Hypothesis / aims of study
First-line behavioral and drug therapies for lower urinary tract symptoms (LUTS) are effective but not usually curative. The primary aim of this study was to determine whether combining behavioral and drug therapy improves outcomes compared to each treatment alone for LUTS in men. The second aim was to compare 3 models for implementing combined therapy: 1) stepped therapy with behavioral therapy started first, 2) stepped therapy with two-drug therapy started first, and 3) initiating both behavioral and drug therapy at the same time.
Study design, materials and methods
This was a 3-site, 2-stage, 3-arm randomized controlled trial conducted 2009-2015. Participants were community-dwelling men, 40 years of age or older, with urgency and 9 or more voids per 24-hours on 7-day bladder diary. They were stratified on voiding frequency and presence/absence of incontinence and randomized to 6 weeks of behavioral treatment alone, two-drug therapy alone, or combined behavioral + drug therapy (stage 1), followed by step-up to combined therapy for an additional 6 weeks for participants who first received monotherapy (stage 2). Behavioral treatment consisted of pelvic floor muscle training with urge suppression strategies and delayed voiding. Two-drug therapy consisted of an anti-muscarinic (sustained-release tolterodine 4mg) + an alpha blocker (tamsulosin 0.4mg).
Seven-day bladder diaries completed before and after each 6-week treatment stage were used to calculate reduction in 24-hour voiding frequency (primary outcome) and other LUTS (urgency, urgency incontinence, and nocturia). Other secondary outcome measures included validated patient global ratings of improvement and satisfaction, the Overactive Bladder Questionnaire (OAB-q) and the International Prostate Symptom Score questionnaire (IPSS).
Based upon the results of an earlier trial, and assuming normally distributed outcomes and a standard deviation of 2.5 for mean number of voids per day, sample sizes of 60 per group would provide 90% power to detect a difference of 1.5 voids with a significance level (alpha) of 0.025 using a one-sided two-sample t-test. The overall sample size was increased to 204 (68 per group) in anticipation of 10% loss to follow-up.
Two hundred four men were randomized, 71 to behavioral treatment alone, 68 to drug alone, and 65 to combined therapy. They ranged in age from 40-92 (mean=64.1) years; 65.2% were white, 26.5% African American, 8.3 other races; and 14.7% were Hispanic. Twenty-one men discontinued and 183 completed treatment.
At 6 weeks (stage 1), mean voids per 24-hour day decreased significantly in all three groups: 24.7% in behavioral alone, 12.7% with drug alone and 30.5% with combined treatment (all p< 0.0001). Intent to treat analyses after multiple imputation indicated that post-treatment mean voiding frequencies were significantly lower in the combined therapy group compared to drug alone (p<0.0001), but not significantly lower than the behavioral alone group (p=0.19) after adjustment for baseline voiding frequency and age. Further, mean voiding frequencies were lower for behavioral alone compared to drug alone (p=0.0005). Similar results were obtained from the complete cases analyses. Significant group differences were also found in favor of combined therapy on the secondary outcomes. Post-treatment, more participants in combined therapy rated themselves as “better” or “much better” (81.2% behavioral; 64.7% drug; 90.1% combined; p=0.0001) and more were completely satisfied (28.1% behavioral; 20.0% drug; 49.2% combined; p=0.0001). Side-effects were lowest in the behavioral group; 51.6% in the behavioral alone group reported no side effects compared to 18.0% in drug alone and 13.1% in combined therapy (p<0.0001).
At 12 weeks (stage 2), after all groups had received combined therapy (either initially or stepped), overall change in voiding frequency was 31.6% in the group that started with behavioral alone, 27.1% in the group that had started with drug alone, and 32.2% in the group that had been treated with combined therapy from the beginning. There were no longer differences between the groups on the primary outcome (p=0.33). Following a similar pattern, at 12 weeks, improvements were greatest in the combined therapy group, but without between group differences on the other bladder diary and questionnaire measures: nocturia, mean urgency, maximum urgency, OAB-q, IPSS. Patient perception of improvement as “better” or “much better” was similar across groups (87.8% behavioral; 85.2% drug; 95.1% combined; p=0.32). Percent of patients completely satisfied had increased in the originally single therapy groups and were more similar to the combined therapy group (51.6% with behavioral first; 52.5% with drug first; 47.5% with combined throughout; p=0.82). Side-effects no longer differed by group (21.0% in the behavioral first group reported no side effects compared to 14.8% in drug therapy first and 20.3% in the combined therapy throughout group; p=0.55).
Interpretation of results
In men with LUTS, combining behavioral and drug therapy yields significantly greater short-term reductions in voiding frequency compared to drug therapy alone, but not compared to behavioral treatment alone. Combined therapy also yields the best outcomes on patient-perceived improvement and satisfaction, but with more side-effects than behavioral alone. Overall, the 12-week outcomes of the 3 models for implementing combined therapy were not significantly different.