1162 Current Drug Targets, 2015, Vol. 16, No. 11
Editorial
Editorial Combination Pharmacological Treatments for LUTS Lower urinary tract symptoms (LUTS) afflict an increasing population of men and women, with current estimates showing that 45% of the worlds’ population experience 1 or more LUTS [1]. LUTS can be bothersome and have a significantly negative impact on patient’s quality of life [Brousil P, Current Drug Targets 2015]. Male LUTS become more prevalent with age, it is estimated that approximately 40% of 50 year olds and 90% of 90-yearold men are bothered by LUTS mainly attributed to benign prostatic hyperplasia (BPH) [3]. At the same time the prevalence of predominantly storage LUTS such as urgency, frequency and urge incontinence, all symptoms suggestive of overactive bladder (OAB), is also increasing. Drug therapy is currently the mainstay of treatment for LUTS. However, the heterogeneity in the aetiology and the groups of patients affected by LUTS results in a variety of different drug categories and drugs being available for use, as monotherapy or in combination, for the alleviation of symptoms. In other words “one size fits all” does not apply to the pharmacological management of LUTS. The complexity of the pathophysiology of LUTS and the clinical implications of its management are held responsible for the high incidence of non-responders to drug treatment which calls for combined or sequential drug therapy for certain patients. Although male LUTS are rapidly and effectively alleviated for the majority of patients on a-blocker monotherapy, a certain patient profile will still fail to respond to a-blockers [4]. Moreover there is evidence that BPH will progress on a-blocker monotherapy for a significant proportion of patients under risk [5]. Sountoulides and Gravas in this issue’s article have underlined that the combination of an a-blocker with a 5-a-reductase inhibitor (5-ARI), by tackling both the dynamic element of LUTS and the anatomic obstruction caused by benign prostatic enlargement (BPE), should be considered as first-line treatment for this cohort of BPH patients at risk of disease progression [6]. The beneficial effects of drug combination for men at risk of BPH progression have been elucidated in a number of studies showing a decreased risk of BPH-related hospitalization and surgery, urinary retention and a positive effect on health-related quality of life [7]. The strong evidence in favor of combination therapy for BPH-associated LUTS has been reflected not only in the guidelines [3] but also in real life practice with studies showing that the increase in the prevalence of combination therapy is accompanied by a decrease in BPH-related hospitalizations [8]. The next hot question relevant to the management of male LUTS is which 5ARI to choose between dutasteride and finasteride. Pirozzi et al. in the current issue have tried to assess this issue. Although there are studies showing a difference in both the risk of acute urinary retention (AUR) and surgical outcomes in favor of dutasteride [9,10], the quality of data and the level of evidence in support of this recommendation is weak. Still, dutasteride seems to show a better profile in reducing the likelihood of prostate surgery and AUR in both short and long term treatment [11]. Male LUTS have also been linked to the concomitant presence of erectile dysfunction in some men, particularly those with a predisposition to the constituents of the metabolic syndrome. This link has been investigated in several studies and a shared pathogenetic mechanism between BPH-associated LUTS and erectile dysfunction has been identified [12]. Subsequently, PDE5 inhibitors have been recommended for the treatment of male LUTS especially in men with concurrent erectile dysfunction, although changes in urinary flow parameters did not correlate with the existing improvements in symptoms seen with PDE-5 inhibitors [13]. Brousil et al. in the current issue have presented an excellent review of the available combinations of PDE-5 inhibitors and the standard medications used for LUTS/BPH, namely a-blockers and 5ARIs. They concluded that the combination of ablockers and PDE-5 inhibitors appears to be more efficacious compared to a-blockers alone, while on the other hand, the evidence in support of a beneficial effect of combining a 5ARI