement surgery, oral 150 mg dabigatran etexilate exhibited a numerically favourable bleeding profile with no difference in efficacy compared with 40 mg enoxaparin. Because safety, particularly bleeding, is of paramount importance in the elderly, the 150 mg once daily dose of dabigatran etexilate is currently recommended by EMEA for this group.

Introduction: Four randomized, double-blind phase III studies (RECORD1–4) investigated the oral, direct Factor Xa inhibitor rivaroxaban for the prevention of venous thromboembolism (VTE) after elective total hip and total knee arthroplasty (THA and TKA). Patients (N=12,729) were randomized to receive oral rivaroxaban 10 mg once daily, or subcutaneous enoxaparin 40 mg once daily (RECORD1–3), or 30 mg twice daily (RECORD4). Those undergoing THA received rivaroxaban or enoxaparin for 31–39 days in RECORD1, and rivaroxaban for 31–39 days or enoxaparin for 10–14 days followed by placebo in RECORD2. In RECORD3 and 4 (TKA), prophylaxis was for 10–14 days.

Methods: A prespecified pooled analysis of all four studies evaluated the effect of rivaroxaban on the composite of symptomatic VTE and all-cause mortality, and bleeding, relative to enoxaparin. The present subgroup analysis investigated potential drug–drug interactions with concomitant non-steroidal anti-inflammatory drugs (NSAIDs) or acetylsalicylic acid (ASA) – commonly used pain medications known to affect bleeding risk. The risk of on-treatment bleeding in the total study duration pool of all four RECORD studies was investigated. These prespecified analyses focused on on-treatment, adjudicated bleeding events, any bleeding, and the composite of major bleeding and clinically relevant non-major bleeding – after the first tablet intake (rivaroxaban or matching placebo). Co-medication use was evaluated over time. Relative bleeding rates with and without co-medication were calculated separately for the rivaroxaban and enoxaparin/placebo groups. Time after surgery (day of surgery was day 1) was stratified into three periods (days 1–3, days 4–7 and day 7 up to 2 days after the last dose), based on the decreasing risk with time of a first bleeding event after surgery and because prevalence of co-medication use can vary over time. Bleeding rates were recorded for each time period over the at-risk period (the day of surgery until the last day of double-blind study medication intake +2 days or until initial event onset). The ratio of the bleeding rate for co-medication exposed vs unexposed patient-days in the rivaroxaban group was compared with the corresponding rate ratio for the enoxaparin/placebo group for bleeding events (Mantel–Haenszel methods).

Results: Concomitant use of ASA in the rivaroxaban groups showed rate ratios similar to those in the enoxaparin/placebo group (1.32 and 1.40, respectively, for any bleeding). Rate ratios were also similar with concomitant use of NSAIDs (1.22 in both groups, for any bleeding).

Conclusion: In the RECORD1–4 subanalysis, there was no indication of increased bleeding associated with the use of these co-medications in patients taking rivaroxaban, compared with enoxaparin.

