EUROPEAN UROLOGY 67 (2015) 271–272
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. 262–270 of this issue
The Evolving Picture of Lower Urinary Tract Symptom Management Andrea Tubaro a,b,*, Cosimo De Nunzio b, Federica Puccini a, Fabrizio Presicce a a
La Sapienza University, Rome, Italy; b Sant’Andrea Hospital, Rome, Italy
The management of lower urinary tract symptoms (LUTS) in men has often been associated with benign prostatic obstruction and managed accordingly. In the last three decades, pharmacologic treatment of LUTS became the standard approach to men bothered by voiding and storage symptoms, leaving surgery as a second-line option. Better understanding of LUTS pathophysiology broadened understanding of a number of mechanisms involved in the genesis of LUTS, including occult neurogenic disorders; hormonal and vascular changes associated with ageing, diabetes, obesity, and other conditions leading to metabolic syndrome; and bladder and urothelial disorders. The composite pathophysiology of male LUTS has not yet fully translated to a more sophisticated therapeutic approach, although a number of properly designed randomised trials are helping refine our therapeutic strategy. The clear success of the medical treatment of male LUTS helped change the treatment management of male LUTS, with a large decrease in surgical procedures in favour of widespread use of medications [1]. The number of treated patients has continued to increase in recent years [1]. Notwithstanding the clear success of the medical treatment of male LUTS, real-life data highlight a number of unmet needs, as some of the patients remain bothered and symptomatic despite treatment. Current medical options include (in order of introduction in the formularies) phytotherapeutic agents, a-blockers, 5a-reductase inhibitors (5-ARIs), antimuscarinics, phosphodiesterase type 5 inhibitors, and b3 agonists. There are no proper animal models of lower urinary tract dysfunction. Animal models of acute urinary obstruction have been somehow misleading and led us believe that storage symptoms such as urgency were caused mainly by
increased outlet resistance and that treatment should be aimed at relieving the obstruction [2]. Long-term analysis of patients undergoing transurethral resection of the prostate showed that urgency and detrusor overactivity are cured in about 50% of patients but often recur, suggesting that the problem is not just in the prostate but rather in the bladder and in that part of the nervous system that controls the micturition cycle [3]. Another example of our poor understanding of LUTS is nocturia, which has always been treated regardless of whether or not it is due to nocturnal polyuria. Our overall approach to the diagnosis and treatment of LUTS has matured enormously over the last decade, but as the picture becomes more complex, treatment difficulties increase accordingly. Randomised trials of pharmacologic treatment of male LUTS showed a significant improvement of symptoms and quality of life, although patients rarely become asymptomatic and symptoms tend to persist, although in milder form [4]. The aetiology of LUTS is multifactorial, and a single drug addresses only part of the problem. Combination treatment of male LUTS is not a novel idea, although it took a long time before the combined use of a-blockers and 5-ARIs proved to be effective over monotherapies [5,6]. A different type of combination treatment was pioneered by Lee and coworkers, who investigated the sequential treatment of LUTS in men with bladder outlet obstruction with or without overactive bladder [7]. Men reporting urgency had a lower chance of improving with a-blockers, but symptoms greatly improved when an antimuscarinic drug was added [7]. The sequential use of drugs is a common way to manage our patients that may certainly be effective, although decisions to step up from single- to dual-drug treatment are often
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2014.07.013. * Corresponding author. Department of Urology, La Sapienza University, Sant’Andrea Hospital, Via di Grottarossa, 1035, Rome, 00189, Italy. Tel. +39 06 3377 7712; Fax: +39 06 3377 5049. E-mail address: [email protected] (A. Tubaro). http://dx.doi.org/10.1016/j.eururo.2014.10.016 0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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based on personal preferences, with large variability among patients, doctors, centres, and countries. The study from Drake et al addresses the issues of safety and efficacy of a fixed-dose combination of a modifiedrelease formulation of tamsulosin (Omnic OCAS) and solifenacin (Vesiker) in the treatment of male LUTS with 1-yr follow-up [8]. Although the subject may not appear new, the study is of importance because no new fixed-dose combination treatment can be registered unless this type of study is conducted. The study design consists of a 40-wk open extension of a 12-wk randomised trial. The results of the study provide evidence of the safety of this combined treatment over a 1-yr period and maintenance of efficacy over the duration of the open-label extension. Symptom improvement was observed as early as 4 wk, with further improvement up to 16 wk and maintenance over the following weeks up to 1 yr. The overall reduction in International Prostate Symptom Score was 9 5.7 points after the 12-wk randomised trial and 10.1 9.2 points at the end of the open-extension study. A 1.1% retention rate was observed during 52 wk of treatment. The study is of interest because it answers a number of questions that are important in real-life practice. We know that the low adherence to antimuscarinics is mainly due to treatment efficacy that is perceived as lower than expected by the patient, and 1-yr data provide a reasonable horizon for understanding what patients can expect from such combination treatment [9]. Another cause of low adherence is side effects, and safety over a 1-yr period is of importance to understand whether prolonged exposure to such treatment can result in unexpected adverse events [9]. The use of fixed-dose combination treatments is not new in medicine or in urology. The aim is to improve patient adherence and to ensure that patients are exposed to the expected drug dosages. The convenience of a single tablet may be of interest for some of our patients and, hopefully, will improve adherence. Will the fixed-dose combination of Omnic OCAS and Vesiker work for everyone? Certainly not, but it is an important option in our armamentarium that will easily fit the needs of many of our patients. Looking into the management of LUTS due to benign prostatic hyperplasia, we know that most of our patients are treated with a-blockers only, and antimuscarinics are clearly underutilised in men compared with female patients [10]. It is too early to know how much this fixed-dose combination will help fill the existing unmet needs in the management of
male LUTS, but its availability will help our fellow urologists consider the use of antimuscarinics in male patients suffering urgency, among other LUTS. The study by Drake et al [8] is a must-read reference for the practising urologist! Conflicts of interest: A. Tubaro is a consultant for Allergan Astellas, GSK, and Pfizer. C. De Nunzio is a consultant for GSK and Pierre-Fabre.
References [1] Souverein PC, Erkens JA, de la Rosette JJ, Leufkens HG, Herings RM. Drug treatment of benign prostatic hyperplasia and hospital admission for BPH-related surgery. Eur Urol 2003;43:528–34. [2] Maciejewski CC, Tredget EE, Metcalfe PD. Urodynamic improvements following oral medical therapy for partial bladder outlet obstruction in an animal model. Neurourol Urodyn. In press. http:// dx.doi.org/10.1002/nau.22528 [3] Thomas AW, Cannon A, Bartlett E, Ellis-Jones J, Abrams P. The natural history of lower urinary tract dysfunction in men: the influence of detrusor underactivity on the outcome after transurethral resection of the prostate with a minimum 10-year urodynamic follow-up. BJU Int 2004;93:745–50. [4] Hutchison A, Farmer R, Verhamme K, Berges R, Navarrete RV. The efficacy of drugs for the treatment of LUTS/BPH, a study in 6 European countries. Eur Urol 2007;51:207–16, discussion 215–6. [5] McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003;349:2387–98. [6] Roehrborn CG, Siami P, Barkin J, et al. The effects of dutasteride, tamsulosin and combination therapy on lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement: 2-year results from the CombAT study. J Urol 2008;179: 616–21, discussion 621. [7] Lee JY, Kim HW, Lee SJ, Koh JS, Suh HJ, Chancellor MB. Comparison of doxazosin with or without tolterodine in men with symptomatic bladder outlet obstruction and an overactive bladder. BJU Int 2004;94:817–20. [8] Drake MJ, Chapple C, Sokol R, et al. Long-term safety and efficacy of single-tablet combinations of solifenacin and tamsulosin oral controlled absorption system in men with storage and voiding lower urinary tract symptoms: results from the NEPTUNE study and NEPTUNE II open-label extension. Eur Urol 2015;67: 262–70. [9] Benner JS, Nichol MB, Rovner ES, et al. Patient-reported reasons for discontinuing overactive bladder medication. BJU Int 2010;105: 1276–82. [10] MacMillan L, Jackson J, Anderson P, Compion G. Underdiagnosis and sub-optimal treatment of LUTS/BPH: results of a real world survey of patients in Europe. Eur Urol Suppl 2014;13:e776.