with a PDE-5 inhibitor is too scarce to lead to solid recommendations [2]. Although the combination of α-blockers with 5-ARIs appears to be the most obvious for BPH-associated LUTS, efforts to combine α-blockers with antimuscarinics are also long-standing [14, 15], acknowledging the clinical fact that male LUTS are rarely just voiding LUTS, but more commonly overlap with storage and post-micturition symptoms [16], while storage LUTS may be even more bothersome than voiding LUTS in the majority of published studies [17, 18]. The use of antimuscarinics for male LUTS opened an unknown treatment territory for the bulk of urologists. It highlighted the fact that a large proportion of patients submitted to prostatectomy for refractory male LUTS may actually had been suffering from overactive bladder unrelated to obstruction: only 69% of those were found to be urodynamically obstructed, leaving at least one out of four with unresolved LUTS post-operatively and with dissatisfaction from treatment. Further, it challenged the fear that the use of antimuscarinics in BPE patients would lead to a pathological post-void residual or even worse, to retention. Several randomizedcontrolled trials as well as urodynamic studies using antimuscarinics either as monotherapy or in combination with an α-blocker were designed to investigate whether there is a clinical basis to such worries [19-24]. They found no detrimental effect on flow rates, detrusor contractile capacity, post-void residuals or acute retention rates. Such results are aligned with the novel notion supporting a lack of effect of antimuscarinics on voiding contractions when administered in therapeutic doses in OAB/DO, but rather a beneficial effect during the storage phase via blockage of the actions of urothelial acetylcholine on mucosal muscarinic acetylcholine receptors [25]. Thus, they minimize detrusor overactivity without significantly suppressing detrusor contractility,
Editorial
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reduce urgency and increase bladder capacity. As either monotherapy or combination, therapy with antimuscarinics was found to be efficacious with a good safety profile, antimuscarinics earned a hard-fought position in the guidelines for the treatment of male, primarily storage, LUTS, albeit with a caution for use in men with BOO [26], which still stands as no one can define what clinically significant BOO is and most studies had excluded patients with ‘severe’ BOO. Nevertheless, two-thirds of men with mixed storage and voiding LUTS will require combination treatment. Longer duration of LUTS, the presence of moderate-to-severe storage LUTS, and a smaller prostate volume were identified as predictive factors for the need of combined treatment [27]. To meet such demands, a fixed-dose combination tablet of solifenacin with tamsulosin has now been approved for use in men with BPE and moderate-to-severe storage LUTS, as it was proven efficacious and overall safe for up to one year of continuous treatment [28, 29]. Real-life results are eagerly expected, while previously a number of studies had already investigated the add-on administration of solifenacin to tamsulosin with mostly complimentary findings to those of the RCTs (see meta-analysis by [30]). Interestingly, although persistence with treatment was found to be statistically in favor of the combination treatment compared to α-blocker monotherapy, differences expressed in proportional values were not spectacular (92.4% versus 89.0% at 3 months, and 50.8% versus 49.6% at 1 year, respectively) [31]. Another study also recorded disappointingly low persistence rates with solifenacin add-on therapy to TOCAS (25% after 52 weeks of use) [32]. Adverse events were the most common reason for discontinuation and, by contrast to earlier publications, aggravation of voiding symptoms was identified as the most common adverse event leading to discontinuation. Persistence with and adherence to treatment is a topical issue for the use of antimuscarinics. As with all chronic diseases, persistence and adherence to pharmacotherapy is low [33], even below average [34, 35]. As meaningful comparative and reallife data on the use of antimuscarinics are missing, findings from persistence and adherence studies could be the closest to information on patient-reported outcomes. In spite