Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients

Background Patients with acute medical illnesses are at prolonged risk for venous thrombosis. However, the appropriate duration of thromboprophylaxis remains unknown. Methods Patients who were hospitalized for acute medical illnesses were randomly assigned to receive subcutaneous enoxaparin (at a dose of 40 mg once daily) for 10±4 days plus oral betrixaban placebo for 35 to 42 days or subcutaneous enoxaparin placebo for 10±4 days plus oral betrixaban (at a dose of 80 mg once daily) for 35 to 42 days. We performed sequential analyses in three prespecified, progressively inclusive cohorts: patients with an elevated d-dimer level (cohort 1), patients with an elevated d-dimer level or an age of at least 75 years (cohort 2), and all the enrolled patients (overall population cohort). The statistical analysis plan specified that if the between-group difference in any analysis in this sequence was not significant, the other analyses would be considered exploratory. The primary efficacy outcome was a composite of asymptomatic proximal deep-vein thrombosis and symptomatic venous thromboembolism. The principal safety outcome was major bleeding. Results A total of 7513 patients underwent randomization. In cohort 1, the primary efficacy outcome occurred in 6.9% of patients receiving betrixaban and 8.5% receiving enoxaparin (relative risk in the betrixaban group, 0.81; 95% confidence interval [CI], 0.65 to 1.00; P=0.054). The rates were 5.6% and 7.1%, respectively (relative risk, 0.80; 95% CI, 0.66 to 0.98; P=0.03) in cohort 2 and 5.3% and 7.0% (relative risk, 0.76; 95% CI, 0.63 to 0.92; P=0.006) in the overall population. (The last two analyses were considered to be exploratory owing to the result in cohort 1.) In the overall population, major bleeding occurred in 0.7% of the betrixaban group and 0.6% of the enoxaparin group (relative risk, 1.19; 95% CI, 0.67 to 2.12; P=0.55). Conclusions Among acutely ill medical patients with an elevated d-dimer level, there was no significant difference between extended-duration betrixaban and a standard regimen of enoxaparin in the prespecified primary efficacy outcome. However, prespecified exploratory analyses provided evidence suggesting a benefit for betrixaban in the two larger cohorts. (Funded by Portola Pharmaceuticals; APEX ClinicalTrials.gov number, NCT01583218. opens in new tab.

Two-Year Outcomes After Aquablation Compared to TURP: Efficacy and Ejaculatory Improvements Sustained

INTRODUCTION: To compare 2-year safety and efficacy outcomes after Aquablation or transurethral resection of the prostate (TURP) for the treatment of lower urinary tract symptoms related to benign prostate hyperplasia (BPH). METHODS: One hundred eighty-one patients with BPH were assigned at random (2:1 ratio) to either Aquablation or TURP. Patients and follow-up assessors were blinded to treatment. Assessments included the International Prostate Symptom Score (IPSS), Male Sexual Health Questionnaire (MSHQ), International Index of Erectile Function and uroflow. The focus of analysis was 2-year outcomes. RESULTS: At 2 years, IPSS scores improved by 14.7 points in the Aquablation group and 14.9 points in TURP (p = .8304, 95% CI for difference - 2.1 to 2.6 points). Two-year improvements in maximum flow rate (Qmax) were large in both groups at 11.2 and 8.6 cc/s for Aquablation and TURP, respectively (p = 0.1880, 95% CI for difference - 1.3 to 6.4). Sexual function as assessed by MSHQ was stable in the Aquablation group and decreased slightly in the TURP group. At 2 years, PSA was reduced significantly in both groups by 0.7 and 1.2 points, respectively; the reduction was similar across groups (p = 0.1816). Surgical retreatment rates after 12 months for Aquablation were 1.7% and 0% for TURP. Over 2 years, surgical BPH retreatment rates were 4.3% and 1.5% (p = 0.4219), respectively. CONCLUSION: Two-year efficacy outcomes after TURP and Aquablation were similar, and the rate of surgical retreatment was low and similar to TURP. TRIAL REGISTRATION: ClinicalTrials.gov no. NCT02505919. FUNDING: PROCEPT BioRobotics

