Martin Homering

Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty. Pooled analysis of four studies.

Four phase III studies compared oral rivaroxaban with subcutaneous enoxaparin for the prevention of venous thromboembolism (VTE) after total hip or knee arthroplasty (THA or TKA). A pooled analysis of these studies compared the effect of rivaroxaban with enoxaparin on symptomatic VTE plus all-cause mortality and bleeding events, and determined whether these effects were consistent in patient subgroups. Patients (N=12,729) aged ≥18 years and scheduled for elective THA or TKA received rivaroxaban 10 mg once daily or enoxaparin 40 mg once daily or 30 mg every 12 hours. The composite of symptomatic VTE and all-cause mortality, the prespecified primary efficacy endpoint and adjudicated bleeding events were analysed in the day 12± 2 active treatment pool. Subgroup analyses of these outcomes were performed over the total treatment period. In the day 12± 2 pool, the primary efficacy endpoint occurred in 29/6,183 patients receiving rivaroxaban (0.5%) versus 60/6,200 patients receiving enoxaparin (1.0%; p=0.001). Major bleeding occurred in 21 (0.3%) versus 13(0.2%) patients, p=0.23; major plus non-major clinically relevant bleeding in 176(2.8%) versus 152 (2.5%) patients, p=0.19; and any bleeding in 409 (6.6%) versus 384 (6.2%) patients, p=0.38, respectively. The reduction of symptomatic VTE plus all-cause mortality was consistent across prespecified subgroups (age, gender, body weight, creatinine clearance) in the total treatment period. Compared with enoxaparin regimens, rivaroxaban reduces the composite of symptomatic VTE and all-cause mortality after elective THA or TKA, with a small increase in bleeding, no signs of compromised liver safety and fewer serious adverse events.

Rivaroxaban for thromboprophylaxis after orthopaedic surgery: pooled analysis of two studies.

Rivaroxaban (BAY 59-7939) is an oral, direct factor Xa inhibitor in clinical development for the prevention and treatment of venous thromboembolism (VTE). This analysis of pooled results from two phase II studies of rivaroxaban for VTE prevention after major orthopaedic surgery aimed to strengthen the conclusions of the individual studies. One study was conducted in patients undergoing total hip replacement (THR; N = 722), and one in patients undergoing total knee replacement (TKR; N = 621). In both studies, patients were randomized, doubleblind, to oral, twice-daily (bid) rivaroxaban beginning after surgery, or subcutaneous enoxaparin (40 mg once daily beginning before THR, and 30 mg bid beginning after TKR). Treatment continued until mandatory bilateral venography was performed 5-9 days after surgery. Total VTE (deep vein thrombosis, pulmonary embolism, and all-cause mortality) occurred in 16.1-24.4% of per-protocol patients receiving rivaroxaban 5-60 mg, and 27.8% receiving enoxaparin (n = 914). There was a flat dose response relationship between rivaroxaban and total VTE (p = 0.39). Major bleeding (safety population, n = 1,317) increased dose-dependently with rivaroxaban (p < 0.001), occurring in 0.9%, 1.3%, 2.1%, 3.9%, and 7.0% of patients receiving rivaroxaban total daily doses of 5, 10, 20, 40, and 60 mg, respectively, versus 1.7% of patients receiving enoxaparin. No routine coagulation monitoring was performed, and there were no significant differences between dose response relationships with rivaroxaban after THR and TKR. Overall, rivaroxaban total daily doses of 5-20 mg had the most favorable balance of efficacy and safety, relative to enoxaparin, for the prevention of VTE after major orthopaedic surgery.