of cost-economics models imposing a more logistic view and enforcing the prescription of less costly drugs (normally the older ones and the IR formulations) as first-line treatments, patients’ preferences of newer ER formulations independent of the cost may shape a different treatment model. Real-life studies using pharmacy claims databases confirm results from meta-analyses on the superiority of ER formulations concerning efficacy and adverse events [36], providing physicians with some information on what patients want. The question, however, of first versus second-line treatment in male LUTS may not be restricted to antimuscarinics. As combination treatments have been proven to be more efficacious in the short and long-term than monotherapies with most classes of drugs used in male LUTS and patients with mixed LUTS represent the bulk of those who seek treatment, studies which would consider a number of confounding factors, such as comorbidities, health-related quality of life issues, persistence with treatment and cost-effectiveness should be designed in order to achieve the goal of successful treatment individualization. REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18]
Irwin DE, Kopp ZS, Agatep B, Milsom I, Abrams P. Worldwide prevalence estimates of lower urinary tract symptoms, overactive bladder, urinary incontinence and bladder outlet obstruction. BJU Int 2011; 108(7): 1132-8. Brousil P, Shabbir M, Zacharakis E, Sahai A. PDE-5 Inhibitors for BPH-Associated LUTS. Curr Drug Targets 2015; 16(11): 1180-6. Gratzke C, Bachmann A, Descazeaud A, et al. EAU Guidelines on the Assessment of Non-neurogenic Male Lower Urinary Tract Symptoms including Benign Prostatic Obstruction. Eur Urol 2015; 67(6): 1099-109. Lee YC, Liu CC, Juan YS, et al. The impact of metabolic syndrome on the responsiveness to a1-blockers in men with BPH/LUTS. Int J Clin Pract 2013; 67(4): 356-62. Roehrborn CG. BPH progression: concept and key learning from MTOPS, ALTESS, COMBAT, and ALF-ONE. BJU Int 2008; 101 Suppl 3: 17-21. Sountoulides P, Gravas S. The impact of combination therapy with a-blockers and 5ARIs on the progression of BPH. Curr Drug Targets 2015; 16(11): 1172-9. Montorsi F, Roehrborn C, Garcia-Penit J, et al. The effects of dutasteride or tamsulosin alone and in combination on storage and voiding symptoms in men with lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH): 4-year data from the Combination of Avodart and Tamsulosin (CombAT) study. BJU Int. 2011; 107(9): 1426-31. Cindolo L, Pirozzi L, Fanizza C, et al. Actual medical management of lower urinary tract symptoms related to benign prostatic hyperplasia: temporal trends of prescription and hospitalization rates over 5 years in a large population of Italian men. Int Urol Nephrol 2014; 46(4): 695-701. Fenter TC, Davis EA, Shah MB, Lin PJ. Dutasteride vs finasteride: assessment of differences in acute urinary retention rates and surgi- cal risk outcomes in an elderly population aged > or =65 years. Am J Manag Care 2008; 14(5 Suppl 2): S154-59. Cindolo L, Berardinelli F, Fanizza C, et al. Clinical effects and economical impact of dutasteride and finasteride therapy in Italian men with LUTS. Arch Ital Urol Androl 2013; 85(4): 200-6. Pirozzi L, Sountoulides P, Castellan P, et al. Current pharmacological treatment for male LUTS due to BPH: dutasteride or finasteride? Curr Drug Targets 2015; 16(11): 1165-71. Gacci M, Carini M, Salvi M, et al. Management of benign prostatic hyperplasia: role of phosphodiesterase-5 inhibitors. Drugs Aging 2014; 31(6): 42539. Porst H, Kim ED, Casabé AR, et al. Efficacy and safety of tadalafil once daily in the treatment of men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: results of an international randomized, double-blind, placebo-controlled trial. Eur Urol 2011; 60(5): 1105-13. Athanasopoulos A, Gyftopoulos K, Giannitsas K, Fisfis J, Perimenis P, Barbalias G. Combination treatment with an alpha-blocker plus an anticholinergic for bladder outlet obstruction: a prospective, randomized, controlled study. J Urol 2003; 169(6): 2253-6. 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(6): 817-20. Chapple CR, Wein AJ, Abrams P, Dmochowski RR, Giuliano F, Kaplan SA, et al. Lower urinary tract symptoms revisited: a broader clinical perspective. Eur Urol 2008; 54(3): 563-9. Apostolidis A. Male lower urinary tract symptoms: a riddle waiting to be solved. Eur Urol 2013; 64(3): 408-10. Sountoulides P, van Dijk MM, Wijkstra H, de la Rosette JJMCH, Michel MC. Role of voiding and storage symptoms for the quality of life before and after treatment in men with voiding dysfunction. World J Urol 2010; 28: 3-8
