Voiding Disorders: Advances in Anticholinergic Pharmacotherapy, Botulinum-A Toxin, and More
Introduction
This year's Meeting of the American Urological Association (AUA) had several important themes in the sessions that focused on voiding dysfunction, female urology, and urinary incontinence. In addition, this year marked the first time that a session was devoted to focusing solely on the management of pelvic prolapse. The focus of this coverage is on several studies that discussed potential therapies for overactive bladder (OAB), including the intravesical injection of botulinum toxin and 2 anticholinergic medications that may be approved for use by the US Food and Drug Association within the next year.
New Indications for Botulinum-A Toxin?
Six studies presented at this year's AUA meeting dealt with the clinical applications of botulinum toxin in the treatment of urinary incontinence. The study with the largest cohort and longest follow-up was European and presented by Reitz and colleagues. Two hundred patients were eligible to receive botulinum toxin; injections were done cystoscopically using 300 units of botulinum toxin (Botox; Allergan; Irvine, California) injected throughout the bladder but sparing the trigone. All but 9 patients responded, with bladder capacity increasing from an average of 277 mL at baseline to 435 mL at 12 weeks and 351 mL at 36 weeks. There were no significant toxic effects related to the botulinum toxin and the therapy lasted an average of 9 months (range, 6-14 months).
Another study, presented by Chancellor and colleagues, reported on the largest cohort from the United States. Their study looked at 10 patients with idiopathic OAB refractory to standard medical therapy as well as 11 patients with neurogenic OAB. They used 100-300 units of botulinum toxin and included the trigone in their injections. Success was noted in 8 of 10 (80%) of the OAB patients and 8 of 11 (73%) of the neurogenic patients. Looking at the idiopathic-OAB patients specifically, bladder capacity increased from a baseline of 165 mL to 288 mL at 6 months post injection, and during that same time frame incontinence episodes/week decreased from 18 to 4. For the neurogenic patients, bladder capacity increased from a baseline of 154 mL to 282 mL and incontinence episodes/week decreased from 21 to 6.
Both of these studies illustrate the potential benefit of botulinum toxin injection into the bladder. However, before this becomes "standard" therapy for OAB, there are several issues that need to be resolved. Questions include: What is the appropriate dose, site of injection (with or without involvement of the trigone), and optimal interval between injections?; What is the best subtype of botulinum toxin for the bladder?; Does botulinum toxin maintain its effect with repeat injection, and is it effective in pediatric patients? In addition, a major hurdle in the United States includes reimbursement. The intravesical injection of botulinum toxin is an off-label use of the drug and may not be covered by insurance carriers. At a cost of approximately $350 per 100 units, this therapy could be prohibitively expensive for many patients.
Advances in Anticholinergic Pharmacotherapy
Two oral anticholinergic medications were reported on at the meeting that may soon become available in the United States. Zinner and colleagues reported on their experiences with 523 patients randomized to either trospium (20 mg twice daily) or placebo over a 12-week period. Inclusion criteria to the study included symptoms of OAB for at least 6 months, urinary frequency (defined as > 70 voids/week), and more than 7 urinary urge incontinence (UUI) episodes/week. Voiding diaries were obtained at baseline and weeks 1, 4, and 12 of treatment, and were used to evaluate treatment efficacy.
At each week of therapy that a voiding diary was obtained, trospium showed a significant improvement over placebo in terms of decrease in number of daily voids. By week 12, trospium patients had 2.37 less voids/day compared with baseline, whereas placebo patients had 1.29 less voids/day compared with baseline (P < .0001). A similar improvement was noted in UUI episodes; by 12 weeks, patients on trospium had a 59% improvement compared with baseline and the placebo patients had a 44% improvement compared with baseline (P < .0001). The final significant outcome parameter was volume voided, which increased by 32.1 mL on trospium at week 12 compared with an increase of 7.7 mL on placebo P < .0001). The primary adverse events were dry mouth and headache, which were identified in 21.8% and 9.5% of patients on trospium, respectively, compared with 6.5% and 3.8% of patients, respectively, on placebo.