Dabigatran etexilate (Pradaxa^®) is an oral direct thrombin inhibitor that was recently approved in Europe and Canada for the prevention of venous thromboembolism (VTE) in patients undergoing total knee arthroplasty (TKA) or total hip arthroplasty (THA) surgery. In the phase III studies, concomitant administration of selective nonsteroidal anti-inflammatory drugs (NSAIDs with t½≤12 hours) and acetylsalicylic acid (ASA; < 160 mg/day) was allowed during treatment with dabigatran etexilate or enoxaparin. Due to the potential additional anticoagulant activity of these concomitant therapies a separate post hoc analysis was conducted to investigate the bleeding risk in these patients. We analysed the pooled study population (8,135 patients) from the three phase III trials in THA and TKA surgery (RE-MOBILIZE, RE-MODEL and RE-NOVATE) for major bleeding events (MBE). All MBE, which included surgical site bleeds, were assessed by an independent, expert adjudication committee. We report the rates of MBE and odds ratios (with 95% confidence intervals [CI]) for comparison of the subgroup concomitantly treated with NSAID (or ASA) versus the subgroup of patients without concomitant antithrombotically active medication. The overall rate of MBE (with and without NSAIDs and ASA) was 1.4% [CI 1.0–1.9], 1.1% [0.7–1.5] and 1.4% [1.0–2.0] with dabigatran etexilate 220 mg, 150 mg, and enoxaparin, respectively. Of the total population, 57.4% of patients received concomitant antithrombotic treatment: 54.1% received NSAID and 4.7% received ASA. The MBE rate in patients receiving dabigatran etexilate or enoxaparin plus NSAIDs was similar to the rate in patients taking only dabigatran etexilate or enoxaparin; 1.5% vs. 1.4% [OR 1.05; 0.55–2.01] for dabigatran etexilate 220 mg, 1.1% vs. 1.0% [OR 1.19; 0.55–2.55] for dabigatran etexilate 150 mg, and 1.6% vs. 1.2% [OR 1.32; 0.67–2.57] for enoxaparin. A similar pattern was seen in patients concomitantly receiving ASA; in this small group only a few patients with MBE were observed: 2 (1.6%) in the dabigatran etexilate 220 mg group, 2 (1.6%) in the 150 mg group, and 4 (3.0%) in the enoxaparin group. No relevant differences in risk for MBE were detected between treatments by co-medication subgroup or within treatment groups when comparing patients receiving dabigatran etexilate or enoxaparin only versus those concomitantly receiving NSAIDs or ASA. In conclusion, patients concomitantly receiving dabigatran etexilate and NSAIDs (with t½ ≤12 hours) or ASA (< 160 mg/day) have a similar risk of MBE to patients taking only dabigatran etexilate. These data support the use of dabigatran etexilate for the prevention of VTE in patients after THA or TKA, when concomitant use of NSAIDs or ASA (< 160 mg/day) is required.

Introduction: Venous thromboembolism (VTE) is a common, potentially fatal complication of major orthopaedic surgery. Although pharmacological thromboprophylaxis is recommended following total hip replacement (THR) for a minimum of 10 days, and up to 35 days, its extended use is not universally accepted – an effective, safe and convenient, oral anticoagulant would improve implementation of these recommendations. This trial compared short-term thromboprophylaxis using enoxaparin with extended thromboprophylaxis using rivaroxaban – a once-daily, oral, direct Factor Xa inhibitor – after THR, in the largest, prospective, randomized clinical trial conducted to date for the evaluation of the risk/benefit of extended prophylaxis.

Method: In this global, double-blind trial, 2509 patients undergoing THR were randomized to receive either subcutaneous enoxaparin 40 mg once daily (od), started the evening before surgery and continued for 10–14 days, followed by placebo until day 35±4 (short-term prophylaxis), or oral rivaroxaban 10 mg od, started 6–8 hours after surgery and continuing for 35±4 days (extended prophylaxis). Mandatory, bilateral venography was conducted on day 36±4. The primary efficacy endpoint was the composite of any deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE), and all-cause mortality. The main secondary efficacy endpoint was major VTE (the composite of proximal DVT, non-fatal PE, and VTE-related death). Safety endpoints included the incidence of major and non-major bleeding.

Results: The incidence of the primary efficacy endpoint was significantly reduced with extended thromboprophylaxis with rivaroxaban compared with short-term enoxaparin (2.0% and 9.3%, respectively; p< 0.001; relative risk reduction [RRR] 79%), as was major VTE (0.6% versus 5.1%; p< 0.001; RRR 88%). The incidence of major bleeding was the same in both groups (0.1%). Non-major bleeding was reported in 6.5% of patients who received extended thromboprophylaxis with rivaroxaban and in 5.5% of those treated with short-term enoxaparin.

Conclusion: Extended duration thromboprophylaxis with rivaroxaban is both significantly more effective and adds no disadvantage, in terms of bleeding, when compared with short-term prophylaxis. These data suggest that extended thromboprophylaxis provides substantial benefits to patients undergoing THR and rivaroxaban provides a safe and effective option for this strategy.

Introduction: After total hip replacement (THR), thromboprophylaxis for at least 10 days and for up to 35 days is recommended – yet a convenient, oral anticoagulant is not currently available. Rivaroxaban – a once-daily, oral, direct Factor Xa inhibitor with a predictable clinical profile – is in advanced clinical development. RECORD1, a multinational, randomized, double-blind, double-dummy, phase III study, compared once-daily oral rivaroxaban with subcutaneous enoxaparin for 5 weeks following THR.

