ORIGINAL ARTICLE
Efficacy and safety of phosphodiesterase type 5 (PDE5) inhibitors in treating erectile dysfunction after bilateral nerve-sparing radical prostatectomy Y. Cui, X. Liu#, L. Shi & Z. Gao Department of Urology, Yantai Yuhuangding Hospital Affiliated to Medical College of Qingdao University, Yantai, China
Keywords Bilateral nerve-sparing radical prostatectomy—erectile dysfunction sexual (penile) rehabilitation—meta-analysis—phosphodiesterase type 5 inhibitors Correspondence Zhenli Gao, NO.20 East Yuhuangding Road, 264000 Yantai, China. Tel.: 86-10-6691999 (O); Fax: 86-10-0535-6691999; E-mail: [email protected] #
Co-first author: Xinjie Liu.
Accepted: December 29, 2014 doi: 10.1111/and.12405
Summary We carried out a systematic review and meta-analysis to assess the efficacy and safety of phosphodiesterase type 5 (PDE5) inhibitors for treating erectile dysfunction (ED) after bilateral nerve-sparing radical prostatectomy (BNSRP). A literature review was performed to identify all published randomised doubleblind, placebo-controlled trials of PDE5 inhibitors for the treatment of ED after BNSRP. The search included the following databases: MEDLINE, EMBASE and the Cochrane Controlled Trials Register. The reference lists of the retrieved studies were also investigated. Six publications involving a total of 1678 patients were used in the analysis, including six RCTs that compared PDE5 inhibitors (tadalafil, sildenafil, avanafil and vardenafil) with placebo. Co-primary efficacy end points: International Index of Erectile Function-Erectile Function (IIEF-EF) domain score [the standardised mean difference (SMD) = 4.04, 95% confidence interval (CI) = 2.87–5.22, P < 0.00001]; successful vaginal penetration (SEP2) [the odds ratio (OR) = 14.87, 95% CI = 4.57–48.37, P < 0.00001]; and successful intercourse (SEP3) (OR = 47, 95%CI = 3–13.98, P < 0.00001) indicated that PDE5 inhibitors was more effective than the placebo. Specific adverse events with PDE5 inhibitors included headache (12.08%), dyspepsia (6.76%) and flushing (6.52%), which were significantly less likely to occur with placebo. This meta-analysis indicates that PDE5 inhibitors to be an effective and well-tolerated treatment for ED after BNSRP.
Introduction Nerve-sparing radical prostatectomy (NSRP) is a commonly used treatment for clinically localised prostate cancer in patients with a life expectancy ≥10 years (Heidenreich et al., 2014). Walsh et al. (1983, 2000) pioneered the technique of anatomical NSRP to preserve the anatomical structures responsible for urinary continence and penile erection. Notwithstanding improvements in surgical techniques, erectile dysfunction (ED) is a common sequela of NSRP (Ficarra et al., 2012; Salonia et al., 2012a,b). Treatment for postoperative ED historically has included the use of vacuum devices, intracavernosal and intra-urethral pharmacotherapy, or placement of a penile implant (Montorsi et al., 1997). Despite the benefit, pain, complications and inconvenience detract from the willingness of patients to use above methods regularly. The 20
advent of phosphodiesterase type 5 (PDE5) inhibitors (tadalafil, sildenafil, avanafil and vardenafil) has provided an oral treatment alternative to patients with post-prostatectomy ED (Viagra, 2010; Cialis, 2011; Levitra, 2011; STENDRA, 2012). So far, we are unaware of any systematic review and quantitative meta-analysis that has formally evaluated the safety and efficacy of PDE5 inhibitors in treating ED after bilateral NSRP (BNSRP). The goal of the present study was to perform a metaanalysis to evaluate the safety and efficacy of PDE5 inhibitors in treating ED after BNSRP. Materials and methods Search strategy Medline (1966 to June 2014), Embase (1974 to June 2014) and Cochrane Controlled Trials Register databases © 2015 Blackwell Verlag GmbH Andrologia 2016, 48, 20–28
PDE5i for ED after BNSRP
Y. Cui et al.
were searched to identify randomised controlled trials (RCTs) that referred to the impact of PDE5 inhibitors in treating ED after BNSRP; we also searched the reference lists of the retrieved studies. The following search terms were used: phosphodiesterase type 5 inhibitors, erectile dysfunction, bilateral nerve-sparing radical prostatectomy and randomised controlled trial. Inclusion criteria and trial selection Randomised controlled trials that met the following criteria were included: (i) The study design included treatment with PDE5 inhibitors; (ii) the study provided accurate data that could be analysed, including the total number of subjects and the values of each index; and (iii) the full text of the study could be accessed. When the same study was published in various journals or in different years, the most recent publication was used for the meta-analysis. If the same group of researchers studied a group of subjects with multiple experiments, then each study was included. A flow diagram of the study selection process is presented in Fig. 1. Quality assessment The quality of the retrieved RCTs, which included assessment of sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting of outcomes and other possible sources of bias, was assessed using the Jadad scale (Jadad, 1998). Only identified RCTs
with high quality were included in the meta-analysis. The methodological quality of each study was assessed according to how patients were allocated to the arms of the study, the concealment of allocation procedures, blinding and data loss due to attrition. The studies were then classified qualitatively according to the guidelines published in the Cochrane Handbook for Systematic Reviews of Interventions v.5.1.0 (Higgins & Green, 2011). Based on the quality-assessment criteria, each study was rated and assigned to one of the three following quality categories: A, if all quality criteria were adequately met, the study was deemed to have a low risk of bias; B, if one or more of the quality criteria was only partially met or was unclear, the study was deemed to have a moderate risk of bias; or C, if one or more of the criteria was not met or not included, the study was deemed to have a high risk of bias. Differences were resolved by discussion among the authors based on the quality-assessment criteria. Data extraction The following information was collected for each study: (i) the name of the first author and the publication year; (ii) the study design and sample size; (iii) the therapy that the patients received; (iv) the country in which the study was conducted; and (v) data including the International Index of Erectile Function-Erectile Function (IIEFEF) domain score, the successful vaginal penetration (SEP2) and successful intercourse (SEP3), headache, dyspepsia and flushing.
