EURURO-6652; No. of Pages 2 EUROPEAN UROLOGY XXX (2016) XXX–XXX

available at www.sciencedirect.com journal homepage: www.europeanurology.com

Platinum Priority – Editorial Referring to the article published on pp. x–y of this issue

Do the Benefits of Phosphodiesterase Type 5 Inhibitors in Male Lower Urinary Tract Symptoms Go Beyond Improved Symptoms? Marcus J. Drake * School of Clinical Sciences, University of Bristol, Bristol, UK

When phosphodiesterase type 5 inhibitors (PDE5Is) were first developed for clinical use, it was the observation of improved erectile function during clinical trials to evaluate their cardiovascular effects that led to investigation of their use for treating erectile dysfunction (ED). This emergence was one of the more spectacular therapeutic developments of the last couple of decades. More recent PDE5I use for lower urinary tract symptoms (LUTS) has arisen in the shadow of this, yet is potentially a big step for two reasons: PDE5Is represent a new class of action for LUTS therapy, and there might be potential for disease modification. To some extent, this application of PDE5Is has polarised opinion among clinicians between enthusiasts and sceptics. Objective markers able to pin down incontrovertible evidence of benefit show conflicting signals, and there is probably modest improvement. In a male LUTS population, the most clear-cut objective marker is the maximum flow rate, for which the modest improvement with PDE5Is might impair the credibility of therapeutic intervention in the minds of many. Nonetheless, storage symptoms are the more bothersome LUTS, and improved urgency delivers real clinical benefit, yet may be achieved without a change in the flow rate or other accepted objective marker. The accumulation of evidence to support PDE5I use in LUTS has been steady, and the review by Gacci and colleagues [1] in this issue of European Urology shows how the arguments are increasingly clear regarding the beneficial response in LUTS. They summarise several key areas that are useful for developing clinical use:  PDE5Is may influence lower urinary tract function and dysfunction at several areas, not only in the prostate but also in the bladder and its associated innervation.

 Physiological, metabolic, and inflammatory effects could all be relevant in the mechanism of action.  Urinary symptoms can improve in terms of both storage and voiding, with improved quality of life.  Younger men with a lower body mass index and severe LUTS may be the best candidates for PDE5Is.  There is a possible additive effect with other drug classes in treating male LUTS.  Some typical adverse effects can be anticipated, including flushing, headache, dyspepsia, dizziness, and nasopharyngitis.  Drugs used to treat male LUTS can influence sexual function (favourably with PDE5Is, unfavourably with a1 adrenergic antagonists), and this should be considered as part of treatment selection.  Patients without ED at baseline have a similar LUTS reduction to those with ED, and ED severity does not substantially affect the International Prostate Symptom Score (IPSS). The last point is particularly important, and is partly where the polarised viewpoints of the profession are centred. In real-life use, all prescribers like to follow how their own patient population reports experiences with a new medication, seeking personal observations to affirm the claims of remote academic publications. In the case of PDE5Is used for LUTS, the indicative improvement in symptoms after initiation of therapy, which would reassure prescribers that a response is linked to treatment, can be slow. This can leave prescribers uncertain, even though patients often vouch for improved quality of life. In effect, the question that has to be resolved to the satisfaction of individual prescribers is whether the improved quality of

DOI of original article: http://dx.doi.org/10.1016/j.eururo.2015.12.048. * Bristol Urological Institute, Southmead Hospital, Bristol, BS10 5NB, UK. Tel. +44 117 4147942; Fax: +44 117 9816099. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.eururo.2016.01.052 0302-2838/# 2016 Published by Elsevier B.V. on behalf of European Association of Urology.

