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New alpha blockers to treat male lower urinary tract symptoms

Hwang, Eu, Changa,b,c; Gandhi, Shreyasd; Jung, Jae, H.b,c,e,f

doi: 10.1097/MOU.0000000000000488
EVIDENCE-BASED MANAGEMENT OF LUTS: Edited by Philipp Dahm and Jae H. Jung
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SDC

Purpose of review To date it is unclear whether the selectivity of new alpha-blockers to alpha-adrenergic receptor subtypes translates into more clinical benefits and less adverse effects in clinical practice. We performed a systematic review of the two new Abs silodosin and naftopidil. With the availability of numerous alpha-blockers to treat lower urinary tract symptoms secondary to benign prostatic hyperplasia, the findings of this review will be highly relevant to the field of urology.

Recent findings Silodosin was found to be more effective than placebo in improving International Prostate Symptom Score (IPSS) and quality of life scores and as effective as other alpha-blockers. Although the incidence of cardiovascular adverse events of silodosin was similar compared with placebo and other alpha-blockers (tamsulosin, naftopidil, alfuzosin), the sexual adverse events were more common with silodosin. No placebo-controlled randomized trial exists investigating the effects of naftopidil in men with lower urinary tract symptoms secondary to benign prostatic hyperplasia. Naftopidil had similar efficacy with regards to IPSS and quality of life compared with tamsulosin. The rate of adverse events was similar compared with tamsulosin.

Summary The two new selective alpha-blockers, silodosin, and naftopidil showed similar efficacy in IPSS and quality of life compared with other alpha-blockers. However, silodosin has more sexual adverse events.

aDepartment of Urology, Chonnam National University Medical School, Gwangju, Republic of Korea

bDepartment of Urology, University of Minnesota

cUrology Section, Minneapolis VA Health Care System, Minneapolis, Minnesota, USA

dDepartment of Urology, Dalhousie University, Halifax, Nova Scotia, Canada

eDepartment of Urology

fInstitute of Evidence-Based Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea

Correspondence to Jae H. Jung, Department of Urology, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju 26420, Republic of Korea. Tel: +82 33 741 0652; e-mail: geneuro95@yonsei.ac.kr

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INTRODUCTION

Benign prostatic hyperplasia (BPH) is one of the most common conditions in elderly men. BPH is described as a proliferative process of smooth muscle and glandular epithelium of the prostate. BPH encroaching upon the prostatic urethra can cause troublesome lower urinary tract symptoms (LUTS) due to smooth muscle hyperplasia or glandular hyperplasia [1▪]. LUTS secondary to BPH (LUTS/BPH) can significantly reduce individual patients’ quality of life and represents a major burden to public health [1▪,2].

Alpha-adrenergic receptor blockers, which reduce smooth-muscle tone in the prostate and bladder neck, have been widely used as first-line therapy for decades [2]. Previous literature has shown that alpha-blockers can typically improve LUTS as well as quality of life [3–5]. Lepor et al. [6] observed that the predominant alpha-adrenergic receptor in the human prostate was the A1 subtype and further research elucidated that the A1a subtype predominates in the human prostate, bladder neck, and urethra. On the other hand, A1b receptor subtypes are mainly expressed in the peripheral vasculature and A1d receptor is expressed in the detrusor muscle of the bladder and the sacral region of the spinal cord [1▪,7,8]. Theoretically, A1a subtype selective antagonist should therefore relieve LUTS without cardiovascular adverse events which are mediated by other subtypes, such as dizziness, headache, and orthostatic hypotension [9].

New subtype selective alpha-blockers with high affinity for A1a (silodosin) or A1d (naftopidil) adrenergic receptors were first approved as the standard of treatment for LUTS/BPH in Japan. In this review, we assessed whether the highly selective alpha-blockers (silodosin and naftopidil) actually translate into more clinical benefits and fewer adverse effects in clinical practice compared with other alpha-blockers.

Box 1

Box 1

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SILODOSIN

Silodosin is a new subtype selective alpha-blocker that was approved in Japan in 2006, which has a very high selectivity for A1a versus A1b adrenergic receptors (162-fold selectivity), modest selectivity (55-fold selectivity) for A1a versus A1d adrenergic receptors show in in-vitro studies [10].

