PERSPECTIVE
Contemporary issues with pharmacotherapy for lower urinary tract symptoms Two articles appeared in the November 2012 edition of the journal evaluating aspects relating to the use of two important pharmacotherapeutic classes for lower urinary tract symptoms (LUTS) in real life clinical practice (1,2). LUTS is a non-specific term that encompasses urine storage, voiding and postmicturition symptoms (3). LUTS is a common bothersome problem affecting both men and women with a comparable prevalence in age-matched patients of both sexes that increases with ageing (4,5). The paper by Kaplan et al. compares the two widely available 5-alpha reductase (5-AR) inhibitors, finasteride and dutasteride based on a retrospective analysis (1). Whereas finasteride inhibits only type II 5-AR, dutasteride inhibits both iso-forms of the enzyme, although this dual inhibition did not seem to increase efficacy in a randomised controlled trial at 1 year (6). This retrospective single-centre review of 378 patients treated with either agent (197 finasteride and 211 dutasteri/de) over a 5-year period evaluated the long-term safety and efficacy of both agents in real life clinical practice. The major limitations of this study are the lack of randomisation and the retrospective nature of the analysis, which has meant that adverse effects leading to discontinuation rather than the absolute number of adverse events were captured. In addition, a large proportion of patients were lost to follow up, 29.4% and 36.5% in the finasteride and dutasteride groups, respectively. Although these issues detract from any definitive conclusions in comparison of the two agents, this observation does highlight the need for prospective long-term comparative effectiveness studies. This study is novel as no previous comparison of these two agents has been published looking beyond 1-year follow up (6). The data showed the two agents to be similar in terms of efficacy end-points including symptom scores, flow rates, postvoid residual measurements, prostate volume and serum PSA. However, when considering adverse effects leading to discontinuation, finasteride faired more favourably than dutasteride with an incidence of erectile dysfunction of 3.6% vs. 7.1%, ejaculatory dysfunction of 3.6% vs. 4.7% and decreased libido of 3.1% vs. 5.2% respectively (all p < 0.01). Finasteride has in many regions reached the end of its patent protection, which will have important implications related to cost particuª 2014 John Wiley & Sons Ltd Int J Clin Pract, May 2014, 68, 5, 541–542. doi: 10.1111/ijcp.12302
larly where the two agents are considered to have comparable efficacy and the cheaper one may be more tolerable! Overactive bladder (OAB) symptom syndrome reflects a coexistence of the storage LUTS affecting the urinary tract and has a similar prevalence in both sexes (7). The mainstay of medical therapy for OAB is antimuscarinic (anti-M) agents, which are traditionally thought to act on the efferent system through blockade of postjunctional muscarinic M3 receptors (8). However, OAB is not always associated with non-voiding detrusor contractions more commonly in women than men (9). It is now thought that anti-M work through an effect on the sensory system including the urothelium and afferent nerves (10). Diabetes, because of its secondary effects both on sensory and autonomic nerves, may result in lower urinary tract dysfunction and therefore be directly responsible for LUTS. Despite demonstrating efficacy in OAB, a common issue with anti-M is poor persistence (up to 90% discontinue therapy within the first year) and adherence to therapy (11). This is commonly attributed to bothersome side effect such as dry mouth and constipation or a perceived lack of efficacy (12). Johnston et al. report a retrospective claims-based analysis comparing persistence and adherence to anti-M in OAB in two large age, sex and geographically matched cohorts of patients with and without diabetes mellitus (2). There are clear drawbacks when using such large claims databases: a reliance on ICD diagnostic coding and the assumption that filing prescriptions equates to taking the medication. A further problem is the inability to correlate the results with severity of symptoms. The small but statistically significant differences between diabetic and non-diabetic patients are supportive of the hypothesis that the former are more likely to adhere and persist with treatments. Likely reasons for this effect may be a familiarity with adhering and persisting with diabetic regimens and better education to the consequence of not doing so. This study confirms the poor adherence and persistence associated with anti-M therapy in OAB and highlights the need to pursue strategies to improve this. As side effects with anti-M increase with dosage and patients differ in their sensitivity to agents, using
Despite being well established, re-evaluation of the practical aspects relating to the use of LUTS pharmacotherapies is essential
541
542
Perspective
a patient-controlled flexible dosing approach may improve efficacy while minimising side effects on an individual basis. Clearly, it is also important to address patients’ expectations of therapy while ensuring adequate follow up. Novel agents with different mechanisms of action, such as b-3 adrenoceptor agonists, are being evaluated and coming into clinical usage, and promise to provide long awaited alternatives in patients unable to tolerate side effects of anti-M (12).