Waterjet Ablation Therapy for Endoscopic Resection of prostate tissue trial (WATER) vs WATER II: comparing Aquablation therapy for benign prostatic hyperplasia in 30-80 and 80-150 mL prostates

OBJECTIVE: To compare the outcomes of Aquablation in 30-80 mL prostates with those in 80-150 mL prostates. Surgical options, especially with short learning curves, are limited when treating large prostates for lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH). Aquablation (AquaBeam System, PROCEPT BioRobotics Inc., Redwood City, CA, USA) could solve this issue with global reproducibility, independent of prostate volume. PATIENTS AND METHODS: Waterjet Ablation Therapy for Endoscopic Resection of prostate tissue (WATER [W-I]; NCT02505919) is a prospective, double-blind, multicentre, international clinical trial comparing Aquablation and transurethral resection of the prostate (TURP) for the treatment of LUTS/BPH in prostates between 30 and 80 mL. WATER II (W-II; NCT03123250) is a prospective, multicentre, single-arm international clinical trial of Aquablation in prostates between 80 and 150 mL. We compare baseline parameters and 12-month outcomes in 116 W-I and 101 W-II study patients. Students' t-test or Wilcoxon tests were used for continuous variables and Fisher's test for binary variables. RESULTS: The mean (SD) operative time was 33 (17) and 37 (13) min in W-I and W-II, respectively. Actual treatment time was 4 and 8 min in W-I and W-II, respectively. The mean change in the International Prostate Symptom Score was substantial averaging (at 12 months) 15.1 in W-I and 17.1 in W-II (P = 0.605). By 3 months, Clavien-Dindo grade ≥II events occurred in 19.8% of W-I patients and 34.7% of W-II patients (P = 0.468). CONCLUSION: Aquablation clinically normalises outcomes between patients with 30-80 mL prostates and patients with 80-150 mL prostates treated for LUTS/BPH, with an expected increase in the risk of complications in larger prostates. Long-term outcomes of procedure durability are needed

Effect of meropenem-vaborbactam vs piperacillin-Tazobactam on clinical cure or improvement and microbial eradication in complicated urinary tract infection the TANGO I randomized clinical trial

IMPORTANCE Meropenem-vaborbactam is a combination carbapenem/beta-lactamase inhibitor and a potential treatment for severe drug-resistant gram-negative infections. OBJECTIVE To evaluate efficacy and adverse events of meropenem-vaborbactam in complicated urinary tract infection (UTI), including acute pyelonephritis. DESIGN, SETTING, AND PARTICIPANTS Phase 3, multicenter, multinational, randomized clinical trial (TANGO I) conducted November 2014 to April 2016 and enrolling patients (18 years) with complicated UTI, stratified by infection type and geographic region. INTERVENTIONS Eligible patients were randomized 1:1 to receive meropenem-vaborbactam (2g/2g over 3 hours; n = 274) or piperacillin-Tazobactam (4g/0.5g over 30 minutes; n = 276) every 8 hours. After 15 or more doses, patients could be switched to oral levofloxacin if they met prespecified criteria for improvement, to complete 10 days of total treatment. MAIN OUTCOMES AND MEASURES Primary end point for FDA criteriawas overall success (clinical cure or improvement and microbial eradication composite) at end of intravenous treatment in the microbiologic modified intent-To-Treat (ITT) population. Primary end point for European Medicines Agency (EMA) criteria was microbial eradication at test-of-cure visit in the microbiologic modified ITT and microbiologic evaluable populations. Prespecified noninferiority margin was 15%. Because the protocol prespecified superiority testing in the event of noninferiority, 2-sided 95%CIs were calculated. RESULTS Among 550 patients randomized, 545 received study drug (mean age, 52.8 years; 361 [66.2%]women; 374 [68.6%] in the microbiologic modified ITT population; 347 [63.7%] in the microbiologic evaluable population; 508 [93.2%] completed the trial). For the FDA primary end point, overall success occurred in 189 of 192 (98.4%) with meropenem-vaborbactam vs 171 of 182 (94.0%) with piperacillin-Tazobactam (difference, 4.5%[95%CI, 0.7%to 9.1%]; P < .001 for noninferiority). For the EMA primary end point, microbial eradication in the microbiologic modified ITT population occurred in 128 of 192 (66.7%) with meropenemvaborbactam vs 105 of 182 (57.7%) with piperacillin-Tazobactam (difference, 9.0%[95%CI, 0.9%to 18.7%]; P < .001 for noninferiority); microbial eradication in the microbiologic evaluable population occurred in 118 of 178 (66.3%) vs 102 of 169 (60.4%) (difference, 5.9%[95%CI, 4.2%to 16.0%]; P < .001 for noninferiority). Adverse eventswere reported in 106 of 272 (39.0%) with meropenem-vaborbactam vs 97 of 273 (35.5%) with piperacillin-Tazobactam. CONCLUSIONSANDRELEVANCE Amongpatient swith complicatedUTI,includingacutepyelonephritis andgrowthof a baseline pathogen,meropenem-vaborbactamvs piperacillin-Tazobactamresulted in a compositeoutcomeofcomplete resolution orimprovementof symptomsalongwith microbial eradication thatmet the noninferiority criterion. Further research is needed to understand the spectrum of patients inwhommeropenem-vaborbactam offers a clinical advantage. © 2018 American Medical Association. All rights reserved