1164 Current Drug Targets, 2015, Vol. 16, No. 11 [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36]
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Lee KS, Choo MS, Kim DY, et al. Combination treatment with propiverine hydrochloride plus doxazosin controlled release gastrointestinal therapeutic system formulation for overactive bladder and coexisting benign prostatic obstruction: a prospective, randomized, controlled multicenter study. J Urol 2005; 174(4 Pt 1): 1334-8. Kaplan SA, Walmsley K, Te AE. Tolterodine extended release attenuates lower urinary tract symptoms in men with benign prostatic hyperplasia. J Urol 2005; 174(6): 2273-5 discussion 5-6. Abrams P, Kaplan S, De Koning Gans HJ, Millard R. Safety and tolerability of tolterodine for the treatment of overactive bladder in men with bladder outlet obstruction. J Urol 2006; 175(3 Pt 1): 999-1004; discussion Kaplan SA, Roehrborn CG, Chancellor M, Carlsson M, Bavendam T, Guan Z. Extended-release tolterodine with or without tamsulosin in men with lower urinary tract symptoms and overactive bladder: effects on urinary symptoms assessed by the International Prostate Symptom Score. BJU Int 2008; 102(9): 1133-9. Staskin DR, Rosenberg MT, Dahl NV, Polishuk PV, Zinner NR. Effects of oxybutynin transdermal system on health-related quality of life and safety in men with overactive bladder and prostate conditions. Int J Clin Pract 2008; 62(1): 27-38. Van Kerrebroeck P, Haab F, Angulo JC, et al. Efficacy and Safety of Solifenacin Plus Tamsulosin OCAS in Men with Voiding and Storage Lower Urinary Tract Symptoms: Results from a Phase 2, Dose-finding Study (SATURN). Eur Urol 2013; 19. Andersson KE. Antimuscarinic mechanisms and the overactive detrusor - an update. Eur Urol 2010; 59(3): 377-86. Oelke M, Bachmann A, Descazeaud A, et al. EAU guidelines on the treatment and follow-up of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur Urol 2013; 64(1): 118-40. Lee HN, Lee KS, Kim JC, et al. Rate and associated factors of solifenacin add-on after tamsulosin monotherapy in men with voiding and storage lower urinary tract symptoms. Int J Clin Pract 2015; 69(4): 444-53. 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(2): 262-70. van Kerrebroeck P, Chapple C, Drogendijk T, et al. Combination therapy with solifenacin and tamsulosin oral controlled absorption system in a single tablet for lower urinary tract symptoms in men: efficacy and safety results from the randomised controlled NEPTUNE trial. Eur Urol 2013; 64(6): 1003-12. Gong M, Dong W, Huang G, et al. Tamsulosin combined with solifenacin versus tamsulosin monotherapy for male lower urinary tract symptoms: a meta-analysis. Curr Med Res Opin 2015; 31(9): 1781-92. Barkin J, Diles D, Franks B, Berner T. Alpha blocker monotherapy versus combination therapy with antimuscarinics in men with persistent LUTS refractory to alpha-adrenergic treatment: patterns of persistence. Can J Urol 2015; 22(4): 7914-23. Lee YS, Lee KS, Kim JC, et al. Persistence with solifenacin add-on therapy in men with benign prostate obstruction and residual symptoms of overactive bladder after tamsulosin monotherapy. Int J Clin Pract 2014; 68(12): 1496-502. Basra RK, Wagg A, Chapple C, Cardozo L, Castro-Diaz D, Pons ME, et al. A review of adherence to drug therapy in patients with overactive bladder. BJU Int 2008; 102(7): 774-9. Wagg A, Compion G, Fahey A, Siddiqui E. Persistence with prescribed antimuscarinic therapy for overactive bladder: a UK experience. BJU Int 2012; 110(11): 1767-74. Veenboer PW, Bosch JL. Long-term adherence to antimuscarinic therapy in everyday practice: a systematic review. J Urol 2014; 191(4): 1003-8. Apostolidis A. Antimuscarinics in the treatment of OAB: is there a first-line and a second-line choice? Curr Drug Targets 2015; 16(11): 1187-97.
Petros Sountoulides
(Guest Editor) Consultant Urologist General Hospital of Veroia Greece E-mail:
[email protected]
Apostolos Apostolidis
(Guest Editor) Assistant Professor in Urology-Neurourology Aristotle University of Thessaloniki Greece
