Improving Urinary Health in Your Practice
Optimizing Therapies, New and Old
Urinary complaints are adversely affecting the quality of life for patients in the primary care setting. To share the best practices and latest advances in the management of patients with urinary symptoms, Astellas held a continuing medical education programme to primary care physicians. Keynote speakers included renowned urologists Dr Tricia Kuo, Dr Tan Yung Khan, and Dr Lincoln Tan.
Prostate Cancer Screening – The Who, When, and How of Catching the Tigers Amongst the Pussy Cats
Prostate cancer is the third most common cancer among Singaporean men (12% of all male cancers), and almost 30% of patients are diagnosed with metastatic disease compared to only 4% in the US.1,2
The low rate of diagnosis of early-stage prostate cancer could be related to low screening rates driven by fears of harms due to overdiagnosis and overtreatment (eg, morbidity from biopsies, false positive readings from elevated prostate-specific antigen [PSA] results, treatment-associated harm, and false negative readings). However, these negative consequences can be reduced if the goal of prostate cancer screening is shifted to the diagnosis of aggressive prostate cancers (“the tigers among the kittens”) in carefully selected candidates. PSA screening can be supplemented with judicious use of other adjunct tests to aid decision making regarding biopsies. Increased adoption of active surveillance for low risk prostate cancer will also reduce the harm from overtreatment of cancers (kittens) and are unlikely to harm the patient.
The prostate health index (PHI) is a mathematical formula that combines total PSA, free PSA, and [-2] proPSA (a novel precursor form of free PSA).3 The PHI has been found to be three times more accurate than PSA in predicting the presence of cancer in a biopsy. The use of PHI can lead to a reduction of up to half of unnecessary biopsies. The PHI has been validated in studies of Asian men including Singaporean and Hong Kong men. Other approaches to improve diagnostic outcomes include the use of transperineal biopsy which has a negligible risk of infection, MRI, and MRI-guided prostate biopsy which can significantly improve the detection of clinically significant cancer, while reducing the overdiagnosis of clinically indolent disease.
Active surveillance (close monitoring at regular intervals to detect disease progression in men with curable prostate cancer) can also help prevent overtreatment of indolent disease. This is usually recommended for younger men with favourable-risk disease or older men with less favourable disease and limited life expectancy. Active surveillance requires regular digital rectal examination and PSA testing, as well as repeat biopsies. While active surveillance has an excellent 10-year cancer specific survival of up to 99.7%, up to one third of patients may drop out due to anxiety or upgrading of cancer risk.
Prostate cancer screening should only be done after discussing the pros and cons with interested men. They should be informed that while screening has been shown to reduce prostate cancer metastasis and mortality, it is associated with harms from overdiagnosis and overtreatment.
These harms can be mitigated by selecting men who will benefit most from screening (ie, men with more than 10-year life expectancy based not only on age but also comorbidities) and use of diagnostic adjuncts discussed above to risk stratify patients before offering prostate biopsy. Men who are confident seeking treatment only for aggressive prostate cancer and living with a diagnosis of low-risk cancer are good candidates for screening. The corollary is that men who are likely to develop anxiety from not being treated for low risk cancer are poor candidates for screening.
Clearly, the decision to screen has several considerations. Men suitable for screening should be actively involved in a shared decision-making process with clinicians.
1. Singapore Cancer Registry Annual Registry Report Trends in Cancer Incidence in Singapore 2010–2014. Singapore: Health Promotion Board; 2015. 2. National Cancer Institute. SEER Cancer Statistics Review 1975–2011. Available at: https://seer.cancer.gov/archive/csr/1975_2011/results_merged/sect_23_prostate.pdf. Accessed 06 Feb 2018. 3. Loeb S, Catalona WJ. Ther Adv Urol 2014;6:74-77.
Overactive Bladder – Red Flags and Solutions to a Wet Problem
Overactive bladder (OAB) is characterized by urinary urgency that is usually accompanied by frequency and nocturia, with or without urgency incontinence, and in the absence of infection or other underlying aetiology.1 It is a clinical entity and a symptomatic complex that is based on diagnosis of exclusion. As such, clinicians should identify red flags that could point to organic causes during initial assessment.
These red flags in the history include:
• Extremes of age (eg, exclude malignancy in the older patient, ketamine bladder is rare but should be considered as a differential diagnosis in at risk youth)
• Occupational history – exposure to chemicals and dyes
• Smoking history
• Gross haematuria
• Pain (eg, pelvic pain due to interstitial cystitis or painful bladder syndrome)
• Treatment-refractory symptoms
• Immunocompromised status (eg, cyclophosphamide- or BK virus-induced haemorrhagic cystitis)
Initial investigations to exclude urinary tract infections (UTI) and organic causes include urine dipstick, urine microscopy and culture, and pertinent radiographic imaging, with PSA testing in men with lower urinary tract symptoms (LUTS).
