| Background Erectile dysfunction (ED), defined as the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual intercourse, is one of the most common sexual disorders among men. Past surveys indicate that about65%were not satisfied with the hardness of their erection. Although ED is a benign disease, but its impact on physical and mental health of the patient and with marked effects on their quality of life, the relationship between sexual partners and family stability.ED also causes a huge economic burden to society. According to the US National Health and Nutrition Examination Survey, the annual costs of ED treatment in the United States could reach＄15billion if all patients sought medical care. PDE5-Is blocking the PDE5enzyme that degrades cyclic guanosine monophosphate and thus results in the relaxation of smooth muscle in the corpus cavernosum, and finally increased blood flow and erection. A large number of studies were conducted after the introduction of PDE5-Is (sildenafil) in1998. Four PDE5-Is (sildenafil, vardenafil, tadalafil, and avanafil) are approved worldwide, and two agents (udenafil and mirodenafil) are approved only in Korea. Lodenafil, a new PDE5-I, is still undergoing clinical trials. However, available studies investigating the comparative effects of different PDE5-Is are limited. Given the variety of PDE5-Is available for prescription to ED patients and the limited evidence regarding the compara-tive efficacy of different PDE5-Is, it is hard for physicians to prescribe the best medicine.Unfortunately, there is no large randomized controlled trials of existing PDE5-Is about their relative efficacy and safety to each other. For evidence of this lack of direct comparison, or you need to select the best interventions for patients with numerous interventions from the randomized controlled trials (RCT), researchers often look for indirect evidence from RCT. Network meta-analysis, in the context of a systematic review, is a meta-analysis in which multiple treatments are compared using both direct comparisons of interventions within randomized controlled trials and indirect comparisons across trials based on a common comparator. Its main function is to do a comprehensive evaluation and sorting of the interventions based on a common comparator simultaneously. Thus, with the network meta-analysis method, we can know the pros and cons of various drugs, screening the most effective PDE5-Is, maximize clinical efficacy, and reduce treatment costs and side effects. As a multifactorial condition, ED is known to be associated with age, ethnicity, and comorbid conditions. Some studies suggested that the effectiveness of PDE5-Is seemed to be better in whites than Asians, but similar among black American, Hispanic American men and whites. Other factors like body mass index (BMI), disease severity/duration, etiology, and comorbidity may also influence the treatment effects, but the evidence has been lacking and some are rather controversial. Sildenafil, the oldest PDE5-Is, is now off-patent. This means that the price of sildenafil will decrease dramatically and it will be affordable for more ED patients. To identify factors that affect the effectiveness of PDE5-Is will affect even more patients.There is no authoritative evidence of comparison efficacy and safety of the different PDE5-Is for the treatment of erectile dysfunction, or research to define the factors affecting the efficacy of PDE5-Is to guide rational drug use. Oral PDE5-Is are currently the first-line therapy for ED, although available studies investigating the comparative effects of different PDE5-Is are limited. However, available studies come to different and even contrary study conclusions, due to the different sample sizes, different study populations, the efficacy determination method and the chance of the result. Therefore, this study will be conducted in two parts. The first part, we carried out a systematic review and network meta-analysis to compare the efficacy and safety between different PDE5-Is for the treatment of ED to draw more reliable conclusions, in order to solve the efficacy comparison between the different PDE5-Is, to provide more information for clinical drug safety using, and to provide an analysis of ideas for other clinical evidence-based evaluation of medicine. The second part, based on results, we carried out the