Fig. 1 A flow diagram of the study selection process. RCT: randomized controlled trial PDE5: phosphodiesterase type 5. ED: erectile dysfunction. BNSRP: bilateral nerve-sparing radical prostatectomy.
© 2015 Blackwell Verlag GmbH Andrologia 2016, 48, 20–28
21
22
sildenafil
vardenafil
avanafil
tadalafil
tadalafil
Padma-Nathan et al., 2008
Montorsi et al., 2008
Mulhall 2013
Seo et al., 2014
Montorsi et al., 2014
placebo
placebo
placebo
placebo
placebo
placebo
Therapy in control group
57.9
69.0
58.4
57.1
56.0
59.7
Age (median)
Nine European countries and Canada
Korea
US
Europe, US, Canada, South Africa
North America, France, Belgium, Australia
Canada, Germany, Italy, The Netherlands, Spain, UK, US
Country
ED, erectile dysfunction; BNSRP, bilateral nerve-sparing radical prostatectomy.
tadalafil
Montorsi et al., 2004
Study
Therapy in experimental group
Table 1 Study and patient characteristics
27
141
282
100
206
42
102
Control
30
98
409
40
201
Experimental
Sample size
Men 0.05, we considered the studies homogeneous and so chose a fixed-effect model for meta-analysis. Otherwise, a random-effect model was used. We quantified inconsistency using the I² statistic, which describes the proportion of heterogeneity across studies that is not due to chance, thus describing the extent of true inconsistency in results across trials (DerSimonian & Laird, 1986). I² < 25% reflects a small level of inconsistency, and I² > 50% reflects significant inconsistency. © 2015 Blackwell Verlag GmbH Andrologia 2016, 48, 20–28
The database search found 69 articles that could have been included in our meta-analysis. Based on the inclusion and exclusion criteria, 58 articles were excluded after reading the titles and abstracts of the articles. Five articles lacked useful data. In all, six articles involving a total of 1678 patients (Montorsi et al., 2004, 2008, 2014; PadmaNathan et al., 2008; Mulhall et al., 2013; Seo et al., 2014), reporting data from a total of six RCTs, were included in the analysis: two RCTs compared PDE5 inhibitors (tadalafil 20 mg on demand and avanafil 100 mg on demand) with a placebo over the short term (≤6 months), and four RCTs compared PDE5 inhibitors (sildenafil 50 mg once daily, avanafil 10 mg nightly or 10 mg on demand and tadalafil 20 mg on demand or 5 mg once daily) with a placebo over the long term (9–12 months) (Fig. 1). The baseline characteristics of the studies included in our meta-analysis are listed in Table 1. Quality of the individual studies All six RCTs were double blinded, and all described the randomisation processes that they had used. All included a power calculation to determine the optimal sample size (Table 2). The level of quality of each identified study was A (Table 2). The funnel plot provided a qualitative estimation of publication bias of the studies, and no evidence of bias was found (Fig. 2). Efficacy IIEF-EF domain score Four RCTs, representing 640 participants (369 in the PDE5 inhibitors group and 271 in the control group) included data on IIEF-EF domain score changes (Fig. 3). 23
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(a)
(b)
(c)
Fig. 3 Forest plots showing changes in (a) the IIEF-EF domain score, (b) SEP2 and (c) the SEP3 in the treatment studies. PDE5-Is: phosphodiesterase type 5 inhibitors IIEF-EF: International Index of Erectile Function- erectile function, SEP2: sexual encounter profile (SEP) question 2, SEP3: SEP question 3, SD:standard deviation, IY:inverse variance, MH:mantel haenszel, Clxonfidence interval.
According to our analysis, no heterogeneity was found among the trials (Fig. 3), and the effect size for metaanalysis was denoted as the SMD. The pooled estimate of SMD was 4.04, and the 95%CI was 2.87–5.22 (P < 0.00001). This result suggests that PDE5 inhibitors showed statistically significant improvement in the IIEFEF domain score compared with placebo. SEP 2 (successful vaginal penetration) and SEP 3 (successful intercourse) Two RCTs, representing 493 participants (295 in the PDE5 inhibitors group and 198 in the control group) included data on SEP 2 and SEP 3 changes (Fig. 3). No heterogeneity was found among the trials (Fig. 3), the pooled estimate of OR was 14.87 (95%CI was 4.57–48.37, P < 0.00001) and 6.47 (95%CI was 3.00–13.98, P < 0.00001) respectively. This result suggests that PDE5 inhibitors showed statistically significantly greater improvement in the SEP 2 and SEP 3 compared with placebo. Safety Headache, dyspepsia and flushing Six RCTs, representing 1678 participants (1060 in the PDE5 inhibitors group and 618 in the control group), 24
included the headache data (Fig. 4). The pooled estimate of OR was 2.86, and the 95%CI was 1.87–4.39 (P < 0.00001). And four RCTs, representing 1423 participants (932 in the PDE5 inhibitors group and 491 in the control group), included the dyspepsia data (Fig. 4). The pooled estimate of OR was 4.86, and the 95%CI was 2.28–10.36 (P < 0.0001). And three RCTs, representing 870 participants (537 in the PDE5 inhibitors group and 333 in the control group), included the flushing data (Fig. 4). The pooled estimate of OR was 5.64, and the 95%CI was 1.99–16.01 (P = 0.001). The result suggests that specific adverse events with PDE5 inhibitors included headache, dyspepsia and flushing were more likely occur with placebo. Subgroup analyses and sensitivity analysis According to the duration of treatment, we divided the included studies into short-term (≤6 months) and longterm (>6 months) treatment group. Our analysis indicated that PDE5 inhibitors showed significant improvement in the IIEF-EF domain score (SMD = 4.07, 95% CI = 2.68–5.47, P < 0.00001 and SMD = 3.97, 95% CI = 1.78–6.16, P = 0.0004) (Fig. 5) in both short-term and long-term treatment group. Sensitivity analysis was performed by dividing the included studies of postoperative PDE5 inhibitor use into two groups: the group of © 2015 Blackwell Verlag GmbH Andrologia 2016, 48, 20–28