Methods: In total, 4541 patients were randomized to receive oral rivaroxaban 10 mg (6–8 hours after surgery and once daily thereafter), or 40 mg enoxaparin (administered subcutaneously the evening before surgery, resumed 6–8 hours after surgery, and continued once daily). Thromboprophylaxis was administered for 35±4 days; mandatory, bilateral venography was conducted the next day. The primary efficacy endpoint was the composite of any deep vein thrombosis (DVT), nonfatal pulmonary embolism (PE), and all-cause mortality. Safety endpoints included major and non-major bleeding during the active treatment period.

Results: The incidence of the composite of DVT, PE, and all-cause mortality was significantly lower for rivaroxaban compared with enoxaparin (1.1% vs 3.7%, respectively; p< 0.001; relative risk reduction [RRR] 70%). The incidence of major VTE was also significantly lower for rivaroxaban compared with enoxaparin (0.2% vs 2.0%, respectively; p< 0.001; RRR 88%). There were no significant differences in the incidence of major bleeding (0.3% vs 0.1%; p=0.178) or non-major bleeding (5.8% vs 5.8%; p=1.000) between rivaroxaban and enoxaparin, respectively. There was no evidence of cardiac or liver safety issues.

Conclusions: Following THR, thromboprophylaxis with once-daily, oral rivaroxaban was shown to be significantly more effective than subcutaneous, once-daily enoxaparin – without an increased risk of bleeding. This trial demonstrates the efficacy and safety of oral rivaroxaban using a fixed, unmonitored, once-daily dose for extended thromboprophylaxis after THR.

Rivaroxaban is an oral, direct Factor Xa inhibitor in clinical development for the prevention of VTE after major orthopaedic surgery. Data from three phase II trials of twice-daily (bid) rivaroxaban in patients undergoing elective, total hip or knee replacement were pooled to determine whether age, gender or weight affected the efficacy or safety of rivaroxaban, and thus whether dose adjustment would be necessary. Patients received 5–9 days of oral rivaroxaban (2.5–30 mg bid, post-operatively), or s.c. enoxaparin. A logistic regression model using total daily dose of rivaroxaban as a covariate, and adjusted for differences between dose groups with respect to study, age and gender, was used to estimate rates of the primary efficacy endpoint (DVT, PE or all-cause mortality; n=1380 intention-to-treat patients) and clinically relevant bleeding (major and non-major clinically relevant bleeding; safety population, n=1854). Rivaroxaban at total daily doses of 5–20 mg had similar efficacy and safety to enoxaparin. Overall, logistic regression showed a positive dose–response relationship with rivaroxaban for clinically relevant bleeding (p< 0.001), and a flat relationship for the primary efficacy endpoint (p=0.115). The risk of VTE increased with age – the efficacy endpoint was estimated to occur in 17.3–9.4%, 18.7–17.3% and 26.6–20.2% of patients aged < 60 yrs, 60–70 yrs and > 70 yrs receiving rivaroxaban (total daily dose 5–60 mg), respectively, in separate regression models. Age was also prognostic for clinically relevant bleeding with rates of 1.4–12.0% (< 60 yrs), 2.7–15.4% (60–70 yrs) and 5.7–15.4% (> 70 yrs). The rates are for a population distributed equally across the studies and genders. Incidences of the efficacy endpoint were higher in females (25.8–20.5%) than males (16.6–10.7%), while clinically relevant bleeding occurred more frequently in males (5.4–16.3%) than in females (1.7–11.6%), after adjustment for age. Weight was not prognostic for the efficacy endpoint or clinically relevant bleeding (p=0.87 and p=0.48, respectively, after adjustment for age, gender and study), nor did it modify the dose–response relationships with rivaroxaban. Incidences of the efficacy endpoint for a population of equal study and gender distribution and of mean patient age were 23.4–15.7% and 19.1–14.6% in patients weighing < 65 kg and ≥90 kg, respectively, with corresponding bleeding rates of 3.3–16.5% and 3.2–17.5%. This analysis indicates that age, gender or weight did not affect the dose–response relationships (or lack thereof) between rivaroxaban and the primary efficacy endpoint or clinically relevant bleeding. As expected, age was prognostic for VTE and bleeding. These findings suggest that rivaroxaban may not require dose adjustment for age, gender or weight in orthopaedic patients.

