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Article of the Week: Impact of dutasteride/tamsulosin combination therapy on sexual function in men with LUTS secondary to BPH

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Every Week, the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this month, it should be this one.

A prospective randomised placebo‐controlled study of the impact of dutasteride/tamsulosin combination therapy on sexual function domains in sexually active men with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH)

 

Claus G. Roehrborn*, Michael J. Manyak†, Juan Manuel Palacios-Moreno‡, Timothy H. Wilson§, Erik P.M. Roos, Javier Cambronero Santos**, Dimitrios Karanastasis††, Janet Plastino‡‡, Francois Giuliano§§ and Raymond C. Rosen¶¶

 

*Department of Urology, University of Texas (UT) Southwestern Medical Center, Dallas, TX, USA, †GlaxoSmithKline (GSK), Washington, DC, USA, ‡GSK, Madrid, Spain, §PAREXEL International, Durham, NC, USA, Antonius Ziekenhuis Sneek, Sneek, The Netherlands, **Hospital Universitario Infanta Leonor, Madrid, Spain, ††Urologic Clinic, General Hospital of Athens ‘Elpis’, Athens, Greece, ‡‡GSK, Collegeville, PA,USA, §§Neuro-Urology R. Poincare Hospital AP-HP, Garches, UMR1179 Inserm-UVSQ-Paris Saclay University, Paris, France, France, and ¶¶New England Research Institutes,nWatertown, MA, USA

 

Abstract

Objective

To prospectively assess the impact of the fixed‐dose combination (FDC) of the 5α‐reductase inhibitor (5ARI), dutasteride 0.5 mg and the α1‐adrenoceptor antagonist, tamsulosin 0.4 mg (DUT‐TAM FDC) therapy on sexual function domain scores in sexually active men with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH), using the Men’s Sexual Health Questionnaire (MSHQ).

Patients and Methods

This European and Australian double‐blind, placebo‐controlled, parallel‐group study was conducted at 51 centres. Inclusion criteria: age ≥50 years, International Prostate Symptom Score ≥12, prostate volume ≥30 cc, prostate‐specific antigen 1.5–10 ng/mL. Patients were randomised 1:1 to DUT‐TAM FDC therapy or placebo for 12 months. The change from baseline to Month 12 on the total MSHQ (primary endpoint) and MSHQ erection, ejaculation and satisfaction domains (secondary outcome) was assessed, using a mixed model repeated measures analysis. Safety was evaluated.

Results

The intention‐to‐treat population included 489 patients (243 DUT‐TAM FDC therapy; 246 placebo). A significant decrease (worsening) was observed with DUT‐TAM FDC therapy versus placebo on the total MSHQ score (−8.7 vs −0.7; standard error [se]: 0.81, 0.78; P < 0.001), and the ejaculation (−7.5 vs −0.6; se: 0.56, 0.55; P < 0.001) and satisfaction (−0.6 vs +0.3; se: 0.3, 0.29, P = 0.047) domains, but not the erection domain (−1.0 vs −0.5; se: 0.19, 0.19, P = 0.091).

Conclusion

This is the first domain‐specific quantitative evaluation of DUT‐TAM FDC therapy on sexual function in men with LUTS secondary to BPH. The observed changes in the MSHQ with DUT‐TAM FDC therapy were mainly driven by changes in the ejaculation domain. These findings will help give context to erectile and ejaculatory dysfunction AEs reported spontaneously in earlier 5ARI studies.

Read more articles of the week

Editorial: Sexual function in patients undergoing combination treatment with α1‐adrenoceptor antagonists and 5α‐reductase inhibitors – a step forward in a still‐open debate

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Combination treatment with α1‐adrenoceptor antagonists and 5α‐reductase inhibitors (5ARIs) is recommended in men with moderate‐to‐severe LUTS and risk of disease progression 1, 2. These drugs can improve symptoms as well as urodynamic markers of BOO 3, 4. Despite the clinical benefits, the potential negative impact of these drugs on sexual function is of major concern, and may be cause for treatment discontinuation. Additionally, in everyday clinical practice, the incidence of sexually‐related adverse events is often perceived to be higher than that reported in clinical trials, and clinicians may consequently be reluctant to prescribe these drugs in younger, sexually active patients 5. Evidence from the literature in this area, however, is low‐level, controversial and inconclusive. Notably, in most clinical studies on combination treatment, assessment of sexual function is based only on the reported incidence of sexually‐related adverse events; a non‐quantitative method that can be biased by the subjective burden of suffering, by a patient’s misinterpretation of symptoms and his propensity to mention them during follow‐up visits.