univariate meta-regressions and multivariate meta-regressions to explore the factors that affect the effectiveness and safety, to evaluate the heterogeneity of PDE5-Is for the treatment of ED, to enhance the credibility and authenticity of the results.Objectives The specific objectives of this study are:(1) To compare the efficacy and safety of different classes of oral PDE5-Is for ED;2) To identify factors that affect the effectiveness and safety of PDE5-Is for the treatment of ED.Materials and methods We carried out an electronic search of Cochrane Library, PubMed, and Embase. We included randomized controlled trials that compared different oral PDE5-Is or oral PDE5-Is versus placebo for ED. The patients in this study were limited to the broad-spectrum population diagnosed with ED. Studies that examined the use of oral PDE5-Is in special population groups (eg, men with diabetes mellitus or hypertension) were excluded. The primary outcomes for this study were the Global Assessment Questionnaire question1(GAQ-1), and change from baseline to study end in the International Index of Erectile Function-Erectile Function domain score (IIEF-EF). The secondary outcomes included (1) change from baseline to study end in Sexual Encounter Profile question2(SEP-2),(2) change from baseline to study end in Sexual Encounter Profile question3(SEP-3), and (3) adverse events (AEs) that included the number of treatment-related adverse events, serious or severe adverse events, patients who experienced any adverse event (AE), and specific AEs. Summary effect size was calculated as mean difference (MD), relative risk (RR), together with their95%confidence intervals (CIs). We also calculated the absolute effects and the relative rank of different PDE5-Is to provide an overview of the efficacy and safety of all PDE5-Is. The methodological quality of included studies was appraised with the Cochrane Collaboration bias appraisal tool. The quality of evidence on GAQ-1, IIEF-EF, SEP-2, and SEP-3was evaluated using the Grading of Recommendations, Assess-ment, Development, and Evaluation (GRADE) system. The comparative effects were initially analyzed by the traditional pairwise meta-analysis method using Cochrane Collaboration review manager software. We applied a random-effects model that accounts for both within-and between-study variability to provide more conservative estimated effects. Heterogeneity among studies was assessed with the chi-square test and the I2index statistic. We explored the associations between the pre-specified study-level factors to the efficacy of PDE5-Is by a random effects meta-regression model. We applied an extension of the Bucher method to check the assumption of consistency. Sensitivity analyses were carried out according to dosage and quality of included studies. Publication bias was examined through visual inspection of funnel plots asymmetry. All the data analyses were undertaken by STATA12.Results118studies including31195patients were included in network meta-analysis. The included studies covered seven different PDE5-Is:sildenafil, tadalafll, vardenafil, udenafil, mirodena-fil, avanafil, and lodenafil. The dosages used in most included trials were within the recommended dose ranges. The overall methodological quality was moderate. The quality of evidence varies in different outcomes and comparisons as measured by the GRADE system. The grade of quality was downgraded primarily due to indirectness and imprecision. The network meta-analysis results reported in the main text are based on random-effects models because they generally showed better goodness of fit and more conservative estimated effects compared with fixed-effects models. There was no major difference between the traditional meta-analysis results and the network meta-analysis results. Network meta-analysis indicated that all of these PDE5-Is were associated with significantly higher GAQ-1positive responses than placebo. Compared with sildenafil (73%vs46%; RR:0.63;95%CI,0.35-0.92), tadalafil (75%vs46%; RR:0.61;95%CI,0.33-0.90), vardenafil (73%vs46%; RR:0.63;95%CI,0.35-0.92), and udenafil (69%vs46%; RR:0.67;95%CI:0.37-0.99), avanafil was associated with significantly lower GAQ-1positive responses. The absolute effects and rank test suggested that tadalafil was the most effective PDE5-I in terms of GAQ-1among the PDE5-Is compared, followed by