Trospium chloride is a nonselective anticholinergic that has been available in Europe for over 10 years. It has a known safety record which is based primarily on its size and lack of drug-drug interactions. Because of its quaternary ammonium structure, there does not appear to be any blood-barrier crossing, which precludes some potential central nervous system side effects. In addition, trospium does not interact with drugs metabolized by the cytochrome P450 system, which is a common source of drug-drug interactions. Dry mouth remains an issue, as it is with current anticholinergic drugs. It is not clear whether this drug is superior to any of the drugs presently available for the therapy of OAB, though its safety may be ideal in older patients who are at greater risk for adverse events due to polypharmacy and Alzheimer's disease.
The last of the potential future drugs for treatment of OAB that was presented at the meeting was solifenacin. A European trial presented by Cardozo and colleagues compared 857 patients treated with either placebo or solifenacin (5 or 10 mg). There were significant improvements in mean change from baseline to end of study between placebo and solifenacin in decreased number of voids/day, urge episodes/day, UUI episodes/day, as well as increase in volume/void; however, there was no significant difference between the 5- and 10-mg doses. Looking at adverse effects, the most common issue was dry mouth, which was identified in 2.3% (placebo), 7.7% (5-mg group), and 23.1% (10-mg group) of patients. The 2 US studies looked at placebo vs only the 10-mg dose in 1208 patients. At the end of the study, solifenacin was significantly superior to placebo in decreasing the mean number of voids/day (-2.7 vs -1.4, P < .001), decrease in incontinence episodes/day (-2.0 vs -1.2, P < .001), and increase in volume voided (+46.8 mL vs +7.7 mL, P < .001). In addition, 53% of patients were completely dry by the end of the study compared with 31.4% of patients on placebo (P < .001). The primary adverse events were dry mouth and constipation, identified in 32.2% and 17.6% of patients on the drug, respectively, vs 4.8% and 3.7% of patients on placebo.
Solifenacin is a selective anticholinergic that is specific for the muscarinic M3 receptor responsible for bladder contraction. The concept behind this drug is that bladder selectivity would allow for better efficacy in terms of control of OAB symptoms with a decrease in potential adverse events. Clearly from the data presented, the drug appears to have good efficacy. Whether the clinical balance of high efficacy and low adverse events is superior to that of the presently available anticholinergics remains to be seen. Adverse effects (such as dry mouth and constipation) are still not eliminated with this class of bladder-specific cholinergic blockade.
Conclusions
The search for the perfect drug for OAB remains. The medications we presently use (tolterodine and oxybutynin) work well but have adverse effects, such as dry mouth. The new therapies that have been discussed hold promise; however, we have yet to find the perfect drug that works only at the level of the bladder, causes no significant adverse events, is cost-effective, and is easily administered. As biotechnology improves, we certainly await advances for the treatment of this bladder disorder that affects over 15 million Americans and will only increase in prevalence as the population ages.
References
This year's Meeting of the American Urological Association (AUA) had several important themes in the sessions that focused on voiding dysfunction, female urology, and urinary incontinence. In addition, this year marked the first time that a session was devoted to focusing solely on the management of pelvic prolapse. The focus of this coverage is on several studies that discussed potential therapies for overactive bladder (OAB), including the intravesical injection of botulinum toxin and 2 anticholinergic medications that may be approved for use by the US Food and Drug Association within the next year.
New Indications for Botulinum-A Toxin?
Six studies presented at this year's AUA meeting dealt with the clinical applications of botulinum toxin in the treatment of urinary incontinence. The study with the largest cohort and longest follow-up was European and presented by Reitz and colleagues. Two hundred patients were eligible to receive botulinum toxin; injections were done cystoscopically using 300 units of botulinum toxin (Botox; Allergan; Irvine, California) injected throughout the bladder but sparing the trigone. All but 9 patients responded, with bladder capacity increasing from an average of 277 mL at baseline to 435 mL at 12 weeks and 351 mL at 36 weeks. There were no significant toxic effects related to the botulinum toxin and the therapy lasted an average of 9 months (range, 6-14 months).