Routine prophylaxis is recommended to prevent venous thromboembolism (VTE) – manifesting as deep vein thrombosis (DVT) and/or pulmonary embolism (PE) – in patients undergoing major orthopaedic surgery. Rivaroxaban (BAY 59-7939) is a novel, oral, direct Factor Xa inhibitor in development for the prevention and treatment of VTE. The efficacy and safety of 5–9 days’ prophylaxis with rivaroxaban were investigated in three randomized, double-blind, phase IIb trials in patients undergoing elective, total hip or knee replacement (THR or TKR), relative to subcutaneous enoxaparin.

Two trials (one in patients undergoing THR, N=722; and one in patients undergoing TKR, N=621) investigated twice-daily (bid) rivaroxaban (at total daily doses of 5–60 mg); the third (in patients undergoing THR, N=873) investigated once-daily (od) rivaroxaban (at doses of 5, 10, 20, 30 or 40 mg od).

Rivaroxaban – at all doses tested – had similar efficacy to enoxaparin in the bid trials. This promising finding was strengthened by the od trial, in which the observed incidences of the primary efficacy endpoint (DVT, non-fatal PE or all-cause mortality) were lower in patients receiving rivaroxaban 5, 10, 20, 30 and 40 mg od (14.9%, 10.6%, 8.5%, 13.5% and 6.4%, respectively) than enoxaparin (25.2%). Although there was no significant dose–response relationship between rivaroxaban and the primary efficacy endpoint in these trials, there was with major VTE (proximal DVT, PE or VTE-related death; p=0.0072) in the od trial (incidences were 8.5%, 2.7%, 0.9%, 1.9% and 1.1% with rivaroxaban 5, 10, 20, 30 and 40 mg od, respectively, vs 2.8% with enoxaparin).

Significant dose–response relationships between rivaroxaban and major bleeding were observed in all three trials. In the bid trials, major bleeding rates with rivaroxaban were similar to those with enoxaparin at total daily doses of 5–20 mg. In the od trial, major bleeding occurred in 2.3%, 0.7%, 4.3%, 4.9% and 5.1% of patients receiving rivaroxaban 5, 10, 20, 30 and 40 mg od, respectively, and in 1.9% of those receiving enoxaparin.

Rivaroxaban was generally well tolerated in the bid and od trials, and the incidence of nausea and vomiting with early post-operative oral rivaroxaban administration was low for all doses tested.

The bid trials suggest that oral rivaroxaban at total daily doses of 5–20 mg may be a safe and effective alternative to enoxaparin for the prevention of VTE after major orthopaedic surgery. The od trial suggests that the more-convenient od regimen is feasible and that 10 mg od, a dose within the range identified by the bid trials, should be investigated further. As a result, oral rivaroxaban 10 mg od is currently being investigated in four phase III trials for the prevention of VTE after major orthopaedic surgery (the RECORD trials).

BACKGROUND: Oral DVT prophylaxis not requiring monitoring is an advantage in orthopaedic patients. Dabigatran etexilate is an oral direct thrombin inhibitor undergoing evaluation for the prevention of venous thromboembolic events (VTE) following orthopaedic surgery.

METHODS: In a phase III, multicenter, non-inferiority, double-blind study, patients undergoing total knee replacement were randomized to 3 treatments. The patients received 8±2 days of oral dabigatran etexilate, 150 or 220 mg once daily starting with a half dose (i.e.75 or 110 mg) 1–4 hours after surgery, or subcutaneous enoxaparin 40 mg once daily starting 12 hours prior to surgery. The primary efficacy outcome was the composite of total VTE and all causes of mortality during the treatment period. All efficacy and safety outcome events were adjudicated by blinded independent committees.

RESULTS: Efficacy could be evaluated for 1541 (75%) treated and operated patients. Total VTE and death occurred in 40.5%, 36.4% and 37.7% of patients assigned to dabigatran etexilate 150 or 220mg once daily or enoxaparin, respectively. Proximal DVT and/ or PE occurred in 3.8%, 2.6% and 3.5% of patients receiving dabigatran 150 or 220mg or enoxaparin, respectively. Three deaths occurred during the treatment period, one in each of the treatment groups. Safety was evaluated for all 2076 patients receiving study treatment. The rate of major bleeding was 1.3%, 1.5% and 1.3% of patients receiving dabigatran 150 or 220mg or enoxaparin. Elevated LFTs (ALT > 3xULN) occurred in 3.7%, 2.8% and 4.0% of the patients treated with 150 and 220 mg dabigatran or enoxaparin during the study. A temporary rise in LFTs was observed during the follow-up period in 0.5% of the patients who had received dabigatran and in 0.4% of the patients who had received enoxaparin.