Roehrborn et al. 1 investigated the impact of a fixed‐dose combination of the 5ARI dutasteride 0.5 mg and the α1‐adrenoceptor antagonist tamsulosin 0.4 mg therapy on sexual function in sexually active men with LUTS, secondary to BPH 1. The authors designed a prospective, randomized, placebo‐controlled study and adopted, for the first time in this setting, the Men’s Sexual Health Questionnaire (MSHQ). Overall, 489 patients, with a mean age of 65.5 years, an IPSS ≥12 and a prostate volume ≥30 mL were randomized to receive combination therapy (n = 243) or placebo (n = 246) for 12 months. Change in sexual function from baseline to month 12, as measured by a change in total MSHQ score, was the primary endpoint of the study. Change from baseline in the MSHQ erection, ejaculation and satisfaction domain scores were among the secondary endpoints. The authors found a statistically significant decrease in the total MSHQ score in the active treatment group compared with placebo at all post‐treatment visits (months 1,3, 6, 9 and 12), indicating a worsening of sexual function 1. The magnitude of the total MSHQ reduction was greater at month 6 and remained substantially unchanged beyond this time point. This change was driven largely by the change in the score for the ejaculatory domain, which showed a similar temporal trend. Changes in terms of the overall satisfaction domain, although statistically significant, were judged to be numerically small and therefore unlikely to be clinically relevant. Changes in terms of erectile domain score were not statistically significant.

The major methodological strength of this study was the adoption of the MSHQ, a clinically validated questionnaire designed to assess quantitatively multiple domains of sexual function, namely erectile function, ejaculatory function and sexual satisfaction. Findings are relevant from both a pathophysiological and clinical viewpoint. Indeed, the temporal trend that characterizes the deterioration of ejaculatory function and therefore the total MSHQ score implies the involvement of both drugs in this process. From a clinical point of view the study provides additional data to counsel patients requiring combination therapy about the deleterious effects on sexual function and particularly on ejaculatory function. The main limitations of the study, as acknowledged by the authors, is the lack of long‐term follow‐up. Indeed, a recent meta‐analysis showed a positive correlation between duration of therapy with 5ARIs and incidence of sexual dysfunction, with long‐term exposure (≥1 year) being associated with a significantly higher risk 6. Consequently, conclusive data about erectile function cannot be drawn based on the results from the present 1‐year‐long study. Additionally, the authors do not report on possible changes in sexual desire. This aspect deserves future investigation as the risk of decreased libido has been reported to be statistically significant in patients assuming therapy with 5ARIs 6. Finally, results from clinical trials do not always correspond to everyday clinical practice, as patient selection for therapies in the real world is often different with respect to inclusion criteria adopted in clinical trials. Specifically, patients who receive therapy with 5ARIs (alone or in combination) in everyday clinical practice are often older than the patients who were enrolled in the present study and in other clinical trials and therefore may have comorbidities that could contribute to the development of sexual side effects during treatment 5.

Ferdinando Fusco and Massimiliano Creta
Department of Neurosciences, Human Reproduction and Odontostomatology, University of Naples Federico II, Naples, Italy

 

References

 

  • 1 Roehrborn CG, Manyak MJ, Palacios‐Moreno JM et al. A prospective randomised placebo‐controlled study of the impact of dutasteride/tamsulosin combination therapy on sexual function domains in sexually active men with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). BJU Int 2018; 121: 647–58

 

  • 2 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 Urol2015; 67: 1099–109

 

  • 3 Fusco F, Creta M, Imperatore V et al. Benign prostatic obstruction relief in patients with lower urinary tract symptoms suggestive of benign prostatic enlargement undergoing endoscopic surgical procedures or therapy with alpha‐blockers: a review of urodynamic studies. Adv Ther2017; 34: 773–83

 

  • 4 Matsukawa Y, Takai S, Funahashi Y et al. Effects of withdrawing α1‐blocker from combination therapy with α1‐blocker and 5α‐reductase inhibitor in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: a prospective and comparative trial using urodynamics. J Urol 2017; 198: 905–12

 

  • 5 Fusco F, Arcaniolo D, Creta M et al. Demographic and comorbidity profile of patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia in a real‐life clinical setting: Are 5‐alpha‐reductase inhibitor consumers different? World J Urol 2015; 33: 685–9

 

  • 6 Liu L, Zhao S, Li F et al. Effect of 5α‐reductase inhibitors on sexual function: a meta‐analysis and systematic review of randomized controlled trials. J Sex Med 2016; 13: 1297–310

 

Ejaculatory Function and Treatment for Male LUTS due to BPH

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This month’s twitter-based international urology journal club discussed “Impact of Medical Treatments for Male LUTS due to BPH on Ejaculatory Function: A Systematic Review and Meta-analysis”, published online in the Journal of Sexual Medicine. The discussion was enriched by the participation of Asst. Prof. Giacomo Novara (@giacomonovara) of the University of Padua, the senior author of the paper.

