【作者】 丁鸿；

【导师】 陈清；

【作者基本信息】 南方医科大学 ， 流行病与卫生统计学， 2014， 博士

【摘要】 研究背景勃起功能障碍(Erectile dysfunction, ED)是指阴茎持续不能达到或维持足够的勃起以进行满意的性交。ED已成为困扰全球男性的重要疾病之一调查显示,约65%的被调查者称对自己的勃起硬度不满意。尽管ED是一种良性病变,但其影响患者的躯体和心理健康,并与患者的生活质量、性伴侣关系、家庭稳定密切相关。同时,ED给社会造成沉重的经济负担,据美国国家健康与营养状况调查,如果所有的患者都寻求药物治疗的话,仅美国每年花费在ED治疗上的费用就将高达150亿。研究发现,5型磷酸二酯酶抑制剂(Phosphodiesterase Type5Inhibitors, PDE5-Is)能够抑制环磷酸鸟苷(cGMP)的降解,使其作为第二信使在阴茎动脉及平滑肌细胞中发挥持久的作用,维持阴茎的长时间勃起。1998年美国辉瑞公司研发上市第一个高选择性PDE5-Is——西地那非(sildenafil,万艾可),此药的问世在ED治疗史上具有划时代的意义。目前,欧盟药品管理局批准作为ED有效治疗PDE5-Is药物有：西地那非(sildenafil,万艾可),他达拉非(tadalafil),伐地那(?)(vardenafil),阿伐那非(avanafil)。另外两种,乌地那非(udenafil)和米罗那非(mirodenafil)仅批准在韩国使用,罗地那(?)(Lodenafil)仍在进行临床试验。虽然大量临床试验表明PDE5-Is与安慰剂相比疗效确切、耐受性良好,适合多种临类型的ED患者,但是,由于不同PDE5-Is的药物成本、使用方式和不良反应等各异,临床医生在选择治疗方案时需要综合考虑各种PDE5-Is药物的相对疗效和安全性。遗憾的是目前尚无大型随机对照试验研究现有PDE5-Is药物相互之间的相对疗效和安全性。对于这种没有直接比较的证据或者需要从众多干预措施中选择对患者最佳干预措施的情况,研究者往往会从随机对照试验(random controlled trail, RCT)中寻找间接证据,将传统直接/头对头比较(direct/head to head comparison)和间接比较同时合并起来进行neta-分析。目前一般多用“网络meta-分析(network meta analysis)”进行合并,其主要功用是对多个能够直接或间接相联系的干预措施进行综合评价并排序。因此,借助网络meta-分析对多种药物进行评价并对其疗效或安全性进行排序,就能知道各种药物的优劣,筛选出最有效的PDE5-Is,最大限度的提高临床疗效,降低治疗成本和副反应。另外,研究证明ED的发生与男性年龄、吸烟,血压、血糖、血脂等升高、精神状态、种族、习俗、地域、社会经济状况等存在关联。ED的发生源于各种因素综合作用所引起的阴茎海绵体血液充盈障碍。有证据显示PDE5-Is的疗效在白种人中优于亚洲人,而美国黑人,西班牙裔美国男性和白种人相当。有研究发现,身体质量指数(body mass index, BMI)、ED严重程度／持续时间、不良生活方式、病因、合并症(动脉粥样硬化、糖尿病)等,也可能会影响PDE5-Is治疗效果,但此类研究较少,一些研究结果颇有争议。随着西地那非的普及和价格的下降,它被越来越多的ED患者选用,因此,明确各种PDE5-IS疗效的影响因素将会使更多ED患者从服药中真正获益。目前尚缺乏综合比较各种PDE5-Is治疗男性勃起功能障碍疗效和安全性的证据,也没有研究能够明确PDE5-Is疗效的影响因素,从而指导临床合理用药。尽管PDE5-Is已经被确定为ED治疗的一线口服药物,但缺少各种药物之间直接比较的证据。已进行的随机对照试验,由于样本含量的不同、研究人群的不同、疗效判断方法的不同等因素,出现了不同甚至相悖的研究结论。