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      Systematic Review and Meta-Analysis of the Use of Phosphodiesterase Type 5 Inhibitors for Treatment of Erectile Dysfunction following Bilateral Nerve-Sparing Radical Prostatectomy

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          Abstract

          Prostate cancer is relatively common cancer occurring in males. Radical prostatectomy (RP) is the most effective treatment for a localized tumor but erectile dysfunction (ED) is common complication, even when bilateral nerve-sparing RP (BNSRP) is performed. Clinical trials have shown varied effectiveness of phosphodiesterase type-5 inhibitors (PDE5-Is) for treatment of post-BNSRP ED, but there remains controversy over the application of this treatment and no formal systematic review and meta-analysis for the use of PDE5-Is for this condition has been conducted. This review was to systematically assess the efficacy and safety of oral PDE5-Is for post-BNSRP ED. A database search was conducted to identify randomized controlled trials (RCTs). The comparative efficacy of treatments was analyzed by fixed or random effect modeling. Erectile function was measured using the International Index of Erectile Function (IIEF), Sexual Encounter Profile (SEP) question-2, 3 and the Global Assessment Question (GAQ). The rate and incidence of adverse events (AEs) were determined. The quality of included studies was appraised using the Cochrane Collaboration bias appraisal tool. Eight RCTs were included in the analyses. PDE5-Is were effective for treating post-BNSRP ED compared to placebo when erectile function was determined using the IIEF score [mean difference (MD) 5.63, 95% confidence interval (CI) (4.26–6.99)], SEP-2 [relative risk (RR) 1.63, 95% CI (1.18–2.25) ], SEP-3 [RR 2.00, 95% CI (1.27–3.15) ] and GAQ [RR 3.35, 95% CI (2.68–4.67) ]. The subgroup analysis could find a trend that longer treatment duration, higher dosage, on-demand dosing, sildenafil and mild ED are associated with more responsiveness to PDE5-Is. PDE5-Is were overall well tolerated with headache being the most commonly reported AE. Our data provides compelling evidence for the use of PDE5-Is as a primary treatment for post-BNSRP ED. However, further studies are required to optomize usage parameters (such as dosage and duration of treatment).

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          Effect of nightly versus on-demand vardenafil on recovery of erectile function in men following bilateral nerve-sparing radical prostatectomy.

          To date, no data have been available from large, well-designed trials comparing on demand and nightly dosing of phosphodiesterase type 5 (PDE5) inhibitors on recovery of erectile function in postprostatectomy patients with erectile dysfunction (ED). To investigate the effect of early postoperative dosing with vardenafil, administered either nightly or on demand, compared with placebo on recovery of erectile function in men with ED following bilateral nerve-sparing radical prostatectomy (NSRP) surgery. A randomised, double-blind, double-dummy, multicentre, parallel group study conducted at 87 centres across Europe, Canada, South Africa, and the United States. For inclusion, patients had to be scheduled to undergo bilateral NSRP within 1 mo of screening and have a normal International Index of Erectile Function erectile function domain (IIEF-EF) score of > or =26 at screening. A total of 628 men, aged 18-64 yr, were randomised to treatment. Study design consisted of a 9-mo double-blind treatment period, a 2-mo single-blind washout period, and an optional 2-mo open-label period. Patients received placebo, nightly vardenafil, or on demand vardenafil. Primary outcome measure was the percentage of subjects with an IIEF-EF score of > or =22 after the 2-mo washout period. Secondary variables included mean per-patient success rates for Sexual Encounter Profile (SEP) questions 2 and 3. No statistically significant differences were observed among treatment groups in the proportion of patients with an IIEF-EF score of > or =22 or in SEP3 success rates after the washout period. On-demand vardenafil treatment resulted in significantly greater IIEF-EF scores and better SEP3 response rates than placebo over the entire treatment period. In this study of men with ED following bilateral NSRP, vardenafil was efficacious when used on demand, supporting a paradigm shift towards on demand dosing with PDE5 inhibitors in this patient group. European clinical trials database (EudraCT; available at http://eudract.emea.europa.eu/). 11336.
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            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.