First-line treatment for all patients should include education on the condition and lifestyle modifications. This endeavour in tertiary centres is aided by continence nurses or advanced nurse practitioners. Patients should be re-educated on normal voiding patterns. Lifestyle modification is tailored to the individual patient based on the 3-day bladder diary or frequency volume chart, for example, decreasing caffeine and/or alcohol intake. Additional conservative management techniques include bladder training, timed voiding, “urge suppression” techniques, and pelvic floor exercises.
Pharmacological treatment options for OAB
Antimuscarinic agents are the traditional mainstay of treatment for OAB.2 These agents inhibit cholinergic tone in the bladder, thus suppressing bladder wall contractions.3 A meta-analysis of antimuscarinic trials have demonstrated the efficacy of antimuscarinic agents in the treatment of OAB.4 However, antimuscarinics are associated with intolerable anticholinergic side effects such as dry mouth, pruritus, headache, constipation, dizziness, somnolence, insomnia and cognitive impairment,4,5 which can be more pronounced in the elderly. In addition, antimuscarinics may be contraindicated in patients with gastrointestinal obstruction, bladder outlet obstruction (BOO) (eg, due to benign prostatic enlargement), myasthenia gravis, and in those with untreated narrow angle glaucoma.
Mirabegron: A first-in-class β3 agonist
For patients who have contraindications to or cannot tolerate antimuscarinics, mirabegron, a potent, selective β3-adrenoceptor agonist, is the preferred pharmacological treatment (Figure 1).6 Mirabegron is the first β3 agonist approved to treat OAB and works differently from antimuscarinics.
Mirabegron induces relaxation of bladder smooth muscles (Figure 2), thus resulting in decreased frequency, increased intervoid intervals, with an associated increase in voided urine volume per micturition.7,8 Importantly, the β3 stimulation does not interfere with the voiding process, hence mirabegron may be administered to patients with concomitant BOO.
Clinical efficacy and side effects of mirabegron
Mirabegron has been studied extensively and found to be safe and effective in the long-term treatment of OAB. A phase III, randomized, active controlled trial of mirabegron in patients with OAB symptoms for ≥3 months showed that mirabegron 50 mg once daily improved OAB symptoms (incontinence, micturitions, and mean volume voided per micturition) as early as 4 weeks of treatment and the efficacy was sustained throughout 12 months compared with tolterodine extended-release 4 mg once daily (Figure 3).9 The most common treatment-emergent adverse effect (TEAE) reported was dry mouth which was higher with tolterodine than with mirabegron (8.6% vs 2.8%).
A post hoc analysis of pooled data from three randomized controlled 12-week studies of mirabegron in incontinent patients with OAB showed that compared with placebo, mirabegron 50 mg improved the mean number of incontinence episodes, micturitions, and urgency episodes per 24 hours and the mean number of voided volume per micturitions from baseline to final visit. Treatment effect increased with increasing severity of incontinence.10
The efficacy of mirabegron coupled with low rates of bothersome TEAEs could be beneficial in improving OAB treatment persistence and adherence. Real-world data from the Clinical Practice Research Datalink GOLD, a large primary care research database covering 674 general practices across the UK, found that patients treated with mirabegron were more likely to remain on treatment vs those on antimuscarinics (Figure 4).11
Adverse events are rare and most side effects are mild (eg, dry mouth). However, clinicians should exercise caution in prescribing β3 agonists in patients with significant cardiovascular risk factors, poorly controlled hypertension, and cardiac arrhythmias.
Non-pharmacological treatment options
OAB that is refractory to pharmacological management should be further investigated with urodynamics before more invasive treatment modalities are commenced. This typical stepladder approach is common in functional disorders, where if a gentle initial approach fails, then more invasive options are considered.
The following modalities are currently available:
• Onabotulinum toxin injection to the detrusor muscle
• Sacral nerve stimulation
• Percutaneous tibial nerve stimulation
Thereafter, should these modalities fail then the last resort would be irreversible surgery including urinary diversion or clam cystoplasty.
The management of OAB consists a spectrum of treatment modalities. A new class of medication, the β3 agonist, has proven efficacy and good tolerability for treating OAB and can help improve treatment persistence. Mirabegron is the preferred treatment option for patients with contraindications or tolerability concerns with antimuscarinic agents.
