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Real-World Safety and Effectiveness of Tadalafil in Patients with Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia: A Japanese Post-Marketing Surveillance Study

Objective To evaluate the long-term safety and effectiveness of tadalafil in Japanese men with lower urinary tract symptoms secondary to benign prostatic hyperplasia in real-world clinical practice; and to investigate the safety profile in patients aged ≥75 years. Patients and Methods This was a prospective, non-interventional, multicenter, post-marketing surveillance study in which Japanese patients with lower urinary tract symptoms secondary to benign prostatic hyperplasia were observed for up to 18 months after initiating tadalafil treatment. The real-world safety and effectiveness outcomes were assessed at baseline and at 1, 3, 6, 12, and 18 months post-treatment or the last day of treatment. Results Most patients received tadalafil 5 mg per day throughout the observation period. Among 1393 patients analyzed for safety, the overall incidence of adverse drug reactions was 8.3%. These adverse drug reactions were generally consistent with the known safety profile of tadalafil and no new safety risks were identified in long-term use. There was no statistical difference in the frequency of adverse drug reactions between patients aged <75 and ≥75 years. The mean change in total International Prostate Symptom Score (IPSS) and IPSS-﻿quality of ﻿life subscore was significantly improved at each timepoint. At 18 months, IPSS had improved by 5.0 points (P < 0.001) and IPSS-﻿quality of ﻿life subscore had improved by 1.5 points (P < 0.001). The mean change in post-voiding residual urine volume from baseline was significant at each time point and was −9.8 mL at 18 months (P < 0.001); there were no significant differences from baseline in maximum urinary flow rate. Conclusion This surveillance demonstrated that tadalafil has favorable safety and effectiveness profiles for long-term use in Japanese men with lower urinary tract symptoms secondary to benign prostatic hyperplasia. In addition, safety profiles in patients aged ≥75 years were similar to patients aged <75 years.


Introduction
Benign prostatic hyperplasia (BPH) is a common urinary condition in aging men, which is characterized by an enlarged prostate gland. This often leads to lower urinary tract symptoms (LUTS), such as increased daytime frequency, nocturia, urinary urgency, and voiding difficulties. [1][2][3] Although LUTS secondary to BPH (BPH/LUTS) is not often life-threatening, it can be bothersome and negatively affect patient quality of life (QOL) by interfering with daily activities and sleep. 4 The prevalence of BPH increases after the age of 40, with a prevalence rate of 73% in men aged ≥70. 5 In 2017, over 473,000 men were estimated to suffer from BPH in Japan, 5 a number that is expected to increase as the elderly population grows.
Until recently, alpha-adrenoreceptor antagonists (alphablockers) and 5-alpha reductase inhibitors (5-ARIs) were considered a first-line medical treatment in men with moderate to severe BPH/LUTS. However, these treatments are not effective in all patients and are associated with adverse sexual outcomes (alpha-blockers and 5-ARIs), orthostatic hypotension (alpha-blockers), and fatigue (alpha-blockers), which all frequently lead to discontinuation of treatment. Tadalafil, a selective phosphodiesterase type 5 inhibitor (PDE-5i), was first approved as an alternative treatment for BPH/LUTS in October 2011 in the United States and was subsequently approved in numerous countries including Japan. 1,6,7 Recently, tadalafil has been accepted by the Japanese Urological Association as a first-line treatment for BPH/ LUTS. 1 Previous randomized, placebo-controlled clinical studies investigating 12-week tadalafil treatment in Asians [8][9][10][11][12] and Caucasians 13,14 have shown that the mean change from baseline in total International Prostate Symptom Score (IPSS) is significantly greater in patients treated with tadalafil compared with placebo. Furthermore, tadalafil was rarely linked to sexual dysfunction or orthostatic blood pressure adverse events that have been previously reported with other BPH treatments. 6,7 While these previous studies show potential for tadalafil as a treatment for BPH/LUTS, few studies have been conducted with large sample sizes, and there is still a lack of information on the long-term use and safety of tadalafil among elderly patients in real-world clinical settings. Although >50% of patients with BPH in Japan are aged ≥75 years, 5 this age group is under-represented in clinical trials (~10% of subjects) and no real-world data are available for this age group. 15 Here, we report the results of a post-marketing surveillance study aimed to evaluate the safety and effectiveness of tadalafil among Japanese men with BPH/LUTS in realworld clinical practice. Because age-related physiologic changes may affect drug safety, we also targeted patients aged ≥75 years and observed differences and similarities to those aged <75 years to further clarify the safety profile of tadalafil. Hence, our results provide insights not only into the long-term safety and effectiveness of this treatment but also into the safety profile of tadalafil in patients ≥75 years.