Association Between Combined TMPRSS2:ERG and PCA3 RNA Urinary Testing and Detection of Aggressive Prostate Cancer.

Importance Potential survival benefits from treating aggressive (Gleason score, ≥7) early-stage prostate cancer are undermined by harms from unnecessary prostate biopsy and overdiagnosis of indolent disease. Objective To evaluate the a priori primary hypothesis that combined measurement of PCA3 and TMPRSS2:ERG (T2:ERG) RNA in the urine after digital rectal examination would improve specificity over measurement of prostate-specific antigen alone for detecting cancer with Gleason score of 7 or higher. As a secondary objective, to evaluate the potential effect of such urine RNA testing on health care costs. Design, Setting, and Participants Prospective, multicenter diagnostic evaluation and validation in academic and community-based ambulatory urology clinics. Participants were a referred sample of men presenting for first-time prostate biopsy without preexisting prostate cancer: 516 eligible participants from among 748 prospective cohort participants in the developmental cohort and 561 eligible participants from 928 in the validation cohort. Interventions/Exposures Urinary PCA3 and T2:ERG RNA measurement before prostate biopsy. Main Outcomes and Measures Presence of prostate cancer having Gleason score of 7 or higher on prostate biopsy. Pathology testing was blinded to urine assay results. In the developmental cohort, a multiplex decision algorithm was constructed using urine RNA assays to optimize specificity while maintaining 95% sensitivity for predicting aggressive prostate cancer at initial biopsy. Findings were validated in a separate multicenter cohort via prespecified analysis, blinded per prospective-specimen-collection, retrospective-blinded-evaluation (PRoBE) criteria. Cost effects of the urinary testing strategy were evaluated by modeling observed biopsy results and previously reported treatment outcomes. Results Among the 516 men in the developmental cohort (mean age, 62 years; range, 33-85 years) combining testing of urinary T2:ERG and PCA3 at thresholds that preserved 95% sensitivity for detecting aggressive prostate cancer improved specificity from 18% to 39%. Among the 561 men in the validation cohort (mean age, 62 years; range, 27-86 years), analysis confirmed improvement in specificity (from 17% to 33%; lower bound of 1-sided 95% CI, 0.73%; prespecified 1-sided P = .04), while high sensitivity (93%) was preserved for aggressive prostate cancer detection. Forty-two percent of unnecessary prostate biopsies would have been averted by using the urine assay results to select men for biopsy. Cost analysis suggested that this urinary testing algorithm to restrict prostate biopsy has greater potential cost-benefit in younger men. Conclusions and Relevance Combined urinary testing for T2:ERG and PCA3 can avert unnecessary biopsy while retaining robust sensitivity for detecting aggressive prostate cancer with consequent potential health care cost savings