Lastly, the future of pharmacological treatment is likely to include combination therapy with both antimuscarinics and β3 agonists. This approach serves to improve efficacy with further reduction of adverse events, optimizing the likelihood of patient adherence and persistence with pharmacotherapy.
1. Abrams P, et al. Neurourol Urodyn 2006;25:293. 2. Am Fam Physician 2013;87:800-803. 3. Chu FM, Dmochowski R. Am J Med 2006;119(3 Suppl 1):3-8. 4. Chapple CR, et al. Eur Urol 2008;54:543-562. 5. Kessler TM, et al. PLoS ONE 2011;6:e16718. 6. Chaplin S, Chapple C. Prescriber 2013;24:39–42. 7. Betmiga® (mirabegron) [prescribing information]. Singapore: Astellas; 2016. 8. Tyagi P, et al. Expert Opin. Drug Safety 2011;10.2: 287-294. 9. Chapple CR, et al. Eur Urol 2013;63:296-305. 10. Chapple CR, et al. Eur Urol 2015;67:11-14. 11. Chapple CR, et al. Eur Urol 2017;72:389-399.
Individualizing the Care of Male Lower Urinary Tract Symptoms
Personalized medicine in the treatment of male lower urinary tract symptoms (LUTS) includes careful evaluation of the patient’s symptoms and clinical characteristics and individualized decision-making aimed at symptom control with minimal adverse effects, in addition to definitive treatment of the underlying cause of LUTS.
Inhibitors of α1 receptors play a significant role in the management of LUTS. These agents block α1A adrenoreceptors in the prostatic stroma, leading to relaxation of the bladder outflow tract, and relief of voiding symptoms.1 In addition, they also inhibit α1D receptors in the bladder detrusor muscles to relieve storage symptoms.
The four most widely available α1 blockers (tamsulosin, terazosin, doxazosin and alfuzosin) seem to have similar efficacy of around 30% reduction in symptom score vs baseline and 15–30% improvement in urine flow2. Maximal benefit can be observed within 4 weeks of treatment.
Of the four α1 blockers, only tamsulosin has greater selectivity for the α1A and α1D subtypes.1 The three other α1 blockers, being nonsubtype-selective, also inhibit the α1B receptor subtype found in vascular smooth muscles, thus causing hypotension in some patients. Meanwhile, tamsulosin is associated with a low risk of hypotension3, making it a preferable agent for majority of patients with LUTS, which are mostly of advanced age.
For patients with moderate-to-severe LUTS due to enlarged prostate (>40 g), 5α-reductase inhibitors may be considered alone or in combination with an α1 blocker.3 These drugs reduce prostate volume by 15% to 25% within 6–12 months of treatment by inducing prostatic cellular apoptosis through inhibition of testosterone conversion to dihydrotestosterone.4 Patients for 5α-reductase therapy should be carefully selected due to the risk of erectile dysfunction, ejaculatory dysfunction, loss of libido, muscle atrophy, and metabolic syndrome associated with these drugs.
Antimuscarinic agents are often used in combination with α1 blockers in patients with storage symptoms. However, these agents should be used with caution in patients with post-voiding residual of >200 mL.5 Side effects include dry mouth, dry eyes, blurring of vision, constipation, and some degree of cognitive decline. For patients with poor response, tolerability issues or contraindications to antimuscarinics (eg, BOO, narrow angle glaucoma, gastrointestinal obstruction or myasthenia gravis), the β3 agonist mirabegron should be considered as the preferred treatment.6
Minimally invasive procedures and surgery may be offered to patients with bothersome moderate or severe LUTS.
Given all these choices, the choice of approach should be made after careful consideration of the patient’s individual presentation and discussion of the potential benefits and risks of each treatment alternative.
1. Schwinn DA, Roehrborn CG. Int J Urol 2008;15:193-199. 2. Djavan B, Marberger M. Eur Urol 1999;36:1-13. 3. Oelke M, et al. Expert Opin Drug Saf 2014;13:1187-1197. 4. Enlarged prostate: A guide to diagnosis and treatment. London: Prostate Cancer UK; 2013. 5. McVary KT, et al. Management of Benign Prostatic Hyperplasia (BPH). American Urological Association. Available at www.auanet.org/guidelines/benign-prostatic-hyperplasia-(2010-reviewed-and-validity-confirmed-2014). Accessed 05 Feb 2018. [guidelines] 6. Chaplin S, Chapple C. Prescriber 2013;24:39-42.