A retrospective analysis comparing persistence and adherence to treatment with free‐ vs fixed‐dose combination of an alpha blocker and an antimuscarinic agent in men with LUTS in Spain

Abstract Introduction Combination therapy with an alpha blocker (AB) plus an antimuscarinic (AM) is recommended for men with moderate‐to‐severe mixed lower urinary tract symptoms (LUTS) when monotherapy is not effective in relieving storage symptoms. This study compared treatment persistence and adherence with an AB plus AM fixed‐dose combination (FDC) vs an AB plus AM free‐dose combination in men with LUTS in Spain. Methods Retrospective study using the Spanish IQVIA Cegedim Electronic Medical Records database. Men prescribed AB plus AM combination therapy were included in an FDC or free‐dose combination cohort based on their index treatment. Treatment persistence was the time from index date to first discontinuation of ≥1 of the two index drugs over 12 months. Adherence was measured using the fixed medication possession ratio (MPR). Results Of 3114 patients identified, 999 were included (FDC, n = 790; free‐dose combination, n = 209). Median (95% CI) persistence was longer in the FDC (125 [109‐151] days) than in the free‐dose combination (31 [31‐36] days) cohort (hazard ratio [HR], 2.9; 95% CI, 2.4‐3.4; P < .0001). The 12‐month persistence rates were 31.1% (FDC cohort) and 8.9% (free‐dose cohort). The mean (SD) fixed MPR was higher in the FDC cohort (48.8 [37.2]) compared with the free‐dose cohort (23.1 [28.4]); more patients in the FDC cohort (34.2%) than in the free‐dose cohort (10.0%) were adherent (MPR ≥ 80%). The probability of treatment persistence and adherence increased with age (>80 vs <65 years, persistence HR, 0.7 [95% CI, 0.5‐0.9]; MPR difference, 12.5), polypharmacy (persistence HR, 0.7 [95% CI, 0.6‐0.9]; MPR difference, 10.7) and previous use of AB (persistence HR, 0.8 [95% CI, 0.7‐1.0]; MPR difference, 5.7) or AB/AM combinations (persistence HR, 0.7 [95% CI, 0.5‐0.9]; MPR difference, 11.1). Conclusions Treatment with an AB/AM FDC is associated with better persistence and adherence vs a free‐dose combination in men with LUTS in Spain.

0.4 mg/solifenacin 6 mg FDC remains the only approved FDC of an AB (tamsulosin) plus an AM (solifenacin) available for the treatment of moderate-to-severe storage and voiding symptoms associated with BPH in men who are not adequately responding to treatment with monotherapy. A retrospective study conducted in the Netherlands showed that in patients with LUTS/BPH, the 12-month persistence rate was significantly higher (51.3% vs 29.9%) among those taking an FDC of solifenacin/tamsulosin (Vesomni) vs a free-dose combination. 20 This FDC has been available in Spain since 2015, but no studies have been conducted to assess treatment persistence and adherence compared with free-dose combination in a Spanish population. Using real-world data, this study investigated the persistence and adherence to treatment with an FDC or a free-dose combination of an AB plus an AM in men with LUTS in Spain.

| Study design and objectives
This was a retrospective, longitudinal, observational study conducted in Spain. Patients' data were extracted from the Spanish IQVIA Cegedim Electronic Medical Records database. This national longitudinal database contains anonymised health records of patients collected through 8000 office-based primary and secondary care physicians, covering approximately 3.0% of the Spanish population. Patient characteristics (age, gender, height and weight), diagnosis dates and codes, and prescriptions from primary and secondary care physicians were collected. Patients were classified into two cohorts (FDC and free-dose combination) based on their index combination treatment with an AB and an AM. The index date was defined as the date of the first prescription of the FDC combination therapy, and for the free-dose combination, if the AB and the AM drugs were not started on the same day but occurred within a 30-day window, the index date would have been the date of the prescription of the second drug. Discontinuation was defined as no prescription renewal within a 30-day grace period after the end of a prescription, and the date of discontinuation was defined as the end date of the last prescription. The primary objective of the study was to compare treatment persistence with an FDC of an AB plus an AM vs a free-dose combination of AB plus AM over 12 months, with adjustment for patient characteristics What's known • Combination therapy with an alpha blocker (AB) plus an antimuscarinic (AM) is recommended in men with lower urinary tract symptoms (LUTS) when monotherapy is not effective.
• Unfortunately, treatment persistence and adherence are low in patients receiving combination therapy.

