Among patients undergoing hip replacement, thromboprophylaxis with apixaban, as compared with enoxaparin, was associated with lower rates of venous thromboembolism, without increased bleeding. (Funded by Bristol-Myers Squibb and Pfizer; ClinicalTrials.gov number, NCT00423319.).
As compared with enoxaparin for efficacy of thromboprophylaxis after knee replacement, apixaban did not meet the prespecified statistical criteria for noninferiority, but its use was associated with lower rates of clinically relevant bleeding and it had a similar adverse-event profile. (ClinicalTrials.gov number, NCT00371683.)
Objective: To investigate the efficacy and safety of abatacept in combination with etanercept in patients with active rheumatoid arthritis during a 1-year, randomised, placebo-controlled, double-blind phase, followed by an open-label, long-term extension (LTE). Methods: Patients continued etanercept (25 mg twice weekly) and were randomised to receive abatacept 2 mg/kg (n = 85) or placebo (n = 36). As the effective dose of abatacept was established as 10 mg/kg in a separate trial, all patients received abatacept 10 mg/kg and etanercept during the LTE. Results: A total of 121 patients were randomised; 80 completed double-blind treatment and entered the LTE. During double-blind treatment, the difference in the percentage of patients achieving the primary end point (modified American College of Rheumatology (ACR) 20 response at 6 months) was not significant between groups (48.2% v 30.6%; p = 0.072). At 1 year, no notable changes in modified ACR responses were observed. Subsequent to the dosing change, similar modified ACR responses were seen during the LTE. Significant improvements in quality of life were observed with abatacept and etanercept versus placebo and etanercept in five of the eight short-form 36 subscales at 1 year. More abatacept and etanercept-treated patients experienced serious adverse events (SAEs) at 1 year than patients receiving placebo and etanercept (16.5% v 2.8%), with 3.5% v 0% experiencing serious infections. Conclusion: The combination of abatacept (at a dose of 2 mg/kg during the double-blind phase and 10 mg/ kg during the LTE) and etanercept was associated with an increase in SAEs, including serious infections, with limited clinical effect. On the basis of the limited efficacy findings and safety concerns, abatacept in combination with etanercept should not be used for rheumatoid arthritis treatment.
Vilazodone is a selective serotonin reuptake inhibitor and 5-HT1A partial agonist approved for major depressive disorder (MDD) treatment in adults. This was a 10-week, multicenter, double-blind, placebo-controlled and active-controlled, fixed-dose trial (NCT01473381). Adult patients with MDD (Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revision criteria) were randomized 1 : 1 : 1 : 1 to vilazodone 20 or 40 mg/day, citalopram 40 mg/day, or placebo. Primary efficacy: Montgomery–Åsberg Depression Rating Scale (MADRS); secondary efficacy: Clinical Global Impressions-Severity and sustained response (MADRS total score≤12 for at least the last two consecutive double-blind visits). The intent-to-treat population comprised 1133 patients, (placebo=281; vilazodone 20 mg/day=288; vilazodone 40 mg/day=284; citalopram=280). MADRS and Clinical Global Impressions-Severity score change from baseline to week 10 was significantly greater for vilazodone 20 mg/day, vilazodone 40 mg/day, and citalopram versus placebo. Sustained response rates were numerically higher, but not significantly different, in all active treatment groups versus placebo. The most common adverse events (≥5% of vilazodone patients, twice the rate of placebo) were diarrhea, nausea, vomiting (vilazodone 40 mg/day only), and insomnia. Improved sexual function (Changes in Sexual Functioning Questionnaire scores) was seen in all groups; between-group differences were not significant. Vilazodone 20 and 40 mg/day demonstrated efficacy and tolerability in the treatment of MDD.