Study Design and Patients
This was a prospective, non-interventional, multicenter, postmarketing surveillance study of Japanese men treated with tadalafil for BPH/LUTS conducted from September 2014 to March 2017 (enrollment from September 2014 to September 2015). The observation period was a maximum of 18 months' follow-up, or up to the last day of treatment (if patients discontinued treatment before 18 months).
This study was conducted in accordance with the standards of Good Post-marketing Study Practice for Drugs (Ordinance No. 171, issued 20 December 2004, the Japanese Ministry of Health, Labour and Welfare). The study protocol adhered to applicable local and countryspecific laws and regulations pertaining to the protection of patient privacy and safety. In accordance with these laws and regulations, this study did not obtain written informed consent from enrolled patients and was exempt from World Health Organization registration criteria.
All sites that purchased tadalafil and were equipped with a web-based system to collect clinical data were invited to participate and a written contract was provided only after the sites agreed to cooperate in this surveillance.
Patients eligible to enroll in the study were those diagnosed with BPH/LUTS by each principal investigator and who had no history of tadalafil use. Patients were excluded if they had contraindications to tadalafil. Dosage of tadalafil, concomitant medication, and treatment for adverse reactions were based on the investigators' discretion. Data were reported in a case report form (CRF) by each investigator and missing laboratory effectiveness data were imputed using the Last Observation Carried Forward (LOCF) approach.

Safety and Effectiveness
Persistence of treatment was estimated by the Kaplan-Meier method. Assessments were conducted at baseline and at each time point during the observation period. Safety data were collected continuously and reported as the frequency of adverse drug reactions (ADRs), which were classified using the Medical Dictionary for Regulatory Activities (MedDRA, version 20.0) preferred terms, and were defined as events for which a causal relation to tadalafil could not be ruled out by investigators. Effectiveness outcomes were assessed at 1 (only for IPSS), 3, 6, 12, and 18 months following treatment initiation. Effectiveness outcomes included the change from baseline at each time point in IPSS, 16

Statistical Analysis
Since this was a noncomparative observational study, statistical analysis was not used for hypothesis testing. Data are reported mainly using estimated means, incidence proportion, mean change from baseline, and 95% confidence intervals (95% CI). Differences between groups were conducted using a one-sample t-test, fisher exact test, or chisquare test to support the evaluations. All analyses were performed using SAS version 9.2 or above (SAS Institute, Cary, NC, USA).

Patient Disposition
A total of 1449 CRFs were collected from 1499 patients who registered for enrollment ( Figure 1). The safety analysis set included 1393 patients, of whom 1387 were included in the effectiveness analysis set ( Figure 1). For the safety analysis set, 56 patients were excluded mainly due to "no-show post-enrollment", while an additional 6 patients were excluded from the effectiveness analysis set due to "unsigned CRF for effectiveness".
Two serious ADRs were reported: atrial fibrillation with complete right bundle branch block in a patient aged 81 years, and myocardial infarction in a patient aged 73 years, both of whom had preexisting cardiovascular risk factors.

Vital Signs
Because elderly patients are susceptible to adverse drug effects, particularly increased risk of hypotension and related symptoms, 17 the influence of tadalafil on blood pressure reduction was carefully monitored during the observation period as part of the safety measurements. Systolic blood pressure before tadalafil treatment was 133.9 ± 16.3 (mean ± SD) mmHg (n = 681) and diastolic blood pressure was 78.1 ± 10.8 mmHg (n = 681). The mean change from baseline to 18 months (LOCF) was −2.1 mmHg (n = 587, P < 0.01) and −2.8 mmHg (n = 586, P < 0.001), respectively (Table 5). However, none of these changes were considered clinically meaningful or significant, and there was no major difference between patients aged <75 and ≥75 years (See Table S1 in the Supplementary material).