An initial randomized controlled trial showed a greater reduction in International Prostate Symptom Score (IPSS) compared with placebo [11]. Furthermore, there was a significant decrease in the IPSS in the silodosin group compared with tamsulosin in the early stages of treatment [11]. There was no significant difference in the rate of cardiovascular adverse events between the silodosin and tamsulosin groups. Although incidences of abnormal ejaculation were higher in the silodosin group than in the tamsulosin group (22.3 versus 1.6%), only five men (2.9%) discontinued treatment due to abnormal ejaculation [11]. There were two large trials conducted in United States and Europe, which provided findings consistent with the results of the initial trial [12,13]. They also found significant changes in IPSS after silodosin treatment compared with both tamsulosin and placebo. However, retrograde ejaculation was the most common drug-related adverse events, although it rarely resulted in discontinuation of treatment [12,13]. In prior systematic reviews and meta-analyses, silodosin had similar efficacy compared with other alpha-blockers and placebo but were associated with a significantly higher incidence of total adverse events and treatment withdrawal [14,15]. However, these systematic reviews only included two to four studies in the meta-analysis [11–13,16].

Recently, we published a Cochrane Review titled ‘Silodosin for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia’ based on a published a-priori protocol [17▪▪]. We searched multiple data sources for published and unpublished randomized controlled trials in any language and reported the effects of silodosin for the treatment of LUTS in men with BPH based on 19 unique studies with 4295 randomized patients across four comparisons (silodosin versus placebo, tamsulosin, naftopidil, and alfuzosin) for short-term follow-up (12 weeks). Silodosin was more effective than placebo [mean difference −2.65, 95% confidence interval (CI) −3.23 to −2.08] and as effective as tamsulosin (mean difference −0.04, 95% CI −1.31 to 1.24) and naftopidil (mean difference −0.85, 95% CI −2.57 to 0.87) in IPSS. Although alfuzosin was statistically superior to silodosin (mean difference 3.83, 95% CI 0.12–7.54) in IPSS, the difference may not be clinically meaningful in men with LUTS. Silodosin was also more effective in quality of life than placebo (mean difference −0.42, 95% CI −0.71 to −0.13) and as effective as tamsulosin (mean difference −0.15, 95% CI −0.53 to 0.22), naftopidil (mean difference −0.17, 95% CI −0.60 to 0.27), and alfuzosin (mean difference 0.14, 95% CI −0.46 to 0.74). With regard to adverse events, the incidence cardiovascular adverse events of silodosin was similar compared with placebo [risk ratio (RR) 1.28, 95% CI 0.67–2.45], tamsulosin (RR 0.77, 95% CI 0.53–1.12), naftopidil (RR 1.02, 95% CI 0.41–2.56), and alfuzosin (RR 0.67, 95% CI 0.36–1.24). However, sexual adverse events such as retrograde ejaculation and anejaculation were more common in the silodosin group compared with the placebo (RR 26.07, 95% CI 12.36–54.97), alfuzosin (RR 37.21, 95% CI 5.32–260.07), tamsulosin (RR 6.05, 95% CI 3.55–10.31), and naftopidil groups (RR 5.93, 95% CI 2.16–16.29). The incidence of adverse events resulting in withdrawal was also higher in the silodosin group than the placebo (RR 1.08, 95% CI 0.70–1.66), tamsulosin (RR 1.96, 95% CI 1.12–3.44), and naftopidil groups (RR 1.38, 95% CI 0.66–2.89). There were no treatment withdrawals due to adverse events in comparisons with silodosin and alfuzosin.

The current Cochrane Review provided quality of evidence ratings using the GRADE approach. The quality of evidence ratings for the comparisons of all desirable and undesirable outcomes except sexual adverse events was low, meaning that the true effect may be substantially different from the estimate of the effect. The review rated the quality of evidence for sexual adverse events as moderate, indicating that the true effect is likely to be close to the estimate of the effect [17▪▪]. The quality of evidence was downgraded for study limitations, inconsistency, and imprecision.

