Efficacy and safety of tolterodine extended‐release in men with overactive bladder symptoms treated with an α‐blocker: effect of baseline prostate‐specific antigen concentration

Study Type – Therapy (RCT)
Level of Evidence 1b OBJECTIVE To determine whether the efficacy and safety of a combination of tolterodine extended‐release (ER) plus α‐blocker treatment varies with high or low levels of serum prostate‐specific antigen (PSA) in men who have persistent overactive bladder (OAB) symptoms after any α‐blocker monotherapy. PATIENTS AND METHODS Men aged ≥40 years were eligible if they reported ≥8 micturitions/24 h, including ≥1 urgency episode/24 h with or without urgency urinary incontinence (UUI), and at least some moderate bladder‐related problems at baseline despite receiving treatment with an α‐blocker for ≥1 month. Exclusion criteria included a postvoid residual urine volume (PVR) of ≥200 mL and history of acute urinary retention requiring catheterization. Subjects were randomly assigned to tolterodine‐ER 4 mg or placebo for 12 weeks; all subjects continued their α‐blocker treatment throughout the study. Subjects completed 5‐day bladder diaries at baseline and week 12, in which they recorded all micturitions and rated the sensation associated with each micturition using the 5‐point Urinary Sensation Scale (USS). For this post hoc analysis, efficacy, safety, and tolerability data were stratified by the study median PSA concentration at baseline (1.41 ng/mL). RESULTS In the tolterodine‐ER +α‐blocker and placebo +α‐blocker groups, 160 and 159 men, respectively, had PSA levels of <1.41 ng/mL, and 166 and 160 men, respectively, had PSA levels of ≥1.41 ng/mL. Men with higher PSA levels were slightly older and had higher PVR at baseline compared with men with lower PSA levels. At week 12, improvements in daytime micturitions, 24‐h urgency episodes, and daytime urgency episodes were significantly greater with tolterodine‐ER +α‐blocker vs placebo +α‐blocker both in men with PSA levels of ≥1.41 ng/mL and those with PSA levels of <1.41 ng/mL ( P < 0.05). Among men with PSA levels of <1.41 ng/mL, improvements in 24‐h micturitions and frequency‐urgency sum (sum of USS ratings for all micturitions) were also significantly greater with tolterodine‐ER +α‐blocker vs placebo +α‐blocker ( P < 0.05). There were no significant treatment differences in change in UUI episodes in either PSA group (although only 19% of subjects reported UUI at baseline), nor in nocturnal micturitions or nocturnal urgency episodes. Among men with PSA levels of ≥1.41 ng/mL, there was a statistically significant increase in PVR ( P = 0.036) and decrease in maximum urinary flow rate (Q max ; P = 0.038) with tolterodine‐ER +α‐blocker vs placebo +α‐blocker ; these changes were not considered clinically meaningful. There were no treatment differences for changes in PVR or Q max among men with PSA levels of <1.41 ng/mL. One subject receiving tolterodine‐ER +α‐blocker (PSA concentration of ≥1.41 ng/mL) and two subjects receiving placebo +α‐blocker (one each in the PSA concentration subgroups of ≥1.41 ng/mL and <1.41 ng/mL) had acute urinary retention requiring catheterization. CONCLUSION In a 12‐week study, the addition of tolterodine‐ER to α‐blocker therapy improved key OAB symptoms and appeared to be well tolerated compared with placebo +α‐blocker in men with persistent OAB symptoms, regardless of subjects’ prostate size as judged by serum PSA concentration.