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early postoperative use (≤4 weeks) and group of late postoperative use (≥6 months). Our analysis indicated that PDE5 inhibitors showed significant improvement in the IIEF-EF domain score (SMD = 3.97, 95%CI = 1.78 to 6.16, P = 0.0004 and SMD = 4.07, 95%CI = 2.68 to 5.47, P < 0.00001) (Fig. 5) in both treatment group. By dividing the included studies into on-demand and once-daily treatment groups, we found that PDE5 inhibitors significantly improved the IIEF-EF domain score (SMD = 4.07, 95%CI = 2.68 to 5.47, P < 0.00001 and SMD = 3.97, 95%CI = 1.78–6.16, P = 0.0004) (Fig. 5) in both ondemand and once-daily treatment group. Discussion Because of the widespread use of prostate specific antigen (PSA) screening, the number of younger patients diagnosed with localised prostate cancer is increasing. Consequently, the issue of postoperative preservation of erectile function is gaining increasing importance. The success of BNSRP provided the substantial evidence of the possibility of preserving erectile function after radical prostatectomy. As a result, specific ED treatment is
PDE5i for ED after BNSRP
necessary in a large proportion of patients undergoing the procedure. This systematic review and quantitative meta-analysis summarises the evidence from randomised controlled clinical trials regarding the efficacy and safety of PDE5 inhibitors (tadalafil, sildenafil, avanafil and vardenafil) for the treatment of ED after BNSRP. The mechanism of action of PDE5 inhibitors is related to the aetiology of ED after BNSRP. When neurologic injury occurs, penile hypoxia and fibrosis lead to the absence of spontaneous nocturnal erections, which decreases the release of nitric oxide (Zippe & Pahlajani, 2007; Defade et al., 2011). The decrease in nitric oxide production leads to a drop in the amount of available cyclic guanosine monophosphate (cGMP) (Raina et al., 2003; Padma-Nathan et al., 2008). PDE5 inhibitors inhibit PDE5, which metabolises cGMP, and this results in an increase in cGMP levels (Raina et al., 2003). This increase in the amount of cGMP coupled with nitric oxide induces corporal smooth muscle relaxation, and this leads to subsequent erection by allowing blood flow to the penis (Lue, 2000; Mydlo et al., 2005; Lagoda et al., 2007, 2008). The whole process requires nerve preservation, because if there is no cGMP,
(a)
(b)
(c)
Fig. 4 Forest plots showing changes in (a) the headache, (b) dyspepsia and (c) flushing in the treatment studies. PDE5-Is: phosphodiesterase type 5 inhibitors; MH:manteI haenszel, Clxonfidence interval.
© 2015 Blackwell Verlag GmbH Andrologia 2016, 48, 20–28
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(a)
(b)
(c)
Fig. 5 Forest plots showing changes in the IIEF-EF domain score in the treatment studies. PDE5-Is: phosphodiesterase type 5 inhibitors; IIEF-EF: International Index of Erectile Function- erectile function, SD:standard deviation, IY:inverse variance, CI:confidence interval.
there is no substrate for PDE5 to metabolise (Raina et al., 2003). Overall, compared with men receiving placebo, those allocated to the PDE5 inhibitors group had a significant improvement in IIEF-EF domain score and higher percentage of successful vaginal penetration and were more likely to have successful intercourse. Besides, Montorsi et al. conducted two RCTs and demonstrated the proportion of patients reaching the IIEF-EF target (score≥22) was significantly higher in the vardenafil and tadalafil group than in the placebo group (Montorsi et al., 2008, 2014). In addition, significant improvements in key secondary efficacy end points of each domain of IIEF (orgasmic function, intercourse satisfaction, sexual desire and overall satisfaction) were observed for PDE5 inhibitors treatment group compared with placebo. 26
Safety data from the trials in this meta-analysis suggests that the incidence of the most frequent adverse events (headache, dyspepsia and flushing) observed in our study was comparable to previously published data for PDE5 inhibitors and, likewise, these adverse events were generally mild (Yuan et al., 2013). All the included RCTs indicated that no clinically significant changes in laboratory tests, electrocardiograms or blood pressure were observed in the PDE5 inhibitors groups. Subgroup analysis demonstrated that both short-term and long-term PDE5 inhibitors are effective treatment for ED after BNSRP. Besides, by dividing the included studies into on-demand and once-daily administration group, we could find that regardless of the administration method (on demand P = 0.0004 or once daily, P < 0.00001), PDE5 © 2015 Blackwell Verlag GmbH Andrologia 2016, 48, 20–28