Introduction:Vilazodone is a potent serotonin (5-HT) reuptake inhibitor and 5-HT 1A receptor partial agonist approved by the US Food and Drug Administration for the treatment of major depressive disorder (MDD) in adults. This study evaluated the efficacy and tolerability of vilazodone in the treatment of MDD.Method: This 8-week, randomized (1:1), doubleblind, placebo-controlled, parallel-group, fixed-dose study conducted from January 2012 to February 2013 compared vilazodone 40 mg/d with placebo in outpatients with DSM-IV-TR-diagnosed MDD. The primary efficacy measure was Montgomery-Asberg Depression Rating Scale (MADRS) total score change from baseline to week 8 analyzed by a mixed-effects model for repeated measures on the intent-to-treat population (placebo = 252, vilazodone = 253). Secondary efficacy outcomes were Clinical Global ImpressionsSeverity of Illness (CGI-S) Scale score change from baseline and MADRS sustained response rate (total score ≤ 12 for at least the last 2 consecutive double-blind visits).Results: Approximately 83% of patients completed the study. Least squares mean differences (95% CI) were statistically significant for vilazodone versus placebo on MADRS (−5.117 [−6.886 to −3.347], P < .00001) and CGI-S (−0.622 [−0.845 to −0.399], P < .00001) change from baseline; statistically significant improvements versus placebo occurred at week 2 and persisted for the study duration. The MADRS sustained response rate was 17% for placebo and 27% for vilazodone (P < .01). Patients taking vilazodone versus placebo had higher rates of diarrhea and nausea; most incidences were mild in severity. Weight increase and sexual dysfunction adverse events were low in both groups. Conclusions:A large and significant treatment effect on the MADRS and statistically significant improvement on the CGI-S demonstrated meaningful depressive symptom improvements. Vilazodone was generally well tolerated.Trial Registration: ClinicalTrials.gov identifier: NCT01473394
192 Thromboprophylaxis after joint replacement surgery is evidence-based standard care. Usually, when thromboprophylaxis regimens with new anticoagulants have been more effective than existing standard practice they have also caused increased bleeding. Apixaban, a novel orally administered factor Xa inhibitor, has been evaluated in three phase 3 randomized, double-blind, double-dummy clinical trials (the ADVANCE studies) for the prevention of venous thromboembolism (VTE) after hip or knee replacement. A pre-specified aim of this program, in order to provide more precise estimates of the incidences of major VTE, bleeding, and the additional safety outcomes of myocardial infarction, stroke, and liver function, was to combine data from the two trials comparing apixaban 2.5 mg twice daily with the same enoxaparin regimen of 40 mg once daily (ADVANCE-2 and 3). Major VTE was defined a priori as the composite of adjudicated symptomatic or asymptomatic proximal deep-vein thrombosis (popliteal, femoral, or iliac vein thrombosis), non-fatal pulmonary embolism, and VTE-related death, counted if they occurred during the intended treatment period for each trial or within 2 days after the last dose of study medication, whichever was longer. The bleeding outcomes of major bleeding (adapted from ISTH criteria), clinically relevant non-major bleeding, and the composite of major and clinically relevant non-major bleeding, were counted if they occurred during the treatment period or within 2 days after the last dose of study medication. In both studies, subcutaneous enoxaparin (or placebo) was started 12±3 hours before operation, and resumed after surgery according to the investigator's standard of care, and oral apixaban (or placebo) was initiated 12 to 24 hours after wound closure (typically on the morning after surgery). Study medications were continued for 10 to 14 days after knee arthroplasty in ADVANCE- 2, and for 32 to 38 days after hip replacement in ADVANCE- 3. In both studies, mandatory bilateral venography was done at the end of the intended treatment period to assess the presence or absence of asymptomatic deep-vein thrombosis, and clinically suspected VTE was confirmed or excluded by objective testing. Patients were followed-up 30±5 and 60±5 days after the last dose of study medication. All venograms and all episodes of suspected VTE, bleeding, myocardial infarction, stroke, or death were adjudicated without knowledge of assigned treatment by an independent central adjudication committee. The