CONCLUSIONS: Non-inferiority for the primary efficacy endpoint was met for both doses of dabigatran etexilate compared to enoxaparin. There was no difference in bleeding rates between the treatment groups. Oral administration of dabigatran etexilate once daily, given early in the postoperative period, was effective and safe for the prevention of total VTE in patients undergoing total knee replacement surgery.

Purpose: Thromboembolic events, such as deep vein thrombosis (DVT) and pulmonary embolism (PE), are a serious risk after major orthopaedic surgery. BAY 59-7939 is a novel, oral, direct Factor Xa inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. The efficacy and safety of BAY 59-7939 for thromboprophylaxis have been determined relative to enoxaparin in two clinical trials, one after elective total hip replacement surgery, and one after elective total knee replacement surgery. This pre-specified analysis combines data from two multicenter, multinational, double-blind, dose-ranging studies; the hip surgery trial was performed in Europe, and the knee surgery trial in North America.

Methods: Patients (N=1343) were randomized to oral BAY 59-7939 at 2.5, 5, 10, 20, or 30 mg twice daily (bid), or subcutaneous enoxaparin (40 mg once daily starting 12 hours before hip surgery, or 30 mg bid starting 12 hours after knee surgery), continuing until mandatory bilateral venography was performed 5–9 days after surgery. The primary efficacy endpoint was a composite of DVT, PE, and all-cause mortality. The primary safety endpoint was major, post-operative bleeding.

Results: The primary efficacy endpoint occurred in 21.6%, 22.9%, 16.1%, 24.4%, and 19.3% of patients receiving BAY 59-7939 2.5, 5, 10, 20, and 30 mg bid, respectively, and 27.8% receiving enoxaparin (n=914). No significant dose–response relationship for efficacy was observed with BAY 59-7939 (P=0.39); this was potentially due to the efficacy achieved with the lower BAY 59-7939 doses. A significant dose–response relationship was observed for major, post-operative bleeding with BAY 59-7939 (P< 0.001), which occurred in 0.9%, 1.3%, 2.1%, 3.9%, and 7.0% of patients receiving BAY 59-7939 2.5, 5, 10, 20, and 30 mg bid, respectively, and 1.7% of patients receiving enoxaparin (n=1317).

Conclusions: This analysis showed that BAY 59-7939 has a wide therapeutic window for the prevention of VTE following major orthopaedic surgery, and, at doses of 2.5–10 mg bid, has similar efficacy and safety to the enoxaparin regimens.

Funding : Commerical funding

Funding Parties : This study was sponsored by Bayer HealthCare AG

Aims: The fondaparinux thromboprophylaxis phase III studies database including 7344 patients in orthopaedic surgery provides information regarding patient management according to country specificities. Methods: 4 randomized double-blind trials were conducted in 376 centers in 23 countries comparing fondaparinux to enoxaparin – 1 in major knee surgery (MKS) in North America (NA); 2 in total hip replacement (THR) in NA and in Europe, respectively; and 1 in hip-fracture (HF) surgery worldwide except in NA. The use of regional anesthesia or cement during surgery, use of stockings during hospitalization, or prolonged prophylaxis (PP) after discharge were left to the investigators. Results: In all studies the majority of patients were women, particularly in HF. The median age was 67 years for THR, 69 years for MKS, and 79 years for HF. In THR studies, regional anesthesia was used more frequently in Europe (59%) than in NA (24.4%). The table summarizes investigators’ practice. Conclusions: There are important differences in the management of orthopedic surgery patients according to country specificities and type of surgery. However, fondaparinux is more effective than enoxaparin for thromboprophylaxis irrespective of patient or surgery characteristics.