References 1 Kaplan SA, Chung DE, Lee RK, Scofield S, Te AE. A 5-year retrospective analysis of 5 alpha-reductase inhibitors in men with benign prostatic hyperplasia: finasteride has comparable urinary symptom efficacy and prostate volume reduction, but less sexual side effects and breast complications than dutasteride. Int J Clin Pract 2012; 66: 1052–5. 2 Johnston S, Janning SW, Haas GP et al. Comparative persistence and adherence to overactive bladder medications in patients with and without diabetes. Int J Clin Pract 2012; 66: 1042–51. 3 Abrams P, Cardozo L, Fall M et al. The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Urology 2003; 61: 37–49. 4 Coyne KS, Sexton CC, Thompson CL et al. The prevalence of lower urinary tract symptoms (LUTS) in the USA, the UK and Sweden: results from the Epidemiology of LUTS (EpiLUTS) study. BJU Int 2009; 104: 352–60. 5 Kupelian V, Wei JT, O’Leary MP et al. Prevalence of lower urinary tract symptoms and effect on
6
7
8
9
10
N. Osman, C. R. Chapple The Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK Correspondence to: Christopher R. Chapple, The Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Glossop Road, Sheffield S10 2JF, UK Tel.: +44 74 271 2559 Fax: +44 74 279 7841 Email: [email protected]
quality of life in a racially and ethnically diverse random sample: the Boston Area Community Health (BACH) Survey. Arch Intern Med 2006; 166: 2381–7. Nickel JC, Gilling P, Tammela TL, Morrill B, Wilson TH, Rittmaster RS. Comparison of dutasteride and finasteride for treating benign prostatic hyperplasia: the Enlarged Prostate International Comparator Study (EPICS). BJU Int 2011; 108: 388–94. Irwin DE, Milsom I, Hunskaar S et al. Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol 2006; 50: 1306–14; discussion 14-5. Hegde SS, Eglen RM. Muscarinic receptor subtypes modulating smooth muscle contractility in the urinary bladder. Life Sci 1999; 64: 419–28. Hashim H, Abrams P. Is the bladder a reliable witness for predicting detrusor overactivity? J Urol 2006; 175: 191–4; discussion 4-5 Andersson K-E, Chapple C, Cardozo L et al. Pharmacological treatment of urinary incontinence. In:
Abrams P, Cardozo L, Khoury S, Wein A, ed. Incontinence 4th International Consultation on Incontinence. Paris: Plymouth Plymbridge Distributors Ltd, 2009: 631–99. 11 Benner JS, Nichol MB, Rovner ES et al. Patient-reported reasons for discontinuing overactive bladder medication. BJU Int 2010; 105: 1276–82. 12 Chapple CR, Kaplan SA, Mitcheson D et al. Randomized double-blind, active-controlled phase 3 study to assess 12-month safety and efficacy of mirabegron, a b(3)-adrenoceptor agonist, in overactive bladder. Eur Urol 2012; 63: 296–305.
Disclosure Christopher Chapple is a consultant and researcher for Allergan, Astellas, Pfizer, Recordati. Nadir Osman has no conflict of interest.
