Defining the Role of Overactive Bladder Treatments in Men with Lower Urinary Tract Symptoms

Gary E Lemack

Disclosures

Nat Clin Pract Urol. 2007;4(4):174-175. 

While it is clear that men with lower urinary tract symptoms (LUTS) can be effectively treated with medical therapies aimed at benign prostatic enlargement, it is equally clear that the degree of improvement is often modest, and that a subset of men show minimal improvement. One explanation for this is our inability to differentiate between symptoms attributable to detrusor overactivity (DO) and those caused by bladder-outlet obstruction (BOO) secondary to benign prostatic enlargement. Several studies have highlighted the difficulties with linking specific LUTS with urodynamic findings, which implies that the choice of medical therapy (i.e. whether it is directed at the bladder or the prostate) is often empirical. A role for antimuscarinic agents has been suggested in men with LUTS, although the selection of men who will benefit most from monotherapy versus combined therapy, and the clarification of long-term safety concerns, remain important and somewhat contentious issues.

There is certainly a rationale for the use of antimuscarinic agents in men with LUTS. The positive correlation between prevalence of overactive bladder (OAB)-type symptoms (i.e. urgency, frequency, and nocturia) and age in both men and women suggests that BOO is unlikely to be the culprit in all cases of male LUTS and that, perhaps, ischemia that causes detrusor dysfunction might be partially responsible for LUTS in both sexes. Furthermore, urodynamic studies have demonstrated that approximately 50% of symptomatic men with BOO also have DO; it is not always clear, however, whether BOO is responsible for the development of DO. In approximately 30-40% of men with BOO and DO, LUTS will persist after surgical therapy and relief of obstruction -- particularly in older men and those with equivocal BOO or predominantly OAB symptoms.[1,2] Improvements in LUTS following transurethral resection of the prostate are not dependent on the relief of obstruction. Overall, reluctance to prescribe OAB-specific agents for LUTS in men is likely to stem from concerns about urinary retention and the belief that either modifying a disease process (e.g. benign prostatic hyperplasia) with 5-alpha-reductase inhibitors or decreasing the obstructive effect of that process with the use of alpha blockers is preferable to treatment of a constellation of symptoms (e.g. OAB).

The safety of antimuscarinic agents in men with LUTS has been demonstrated in short-term studies; safety trials have primarily been directed at patients with BOO, who might be expected to be at greatest risk of acute urinary retention (AUR). After 12 weeks of treatment with tolterodine (2 mg twice daily), men with urodynamically confirmed BOO showed no change in maximum flow rate and no patients developed urinary retention when compared to placebo-treated men, although a slight increase in post-void residual volume of 25 ml was observed.[3] Similarly, in an open-label study of 39 men with LUTS refractory to alpha blockers, no patients developed AUR after treatment with extended-release tolterodine.[4] Larger studies that reviewed data on antimuscarinic agents from registration trials and included both men and women have demonstrated that only oxybutynin was associated with an increased risk of AUR.[5] When examined together, these data suggest that, in the short term, even men with BOO do not seem to be at elevated risk of AUR after antimuscarinic therapy; it is not yet clear whether long-term administration of these drugs will result in significant complications, nor is it clear how to identify the men who might be at greatest risk of AUR (or, more likely, progressively impaired bladder emptying).

Encouragingly, antimuscarinic agents had a good safety profile in these short trials, although since there is essentially no risk of AUR associated with alpha blocker and 5-alpha-reductase inhibitor therapies, efficacy would need to be superior to allow one to consider using antimuscarinics -- at least in a defined population of men who do not respond to conventional prostate-directed pharmacotherapy. Published data suggest that men who either cannot tolerate or do not respond to alpha blockers might respond better to extended-release tolterodine, both in terms of daytime and nighttime frequency. Another subgroup that might benefit from the addition of extended-release tolterodine to tamsulosin treatment comprises men with urodynamic evidence of mild to moderate BOO and concomitant DO while on alpha blocker therapy; patients treated with both extended-release tolterodine and tamsulosin had improved quality-of-life scores after treatment.[6]

Urodynamic information might be helpful in determining which patients would benefit most from alpha blocker monotherapy or combination therapy, respectively. Among 144 men with BOO, half of whom had concomitant DO, 79% of men with only BOO showed an improvement in symptoms on doxazosin monotherapy, whereas only 35% of those with both DO and BOO improved.[7] Among men with both DO and BOO that did not improve on alpha-blocker monotherapy, 73% did show symptomatic improvement after 3 months of tolterodine treatment.

Urge urinary incontinence, a very troublesome symptom that might not respond to alpha blockade and can occasionally be worsened by surgical therapy, does seem to be improved by antimuscarinic treatment. A post-hoc analysis of men with urge urinary incontinence who entered an extended-release tolterodine registration trial demonstrated that urge urinary incontinence episodes recorded in voiding diaries were reduced by 30% compared to placebo (71% vs 40% improvement), which suggests a clear benefit of tolterodine in the treatment of this highly symptomatic group of men.[8]

A recently completed placebo-controlled 12-week trial that compared the efficacy of tamsulosin, extended-release tolterodine and a combination of both for the treatment of LUTS in men raised more questions than it answered.[9] This provocative study included 789 moderately to severely symptomatic men with both high urinary frequency (mean 11.9 voids daily) and urgency (mean 7.2 urgency episodes daily), but without clear evidence of BOO from noninvasive studies. The primary outcome measure was perceived treatment benefit, as reported by the patient. Interestingly, only the combination-therapy group demonstrated a significant improvement compared to the placebo-treated group (80% versus 62%; P <0.0001). Patients who received either tamsulosin (71%) or tolterodine monotherapy (65%) reported no more treatment benefits than placebo-treated patients. At week 12, all diary parameters (micturitions, urge episodes, and urge incontinence) were markedly improved among patients who received combination therapy, while only urge incontinence episodes were improved in tolterodine-treated patients, and no diary parameters were improved among tamsulosin-treated patients. No differences in adverse events were noted between the groups. These findings certainly call into question the roles of alpha blocker and antimuscarinic agent monotherapies in men with predominantly OAB symptoms. A post-hoc analysis of subgroups (e.g. stratified by prostate size) might further elucidate which patients will benefit most from monotherapy versus combination therapy.

As there are various etiologies for LUTS in men, it follows that there must also be various approaches to symptom management. The identification of patients who would benefit most from each intervention -- be it treatment with alpha blockers, 5-alpha reductase inhibitors, antimuscarinic agents or a combination thereof -- remains a challenge; future work must be directed towards resolution of this clinical dilemma. Without doubt, recent studies have opened our eyes to the fact that one size most assuredly does not fit all when it comes to the medical management of male patients with LUTS.


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