Medical Management of the Overactive Bladder: AUA 2006 Highlights
Roger Dmochowski, MD
Introduction
The pharmacologic management of the overactive bladder (OAB) continues to evolve as further
evaluations of current and developmental agents continue. Several studies presented at the annual
American Urologic Association (AUA) meeting in Atlanta, Georgia, May 20-25, 2006, further elucidated
these results. Much debate has centered on variability in results reporting and difficulty in crosscomparing agents used for the management of OAB. Systematic review of drug therapy for OAB reveals
substantiated effect using meta-analytic techniques. Continued evidence of the effect of botulinum toxin
type A (BTX-A) in patients with OAB, including the possibility of prolonged symptom modification,
demonstrated robust effect of this toxin. However, method of injection remains to be standardized, and
concerns regarding dosing magnitude, depth of toxin delivery, and overall adverse events have also been
raised. OAB often presents in association with obstructive symptoms in women, yet little is known about
the benefit of additional pharmacotherapies in this mixed-symptom group. Alpha-blocking agents may
provide this benefit. Continued evolution of the antimuscarinic class of agents continues. Fesoterodine
represents another agent recently studied in phase 3 trials in the United States. Increased understanding
of the impact of OAB in men is being recognized in demographic studies.
Pharmacologic Intervention for OAB
A systematic review of drug trials for OAB was conducted to assess the magnitude of benefit associated
with ingestion of anticholinergic drugs.[1] Sixty-one trials were identified that met the initial criteria for
review inclusion. The primary outcome assessed was reduction in or resolution of incontinence episodes.
Secondary parameters included adverse events, urodynamic outcomes, and economic measures.
Fifty trials were fully analyzed, of which 19 actually used a cross-over design. A significant benefit for
incontinence cure or reduction compared with placebo was noted with the anticholinergic class of drugs
(with a relative risk of 1.41). The risk for xerostomia was 2.5 times greater in the active drug arms
compared with placebo, with other class-related adverse events also being more frequently in the active
treatment arms. However, these adverse events did not result in an increased risk for withdrawals
compared with the placebo arms. Quality of life (QOL) appeared to be strongly benefited by active drug
treatment.
The authors concluded that sufficient benefit was attained in subjects with OAB who ingested
anticholinergic drugs. Economic measures, however, were lacking. The importance of these findings is
underscored by the number of studies employing a cross-over design, which further magnifies the relative
benefit of active drug ingestion compared with placebo. The recent inclusion of QOL criteria as being
significant from a regulatory standpoint further amplifies the importance of these results. However, the
question remains as to how much subjective and objective benefit must be attained in a chronic
symptomatic, but not life-threatening syndrome, to justify healthcare cost expenditure.
The actual mechanism of action of antimuscarinic agents has recently been reconsidered. The putative
role of this class of agents as solely affecting detrusor motor function, as has historically been posited,
now seems uncertain. Evidence is accruing that this class of drugs may actually have a significant, if not
predominant, role on bladder afferent behavior. In an interesting study of healthy women volunteers,
tolterodine was administered followed by bladder sensory testing with urodynamics and also with
intravesical electrical stimulation.[2] Various sensory thresholds were analyzed using different frequencies
and duration of current stimulation. Urodynamics and electrical stimulation were performed at baseline
and 2 hours after administration of 4 mg of tolterodine. Significant changes in electrical stimulation
sensory perceptions were noted after any type of electrical stimulation, but the subjective sensory
perceptions noted by means of urodynamics (ie, volumes at which sensations of filling were perceived)
were unchanged. The authors concluded that the effects of drug therapy noted with electrical stimulation
were representative of antimuscarinic activity on sensory afferents arising from the urothelium (as larger
nerve fibers in the detrusor musculature which produce stretch sensation during bladder filling were
unaffected on the basis of sensory response). These data give further currency to the significance of the
recently identified urothelial muscarinic receptors, which had been presumed to be sensory in nature, but
without any supporting physiologic data. The increasing recognition of these afferents will no doubt have
significance as new therapeutic modalities are evaluated for lower urinary tract storage disorders.
BTX-A
Debate over the appropriate dosing magnitude and method of injection when using BTX-A for OAB
continues. In addition, durability of effect and methods of outcomes reporting also remain to be optimally
reported when using this biologic toxin.
A group of 150 patients with nonneurogenic OAB was treated with relatively low-dose BTX-A (100 units in
30 injected sites).[3] All individuals were evaluated with voiding diary, urodynamics (bladder capacity,
bladder compliance, urinary volume at first desire to void, and urinary volume at strong desire to void),
symptomatic urgency change, and QOL assessments. Eighty-eight percent showed significant
improvement in both objective and subjective parameters of bladder function. At 2 weeks postinjection,
subjective urgency disappeared in 76% and incontinence resolved in 82% of study individuals. The mean
increase in bladder capacity was 56% and detrusor overactivity resolved in 74% of those studied. No
severe side effects were noted. Five short-term urinary retention episodes occurred. QOL results
demonstrated substantial improvement. The only patients who did not demonstrate improved QOL were
those who had poor detrusor compliance prior to injection.