Aims: To assess whether there was a relationship between the timing of the first administration of fondaparinux and its efficacy and safety in preventing venous thromboembolism (VTE) in orthopaedic surgery. Methods: Overall, 3616 patients received fondaparinux in 4 randomized, double-blind studies in this setting. We performed a post-hoc analysis of the effect of this timing on VTE up to day 11 (primary efficacy) and bleeding with a bleeding index (BI) ≥2, using logistic regression. These 2 parameters were also analyzed according to whether fondaparinux started before 6 hours or at 6 hours or later postoperation. Results: Logistic regression showed that the efficacy of fondaparinux was not affected by the timing of its first administration (p=0.67). However, there was a statistically significant relationship between this timing and bleeding with a BI ≥2 (p=0.008). The table gives the incidence of VTE and bleeding with a BI ≥2 according to the interval between skin closure and the first fondaparinux injection. Conclusions: The efficacy of fondaparinux in preventing VTE in orthopaedic surgery was not related to the timing of its first administration. In addition, a significant reduction in the incidence of bleeding with a BI ≥2 was observed when the first fondaparinux injection took place between 6 and 9 hours after skin closure.

Aims: In major orthopedic surgery, fondaparinux provided a major benefit over enoxaparin, with an overall venous thromboembolsim (VTE) risk reduction of > 50% and similar safety profile regarding clinically relevant bleeding (leading to death or reoperation, or occurring in critical organ). The aim of the present study was to analyze this superior efficacy according to patients and surgery characteristics. Methods: In four phase III trials, the primary efficacy outcome was the VTE incidence up to day 11, defined as deep-vein thrombosis (DVT) detected by mandatory bilateral venography or documented symptomatic DVT or pulmonary embolism. Primary efficacy was further analyzed according to predefined categorical covariates using a logistic regression model. Results: Fondaparinux was more effective than enoxaparin irrespective of age, gender, obesity, the use of cement or surgery duration (odds reduction from −46.9% to −59.7% in favor of fondaparinux. Clinically relevant bleeding did not differ between the two groups according to predefine covariates. Conclusions: For VTE prevention in major orthopaedic surgery, the superiority of fondaparinux over enoxaparin was consistent irrespective of patient or surgery characteristics.

Aims: In orthopedic surgery, the optimal duration of thromboprophylaxis is debated, and very few data are available in hip fracture. We addressed these issues in 5 randomized double-blind clinical trials of fondaparinux. Methods: In four studies in 7344 orthopedic surgery patients, fondaparinux was administered up to 11 days and compared to approved enoxaparin regimens. In the PENTHIFRA-Plus study in 656 hip fracture surgery patients, after an initial treatment with fondaparinux for 7±1 days, patients were randomized to fondaparinux or placebo for additional 21±2 days. In all trials, primary efficacy was venous thromboembolism (VTE), at the end of the treatment period. Results: In the four 11-day prophylaxis studies, fondaparinux reduced the incidence of VTE from 13.7% with enoxaparin to 6.8% (risk reduction [RR]: 55.2%; P< 0.001). Fondaparinux efficacy was significantly influenced by treatment duration (P< 0.001): for instance, the incidence of VTE was lower in patients treated for 9 to11 days (5.2%) than in patients treated for ≤5 days (8.7%, P= 0.038). In the PENTHIFRA-Plus study, the incidence of VTE up to 4 weeks was reduced to 1.4% compared with 35.0% with placebo (relative RR: 95.9%, P< 0.001). The incidence of symptomatic VTE was also significantly lower with fondaparinux (0.3%) than with placebo (2.7%, relative RR: 88.8%, P=0.021). Conclusions: Fondaparinux efficacy in preventing VTE in orthopedic surgery increased significantly with a longer duration of treatment. Hip fracture surgery patients are at high risk of VTE up to 4 weeks after surgery and treatment with fondaparinux for 4 weeks postoperatively provides greater benefit than active treatment for only 1 week.

Aims: To evaluate the inßuence of the type of anesthesia on the superior efþcacy of fondaparinux over enoxaparin in preventing venous thromboembolism (VTE) in orthopedic surgery (RRR > 50%; P< 0.0001). Methods: 4 randomized, double-blind trials were performed: 2 in hip replacement (THR), 1 in North America (NA) and 1 in Europe; 1 in knee surgery (MKS); and 1 in hip-fracture surgery (HF). The choice of anesthesia was left to the investigators. A predeþned covariate analysis according to the type of anesthesia was performed on primary efþcacy.

Conclusions: Fondaparinux once-daily started postoperatively provided superior efþcacy versus enoxaparin in preventing VTE whatever the type of anesthesia and may improve convenience in current practice.