Please cite this article in press as: Drake MJ. Do the Benefits of Phosphodiesterase Type 5 Inhibitors in Male Lower Urinary Tract Symptoms Go Beyond Improved Symptoms? Eur Urol (2016), http://dx.doi.org/10.1016/j.eururo.2016.01.052

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EUROPEAN UROLOGY XXX (2016) XXX–XXX

life is LUTS-specific or global. While demonstration of this point has been slow, it is increasingly clear that qualityof-life improvement does have a LUTS-specific component, as described by Gacci and colleagues. Although a favourable response in the patient population and increasing prescriber adoption are evident, funding bodies have been reluctant to allow unrestricted PDE5I use. This is not just because objective markers, independent of ancillary response mechanisms, are difficult and insensitive. For funding organisations, data on reductions in disease progression, long-term outcomes, and costeffectiveness analyses are still lacking. Yet these are crucial aspects of modern healthcare in economically stressed times, when targeting of resources has to consider maximum yield for available funding. Furthermore, public sentiment remains influential. Given that male LUTS receives little public attention, and the drug class in question is inextricably linked to enhancement of sexual function in public perception, the negotiating position for those seeking health delivery adoption of this therapy is made more challenging. Storage LUTS in men have historically been mislabelled as ‘‘prostatism’’ [2], but are far more appropriately described as overactive bladder (OAB) syndrome to avoid simplistically ‘‘blaming the prostate’’. The persisting failure of the medical profession to recognise that OAB is a problem for men, and is often a dominant factor in driving patients to seek treatment, means that men may be undermanaged (not treated for their main complaint) or inappropriately managed (eg, undergoing transurethral prostate resection in the absence of voiding dysfunction). PDE5Is may in theory have a relevant influence on storage parameters, and the reporting of reduced inflammation could point to dual mechanisms of influence. If the benefit of PFE5Is is mainly in terms of storage LUTS, they face the same challenges as faced by therapies for OAB. These include difficulty in demonstrating objective as opposed to subjective improvement, the complex pathophysiology, and multifactorial influences (notably so in the case of nocturia [3,4]). Reduction in overall IPSS is beyond dispute, and this is the platform that supports PDE5I use in LUTS. It would be

interesting to see if a greater effect could be achieved with some of the modern, more sensitive instruments such as the International Consultation on Incontinence Questionnaire [5]. Mechanisms of action are unclear, and the reality is that we have some way to go to before we know what actually happens when a patient reports clinical benefit. Nonetheless, there are many locations at which alterations in the cellular second messengers controlled by phosphodiesterases could have an impact within the complexity of LUT pathophysiology. Accordingly, it is not appropriate to be too sceptical; instead we need to push for the research to deliver clearer insight into site(s) of action. It will be particularly beneficial (and challenging) to understand the potential for disease modification. If a link can be made between issues such as metabolic syndrome and LUTS, along with demonstration that PDE5Is can counteract the effects of metabolic syndrome in the lower urinary tract, then a new approach based on early intervention aimed at prevention comes into consideration. Prevention of progression, in conjunction with preservation or restoration of sexual function and symptom control, would really focus PDE5Is as a central part of male LUTS management. Conflicts of interest: The author has received advisory board, research, and speaker honoraria from Allergan, Astellas, and Ferring.

References [1] Gacci M, Andersson K-E, Chapple CR, et al. Latest evidence on the use of phosphodiesterase type 5 inhibitors for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo. 2015.12.048 [2] Abrams P. New words for old: lower urinary tract symptoms for ‘‘prostatism’’. BMJ 1994;308:929–30. [3] Gulur DM, Mevcha AM, Drake MJ. Nocturia as a manifestation of systemic disease. BJU Int 2011;107:702–13. [4] Drake MJ. Should nocturia not be called a lower urinary tract symptom? Eur Urol 2015;67:289–904. [5] Abrams P, Avery K, Gardener N, Donovan J. The International Consultation on Incontinence Modular Questionnaire: www.iciq.net. J Urol 2006;175:1063–6.

Please cite this article in press as: Drake MJ. Do the Benefits of Phosphodiesterase Type 5 Inhibitors in Male Lower Urinary Tract Symptoms Go Beyond Improved Symptoms? Eur Urol (2016), http://dx.doi.org/10.1016/j.eururo.2016.01.052

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