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inhibitors are effective in treating ED after BNSRP. And sensitivity analysis suggested PDE5 inhibitors showed statistically significant improvement in the IIEF-EF domain score in both commencement of PDE5 inhibitor use of early period of postoperation and late period of postoperation group. However, PDE5 inhibitors have different pharmacokinetic properties (i.e. half-lives) that make the comparison/merge of results of comparisons of different treatment-options difficult. Further high-quality, prospective studies are required to confirm the observation. This meta-analysis includes studies which are all findings from randomised double-blind, placebo-controlled trials. According to the quality-assessment scale that we developed, the quality of the individual studies in the meta-analysis was conforming. The results of this analysis acquire great importance from scientific standpoint but also in the everyday clinical practice. However, the number of included studies was not many. The longer term safety, efficacy and persistence of PDE5 inhibitors cannot be extrapolated exactly from this article. In addition, the questions on the ultimate goal for patients with ED following nerve-sparing prostatectomy remains unanswered. Therefore the impact of PDE5 inhibitors on the recovery of natural erectile function will be one of the heated topics in the future that attract high-quality clinical research. These factors may have resulted in a bias. More high-quality trials with larger samples are proposed to learn more about the efficacy and safety of the therapy on ED after BNSRP. Conclusion This meta-analysis indicates that PDE5 inhibitors to be an effective and well-tolerated treatment for ED after BNSRP. Further high-quality, prospective studies are required to confirm this observation. Conflict of interest statement The authors had no conflicts of interest to declare in relation to this article. References Cialis (2011) Cialis (tadalafil) Tablets Prescribing Information. Eli Lilly and Company, Indianapolis, Indiana. Defade BP, Carson CC 3rd, Kennelly MJ (2011) Postprostatectomy erectile dysfunction: the role of penile rehabilitation. Rev Urol 13:6–13. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188. Ficarra V, Novara G, Ahlering TE, Costello A, Eastham JA, Graefen M, Guazzoni G, Menon M, Mottrie A, Patel VR
© 2015 Blackwell Verlag GmbH Andrologia 2016, 48, 20–28
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(2012) Systematic review and meta-analysis of studies reporting potency rates after robot-assisted radical prostatectomy. Eur Urol 62:418–430. Heidenreich A, Bastian PJ, Bellmunt J, Bolla M, Joniau S, van der Kwast T, Mason M, Matveev V, Wiegel T, Zattoni F (2014) EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol 65:467–479. Higgins JPT, Green S, editors. 2011 Cochrane handbook for systematic reviews of interventions, v.5.1. Cochrane Collaboration Web site. http://www.cochrane-handbook.org/ Jadad AR (1998) Randomized Controlled Trials. BMJ Publishing Group, London. Lagoda G, Jin L, Lehrfeld TJ, Liu T, Burnett AL (2007) FK506 and sildenafil promote erectile function recovery after cavernous nerve injury through antioxidative mechanisms. J Sex Med 4:908–916. Lagoda G, Sezen SF, Liu T, Hoke A, Burnett AL (2008) FK506-binding protein localizations in human penile innervation. BJU Int 101:604–609. Levitra (2011) Levitra (vardenafil HCL) Tablets Prescribing Information. Bayer HealthCare Pharmaceuticals, Wayne, New Jersey. Lue TF (2000) Erectile dysfunction. N Engl J Med 342: 1802–1813. Montorsi F, Guazzoni G, Strambi LF, Da Pozzo LF, Nava L, Barbieri L, Rigatti P, Pizzini G, Miani A (1997) Recovery of spontaneous erectile function after nerve-sparing radical retropubic prostatectomy with and without early intracavernous injections of alprostadil: results of a prospective, randomized trial. J Urol 158:1408–1410. Montorsi F, Nathan HP, McCullough A, Brock GB, Broderick G, Ahuja S, Whitaker S, Hoover A, Novack D, Murphy A (2004) Tadalafil in the treatment of erectile dysfunction following bilateral nerve sparing radical retropubic prostatectomy: a randomized, double-blind, placebo controlled trial. J Urol 172:1036–1041. Montorsi F, Brock G, Lee J, Shapiro J, Van Poppel H, Graefen M, Stief C (2008) Effect of nightly versus on-demand vardenafil on recovery of erectile function in men following bilateral nerve-sparing radical prostatectomy. Eur Urol 54:924–931. Montorsi F, Brock G, Stolzenburg JU, Mulhall J, Moncada I, Patel HR, Chevallier D, Krajka K, Henneges C, Dickson R (2014) Effects of tadalafil treatment on erectile function recovery following bilateral nerve-sparing radical prostatectomy: a randomised placebo-controlled study (REACTT). Eur Urol 65:587–596. Mulhall JP, Burnett AL, Wang R, McVary KT, Moul JW, Bowden CH, DiDonato K, Shih W, Day WW (2013) A phase 3, placebo controlled study of the safety and efficacy of avanafil for the treatment of erectile dysfunction after nerve sparing radical prostatectomy. J Urol 189:2229–2236. Mydlo JH, Viterbo R, Crispen P (2005) Use of combined intracorporal injection and a phosphodiesterase-5 inhibitor
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therapy for men with a suboptimal response to sildenafil and/or vardenafil mono-therapy after radical retropubic prostatectomy. BJU Int 95:843–846. Padma-Nathan H, McCullough AR, Levine LA, Lipshultz LI, Siegel R, Montorsi F, Giuliano F, Brock G (2008) Randomized, double-blind, placebo-controlled study of postoperative nightly sildenafil citrate for the prevention of erectile dysfunction after bilateral nerve-sparing radical prostatectomy. Int J Impot Res 20:479–486. Raina R, Lakin MM, Agarwal A, Sharma R, Goyal KK, Montague DK, Klein E, Zippe CD (2003) Long-term effect of sildenafil citrate on erectile dysfunction after radical prostatectomy:3-year follow-up. Urology 62:110–115. Salonia A, Burnett AL, Graefen M, Hatzimouratidis K, Montorsi F, Mulhall JP, Stief C (2012a) Prevention and management of postprostatectomy sexual dysfunctions. Part 1: choosing the right patient at the right time for the right surgery. Eur Urol 62:261–272. Salonia A, Burnett AL, Graefen M, Hatzimouratidis K, Montorsi F, Mulhall JP, Stief C (2012b) Prevention and management of postprostatectomy sexual dysfunctions part 2: recovery and preservation of erectile function, sexual desire, and orgasmic function. Eur Urol 62:273–286.