Discussion
In this post-marketing surveillance study, we examined the real-world safety and effectiveness of tadalafil in Japanese men with BPH/LUTS. In general, ADRs were consistent with the known safety profile of tadalafil from previous clinical trials and no new safety risks were identified. 11 Similarly, there were no additional safety concerns observed with long-term use (18 months) of tadalafil, which provides further reassurance that the safety profile of tadalafil is favorable (Table 4). Since most previous clinical trials have focused on 12 weeks of treatment [8][9][10][11][12][13][14] or an open-label extension period of up to 42 weeks 8 our observational findings provide extended insights into the long-term safety of tadalafil. Among the frequently reported ADRs (≥3 incidence), headache, dyspepsia, spontaneous penile erection, palpitations, diarrhea, pollakiuria, and blood pressure decreased occurred relatively early after tadalafil was administered (within 3 months) and decreased over time (Table 4). This could imply that ADRs associated with tadalafil in BPH/ LUTS treatment are often seen at the beginning of treatment. Moreover, more than 50% of patients were able to continue tadalafil treatment for 18 months (Figure 2), which might have been influenced by the low incidence of ADRs and the fact that there were only few reports of serious ADRs (Table 3). However, we cannot conclude that tadalafil is safer or has more effect than other urinary functionimproving drugs because the present study lacks concurrent control and comparator groups. In patients aged ≥75 years, the frequency of ADRs was slightly higher than in those aged <75 years; however, there were no clinically relevant differences between the two age groups (Table 3). These results thus suggest that tadalafil is well tolerated not only for patients aged <75 Note: *Frequently reported ADRs (≥3 incidence) over an entire period and ADRs reported after 12 months were selected. Abbreviations: ADRs, adverse drug reactions; M, months; MedDRA, Medical Dictionary for Regulatory Activities version 20.0; PT, preferred term. years but also for those aged ≥75 years. In a meta-analysis report based on Phase 2 and Phase 3 clinical studies, tadalafil was well tolerated regardless of age, which supports our observational results in a real-world clinical setting. 15 In terms of effectiveness, PVR decreased significantly after 3 months of treatment and the effects were sustained for a maximum of 18 months (Table 6). In contrast, Q max showed no changes from baseline (Table 6). Similar outcomes were also observed in other 12-week clinical trials where Q max remained largely unchanged during the study with no statistically significant or clinically meaningful difference between tadalafil and placebo. [8][9][10] Interestingly, though, in a one-armed, open-label, prospective study, both PVR and Q max significantly improved during 12 months of treatment. 18 This could be because patients in this 12-month study were carefully selected to have a relatively high Bladder Outlet Obstruction index. 18 In addition to PVR, other measures of effectiveness such as total IPSS and IPSS-QOL improved during the current  study. Both total IPSS and IPSS-QOL scores decreased significantly after only 1 month of treatment and continued to improve with time (Table 7). These results are consistent with the 12-week findings from previous randomized, placebo-controlled clinical studies investigating tadalafil treatment in Asians [8][9][10][11][12] and Caucasians 13,14 with BPH/LUTS. A series of analyses integrating the data pooled from different subsets of these clinical trials consistently found that tadalafil progressively and significantly improved total IPSS scores over 12 weeks compared with placebo. 15 Similar results were also observed in a Korean postmarketing surveillance study, which had a shorter investigation period from the present study, and was mainly investigating 12-week tadalafil treatment. 19 Due to the observational nature of post-marketing surveillance studies, they can be prone to bias and findings cannot be attributed to causation. Notably, the present study lacked concurrent control and comparator groups, and the outcomes of tadalafil could only be determined based on the mean change from baseline. Additionally, the need to address missing data is frequently encountered in longitudinal studies where outcome data are collected repeatedly at several time points, and in observational studies, including those conducted in registries.

Conclusion
In conclusion, this post-marketing surveillance study has demonstrated that the safety and effectiveness profiles of tadalafil are favorable during long-term use in Japanese men with BPH/LUTS in real-world clinical practice, and that the characteristics of ADRs during long-term use in patients aged ≥75 years are similar to those aged <75 years.