vardenafil. After adjusting for dosage, the conclusion remained the same. Safety analysis showed there was no major difference among different agents. The safety between different classes of PDE-5inhibitors was similar, except tadalafil caused a higher incidence of myalgia than sildenafil (RR:4.69;95%CI,1.39-14.21). The test of heterogeneity in pairwise meta-analysis was generally moderate or small. Among all outcomes, there were27pairwise compar-isons when direct and indirect data were combined together, of which two comparisons showed inconsistency by the extension of the Bucher test:sildenafil versus vardenafil on GAQ-1(P=0.0004) and tadalafil versus sildenafil on flushing (P=0.0007). Sensitivity analysis of the drug dosage and the methodological quality of included studies did not show any major change on GAQ-1and IIEF-EF. Visual inspection suggested asymmetry in the sildenafil, varde-nafil, and tadalafil funnel plots for GAQ-1, but funnel plots on other efficacy outcomes did not show any asymmetry.93studies with26139patients were included in meta-regression analysis. When PDE5-Is were taken as a whole, meta-regressions demonstrated that ethnicity and baseline IIEF-EF were significantly associated with RR for GAQ-1and MD for post-treatment IIEF-EF; ED duration were significantly associated with MD for post-treatment IIEF-EF. Specifically, white ethnicity was associated with23.061%(95%CI:7.104%to41.396%) increase in RR for GAQ-1, and1.880(95%CI:1.071to2.689) score increase in MD for post-treatment IIEF-EF compare to Asian ethnicity; a one-score increase in baseline IIEF-EF was associated with5.138%(95%CI:-8.021%to-2.166%) reduction in RR for GAQ-1, and0.329(95%CI:-0.536to-0.121) score decrease in MD for post-treatment IIEF-EF. ED duration was significantly associated with RR for GAQ-1(%reduction in RR:6.885%;95%CI:1.196%to12.895%) but not with MD for post-treatment IIEF-EF (Change in MD:0.086;95%CI:-0.291to0.463). Other factors including age, weight, BMI, height, proportion of smokers, proportion of drinkers, and ED etiology showed no significant relationships with the treatment effect. When PDE5-Is taken as a whole, ethnicity and baseline IIEF-EF were significantly associated with RR for GAQ-1and MD for post-treatment IIEF-EF. This was consistent with the results from univariate meta-regressions. Specifically, the white ethnicity was associated with15.636%(95%CI:0.858%to32.579%) increase in RR for GAQ-1, and1.473(95%CI:0.406to2.338) score increase in MD for post-treatment IIEF-EF when compared to Asian ethnicity; A one-score increase in baseline IIEF-EF was associated with5.635%(95%CI:-9.120%to-2.017%) reduction in RR for GAQ-1, and0.229(95%CI:-0.425to-0.042) score decrease in MD for post-treatment IIEF-EF. In multivariate meta-regressions for individual PDE5-Is, white ethnicity was generally positively associated with the effectiveness compared to Asian ethnicity, and the baseline IIEF-EF was negatively associated the effectiveness. However, statistical significance was only achieved in the meta-regression of post-treatment IIEF-EF on ethnicity for sildenafil (Change in MD:2.231;95%CI:0.173to4.289), and GAQ-1on baseline IIEF-EF for vardenafil (%change in RR:-5.809%;95%CI:-10.943%to-0.379%). Sensitivity analysis according to drug dosage and the methodological quality of included studies did not show any major change on the regression results. Visual inspection suggested asymmetry in the funnel plots for GAQ-1but not post-treatment IIEF-EF, and this was confirmed by Egger’s test (GAQ-1:P=0.001; IIEF-EF:P=0.354).Conclusions For practitioners, the findings indicate that, in recommended dosage, oral PDE5-Is are more effective than placebo for ED. Tadalafil is likely to be the most effective PDE5-I for ED, followed by vardenafil. PDE5-Is are generally safe and well tolerated, and there is no major difference among them. PDE5-Is are more effective in whites than in Asians, and in graver ED patients than in lighter ones. Overall, PDE5-Is as a whole are more effective in whites than in Asians, and in graver ED patients than in lighter ones. Age, weight, BMI, height, comorbidity (diabetes mellitus, hypertension, benign prostatic hyperplasia, and hyperlipidemia), smoking, alcohol consumption, and ED etiology are unlikely to associate with the effectiveness of PED5-Is. |
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