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Seo YE, Kim SD, Kim TH, Sung GT (2014) The efficacy and safety of tadalafil 5 mg once daily in the treatment of erectile dysfunction after robot-assisted laparoscopic radical prostatectomy: 1-Year follow-up. Korean J Urol 55:112–119. STENDRA (2012) STENDRA (avanafil) Tablets Prescribing Information. VIVUS, Inc, Mountain View, California. Viagra (2010) Viagra (sildenafil citrate) Tablets Prescribing In-Formation. Pfizer Labs, New York, New York. Walsh PC, Lepor H, Eggleston JC (1983) Radical prostatectomy with preservation of sexual function: anatomical and pathological considerations. Prostate 4:473. Walsh PC, Marschke P, Ricker D, Burnett AL (2000) Patient-reported urinary continence and sexual function after anatomic radical prostatectomy. Urology 55:58. Yuan J, Zhang R, Yang Z, Lee J, Liu Y, Tian J, Qin X, Ren Z, Ding H, Chen Q (2013) Comparative effectiveness and safety of oral phosphodiesterase type 5 inhibitors for erectile dysfunction: a systematic review and network meta-analysis. Eur Urol 63:902–912. Zippe CD, Pahlajani G (2007) Penile rehabilitation following radical prostatectomy: role of early intervention and chronic therapy. Urol Clin North Am 34:601–618.
© 2015 Blackwell Verlag GmbH Andrologia 2016, 48, 20–28
Efficacy and safety of phosphodiesterase type 5 (PDE5) inhibitors in treating erectile dysfunction after bilateral nerve-sparing radical prostatectomy Y. Cui, X. Liu#, L. Shi & Z. Gao Department of Urology, Yantai Yuhuangding Hospital Affiliated to Medical College of Qingdao University, Yantai, China
Keywords Bilateral nerve-sparing radical prostatectomy—erectile dysfunction sexual (penile) rehabilitation—meta-analysis—phosphodiesterase type 5 inhibitors Correspondence Zhenli Gao, NO.20 East Yuhuangding Road, 264000 Yantai, China. Tel.: 86-10-6691999 (O); Fax: 86-10-0535-6691999; E-mail: [email protected] #
Co-first author: Xinjie Liu.
Accepted: December 29, 2014 doi: 10.1111/and.12405
Summary We carried out a systematic review and meta-analysis to assess the efficacy and safety of phosphodiesterase type 5 (PDE5) inhibitors for treating erectile dysfunction (ED) after bilateral nerve-sparing radical prostatectomy (BNSRP). A literature review was performed to identify all published randomised doubleblind, placebo-controlled trials of PDE5 inhibitors for the treatment of ED after BNSRP. The search included the following databases: MEDLINE, EMBASE and the Cochrane Controlled Trials Register. The reference lists of the retrieved studies were also investigated. Six publications involving a total of 1678 patients were used in the analysis, including six RCTs that compared PDE5 inhibitors (tadalafil, sildenafil, avanafil and vardenafil) with placebo. Co-primary efficacy end points: International Index of Erectile Function-Erectile Function (IIEF-EF) domain score [the standardised mean difference (SMD) = 4.04, 95% confidence interval (CI) = 2.87–5.22, P < 0.00001]; successful vaginal penetration (SEP2) [the odds ratio (OR) = 14.87, 95% CI = 4.57–48.37, P < 0.00001]; and successful intercourse (SEP3) (OR = 47, 95%CI = 3–13.98, P < 0.00001) indicated that PDE5 inhibitors was more effective than the placebo. Specific adverse events with PDE5 inhibitors included headache (12.08%), dyspepsia (6.76%) and flushing (6.52%), which were significantly less likely to occur with placebo. This meta-analysis indicates that PDE5 inhibitors to be an effective and well-tolerated treatment for ED after BNSRP.
Introduction Nerve-sparing radical prostatectomy (NSRP) is a commonly used treatment for clinically localised prostate cancer in patients with a life expectancy ≥10 years (Heidenreich et al., 2014). Walsh et al. (1983, 2000) pioneered the technique of anatomical NSRP to preserve the anatomical structures responsible for urinary continence and penile erection. Notwithstanding improvements in surgical techniques, erectile dysfunction (ED) is a common sequela of NSRP (Ficarra et al., 2012; Salonia et al., 2012a,b). Treatment for postoperative ED historically has included the use of vacuum devices, intracavernosal and intra-urethral pharmacotherapy, or placement of a penile implant (Montorsi et al., 1997). Despite the benefit, pain, complications and inconvenience detract from the willingness of patients to use above methods regularly. The 20
advent of phosphodiesterase type 5 (PDE5) inhibitors (tadalafil, sildenafil, avanafil and vardenafil) has provided an oral treatment alternative to patients with post-prostatectomy ED (Viagra, 2010; Cialis, 2011; Levitra, 2011; STENDRA, 2012). So far, we are unaware of any systematic review and quantitative meta-analysis that has formally evaluated the safety and efficacy of PDE5 inhibitors in treating ED after bilateral NSRP (BNSRP). The goal of the present study was to perform a metaanalysis to evaluate the safety and efficacy of PDE5 inhibitors in treating ED after BNSRP. Materials and methods Search strategy Medline (1966 to June 2014), Embase (1974 to June 2014) and Cochrane Controlled Trials Register databases © 2015 Blackwell Verlag GmbH Andrologia 2016, 48, 20–28