Another study, presented by Chancellor and colleagues, reported on the largest cohort from the United States. Their study looked at 10 patients with idiopathic OAB refractory to standard medical therapy as well as 11 patients with neurogenic OAB. They used 100-300 units of botulinum toxin and included the trigone in their injections. Success was noted in 8 of 10 (80%) of the OAB patients and 8 of 11 (73%) of the neurogenic patients. Looking at the idiopathic-OAB patients specifically, bladder capacity increased from a baseline of 165 mL to 288 mL at 6 months post injection, and during that same time frame incontinence episodes/week decreased from 18 to 4. For the neurogenic patients, bladder capacity increased from a baseline of 154 mL to 282 mL and incontinence episodes/week decreased from 21 to 6.
Both of these studies illustrate the potential benefit of botulinum toxin injection into the bladder. However, before this becomes "standard" therapy for OAB, there are several issues that need to be resolved. Questions include: What is the appropriate dose, site of injection (with or without involvement of the trigone), and optimal interval between injections?; What is the best subtype of botulinum toxin for the bladder?; Does botulinum toxin maintain its effect with repeat injection, and is it effective in pediatric patients? In addition, a major hurdle in the United States includes reimbursement. The intravesical injection of botulinum toxin is an off-label use of the drug and may not be covered by insurance carriers. At a cost of approximately $350 per 100 units, this therapy could be prohibitively expensive for many patients.
Advances in Anticholinergic Pharmacotherapy
Two oral anticholinergic medications were reported on at the meeting that may soon become available in the United States. Zinner and colleagues reported on their experiences with 523 patients randomized to either trospium (20 mg twice daily) or placebo over a 12-week period. Inclusion criteria to the study included symptoms of OAB for at least 6 months, urinary frequency (defined as > 70 voids/week), and more than 7 urinary urge incontinence (UUI) episodes/week. Voiding diaries were obtained at baseline and weeks 1, 4, and 12 of treatment, and were used to evaluate treatment efficacy.
At each week of therapy that a voiding diary was obtained, trospium showed a significant improvement over placebo in terms of decrease in number of daily voids. By week 12, trospium patients had 2.37 less voids/day compared with baseline, whereas placebo patients had 1.29 less voids/day compared with baseline (P < .0001). A similar improvement was noted in UUI episodes; by 12 weeks, patients on trospium had a 59% improvement compared with baseline and the placebo patients had a 44% improvement compared with baseline (P < .0001). The final significant outcome parameter was volume voided, which increased by 32.1 mL on trospium at week 12 compared with an increase of 7.7 mL on placebo P < .0001). The primary adverse events were dry mouth and headache, which were identified in 21.8% and 9.5% of patients on trospium, respectively, compared with 6.5% and 3.8% of patients, respectively, on placebo.
Trospium chloride is a nonselective anticholinergic that has been available in Europe for over 10 years. It has a known safety record which is based primarily on its size and lack of drug-drug interactions. Because of its quaternary ammonium structure, there does not appear to be any blood-barrier crossing, which precludes some potential central nervous system side effects. In addition, trospium does not interact with drugs metabolized by the cytochrome P450 system, which is a common source of drug-drug interactions. Dry mouth remains an issue, as it is with current anticholinergic drugs. It is not clear whether this drug is superior to any of the drugs presently available for the therapy of OAB, though its safety may be ideal in older patients who are at greater risk for adverse events due to polypharmacy and Alzheimer's disease.