Concomitant use of medication with antiplatelet effects in patients receiving either rivaroxaban or enoxaparin after total hip or knee arthroplasty

INTRODUCTION The RECORD programme compared oral rivaroxaban with enoxaparin for prevention of venous thromboembolism after elective total hip or knee replacement. This analysis compared the safety of concomitant use of specified medications with rivaroxaban and enoxaparin by evaluating postoperative bleeding rates from the pooled RECORD1-4 data. MATERIALS AND METHODS The co-medications were non-steroidal anti-inflammatory drugs and platelet function inhibitors, including acetylsalicylic acid (no dose restriction). The endpoints evaluated were the composite of major and non-major clinically relevant bleeding and any bleeding occurring after first oral study drug intake. The time relative to surgery was stratified into three time periods: day 1-3, day 4-7 and after day 7. Relative bleeding rate ratios for co-medication use versus non-use were derived using stratified Mantel-Haenszel methods and compared between rivaroxaban and enoxaparin groups. RESULTS Co-medication use with rivaroxaban or enoxaparin resulted in non-significant increases in bleeding events. Respective rate ratios were not significantly different between rivaroxaban and enoxaparin for all bleeding endpoints with concomitant use of non-steroidal anti-inflammatory drugs (any bleeding, 1.22 vs 1.22; major and non-major clinically relevant bleeding, 1.28 vs 0.90) and with concomitant use of platelet function inhibitors/acetylsalicylic acid (any bleeding, 1.32 vs 1.40; major and non-major clinically relevant bleeding, 1.11 vs 1.13). CONCLUSIONS This explorative analysis indicates that there is no significant increase in bleeding risk for rivaroxaban compared with enoxaparin when co-administered with non-steroidal anti-inflammatory drugs or acetylsalicylic acid, although, because of low usage, the experience with platelet function inhibitors (except acetylsalicylic acid) was limited.

Vardenafil is effective and well-tolerated for treating erectile dysfunction in a broad population of men, irrespective of age

To assess the efficacy and safety of vardenafil in the treatment of erectile dysfunction (ED) in men of different age groups.

The COUPLES-project: a pooled analysis of patient and partner treatment satisfaction scale (TSS) outcomes following vardenafil treatment

Associate Editor

Benefit–risk assessment of rivaroxaban versus enoxaparin for the prevention of venous thromboembolism after total hip or knee arthroplasty

Purpose Venous thromboembolism is a common complication after major orthopedic surgery. When prescribing anticoagulant prophylaxis, clinicians weigh the benefits of thromboprophylaxis against bleeding risk and other adverse events. Previous benefit–risk analyses of the REgulation of Coagulation in ORthopaedic surgery to prevent Deep vein thrombosis and pulmonary embolism (RECORD) randomized clinical studies of rivaroxaban versus enoxaparin after total hip (THA) or knee (TKA) arthroplasty generally used pooled THA and TKA results, counted fatal bleeding as both an efficacy and a safety event, and included the active and placebo-controlled portions of RECORD2, which might confound benefit–risk assessments. We conducted a post hoc analysis without these constraints to assess benefit–risk for rivaroxaban versus enoxaparin in the RECORD studies. Patients and methods Data from the safety population of the two THA and two TKA studies were pooled separately. The primary analysis compared the temporal course of event rates and rate differences between rivaroxaban and enoxaparin prophylaxis for symptomatic venous thromboembolism plus all-cause mortality (efficacy events) versus nonfatal major bleeding (safety events). Additionally, these rates were used to derive measures of net clinical benefit, number needed to treat (NNT), and number needed to harm (NNH) for these two end points. Results After THA or TKA, and compared with enoxaparin, rivaroxaban therapy resulted in more efficacy events prevented than safety events caused, with benefits exceeding harms early and throughout treatment and follow-up. Relative to enoxaparin, rivaroxaban treatment prevented six efficacy events per harm event caused for THA, with NNT =262/NNH =1,711. For TKA, rivaroxaban treatment prevented four to five efficacy events per harm event caused, with NNT =102/NNH =442. Sensitivity analysis that included surgical-site bleeding resulted in NNH =345 for THA and NNH =208 for TKA. Conclusion In the RECORD studies, considering death, symptomatic venous thromboembolism, and major bleeding, rivaroxaban resulted in greater benefits than harms compared with enoxaparin. When incorporating surgical-site bleeding, rivaroxaban also results in greater benefit than harm for TKA and is balanced with enoxaparin for THA.