Intriguingly, mean duration of toxin effect was 9 months. Twenty-three percent of the study group required
reinjection, and the interval to second injection was a mean of 11 months. Only 4 individuals received a
third injection; the mean duration between second and third injection was 16 months. The authors
concluded that duration of effect actually increased with subsequent injection, a finding not previously
noted by other groups. If indeed these results can be replicated in larger study groups and by other
centers, the possibility of disease state modification exists, which heretofore has been a chimeric hope in
the pharmacologic management of OAB.
Another area of significant debate surrounding BTX-A use has been the appropriate administration
technique. Among the issues not yet resolved are the optimal location for injection within the bladder
(above the trigone with or without sparing of the dome have both been posited as reasonable areas for
toxin delivery), the appropriate degree of dilution of the toxin, and optimal volume of diluent with which to
deliver toxin. Also, depth of injection has been a subject of controversy; some support only intramuscular
detrusor injection, some are in favor of suburothelial injection, and some suggest that a combination
technique is best
Sixty patients with OAB underwent a suburothelial-only technique, with random assignment to doses of
100,150, or 200 units.[4] Patients were assessed with subjective (QOL) and objective (urodynamic)
parameters at baseline and again at 3 months. Similar magnitude of incontinence and symptom reduction
benefit was noted between the 150-unit and 200-unit arms, with substantially less overall benefit being
attained in the 100-unit arm. However, difficult urination (hesitancy and strangury) was noted in 70% of
those subjects receiving 200 units compared with 50% of those in the 150-unit dosing arm. Ten percent of
those in the 150-unit arm experienced retention, while 20% of those in the 200-unit arm did so. The
authors concluded that although increased dosing conferred added benefit, the risk for urinary
dysfunction including retention was noted. Postvoid residual volume (PVR) appeared to be a predictor of
this adverse group of outcomes. The authors also proposed that 150 units was probably the ideal dosing
magnitude. Notably, others have not found such marked rates of voiding difficulty or retention with similar
dosing amounts. Also, controversy exists as to whether it is even possible to limit toxin delivery only to
specific areas within the bladder wall with suburothelial injection, as toxin dispersion in the mural
components of the bladder is clearly needed for optimum toxin effect.
Alpha Blockers and Lower Urinary Tract Symptoms in Women
Because obstructive symptoms often complicate the management of OAB in women, efforts to address
mixed lower urinary tract symptoms (LUTS) in women continue. Other drug classes have been used
anecdotally, but little evidence supports other pharmacotherapeutic strategies in this complicated
presentation.
Sixty-two women with LUTS including AUA symptom scores of > 15, urinary flow rates of < 15 mL/sec,
and PVRs of > 150 mL were included in a single-arm trial of doxazosin (4 mg/day). The patients were
assessed after 4 weeks on treatment with repeat AUA symptom scores, bothersome score, satisfaction
estimation, and urodynamics.[5] At study end, highly significant changes in AUA symptom scores (22.26 to
14.81 mean), storage scores (8.1 to 6.16), obstruction scores (14.16 to 8.65), bothersome scores (4.61 to
2.92), maximum flow rates (10.93 to 15.85), and PVRs (56.43 to 42.04) were noted across the study
group. Two cases of either de-novo or exacerbated stress incontinence were noted. Overall, 75.8% were
either satisfied or slightly satisfied. The authors summarized by saying that the alpha-adrenoreceptor
antagonists may provide initial therapy for women with complex LUTS. Obviously, the role of these
agents in a combined strategy with anticholinergics needs to be examined to assess the possible benefit
of combined-effect therapy. Another concern is the durability of effect of the adrenoreceptor class for this
indication.
New Anticholinergics
Tolerability and efficacy continue to limit the overall utility of the antimuscarinic class of drugs. Continued
investigation is ongoing to identify new agents which may, in reality, offer an improved therapeutic index,
either with substantive improvement in efficacy or with reduced tolerability concerns. Fesoterodine is an
antimuscarinic compound that has completed phase 3 trials in the United States. [6] In a randomized,
placebo-controlled trial, this compound was evaluated in patients with OAB. The primary outcomes were
reduction in incontinence episodes, reduction in micturition frequency, and treatment response based on
a dichotomous scale. A total of 836 subjects were enrolled; 681 completed the 3-month trial. Subjects
received either placebo or fesoterodine in a 4-mg or 8-mg dose. Both drug doses significantly decreased
micturition frequency and number of urge urinary incontinence episodes, and both doses produced
significantly higher approval ratings than placebo. Efficacy, noted at 2 weeks, was proportional to drug
dose, with increasing magnitude of benefit associated with higher drug doses. Tolerability concerns
centered on xerostomia, which occurred in 7% (placebo), 16% (4 mg fesoterodine), and 36% (8 mg
fesoterodine) of study subjects. No other significant tolerability concerns were encountered. The ability to
dose-escalate in patients who respond to antimuscarinic therapy is a useful strategy and allows
individualization of treatment paradigms. Overall parameters of this agent appear to be on par with the
general performance of other agents within this drug class.