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. 262–270 of this issue
The Evolving Picture of Lower Urinary Tract Symptom Management Andrea Tubaro a,b,*, Cosimo De Nunzio b, Federica Puccini a, Fabrizio Presicce a a
La Sapienza University, Rome, Italy; b Sant’Andrea Hospital, Rome, Italy
The management of lower urinary tract symptoms (LUTS) in men has often been associated with benign prostatic obstruction and managed accordingly. In the last three decades, pharmacologic treatment of LUTS became the standard approach to men bothered by voiding and storage symptoms, leaving surgery as a second-line option. Better understanding of LUTS pathophysiology broadened understanding of a number of mechanisms involved in the genesis of LUTS, including occult neurogenic disorders; hormonal and vascular changes associated with ageing, diabetes, obesity, and other conditions leading to metabolic syndrome; and bladder and urothelial disorders. The composite pathophysiology of male LUTS has not yet fully translated to a more sophisticated therapeutic approach, although a number of properly designed randomised trials are helping refine our therapeutic strategy. The clear success of the medical treatment of male LUTS helped change the treatment management of male LUTS, with a large decrease in surgical procedures in favour of widespread use of medications [1]. The number of treated patients has continued to increase in recent years [1]. Notwithstanding the clear success of the medical treatment of male LUTS, real-life data highlight a number of unmet needs, as some of the patients remain bothered and symptomatic despite treatment. Current medical options include (in order of introduction in the formularies) phytotherapeutic agents, a-blockers, 5a-reductase inhibitors (5-ARIs), antimuscarinics, phosphodiesterase type 5 inhibitors, and b3 agonists. There are no proper animal models of lower urinary tract dysfunction. Animal models of acute urinary obstruction have been somehow misleading and led us believe that storage symptoms such as urgency were caused mainly by
increased outlet resistance and that treatment should be aimed at relieving the obstruction [2]. Long-term analysis of patients undergoing transurethral resection of the prostate showed that urgency and detrusor overactivity are cured in about 50% of patients but often recur, suggesting that the problem is not just in the prostate but rather in the bladder and in that part of the nervous system that controls the micturition cycle [3]. Another example of our poor understanding of LUTS is nocturia, which has always been treated regardless of whether or not it is due to nocturnal polyuria. Our overall approach to the diagnosis and treatment of LUTS has matured enormously over the last decade, but as the picture becomes more complex, treatment difficulties increase accordingly. Randomised trials of pharmacologic treatment of male LUTS showed a significant improvement of symptoms and quality of life, although patients rarely become asymptomatic and symptoms tend to persist, although in milder form [4]. The aetiology of LUTS is multifactorial, and a single drug addresses only part of the problem. Combination treatment of male LUTS is not a novel idea, although it took a long time before the combined use of a-blockers and 5-ARIs proved to be effective over monotherapies [5,6]. A different type of combination treatment was pioneered by Lee and coworkers, who investigated the sequential treatment of LUTS in men with bladder outlet obstruction with or without overactive bladder [7]. Men reporting urgency had a lower chance of improving with a-blockers, but symptoms greatly improved when an antimuscarinic drug was added [7]. The sequential use of drugs is a common way to manage our patients that may certainly be effective, although decisions to step up from single- to dual-drug treatment are often
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2014.07.013. * Corresponding author. Department of Urology, La Sapienza University, Sant’Andrea Hospital, Via di Grottarossa, 1035, Rome, 00189, Italy. Tel. +39 06 3377 7712; Fax: +39 06 3377 5049. E-mail address: [email protected] (A. Tubaro). http://dx.doi.org/10.1016/j.eururo.2014.10.016 0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
272
EUROPEAN UROLOGY 67 (2015) 271–272