Adverse Event Analysis and MedDRA: Business as Usual or Challenge?*

The Medical Dictionary for Regulatory Activities (MedDRA) is a dictionary of medical terms which covers signs and symptoms; diseases; diagnoses; therapeutic indications; names and qualitative results of indications; surgical and medical procedures; and medical, social, and family history. Until now, the pharmaceutical industry was only obligated to use MedDRA for submissions of individual case safety reports. Neither the MedDRA Maintenance and Support Services Organization nor regulatory bodies provided any recommendations on the use of MedDRA for analyses and reporting of clinical trial data. As the pharmaceutical industry introduces MedDRA in its day-to-day processes, there is an urgent need to fill this gap. The Biometry Subgroup of the German Association of Research-Based Pharmaceutical Companies has established a working group which will provide recommendations on the use of MedDRA in reporting and labeling. This paper aims to start a discussion about the use of MedDRA in the analysis of clinical trials.

Risk of recurrent venous thromboembolism according to baseline risk factor profiles

The optimal duration of anticoagulation for venous thromboembolism (VTE) is uncertain. In this prespecified analysis, we used data from 2 randomized trials, which compared once-daily rivaroxaban (20 mg or 10 mg) with aspirin (100 mg) or placebo for extended VTE treatment to estimate the risk of recurrence according to baseline risk factor profiles. Index VTE events were centrally classified as unprovoked, or provoked by major transient or persistent, or minor transient or persistent risk factors, and rates of recurrence at 1 year were calculated. A total of 2832 patients received rivaroxaban; 1131 received aspirin, and 590 received placebo. With unprovoked VTE, rates of recurrence in the 1173 patients given rivaroxaban, the 468 given aspirin, and the 243 given placebo were 2.0%, 5.9%, and 10.0%, respectively. There were no recurrences in patients with VTE provoked by major transient risk factors. With VTE provoked by minor persistent risk factors, recurrence rates in the 1184 patients given rivaroxaban, the 466 given aspirin, and the 248 given placebo were 2.4%, 4.5%, and 10.7%, respectively. For patients with minor transient risk factors, recurrence rates were 0.4% in the 268 patients given rivaroxaban, 4.2% in the 121 given aspirin, and 7.1% in the 56 given placebo. Recurrence rates in patients with VTE provoked by minor persistent or minor transient risk factors were not significantly lower than that with unprovoked VTE (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.56-1.16; and HR, 0.68; 95% CI, 0.32-1.30, respectively). Therefore, such patients may also benefit from extended anticoagulation therapy.

Benefits and risks of extended treatment of venous thromboembolism with rivaroxaban or with aspirin.

BACKGROUND Full- or lower-dose anticoagulant therapy or aspirin can be used for extended therapy in patients with venous thromboembolism (VTE), but information on their relative benefit-risk profiles is limited. METHODS Data from the EINSTEIN-CHOICE trial were used to compare the benefit-risk profiles of extended treatment with rivaroxaban (20 or 10 mg once daily) and aspirin (100 mg once daily) in VTE patients who had completed 6 to 12 months of anticoagulation therapy. One-year cumulative incidences of recurrent VTE and major bleeding were estimated and benefits and risks were calculated by determining the between group differences in a hypothetical population of 10,000 VTE patients treated for 1 year. FINDINGS A total of 1107 patients were treated with 20 mg of rivaroxaban, 1127 with 10 mg of rivaroxaban, and 1131 with aspirin. The cumulative incidences of recurrent VTE in the rivaroxaban 20-mg, rivaroxaban 10-mg and aspirin groups were 1.9%, 1.6%, and 5.0%, respectively, whereas the cumulative incidences of major bleeding were 0.7%, 0.4% and 0.5%, respectively. The incidences of the combined outcome of recurrent VTE and major bleeding were 2.8% and 3.4% lower in the rivaroxaban 20-mg and 10-mg groups than in the aspirin group. For 10,000 patients treated for 1 year, there would be 284 (95% confidence interval [CI] 106 to 462) and 339 (95% CI 165 to 512) fewer events with rivaroxaban 20 mg or 10 mg than with aspirin. INTERPRETATION Compared with aspirin, extended anticoagulation with once daily rivaroxaban reduces recurrent VTE with a favourable benefit-risk profile. FUNDING Bayer AG.