The last of the potential future drugs for treatment of OAB that was presented at the meeting was solifenacin. A European trial presented by Cardozo and colleagues compared 857 patients treated with either placebo or solifenacin (5 or 10 mg). There were significant improvements in mean change from baseline to end of study between placebo and solifenacin in decreased number of voids/day, urge episodes/day, UUI episodes/day, as well as increase in volume/void; however, there was no significant difference between the 5- and 10-mg doses. Looking at adverse effects, the most common issue was dry mouth, which was identified in 2.3% (placebo), 7.7% (5-mg group), and 23.1% (10-mg group) of patients. The 2 US studies looked at placebo vs only the 10-mg dose in 1208 patients. At the end of the study, solifenacin was significantly superior to placebo in decreasing the mean number of voids/day (-2.7 vs -1.4, P < .001), decrease in incontinence episodes/day (-2.0 vs -1.2, P < .001), and increase in volume voided (+46.8 mL vs +7.7 mL, P < .001). In addition, 53% of patients were completely dry by the end of the study compared with 31.4% of patients on placebo (P < .001). The primary adverse events were dry mouth and constipation, identified in 32.2% and 17.6% of patients on the drug, respectively, vs 4.8% and 3.7% of patients on placebo.
Solifenacin is a selective anticholinergic that is specific for the muscarinic M3 receptor responsible for bladder contraction. The concept behind this drug is that bladder selectivity would allow for better efficacy in terms of control of OAB symptoms with a decrease in potential adverse events. Clearly from the data presented, the drug appears to have good efficacy. Whether the clinical balance of high efficacy and low adverse events is superior to that of the presently available anticholinergics remains to be seen. Adverse effects (such as dry mouth and constipation) are still not eliminated with this class of bladder-specific cholinergic blockade.
Conclusions
The search for the perfect drug for OAB remains. The medications we presently use (tolterodine and oxybutynin) work well but have adverse effects, such as dry mouth. The new therapies that have been discussed hold promise; however, we have yet to find the perfect drug that works only at the level of the bladder, causes no significant adverse events, is cost-effective, and is easily administered. As biotechnology improves, we certainly await advances for the treatment of this bladder disorder that affects over 15 million Americans and will only increase in prevalence as the population ages.
References
Reitz A, Stöhrer M, Kramer G, et al. European experience of 200 cases treated with botulinum-A toxin injections into the detrusor muscle for neurogenic incontinence. Program and abstracts of the American Urological Association 98th Annual Meeting; April 26-May 1, 2003; Chicago, Illinois. Abstract 1393.
Chancellor MB, O'Leary M, Erickson J. Successful use of bladder botulinum toxin injection to treat refractory overactive bladder. Program and abstracts of the American Urological Association 98th Annual Meeting; April 26-May 1, 2003; Chicago, Illinois. Abstract DP50.
Zinner N, Gittelman M, Harris R, Susset J, Kanellos A, Auerbach S. Trospium chloride improves overactive bladder symptoms: A multicenter phase III trial. Program and abstracts of the American Urological Association 98th Annual Meeting; April 26-May 1, 2003; Chicago, Illinois. Abstract DP51.
Cardozo L, Kuzmin I, Lisec ML.YM90 in symptomatic overactive bladder: Results of a phase 3a randomised, placebo-controlled trial. Program and abstracts of the American Urological Association 98th Annual Meeting; April 26-May 1, 2003; Chicago, Illinois. Abstract DP47.
Kaufman J, Knapp P, Siami P, Harris R, Smith N, Ridge S, Tempel D. YM905 10mg increases the proportion of male and female patients with overactive bladder who become continent. Program and abstracts of the American Urological Association 98th Annual Meeting; April 26-May 1, 2003; Chicago, Illinois. Abstract DP49.
Gittelman M, Chu FM, Klimberg I, et al. Two randomized double-blind, placebo-controlled, parallel-group, fixed-dose, multicenter studies assess the efficacy and safety of daily oral administration of 10mg YM905 versus placebo in male and female subjects with overactive bladder. Program and abstracts of the American Urological Association 98th Annual Meeting; April 26-May 1, 2003; Chicago, Illinois. Abstract DP43.
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