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Unravelling the puzzle of lower urinary tract symptoms to optimize management of overactive bladder: An experience-sharing interview

Prof Wachira Kochakarn
Division of Urology 
Department of Surgery
Faculty of Medicine
Ramathibodi Hospital
Bangkok, Thailand
26 Sep 2017

Patient presentation and management

Case 1
• A 67-year-old male had frequent urination, poor stream and occasional urgency for 3 years. He also experienced nocturia, waking up 3-4 times to urinate.
• He had mild hypertension, which was controlled with an antihypertensive.
• He consulted at another hospital, where his International Prostate Symptom Score (IPSS) was noted as 24 points.
• Physical examination showed mild enlargement of the prostate gland. Results of laboratory tests were normal.
• He was treated with an alpha-blocker for benign prostatic hyperplasia (BPH), but he experienced only some symptom relief. He was switched to another alpha-blocker, with no improvement.
• At our clinic, physical examination and other test findings were consistent with previous results.
• However, his IPSS was 27 points. Points were mainly derived from questions for storage symptoms (frequency, urgency and nocturia; Figure 1).
• A voiding diary showed that his intake was approximately 3 L and urine output was approximately 2.1 L per day; he urinated every 1.5 hours, with an output of 70-160 mL each time. Uroflowmetry was not performed because he could not postpone urination, but no residual urine was observed.
• Tolterodine 4 mg was prescribed as monotherapy. At follow-up, IPSS improved to 16, and all storage symptoms were reduced.

Case 2
• A 35-year-old female experienced urgency, urge incontinence and nocturia for 3 years. She would wake up 3 times per night to urinate.
• She was very uncomfortable at work because she could not reach the toilet on time during busy hours, and used diapers (4 pads/day) due to these symptoms.
• She had no other medical conditions.
• Her gynecologist prescribed tolterodine 4 mg for overactive bladder (OAB). Urgency and urinary incontinence were reduced, and she only needed one diaper per day.
• However, after 2 weeks, she discontinued medication due to side effects of dry mouth and constipation. Her symptoms worsened and she resumed the use of four pads per day.
• At our clinic, a review of her symptoms included urinary frequency, urgency and urge incontinence. She woke up twice per night to urinate.
• Physical examination showed normal findings.
• A voiding diary revealed her intake was approximately 2 L and her urine output was approximately 1.6 L per day; her voiding volume was 100-140 mL each time. Frequent occurrences of urgency and urge incontinence were also noted.
• At our clinic, the diagnosis of OAB was confirmed. Treatment options were discussed, such as the use of a beta 3-receptor agonist, reducing the dose of the anticholinergic, and intravesical botulinum toxin injection.
• The patient preferred treatment with an anticholinergic but was concerned about side effects.
• Tolterodine 2 mg was prescribed.
• Her symptoms improved after 2 weeks. She only needed one pad during the day and another at night. She continued to use tolterodine 2 mg, and experienced a mild degree of dry mouth, but no constipation.

1. How can we improve the diagnosis of OAB and lower urinary tract symptoms (LUTS)?  How important are the use of voiding diaries and the IPSS questionnaire?

A voiding diary and the IPSS questionnaire are important tools in the diagnosis and management of OAB and LUTS. Variables of a voiding diary show significant correlation with symptoms of OAB,1 such that information from a diary may help in the differential diagnosis when patients complain of urgency, frequency and urge incontinence. IPSS is another simple tool for the management of OAB and LUTS (Figure 1).2,3 We can separate scores for storage and voiding symptoms for analysis. Most patients with predominantly storage symptoms based on IPSS may have OAB.4

HK-PFR-546a4_fig1_v1 (18 Aug)

2. 
How do you make the decision to use an anticholinergic agent for patients with OAB-LUTS?
Anticholinergic medications are part of the first-line pharmacological treatment for OAB,5,6 and extended-release formulations are preferred because of lower rates of dry mouth.5 Side effects should be considered prior to prescription. Vigilance should be particularly given to the selection of anticholinergic drugs for elderly patients with or at risk of cognitive dysfunction.7


3. Is tolterodine more effective for your patients with OAB-LUTS, compared with other agents?  Are there certain patients who may benefit more from treatment with tolterodine than with other agents? 
Studies have provided information that tolterodine is an effective medication in the management of OAB. A randomized trial showed that tolterodine improved storage symptoms in patients with OAB and already on alpha-blocker therapy.8 Systematic reviews have also confirmed the efficacy of tolterodine over placebo for OAB-LUTS.6,9 However, there is no consistent evidence that any one anticholinergic agent is superior to another in terms of efficacy and safety.5