PDE5i for ED after BNSRP
Y. Cui et al.
were searched to identify randomised controlled trials (RCTs) that referred to the impact of PDE5 inhibitors in treating ED after BNSRP; we also searched the reference lists of the retrieved studies. The following search terms were used: phosphodiesterase type 5 inhibitors, erectile dysfunction, bilateral nerve-sparing radical prostatectomy and randomised controlled trial. Inclusion criteria and trial selection Randomised controlled trials that met the following criteria were included: (i) The study design included treatment with PDE5 inhibitors; (ii) the study provided accurate data that could be analysed, including the total number of subjects and the values of each index; and (iii) the full text of the study could be accessed. When the same study was published in various journals or in different years, the most recent publication was used for the meta-analysis. If the same group of researchers studied a group of subjects with multiple experiments, then each study was included. A flow diagram of the study selection process is presented in Fig. 1. Quality assessment The quality of the retrieved RCTs, which included assessment of sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting of outcomes and other possible sources of bias, was assessed using the Jadad scale (Jadad, 1998). Only identified RCTs
with high quality were included in the meta-analysis. The methodological quality of each study was assessed according to how patients were allocated to the arms of the study, the concealment of allocation procedures, blinding and data loss due to attrition. The studies were then classified qualitatively according to the guidelines published in the Cochrane Handbook for Systematic Reviews of Interventions v.5.1.0 (Higgins & Green, 2011). Based on the quality-assessment criteria, each study was rated and assigned to one of the three following quality categories: A, if all quality criteria were adequately met, the study was deemed to have a low risk of bias; B, if one or more of the quality criteria was only partially met or was unclear, the study was deemed to have a moderate risk of bias; or C, if one or more of the criteria was not met or not included, the study was deemed to have a high risk of bias. Differences were resolved by discussion among the authors based on the quality-assessment criteria. Data extraction The following information was collected for each study: (i) the name of the first author and the publication year; (ii) the study design and sample size; (iii) the therapy that the patients received; (iv) the country in which the study was conducted; and (v) data including the International Index of Erectile Function-Erectile Function (IIEFEF) domain score, the successful vaginal penetration (SEP2) and successful intercourse (SEP3), headache, dyspepsia and flushing.
Fig. 1 A flow diagram of the study selection process. RCT: randomized controlled trial PDE5: phosphodiesterase type 5. ED: erectile dysfunction. BNSRP: bilateral nerve-sparing radical prostatectomy.
© 2015 Blackwell Verlag GmbH Andrologia 2016, 48, 20–28
21
22
sildenafil
vardenafil
avanafil
tadalafil
tadalafil
Padma-Nathan et al., 2008
Montorsi et al., 2008
Mulhall 2013
Seo et al., 2014
Montorsi et al., 2014
placebo
placebo
placebo
placebo
placebo
placebo
Therapy in control group
57.9
69.0
58.4
57.1
56.0
59.7
Age (median)
Nine European countries and Canada
Korea
US
Europe, US, Canada, South Africa
North America, France, Belgium, Australia
Canada, Germany, Italy, The Netherlands, Spain, UK, US
Country
ED, erectile dysfunction; BNSRP, bilateral nerve-sparing radical prostatectomy.
tadalafil
Montorsi et al., 2004
Study
Therapy in experimental group
Table 1 Study and patient characteristics
27
141
282
100
206
42
102
Control
30
98
409
40
201
Experimental
Sample size
Men 0.05, we considered the studies homogeneous and so chose a fixed-effect model for meta-analysis. Otherwise, a random-effect model was used. We quantified inconsistency using the I² statistic, which describes the proportion of heterogeneity across studies that is not due to chance, thus describing the extent of true inconsistency in results across trials (DerSimonian & Laird, 1986). I² < 25% reflects a small level of inconsistency, and I² > 50% reflects significant inconsistency. © 2015 Blackwell Verlag GmbH Andrologia 2016, 48, 20–28
The database search found 69 articles that could have been included in our meta-analysis. Based on the inclusion and exclusion criteria, 58 articles were excluded after reading the titles and abstracts of the articles. Five articles lacked useful data. In all, six articles involving a total of 1678 patients (Montorsi et al., 2004, 2008, 2014; PadmaNathan et al., 2008; Mulhall et al., 2013; Seo et al., 2014), reporting data from a total of six RCTs, were included in the analysis: two RCTs compared PDE5 inhibitors (tadalafil 20 mg on demand and avanafil 100 mg on demand) with a placebo over the short term (≤6 months), and four RCTs compared PDE5 inhibitors (sildenafil 50 mg once daily, avanafil 10 mg nightly or 10 mg on demand and tadalafil 20 mg on demand or 5 mg once daily) with a placebo over the long term (9–12 months) (Fig. 1). The baseline characteristics of the studies included in our meta-analysis are listed in Table 1. Quality of the individual studies All six RCTs were double blinded, and all described the randomisation processes that they had used. All included a power calculation to determine the optimal sample size (Table 2). The level of quality of each identified study was A (Table 2). The funnel plot provided a qualitative estimation of publication bias of the studies, and no evidence of bias was found (Fig. 2). Efficacy IIEF-EF domain score Four RCTs, representing 640 participants (369 in the PDE5 inhibitors group and 271 in the control group) included data on IIEF-EF domain score changes (Fig. 3). 23
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(a)
(b)
(c)
Fig. 3 Forest plots showing changes in (a) the IIEF-EF domain score, (b) SEP2 and (c) the SEP3 in the treatment studies. PDE5-Is: phosphodiesterase type 5 inhibitors IIEF-EF: International Index of Erectile Function- erectile function, SEP2: sexual encounter profile (SEP) question 2, SEP3: SEP question 3, SD:standard deviation, IY:inverse variance, MH:mantel haenszel, Clxonfidence interval.