As a result, the efficacy of silodosin appears similar to that of other alpha-blockers. However, clinician should bear in mind that silodosin was associated with increased sexual adverse effects, specifically, abnormal ejaculation, which may be problematic to sexually active men with LUTS.

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NAFTOPIDIL

Naftopidil is selective for the A1d adrenergic receptor with a 3–17-fold higher affinity than for the A1a and A1b adrenergic receptor subtypes based on in-vitro studies and was approved in Japan in 1998 [18]. Theoretically, naftopidil should be more effective for storage symptoms measured by the IPSS due to its selectivity for the bladder via the A1d receptor subtype.

Initial randomized controlled trials showed no significant difference in IPSS and quality of life compared with tamsulosin [19,20]. Ikemoto et al. [20] found that the improvement of storage symptoms in IPSS was more prominent with naftopidil. Several randomized controlled trials also reported that naftopidil was as effective as tamsulosin [21–23]. Also two studies showed that naftopidil had a faster onset of action and more improvement in irritative symptom compared with tamsulosin [24,25]. However, Gotoh et al. [26] found that naftopidil had an inferior efficacy in IPSS (mean difference 2.50, 95% CI 0.41–4.59). Adverse events were comparable in both naftopidil and tamsulosin groups [19–24]. Previous systematic reviews and meta-analyses confirmed that naftopidil is as effective and well tolerated as tamsulosin [27,28]. However, Castiglione et al. [27] was a narrative review without meta-analysis and Garimella et al. [28] published in 2009 must be considered outdated.

Recently, Cochrane Urology updated the naftopidil review performed by Garimella et al. [28]. Based on an ongoing review (E.C.H., S.G., J.H.J., M.I., R.P., M.H.K., P.D.) of 16 randomized controlled trials with 1799 randomized participants, no placebo-controlled randomized trial exists investigating the effects of naftopidil in men with LUTS/BPH. Naftopidil was as effective as tamsulosin in IPSS (mean difference −0.01, 95% CI −0.65 to 0.63) and quality of life (mean difference 0.03, 95% CI −0.16 to 0.23). With regard to adverse events, the incidence of cardiovascular (RR 1.06, 95% CI 0.46–2.43) and sexual adverse events (RR 0.55, 95% CI 0.21–1.40) of naftopidil was similar compared with tamsulosin. The incidence of adverse events resulting in withdrawal was also similar compared with tamsulosin (RR 1.24, 95% CI 0.39–4.01). The results compared with silodosin were previously described (see above). In addition, the quality of evidence was rated as low for comparisons of all desirable and undesirable outcomes except sexual adverse events, which were rated as moderate. The quality of evidence was downgraded for study limitations, inconsistency, and imprecision (unpublished data: E.C.H., S.G., J.H.J., M.I., R.P., M.H.K., P.D.).

As a result, naftopidil appears to have similar effects compared with tamsulosin. Naftopidil, however, is not yet available in Western countries, potentially due to the limited number of non-Asian clinical reports (randomized controlled trials were mainly performed in China, Japan, and South Korea) and the lack of long-term randomized, placebo-controlled studies [27].

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CONCLUSION

Traditionally, alpha-blockers have been used as a first-line treatment modality for LUTS/BPH. However, there are nonnegligible drug-related adverse events such as cardiovascular or sexual side effects. Compared with other alpha-blockers, silodosin and naftopidil showed similar efficacy in IPSS and quality of life. However, silodosin had more sexual adverse events compared with alpha-blockers.

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Acknowledgements

We are very grateful to the Cochrane Review authors. We acknowledge the support received from M.I. and R.P. by translating Japanese and Chinese articles, respectively. We thank Cochrane Urology for supporting this review.

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Financial support and sponsorship

None.

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Conflicts of interest

E.C.H. is a Cochrane Urology Fellow, S.G. has no intellectual conflicts of interest to disclose, J.H.J. serves as Contact Editor of Cochrane Urology for the international Cochrane Collaboration. He is also a member of the GRADE Working Group and the US GRADE Network.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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REFERENCES

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A recent narrative review on historical perspective and pharmacologic effects of alpha-blockers.

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Keywords:

adrenergic alpha-antagonists; lower urinary tract symptoms; naftopidil; prostatic hyperplasia; silodosin

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