Paper received August 2013, accepted August 2013
ª 2014 John Wiley & Sons Ltd Int J Clin Pract, May 2014, 68, 5, 541–542
Contemporary issues with pharmacotherapy for lower urinary tract symptoms Two articles appeared in the November 2012 edition of the journal evaluating aspects relating to the use of two important pharmacotherapeutic classes for lower urinary tract symptoms (LUTS) in real life clinical practice (1,2). LUTS is a non-specific term that encompasses urine storage, voiding and postmicturition symptoms (3). LUTS is a common bothersome problem affecting both men and women with a comparable prevalence in age-matched patients of both sexes that increases with ageing (4,5). The paper by Kaplan et al. compares the two widely available 5-alpha reductase (5-AR) inhibitors, finasteride and dutasteride based on a retrospective analysis (1). Whereas finasteride inhibits only type II 5-AR, dutasteride inhibits both iso-forms of the enzyme, although this dual inhibition did not seem to increase efficacy in a randomised controlled trial at 1 year (6). This retrospective single-centre review of 378 patients treated with either agent (197 finasteride and 211 dutasteri/de) over a 5-year period evaluated the long-term safety and efficacy of both agents in real life clinical practice. The major limitations of this study are the lack of randomisation and the retrospective nature of the analysis, which has meant that adverse effects leading to discontinuation rather than the absolute number of adverse events were captured. In addition, a large proportion of patients were lost to follow up, 29.4% and 36.5% in the finasteride and dutasteride groups, respectively. Although these issues detract from any definitive conclusions in comparison of the two agents, this observation does highlight the need for prospective long-term comparative effectiveness studies. This study is novel as no previous comparison of these two agents has been published looking beyond 1-year follow up (6). The data showed the two agents to be similar in terms of efficacy end-points including symptom scores, flow rates, postvoid residual measurements, prostate volume and serum PSA. However, when considering adverse effects leading to discontinuation, finasteride faired more favourably than dutasteride with an incidence of erectile dysfunction of 3.6% vs. 7.1%, ejaculatory dysfunction of 3.6% vs. 4.7% and decreased libido of 3.1% vs. 5.2% respectively (all p < 0.01). Finasteride has in many regions reached the end of its patent protection, which will have important implications related to cost particuª 2014 John Wiley & Sons Ltd Int J Clin Pract, May 2014, 68, 5, 541–542. doi: 10.1111/ijcp.12302
larly where the two agents are considered to have comparable efficacy and the cheaper one may be more tolerable! Overactive bladder (OAB) symptom syndrome reflects a coexistence of the storage LUTS affecting the urinary tract and has a similar prevalence in both sexes (7). The mainstay of medical therapy for OAB is antimuscarinic (anti-M) agents, which are traditionally thought to act on the efferent system through blockade of postjunctional muscarinic M3 receptors (8). However, OAB is not always associated with non-voiding detrusor contractions more commonly in women than men (9). It is now thought that anti-M work through an effect on the sensory system including the urothelium and afferent nerves (10). Diabetes, because of its secondary effects both on sensory and autonomic nerves, may result in lower urinary tract dysfunction and therefore be directly responsible for LUTS. Despite demonstrating efficacy in OAB, a common issue with anti-M is poor persistence (up to 90% discontinue therapy within the first year) and adherence to therapy (11). This is commonly attributed to bothersome side effect such as dry mouth and constipation or a perceived lack of efficacy (12). Johnston et al. report a retrospective claims-based analysis comparing persistence and adherence to anti-M in OAB in two large age, sex and geographically matched cohorts of patients with and without diabetes mellitus (2). There are clear drawbacks when using such large claims databases: a reliance on ICD diagnostic coding and the assumption that filing prescriptions equates to taking the medication. A further problem is the inability to correlate the results with severity of symptoms. The small but statistically significant differences between diabetic and non-diabetic patients are supportive of the hypothesis that the former are more likely to adhere and persist with treatments. Likely reasons for this effect may be a familiarity with adhering and persisting with diabetic regimens and better education to the consequence of not doing so. This study confirms the poor adherence and persistence associated with anti-M therapy in OAB and highlights the need to pursue strategies to improve this. As side effects with anti-M increase with dosage and patients differ in their sensitivity to agents, using
Despite being well established, re-evaluation of the practical aspects relating to the use of LUTS pharmacotherapies is essential
541
542
Perspective
a patient-controlled flexible dosing approach may improve efficacy while minimising side effects on an individual basis. Clearly, it is also important to address patients’ expectations of therapy while ensuring adequate follow up. Novel agents with different mechanisms of action, such as b-3 adrenoceptor agonists, are being evaluated and coming into clinical usage, and promise to provide long awaited alternatives in patients unable to tolerate side effects of anti-M (12).