based on personal preferences, with large variability among patients, doctors, centres, and countries. The study from Drake et al addresses the issues of safety and efficacy of a fixed-dose combination of a modifiedrelease formulation of tamsulosin (Omnic OCAS) and solifenacin (Vesiker) in the treatment of male LUTS with 1-yr follow-up [8]. Although the subject may not appear new, the study is of importance because no new fixed-dose combination treatment can be registered unless this type of study is conducted. The study design consists of a 40-wk open extension of a 12-wk randomised trial. The results of the study provide evidence of the safety of this combined treatment over a 1-yr period and maintenance of efficacy over the duration of the open-label extension. Symptom improvement was observed as early as 4 wk, with further improvement up to 16 wk and maintenance over the following weeks up to 1 yr. The overall reduction in International Prostate Symptom Score was 9 5.7 points after the 12-wk randomised trial and 10.1 9.2 points at the end of the open-extension study. A 1.1% retention rate was observed during 52 wk of treatment. The study is of interest because it answers a number of questions that are important in real-life practice. We know that the low adherence to antimuscarinics is mainly due to treatment efficacy that is perceived as lower than expected by the patient, and 1-yr data provide a reasonable horizon for understanding what patients can expect from such combination treatment [9]. Another cause of low adherence is side effects, and safety over a 1-yr period is of importance to understand whether prolonged exposure to such treatment can result in unexpected adverse events [9]. The use of fixed-dose combination treatments is not new in medicine or in urology. The aim is to improve patient adherence and to ensure that patients are exposed to the expected drug dosages. The convenience of a single tablet may be of interest for some of our patients and, hopefully, will improve adherence. Will the fixed-dose combination of Omnic OCAS and Vesiker work for everyone? Certainly not, but it is an important option in our armamentarium that will easily fit the needs of many of our patients. Looking into the management of LUTS due to benign prostatic hyperplasia, we know that most of our patients are treated with a-blockers only, and antimuscarinics are clearly underutilised in men compared with female patients [10]. It is too early to know how much this fixed-dose combination will help fill the existing unmet needs in the management of
male LUTS, but its availability will help our fellow urologists consider the use of antimuscarinics in male patients suffering urgency, among other LUTS. The study by Drake et al [8] is a must-read reference for the practising urologist! Conflicts of interest: A. Tubaro is a consultant for Allergan Astellas, GSK, and Pfizer. C. De Nunzio is a consultant for GSK and Pierre-Fabre.
References [1] Souverein PC, Erkens JA, de la Rosette JJ, Leufkens HG, Herings RM. Drug treatment of benign prostatic hyperplasia and hospital admission for BPH-related surgery. Eur Urol 2003;43:528–34. [2] Maciejewski CC, Tredget EE, Metcalfe PD. Urodynamic improvements following oral medical therapy for partial bladder outlet obstruction in an animal model. Neurourol Urodyn. In press. http:// dx.doi.org/10.1002/nau.22528 [3] Thomas AW, Cannon A, Bartlett E, Ellis-Jones J, Abrams P. The natural history of lower urinary tract dysfunction in men: the influence of detrusor underactivity on the outcome after transurethral resection of the prostate with a minimum 10-year urodynamic follow-up. BJU Int 2004;93:745–50. [4] Hutchison A, Farmer R, Verhamme K, Berges R, Navarrete RV. The efficacy of drugs for the treatment of LUTS/BPH, a study in 6 European countries. Eur Urol 2007;51:207–16, discussion 215–6. [5] McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003;349:2387–98. [6] Roehrborn CG, Siami P, Barkin J, et al. The effects of dutasteride, tamsulosin and combination therapy on lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement: 2-year results from the CombAT study. J Urol 2008;179: 616–21, discussion 621. [7] Lee JY, Kim HW, Lee SJ, Koh JS, Suh HJ, Chancellor MB. Comparison of doxazosin with or without tolterodine in men with symptomatic bladder outlet obstruction and an overactive bladder. BJU Int 2004;94:817–20. [8] Drake MJ, Chapple C, Sokol R, et al. Long-term safety and efficacy of single-tablet combinations of solifenacin and tamsulosin oral controlled absorption system in men with storage and voiding lower urinary tract symptoms: results from the NEPTUNE study and NEPTUNE II open-label extension. Eur Urol 2015;67: 262–70. [9] Benner JS, Nichol MB, Rovner ES, et al. Patient-reported reasons for discontinuing overactive bladder medication. BJU Int 2010;105: 1276–82. [10] MacMillan L, Jackson J, Anderson P, Compion G. Underdiagnosis and sub-optimal treatment of LUTS/BPH: results of a real world survey of patients in Europe. Eur Urol Suppl 2014;13:e776.