site of bleeding was analysed as reported by the investigator. The pooled analysis was stratified by the type of joint replacement (hip or knee) for statistical calculations. A total of 8,564 patients were randomized in the ADVANCE-2 and 3 trials. Major VTE occurred in 23 of 3,394 evaluable patients (0.68%) in the apixaban group and in 51 of 3,394 (1.50%) evaluable patients in the enoxaparin group (absolute risk difference, -0.76%, 95% CI, -1.23% to -0.30%). Major bleeding occurred in 31 of 4,174 patients (0.74%) who received apixaban (18 occurred before the first dose) and in 32 of 4,167 patients (0.77%) given enoxaparin (absolute risk difference -0.02%, 95% CI, -0.40% to 0.35%). Major bleeding at the surgical site occurred in 26 apixaban and 27 enoxaparin patients (absolute risk difference -0.02%, 95% CI, -0.37% to 0.32%). The composite of major or clinically relevant non-major bleeding occurred in 182 patients (4.36%) given apixaban, compared with 206 patients (4.94%) given enoxaparin (absolute risk difference -0.58%, 95% CI, -1.49% to 0.32%); these bleeding events occurred at the surgical site in 135 (3.23%) apixaban patients, and in 155 (3.72%) enoxaparin patients (absolute risk difference -0.49%, 95% CI, -1.27% to 0.30%). Myocardial infarction or stroke during treatment or follow-up occurred in 13 patients (0.31%) in the apixaban group and in 10 patients (0.24%) in the enoxaparin group (absolute risk difference 0.07%, 95% CI, -0.15% to 0.30%). Elevated levels (>3 times upper normal limit) of enzymes ALT or AST occurred in 2.2% and 2.8% of apixaban patients respectively, and in 3.0% and 2.8% of enoxaparin patients respectively. The apixaban regimen was more effective than enoxaparin 40 mg once daily for preventing major VTE, without increased bleeding, and has the clinical advantages of oral administration and later initiation 12 to 24 hours post-operatively. Disclosures: Raskob: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Johnson and Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda R and D: Consultancy; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Consultancy. Off Label Use: Apixaban is an experimental drug being evaluated in phase 3 clinical trials for the prevention and treatment of thromboembolic disease. Research reults will be discussed. Gallus:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy; Progen: Membership on an entity's Board of Directors or advisory committees. Pineo:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Chen:BMS: Employment. Ramirez:BMS: Employment. Lassen:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Speakers Bureau; Sanofi Aventis: Consultancy; Astellas Pharma: Consultancy; GSK: Consultancy.
Summary. Background: New oral anticoagulants for thromboprophylaxis after hip or knee arthroplasty have been given as fixed-dose regimens. Objective: To evaluate the consistency of the antithrombotic efficacy and bleeding risk of apixaban 2.5 mg twice daily compared with enoxaparin 40 mg once daily after knee or hip arthroplasty across the clinical characteristics of age, gender, body weight, body mass index (BMI) and creatinine clearance. Methods: The pooled results of the ADVANCE-2 (knee arthroplasty) and -3 (hip arthroplasty) randomized trials were used to evaluate if treatment had a statistically significantly different effect (P < 0.10) on major venous thromboembolism (VTE) and bleeding for the characteristics of age, gender, body weight, BMI and creatinine clearance. Both univariate analysis and multivariate logistic regression were used. Results: Univariate analyses identified statistically significant interactions for age and major VTE (P = 0.09); for both age (P = 0.07) and body weight (P = 0.07) and the outcome of major bleeding; and for creatinine clearance (P = 0.03) and the composite outcome of major and clinically relevant non-major bleeding. Estimates of these possible differences were not precise, with wide 95% confidence intervals (CIs) that included a zero difference for several subgroups. Multivariate logistic regression analysis did not detect a statistically significant interaction for any outcomes. Conclusions: This analysis found no convincing evidence that age, weight, gender, BMI or creatinine clearance influenced the balance of benefit to risk for apixaban compared with enoxaparin. Because only 5% of patients had a creatinine clearance between 30 and 50 mL min , further data are needed in such patients.
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