References 1 Kaplan SA, Chung DE, Lee RK, Scofield S, Te AE. A 5-year retrospective analysis of 5 alpha-reductase inhibitors in men with benign prostatic hyperplasia: finasteride has comparable urinary symptom efficacy and prostate volume reduction, but less sexual side effects and breast complications than dutasteride. Int J Clin Pract 2012; 66: 1052–5. 2 Johnston S, Janning SW, Haas GP et al. Comparative persistence and adherence to overactive bladder medications in patients with and without diabetes. Int J Clin Pract 2012; 66: 1042–51. 3 Abrams P, Cardozo L, Fall M et al. The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Urology 2003; 61: 37–49. 4 Coyne KS, Sexton CC, Thompson CL et al. The prevalence of lower urinary tract symptoms (LUTS) in the USA, the UK and Sweden: results from the Epidemiology of LUTS (EpiLUTS) study. BJU Int 2009; 104: 352–60. 5 Kupelian V, Wei JT, O’Leary MP et al. Prevalence of lower urinary tract symptoms and effect on
6
7
8
9
10
N. Osman, C. R. Chapple The Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK Correspondence to: Christopher R. Chapple, The Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Glossop Road, Sheffield S10 2JF, UK Tel.: +44 74 271 2559 Fax: +44 74 279 7841 Email: [email protected]
quality of life in a racially and ethnically diverse random sample: the Boston Area Community Health (BACH) Survey. Arch Intern Med 2006; 166: 2381–7. Nickel JC, Gilling P, Tammela TL, Morrill B, Wilson TH, Rittmaster RS. Comparison of dutasteride and finasteride for treating benign prostatic hyperplasia: the Enlarged Prostate International Comparator Study (EPICS). BJU Int 2011; 108: 388–94. Irwin DE, Milsom I, Hunskaar S et al. Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol 2006; 50: 1306–14; discussion 14-5. Hegde SS, Eglen RM. Muscarinic receptor subtypes modulating smooth muscle contractility in the urinary bladder. Life Sci 1999; 64: 419–28. Hashim H, Abrams P. Is the bladder a reliable witness for predicting detrusor overactivity? J Urol 2006; 175: 191–4; discussion 4-5 Andersson K-E, Chapple C, Cardozo L et al. Pharmacological treatment of urinary incontinence. In:
Abrams P, Cardozo L, Khoury S, Wein A, ed. Incontinence 4th International Consultation on Incontinence. Paris: Plymouth Plymbridge Distributors Ltd, 2009: 631–99. 11 Benner JS, Nichol MB, Rovner ES et al. Patient-reported reasons for discontinuing overactive bladder medication. BJU Int 2010; 105: 1276–82. 12 Chapple CR, Kaplan SA, Mitcheson D et al. Randomized double-blind, active-controlled phase 3 study to assess 12-month safety and efficacy of mirabegron, a b(3)-adrenoceptor agonist, in overactive bladder. Eur Urol 2012; 63: 296–305.
Disclosure Christopher Chapple is a consultant and researcher for Allergan, Astellas, Pfizer, Recordati. Nadir Osman has no conflict of interest.
Paper received August 2013, accepted August 2013
ª 2014 John Wiley & Sons Ltd Int J Clin Pract, May 2014, 68, 5, 541–542