What's new
• Our data suggest that persistence and adherence increase in men with LUTS treated with a fixed-dose combination vs a free-dose combination of an AB plus an AM; this increase could improve patient outcomes and reduce healthcare costs.
at treatment initiation. Secondary objectives included comparing adherence between the two treatment groups and comparing treatment persistence and adherence with an FDC vs a free-dose combination of tamsulosin/solifenacin.

| Study population
Patients were men with LUTS aged ≥45 years at the index date who had received a combination therapy of an AB plus an AM, either as FDC or free-dose combination from 1 February 2016 to 31 December 2016. Patients had to have ≥12 months of continuous enrolment before the index date without prescription of the same combination selected as index date combination therapy, and a 12-month follow-up period from the index date.

| Endpoints
The primary endpoint was treatment persistence with an index FDC therapy of an AB plus an AM drug or a free-dose combination of an AB plus an AM drug. Persistence was defined as the time from the index date to the first discontinuation of at least one of the two index drugs during a 12-month follow-up period. The persistence rate during the 12-month follow-up period was calculated as the proportion of patients who had not discontinued either of the two index drugs 12 months after the index date. Adherence to treatment with an FDC or with a free-dose combination therapy was a secondary endpoint. Adherence over the 12-month follow-up period was measured using the fixed medication possession ratio (MPR) 21 ([total number of days of supply of both index drugs during the post-index period/2]/365 × 100). Patients were considered adherent if they had an MPR ≥ 80.0%. 22 Adherence rate, defined as the proportion of adherent patients at the 12-month post-index date, was also calculated. Exploratory endpoints included (a) the proportion of men switching index combination therapy, where switching was defined as discontinuing one or both of the drugs of the index combination therapy and initiating a new drug of the same class within 30 days after discontinuation, and (b) assessment of healthcare resource utilisation during the 12-month follow-up period, including the number of general practitioner (GP) and specialist visits.

| Statistical analysis
Demographic and baseline characteristics were summarised using descriptive statistics. Kaplan-Meier analysis was used to describe the time to treatment discontinuation for the FDC and free-dose combination groups. Discontinuation was the target event and censoring occurred in patients switching from an FDC to a free-dose combination with the same molecules (ie, tamsulosin and solifenacin). Comparisons between FDC and free-dose combinations for the time to discontinuation were conducted using univariate and multivariate Cox proportional hazards models adjusting for potential confounding factors.
Hazard ratios (HRs) were estimated from these models using FDC as a reference, and represented the relative probability of stopping treatment. Univariate and multivariate analyses, using linear regression models, were used to compare the MPR between FDC and free-dose combinations and investigate the impact of patient baseline characteristics. The patient characteristics to be included in the multivariate regression models were selected based on their clinical relevance and on the univariate analysis using a threshold level of α = 0.10. To compare the FDC vs free-dose combinations, a stepwise approach was applied to identify the covariates to be used in the multivariate regression models. Sensitivity analyses were performed to test the impact of the definitions used in the study and were conducted by varying the grace period (considering treatment as discontinued with grace periods of 45, 60 and 90 days of the most recent prescription), the persistence definition, the combination definition and the prescriber's specialty.

| Demographics and baseline characteristics
The mean (SD) age was lower among patients taking the FDC than among those taking the free-dose combinations (69. 4 Table 2).
The combination therapies prescribed at the index date are summarised in Table 3. In the free-dose combination cohort, the most frequent combinations were tamsulosin plus solifenacin (n = 53, 25.4%) and tamsulosin plus oxybutynin (n = 49, 23.4%).

| Treatment persistence
Based on Kaplan-Meier analysis, the median (95% CI) time to discontinuation was 125 [109-151] days in the FDC cohort and 31 [31][32][33][34][35][36] days in the free-dose combination cohort. The highest rate of discontinuation was observed during the first 30 days, particularly in the free-dose combination cohort ( Figure 2). The 12-month persistence rate was 31.1% in the FDC cohort and 8.9% in the free-dose cohort. Multivariate Cox regression analysis showed that patients in the FDC cohort were approximately three times less likely to discontinue combination treatment than those in the free-dose combination cohort (HR, 2.9; 95% CI, 2.4-3.4; P < .0001). The probability of treatment persistence increased with age; patients aged >80 years were more likely to remain on treatment than those <65 years (HR, 0.7; 95% CI, 0.5- Note: Percentages refer to the number of patients treated with each drug within each column. Abbreviations plus an AM (other than the index therapy) or an AB plus a 5-ARI (HR, 0.7; 95% CI, 0.5-0.9; P = .0227) ( Table 4).
The results of all sensitivity analyses confirmed that patients on FDC treatment were significantly less likely to discontinue compared with those treated with a free-dose combination, with HRs between 2.0 and 3.2 in the multivariate analyses (P < .0001).

| Treatment adherence
The mean (SD) fixed MPR was higher in the FDC cohort (48. 8     Our findings are in line with those from a similar retrospective,