Side effects, or in some cases, adverse events, have plagued the antimuscarinic class since the inception
of their use 3 decades ago. Recently investigators have begun to clarify the safety and tolerability profiles
of the various agents in this class, and to identify specific subpopulations who might be at risk for various
side effects and adverse events. An analysis presented at this year's meeting of 2 agents within this
class[7] demonstrated intriguing results as to compound differences and also the methods used to assess
and quantitate specific adverse events. A group of otherwise healthy adults older than 60 years of age
were randomized to 1 of 3 dose groups: 7.5 mg/d of darifenacin at week 1 titrated to 15 mg/d at week 3;
extended-release oxybutynin 10 mg at week 1, titrated to 15 mg/d at week 2, and 20 mg/d at week 3; or
placebo. All study participants were subjected to a variety of memory recall analyses (name/face recall)
after each titration. The authors found that darifenacin showed no difference as compared with placebo
for cognitive function, whereas extended-release oxybutynin had a significantly adverse effect on recall
ability as well as several other cognitive factors. The authors concluded that the changes noted with
extended-release oxybutynin ingestion were similar in magnitude to those associated with 10 years of
aging on the central nervous system. Whether these differences can be attributed to variability in
muscarinic receptor behavior or diversity of activity of specific compounds with regard to blood-brain
barrier penetration remains to be seen.
OAB in Men
The triad symptoms of OAB have been heretofore presumed to occur predominantly in women. However,
increasing evidence implies that these symptoms actually occur in men to a similar degree as in woman
and are not all related to prostatic factors.
In a large-scale analysis of men, a 10-year follow-up was performed to determine whether OAB
symptoms and other LUTS increased with age.[8] A total of 7763 men comprised the initial study group.
Ten years later, 4072 were available for reevaluation. Both OAB and other LUTS increased significantly.
Of interest, urgency and nocturia were key components of the worsening LUTS. These findings suggest
an independent contribution of aging to OAB in men, one that is not simply linked to prostate disorder and
one that will need further elucidation with both population-based and pathophysiologic studies.
In light of the increasing awareness of OAB in men, better evaluation of these symptoms is becoming
paramount. Previously, symptom scores were used almost solely to assess baseline bother and
treatment impact on men with LUTS. To assess alpha adrenoreceptor activity in males with urinary
symptoms, 267 men were treated with either of 2 alpha agents (tamsulosin or alfuzosin). [9] They were
assessed with flow rates, International Prostate Symptom Score (IPSS), and voiding diary. After 3 months
on active therapy, percent changes in urinary frequency (33.7%) and nocturia (33%) were more
substantive than changes seen in either flow rate (15%) or IPSS (25.7%). The authors concluded that
traditional outcomes used to assess voiding dysfunction in men may not be sensitive enough to recognize
significant changes in OAB symptoms, therefore underestimating efficacy of interventions. These findings
are very important because historical methods used to assess LUTS in men may not be sufficient for
evaluating complex storage symptoms. Clearly, more robust outcomes data will be necessary to fully
assess OAB outcomes in this population.
MacDiarmid and colleagues[10] analyzed the efficacy of alpha blockade with placebo vs alpha blockade
with anticholinergic therapy in men with LUTS (defined as IPSS ≥ 13 with accompanying irritative
symptom subscore of ≥ 8). Entry criteria included PVR ≤ 150 cc and flow rate of ≥ 8 cc/min. Four hundred
and eighteen male subjects were randomized to receive tamsulosin 0.4 mg/d with placebo or tamsulosin
0.4 mg/d with extended-release oxybutynin 10 mg/d in a 3-month trial. Primary efficacy outcomes were
change in IPSS total score, with secondary outcomes of IPSS irritative subscore and QOL. Men who
received combined active therapy had statistically greater improvement in all efficacy outcome
parameters as compared with those who received alpha blockade and placebo in combination. Retention
as defined by PVR > 300 cc occurred in 6 men (2.9%) who received combined active therapy and 1 man
(0.5%) who received alpha blockade and placebo. No significant flow rate changes were seen between
study groups. These data clearly reveal the benefit of combined therapy in men with LUTS with significant
irritative symptom bother, and further add compelling support to the use of this strategy in these men. It is
to be noted that the retention rate in the combined group is higher than previously reported with
antimuscarinic use and gives some pause to the unmonitored use of the antimuscarinic class in men with
LUTS.
References
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