According to our analysis, no heterogeneity was found among the trials (Fig. 3), and the effect size for metaanalysis was denoted as the SMD. The pooled estimate of SMD was 4.04, and the 95%CI was 2.87–5.22 (P < 0.00001). This result suggests that PDE5 inhibitors showed statistically significant improvement in the IIEFEF domain score compared with placebo. SEP 2 (successful vaginal penetration) and SEP 3 (successful intercourse) Two RCTs, representing 493 participants (295 in the PDE5 inhibitors group and 198 in the control group) included data on SEP 2 and SEP 3 changes (Fig. 3). No heterogeneity was found among the trials (Fig. 3), the pooled estimate of OR was 14.87 (95%CI was 4.57–48.37, P < 0.00001) and 6.47 (95%CI was 3.00–13.98, P < 0.00001) respectively. This result suggests that PDE5 inhibitors showed statistically significantly greater improvement in the SEP 2 and SEP 3 compared with placebo. Safety Headache, dyspepsia and flushing Six RCTs, representing 1678 participants (1060 in the PDE5 inhibitors group and 618 in the control group), 24
included the headache data (Fig. 4). The pooled estimate of OR was 2.86, and the 95%CI was 1.87–4.39 (P < 0.00001). And four RCTs, representing 1423 participants (932 in the PDE5 inhibitors group and 491 in the control group), included the dyspepsia data (Fig. 4). The pooled estimate of OR was 4.86, and the 95%CI was 2.28–10.36 (P < 0.0001). And three RCTs, representing 870 participants (537 in the PDE5 inhibitors group and 333 in the control group), included the flushing data (Fig. 4). The pooled estimate of OR was 5.64, and the 95%CI was 1.99–16.01 (P = 0.001). The result suggests that specific adverse events with PDE5 inhibitors included headache, dyspepsia and flushing were more likely occur with placebo. Subgroup analyses and sensitivity analysis According to the duration of treatment, we divided the included studies into short-term (≤6 months) and longterm (>6 months) treatment group. Our analysis indicated that PDE5 inhibitors showed significant improvement in the IIEF-EF domain score (SMD = 4.07, 95% CI = 2.68–5.47, P < 0.00001 and SMD = 3.97, 95% CI = 1.78–6.16, P = 0.0004) (Fig. 5) in both short-term and long-term treatment group. Sensitivity analysis was performed by dividing the included studies of postoperative PDE5 inhibitor use into two groups: the group of © 2015 Blackwell Verlag GmbH Andrologia 2016, 48, 20–28
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early postoperative use (≤4 weeks) and group of late postoperative use (≥6 months). Our analysis indicated that PDE5 inhibitors showed significant improvement in the IIEF-EF domain score (SMD = 3.97, 95%CI = 1.78 to 6.16, P = 0.0004 and SMD = 4.07, 95%CI = 2.68 to 5.47, P < 0.00001) (Fig. 5) in both treatment group. By dividing the included studies into on-demand and once-daily treatment groups, we found that PDE5 inhibitors significantly improved the IIEF-EF domain score (SMD = 4.07, 95%CI = 2.68 to 5.47, P < 0.00001 and SMD = 3.97, 95%CI = 1.78–6.16, P = 0.0004) (Fig. 5) in both ondemand and once-daily treatment group. Discussion Because of the widespread use of prostate specific antigen (PSA) screening, the number of younger patients diagnosed with localised prostate cancer is increasing. Consequently, the issue of postoperative preservation of erectile function is gaining increasing importance. The success of BNSRP provided the substantial evidence of the possibility of preserving erectile function after radical prostatectomy. As a result, specific ED treatment is
PDE5i for ED after BNSRP
necessary in a large proportion of patients undergoing the procedure. This systematic review and quantitative meta-analysis summarises the evidence from randomised controlled clinical trials regarding the efficacy and safety of PDE5 inhibitors (tadalafil, sildenafil, avanafil and vardenafil) for the treatment of ED after BNSRP. The mechanism of action of PDE5 inhibitors is related to the aetiology of ED after BNSRP. When neurologic injury occurs, penile hypoxia and fibrosis lead to the absence of spontaneous nocturnal erections, which decreases the release of nitric oxide (Zippe & Pahlajani, 2007; Defade et al., 2011). The decrease in nitric oxide production leads to a drop in the amount of available cyclic guanosine monophosphate (cGMP) (Raina et al., 2003; Padma-Nathan et al., 2008). PDE5 inhibitors inhibit PDE5, which metabolises cGMP, and this results in an increase in cGMP levels (Raina et al., 2003). This increase in the amount of cGMP coupled with nitric oxide induces corporal smooth muscle relaxation, and this leads to subsequent erection by allowing blood flow to the penis (Lue, 2000; Mydlo et al., 2005; Lagoda et al., 2007, 2008). The whole process requires nerve preservation, because if there is no cGMP,
(a)
(b)
(c)
Fig. 4 Forest plots showing changes in (a) the headache, (b) dyspepsia and (c) flushing in the treatment studies. PDE5-Is: phosphodiesterase type 5 inhibitors; MH:manteI haenszel, Clxonfidence interval.
© 2015 Blackwell Verlag GmbH Andrologia 2016, 48, 20–28
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(a)
(b)
(c)
Fig. 5 Forest plots showing changes in the IIEF-EF domain score in the treatment studies. PDE5-Is: phosphodiesterase type 5 inhibitors; IIEF-EF: International Index of Erectile Function- erectile function, SD:standard deviation, IY:inverse variance, CI:confidence interval.