There was general consensus that this was a well constructed paper addressing an important and sometimes neglected side-effect of a group of medications that most urologists use commonly. The principal messages of the paper were:

  1. Ejaculatory dysfunction (EjD) was significantly more common with alphablockers (ABs) in general than placebo
  2. This effect was mainly seen with selective ABs (tamsulosin and sildosin). Non-selective ABs (doxazosin and terazosin) had similar rates of EjD to placebo.
  3. Finasteride and dutasteride both cause EjD, and to a similar extent as each other.
  4. Combination therapy (5ARI + AB) resulted in a three-fold increase in EjD compared to either monotherapy

The authors were congratulated on the amount of work that had obviously gone into the analysis. There was a discussion of some of the technical aspects of how to conduct a systematic review (SR) and meta-analysis. The PRISMA guidelines are a mandatory standard, and are recommended to anyone considering undertaking one. @LoebStacy also recommended the Cochrane handbook as a useful source of info. @DrHWoo asked whether Jadad scores had been used to rate RCT quality. They were not used in this study, but are one method of assessing RCT quality for an SR. @chrisfilson and @jleow advocated the Cochrane Collaboration’s tool for risk of bias assessment (found in Section 8.5 of the handbook), as an alternative.

After the technical aspects, discussion focussed on how best to avoid EjD in men who are concerned about it. @linton_kate asked whether PDE5 inhibitors were an option in this regard. General consensus was that they are an option, especially where LUTS and erectile dysfunction (ED) coexist, but concerns were expressed about the cost (which varied country by country, but is generally far in excess of the cost of ABs) and by @nickbrookMD about the uncertainty surrounding their mechanism of action for LUTS improvement.

Several correspondants were using PDE5Is in clinical practice for this indication however, including @VMisrai. It was pointed out however, that alfuzosin also offers a reduced risk of EjD compared to other ABs, and is substantially less expensive than PDE5Is. Alfuzosin was not evaluated in this paper, however @giacomonovara agreed that it was an option in men with LUTS who wish to avoid EjD, especially where ED is not a concern. @DrHWoo pointed out the Rosen data demonstrating the correlation between increasing LUTS and decreasing erectile function, but indeed (as suggested by @JCLinMD) treatment of LUTS, e.g. with an AB, may in itself improve erectile function.

Discussion moved on to 5ARIs. @giacomonovara stated that these agents had a broad spectrum of potential effects on ejaculatory/erectile function. @shomik_S raised the issue of whether 5ARIs could cause irreversible sexual side-effects. This is certainly a medicolegal concern, and undoubtedly some men report persistent effects on libido and sexual function, although a firm causal link has not been established.

The medicolegal theme was further explored with a discussion on what to warn patients of when commencing these medications. All were agreed that patients commencing ABs/5ARIs, including those undergoing medical expulsive therapy for stones should be warned about EjD. There was some discussion however, about whether patients commencing a 5ARI should be warned about the increased rates of high-grade prostate cancer seen in the PCPT and REDUCE trials. This increase may be an artefact of more effective cancer detection, but none-the-less @loebStacy was of the opinion that it should be included in pre-treatment counselling.

 

But is all the concern about sexual side-effects justified? It was pointed out that many patients are prepared to tolerate sexual side-effects in return for improvement in their LUTS.

Regardless, this paper from @giacomonovara and co-authors provided useful insight and stimulated a valuable discussion. Undoubtedly, some patients are very concerned about EjD and this paper will help all urologists who treat male LUTS to address these concerns.

Winner of the Best Tweet Prize was David Gillatt for his response to the discussion regarding the needs of various nationalities for PDE5I. Special thanks to the SIU for offering a prize of free registration to the 2014 SIU Congress in Glasgow. Also special thanks to Wiley for allowing open access of the article for the May #urojc discussion.

Ben Jackson has completed urological training in the East Midlands, and is now undertaking a fellowship at St. Vincent’s Hospital, Sydney. His principal clinical interest is urologic oncology.
Twitter @Ben_L_Jackson

 

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