            This study was aimed at assessing prospectively the effect of postoperative intracavernous injections of alprostadil on the recovery of spontaneous erectile function after nerve-sparing radical retropubic prostatectomy. A total of 30 potent patients with clinically localized prostate cancer (clinical stage B1 or B2, Gleason sum 7 or greater, prostatic specific antigen less than 20 ng./ml.) underwent nerve-sparing radical retropubic prostatectomy and was subsequently randomized to alprostadil injections 3 times per week for 12 weeks (group 1, 15 patients) or observation without any erectogenic treatment (group 2, 15 patients). Patients were assessed at the 6-month followup by sexual history, physical examination, color Doppler sonography of the cavernous arteries and polisomnographic recording of nocturnal erections. In group 1, 12 patients (80%) completed the entire treatment schedule and were evaluated at the long-term followup. Eight patients in this group (67%) reported the recovery of spontaneous erection sufficient for satisfactory sexual intercourse, compared with 3 patients (20%) in group 2. The difference between the 2 groups was statistically significant (p <0.01). In group 1, all but 1 patient reporting normal postoperative erections also showed normal erections at nocturnal testing, whereas color Doppler sonography demonstrated normal penile hemodynamics in all of them. In these patients, failures were the result of cavernous veno-occlusive dysfunction (2 cases, 17%) and cavernous nerve injury (2 cases, 17%). In group 2, patients with normal erections showed both normal nocturnal testing and penile hemodynamics, whereas failures were the result of cavernous veno-occlusive dysfunction (8 cases, 53%), cavernous arterial insufficiency (2 cases, 13%) or cavernous nerve injury (3 cases, 20%). Complications in patients treated with alprostadil injections accounted for 2 cases (13%) of a penile nodule and 1 further case (6%) of prolonged penile erection. Complications were not seen in group 2 patients. Early postoperative administration of alprostadil injections significantly increases the recovery rate of spontaneous erections after nerve-sparing radical retropubic prostatectomy. It is our belief that programmed vasoactive injections improve cavernous oxygenation, thereby limiting the development of hypoxia-induced tissue damage. The potential complications related to the use of intracavernous injections must be clearly explained to patients.
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              Potency, continence and complications in 3,477 consecutive radical retropubic prostatectomies.

              We report results in a series of 3,477 consecutive patients treated with anatomical nerve sparing radical retropubic prostatectomy (RRP) in terms of recovery of erectile function, urinary continence and postoperative complications. From May 1983 through February 2003, 1 surgeon (WJC) performed anatomical RRP using a unilateral or bilateral nerve sparing modification when possible. Urinary continence and recovery of erections were evaluated in men with a minimum followup of 18 months. Excluded from potency analysis were men who were not reliably potent before surgery, those who did not undergo a nerve sparing procedure and those who received postoperative adjuvant radiotherapy or hormonal therapy within 18 months of surgery. Other postoperative complications in this patient population were also evaluated. Erections sufficient for intercourse occurred in 76% of preoperatively potent men treated with bilateral (1,770) and 53% of men treated with unilateral or partial nerve sparing (64) surgery. Adequate erectile function was more common following bilateral than unilateral nerve sparing surgery in men younger than 70 years old (78% versus 53%, p = 0.001) compared with those 70 years old or older (52% versus 56%, p = 0.6). Recovery of urinary continence occurred in 93% of all men and was associated with younger age (p = 0.001) but not nerve sparing surgery, tumor stage, prostate specific antigen (PSA), Gleason grade or number of prior prostatectomies performed by the surgeon. Postoperative complications occurred in 320 (9%) of patients and were associated with older age (p <0.0001), nonnerve sparing surgery (p = 0.001), PSA era (p <0.0001) and surgeon experience. Complications were not significantly correlated with clinical stage, pathological stage, preoperative PSA or Gleason grade. There was no perioperative mortality. Nerve sparing RRP can be performed with favorable potency and urinary continence. Better results are achieved in younger men. Other complications are reduced with increasing surgeon experience.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                11 March 2014
                : 9
                : 3
                : e91327
                Affiliations
                [1 ]Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan city, Hubei province, P. R. China
                [2 ]Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan city, Hubei province, P. R. China
                [3 ]Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan city, Hubei province, P. R. China
                Eberhard-Karls University, Germany
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: XHZ XHW. Performed the experiments: XW TL QWH YPW. Analyzed the data: XW XHZ. Contributed reagents/materials/analysis tools: TL QWH YPW. Wrote the paper: XW XHZ XHW.

                Article
                PONE-D-13-46119
                10.1371/journal.pone.0091327
                3949994
                24618671
                3b85aed1-5ef8-4503-b134-e6d35365d5f9
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 4 November 2013
                : 9 February 2014
                Page count
                Pages: 10
                Funding
                X.H.Z. is supported by National Natural Science Foundation of China (N.81270843). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine
                Drugs and Devices
                Drug Information
                Endocrinology
                Oncology
                Cancer Treatment
                Oncology Agents
                Oral Medicine
                Surgery
                Surgical Oncology
                Urology
                Prostate Diseases
                Prostate Cancer

                Uncategorized
                Uncategorized

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