there is no substrate for PDE5 to metabolise (Raina et al., 2003). Overall, compared with men receiving placebo, those allocated to the PDE5 inhibitors group had a significant improvement in IIEF-EF domain score and higher percentage of successful vaginal penetration and were more likely to have successful intercourse. Besides, Montorsi et al. conducted two RCTs and demonstrated the proportion of patients reaching the IIEF-EF target (score≥22) was significantly higher in the vardenafil and tadalafil group than in the placebo group (Montorsi et al., 2008, 2014). In addition, significant improvements in key secondary efficacy end points of each domain of IIEF (orgasmic function, intercourse satisfaction, sexual desire and overall satisfaction) were observed for PDE5 inhibitors treatment group compared with placebo. 26
Safety data from the trials in this meta-analysis suggests that the incidence of the most frequent adverse events (headache, dyspepsia and flushing) observed in our study was comparable to previously published data for PDE5 inhibitors and, likewise, these adverse events were generally mild (Yuan et al., 2013). All the included RCTs indicated that no clinically significant changes in laboratory tests, electrocardiograms or blood pressure were observed in the PDE5 inhibitors groups. Subgroup analysis demonstrated that both short-term and long-term PDE5 inhibitors are effective treatment for ED after BNSRP. Besides, by dividing the included studies into on-demand and once-daily administration group, we could find that regardless of the administration method (on demand P = 0.0004 or once daily, P < 0.00001), PDE5 © 2015 Blackwell Verlag GmbH Andrologia 2016, 48, 20–28
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inhibitors are effective in treating ED after BNSRP. And sensitivity analysis suggested PDE5 inhibitors showed statistically significant improvement in the IIEF-EF domain score in both commencement of PDE5 inhibitor use of early period of postoperation and late period of postoperation group. However, PDE5 inhibitors have different pharmacokinetic properties (i.e. half-lives) that make the comparison/merge of results of comparisons of different treatment-options difficult. Further high-quality, prospective studies are required to confirm the observation. This meta-analysis includes studies which are all findings from randomised double-blind, placebo-controlled trials. According to the quality-assessment scale that we developed, the quality of the individual studies in the meta-analysis was conforming. The results of this analysis acquire great importance from scientific standpoint but also in the everyday clinical practice. However, the number of included studies was not many. The longer term safety, efficacy and persistence of PDE5 inhibitors cannot be extrapolated exactly from this article. In addition, the questions on the ultimate goal for patients with ED following nerve-sparing prostatectomy remains unanswered. Therefore the impact of PDE5 inhibitors on the recovery of natural erectile function will be one of the heated topics in the future that attract high-quality clinical research. These factors may have resulted in a bias. More high-quality trials with larger samples are proposed to learn more about the efficacy and safety of the therapy on ED after BNSRP. Conclusion This meta-analysis indicates that PDE5 inhibitors to be an effective and well-tolerated treatment for ED after BNSRP. Further high-quality, prospective studies are required to confirm this observation. Conflict of interest statement The authors had no conflicts of interest to declare in relation to this article. References Cialis (2011) Cialis (tadalafil) Tablets Prescribing Information. Eli Lilly and Company, Indianapolis, Indiana. Defade BP, Carson CC 3rd, Kennelly MJ (2011) Postprostatectomy erectile dysfunction: the role of penile rehabilitation. Rev Urol 13:6–13. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188. Ficarra V, Novara G, Ahlering TE, Costello A, Eastham JA, Graefen M, Guazzoni G, Menon M, Mottrie A, Patel VR
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(2012) Systematic review and meta-analysis of studies reporting potency rates after robot-assisted radical prostatectomy. Eur Urol 62:418–430. Heidenreich A, Bastian PJ, Bellmunt J, Bolla M, Joniau S, van der Kwast T, Mason M, Matveev V, Wiegel T, Zattoni F (2014) EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol 65:467–479. Higgins JPT, Green S, editors. 2011 Cochrane handbook for systematic reviews of interventions, v.5.1. Cochrane Collaboration Web site. http://www.cochrane-handbook.org/ Jadad AR (1998) Randomized Controlled Trials. BMJ Publishing Group, London. Lagoda G, Jin L, Lehrfeld TJ, Liu T, Burnett AL (2007) FK506 and sildenafil promote erectile function recovery after cavernous nerve injury through antioxidative mechanisms. J Sex Med 4:908–916. Lagoda G, Sezen SF, Liu T, Hoke A, Burnett AL (2008) FK506-binding protein localizations in human penile innervation. BJU Int 101:604–609. Levitra (2011) Levitra (vardenafil HCL) Tablets Prescribing Information. Bayer HealthCare Pharmaceuticals, Wayne, New Jersey. Lue TF (2000) Erectile dysfunction. N Engl J Med 342: 1802–1813. Montorsi F, Guazzoni G, Strambi LF, Da Pozzo LF, Nava L, Barbieri L, Rigatti P, Pizzini G, Miani A (1997) Recovery of spontaneous erectile function after nerve-sparing radical retropubic prostatectomy with and without early intracavernous injections of alprostadil: results of a prospective, randomized trial. J Urol 158:1408–1410. Montorsi F, Nathan HP, McCullough A, Brock GB, Broderick G, Ahuja S, Whitaker S, Hoover A, Novack D, Murphy A (2004) Tadalafil in the treatment of erectile dysfunction following bilateral nerve sparing radical retropubic prostatectomy: a randomized, double-blind, placebo controlled trial. J Urol 172:1036–1041. Montorsi F, Brock G, Lee J, Shapiro J, Van Poppel H, Graefen M, Stief C (2008) Effect of nightly versus on-demand vardenafil on recovery of erectile function in men following bilateral nerve-sparing radical prostatectomy. Eur Urol 54:924–931. Montorsi F, Brock G, Stolzenburg JU, Mulhall J, Moncada I, Patel HR, Chevallier D, Krajka K, Henneges C, Dickson R (2014) Effects of tadalafil treatment on erectile function recovery following bilateral nerve-sparing radical prostatectomy: a randomised placebo-controlled study (REACTT). Eur Urol 65:587–596. Mulhall JP, Burnett AL, Wang R, McVary KT, Moul JW, Bowden CH, DiDonato K, Shih W, Day WW (2013) A phase 3, placebo controlled study of the safety and efficacy of avanafil for the treatment of erectile dysfunction after nerve sparing radical prostatectomy. J Urol 189:2229–2236. Mydlo JH, Viterbo R, Crispen P (2005) Use of combined intracorporal injection and a phosphodiesterase-5 inhibitor
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