4. Patients are often concerned about the risk of side effects with OAB treatment. How often do your patients experience side effects associated with anticholinergic treatment? How do you balance treatment efficacy with the risk of side effects?
In my experience, adverse effects can occur in 25% of patients with some OAB treatments. The most common adverse events are dry mouth, constipation and palpitations but after continuing with treatment, most patients are able to tolerate the side effects. From my experience, withdrawal from tolterodine is approximately 5%, while results from a previous systematic review showed tolterodine to have the lowest rate of discontinuations among antimuscarinics (Figure 2).10
Importantly, some anticholinergics may cause a greater risk of central nervous system adverse effects such as dizziness, insomnia and cognitive impairment,7 or cardiovascular adverse effects such as QT interval prolongation.11 These side effects should be considered prior to initiating treatment, particularly among more vulnerable populations such as the elderly.5,6

HK-PFR-546a4_fig2_v1 (18 Aug)

5. 
Please explain the importance of counseling patients on the available treatment options and their associated side effects.
Counseling is important because patients may stop taking medications due to side effects. The most common side effect of anticholinergics is dry mouth, reported by approximately 20-30% patients.6,11 With tolterodine sustained release (SR), other common side effects can include headache, fatigue, dyspepsia, constipation, dry eyes, and abnormal vision; impaired cognition is uncommon.12,13 All treatment options should therefore be explained and discussed, including other medication classes and minimally invasive treatment.

6. What key messages do you want physicians to take away from these cases?
As shown in the first case, almost all doctors treat male patients who come with LUTS as BPH. Some prescribe medication and after treatment failure, usually perform surgery. If we pay attention to IPSS, especially storage symptoms, and ask patients to keep a voiding diary, the diagnosis of OAB may be clarified for appropriate management.
The second is a simple case of OAB. However, the patient could not tolerate the full dose of tolterodine so the dose was reduced and she was able to continue treatment with reduced side effects.

Pfizer
[Zuellig]
Regulatory Class: POM
Contents: Tolterodine tartrate
Indications: Treatment of overactive bladder with symptoms of urinary urgency, frequency and or urge incontinence.
Dosage: Detrusitol Adult including the elderly 2 mg twice daily. Patients with impaired hepatic/renal function or receiving concomitant medications example, ketoconazole or other potent CYP3A4 inhibitors 1 mg twice daily. Detrusitol Sustained Release Adult including the elderly 4 mg once daily. Patients with impaired hepatic/renal function or receiving concomitant medication example, ketoconazole or other potent CYP3A4 inhibitors 2 mg once daily.
Administration: Take with or without food: Sustained Release tablet: Swallow whole, do not chew/crush.
Contraindications: Urinary retention and uncontrolled narrow-angle glaucoma.
Special Precautions: Hepatic or renal impairment. Patients at risk for urinary retention, decreased gastrointestinal motility and myasthenia gravis. Congenital or documented acquired QT prolongation. Patients receiving class IA (example, quinidine, procainamide) or III (example, amiodarone, sotalol) antiarrhythmics. May impair ability to drive or operate machinery. Pregnancy and lactation. Children.
Adverse Reactions: Bronchitis, sinusitis, allergic reactions, confusions, dizziness, headache, somnolence, abnormal vision (including abnormal accommodation), dry eyes, vertigo, flushed skin, dry mouth, abdominal pain, constipation, dyspepsia, flatulence, gastroesophageal reflux disease, dry skin, dysuria, urinary retention, chest pain, fatigue, increased weight.
Interactions: Ketoconazole and other potent CYP3A4 or CYP2D6 inhibitors.
Presentation and Packing: Detrusitol tablet 1 mg x 56's. 2 mg x 56's. Detrusitol Sustained Release capsule 4 mg x 30's.
API-DET-SIN-0408/29 April 2008; API-DET SR-SIN-0809/13 October 2010
ATC Code: G04BD07

References:

1. Brown JS, et al. Urology 2003;61:802-809.
2. Barry MJ, et al. J Urol 1992;148:1549–1557.
3. Rosenberg MT, et al. Can J Urol 2014;21(Suppl 2):12-24.
4. Hsiao SM, et al. Int Urogynecol J 2013;24:263-267.
5. European Association of Urology (EAU). EAU Guidelines on Urinary Incontinence 2016. Available at:  http://uroweb.org/guideline/urinary-incontinence/. Accessed: 3 July 2017.
6. Chapple CR, et al. Eur Urol 2008;54:543–562.
7. Chancellor M, Boone T. CNS Neurosci Ther 2012;18:167-174.
8. Chapple C, et al. Eur Urol 2009;56:534-543.
9. Gacci M, et al. BMC Urol 2014;14:84.
10. Shamliyan T, et al. Nonsurgical treatments for urinary incontinence in adult women: Diagnosis and comparative effectiveness. Agency for Healthcare Research and Quality, 2012. Rockville, MD, US.
11. Hesch K. Proc (Bayl Univ Med Cent) 2007;20:307-314.
12. Detrusitol SR HSA approved Prescribing Information, Oct 2010.
13. Electronic Medicines Compendium (eMC). Detrusitol XL 4mg [Summary of Product Characteristics]. Updated August 2015. Available at: http://www.medicines.org.uk/emc/medicine/7685/SPC/Detrusitol+XL+4mg/. Accessed 7 September 2017. 

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