为解决上述问题,本研究分两个阶段进行：第一阶段,采用网络meta-分析方法对以往的文献进行综合分析,以期判定不同PDE5-Is之间的疗效的优劣,为PDE5-Is的临床安全用药提供更多参考,也为其他临床药物的循证评价提供分析思路；第二阶段,在第一阶段研究的基础上,采用采用综合研究因素和个体因素两水平的meta-回归分析方法,评价研究间异质性的大小及来源,进一步明确影响PDE5-Is疗效和安全性的影响因素。研究目的本研究的主要研究目的为：(1)对各种PDE5-Is治疗男性勃起功能障碍的疗效和安全性进行系统评价；(2)明确PDE5-Is疗效和安全性的影响因素,指导临床合理用药。材料和方法对Cochrane图书馆、PubMed、Embase等进行全面的计算机文献检索。纳入了对不同种类口服PDE5-Is治疗ED进行比较、或将口服PDE5-Is与安慰剂对照治疗ED进行比较的随机对照试验或交叉实验。本研究中纳入的病例被限定为普通人群中被诊断为ED的患者,种族、疾病的严重程度或患病时间不限,排除口服PDE5-Is但患有糖尿病或高血压的特定人群。本研究的主要观察终点为综合评估问卷问题1(Global Assessment Question, GAQ-1)评分及从基线状态到研究终止时国际勃起功能指数-勃起功能评分(International Index of Erectile Function erectile function, IIEF-EF)的改变情况。本研究的次要观察终点包括如下几项：(1)从基线状态到研究终止时性活动日记中性接触状况问题2(sexual encounter profile question2, SEP-2)评分的改变；(2)从基线状态到研究终止时性活动日记中性接触状况问题3(sexual encounter profile question2,SEP-3)评分的改变；(3)不良事件(adverse events, AEs)发生情况。效应量评估采用均数差(mean difference, MD)、相对危险度(relative risk, RR)及其95%可信区间(confidence intervals, CIs)来计算。同时还计算了绝对效应值及不同PDE5-Is的相对排序。对纳入的研究进行方法学质量评估使用的是Cochrane协作组偏倚评估工具,而对GAQ-1、IIEF-EF、SEP-2.及SEP-3证据质量的评估使用的是推荐等级的评估、制定与评价(Grading of Recommendations, Assessment, Development, and Evaluation, GRADE)系统。利用Cochrane协作组Review manager软件对效应比较结果进行传统的配对meta-分析。研究间存在异质性时,采用随机效应模型进行效应指标的合并。利用卡方检验和I2指数对研究的异质性进行评估。通过随机效应的meta-回归模型检测预先指定的研究因素在纳入研究间的相似性。采用Bucher方法来进行网络meta-分析的一致性检验。采用敏感性分析检测改变入选标准时对meta-分析结果的影响。绘制Funnel漏斗图并对其对称性进行观察以评估发表偏倚。本研究的数据统计采用STATA12.0,及Winbugs软件完成。结果共计118项临床试验研究(31195例患者)纳入疗效和安全性评价meta-分析。这些纳入的文献共涉及7种不同的PDE5-Is药物,包括：西地那非、他达拉非、伐地那非、乌地那非、米罗那非、阿伐那非及罗地那非。大多数纳入的研究中,PDE5-Is的应用剂量均在推荐剂量范围内。纳入研究的方法学总体质量评估为中等。利用GRADE系统对证据质量进行评估时,发现不同观察终点及进行不同比较时,证据质量各不相同。证据质量的降级因素主要是证据的非直接性和不精确,及纳入研究方法学质量的局限。由于随机效应模型分析所获得的估计效应比固定效应模型的估计效应具有更好的拟合优度,且更结果保守,因此本文中汇报的网络meta-分析结果为随机效应模型分析结果。传统meta-分析与网络meta-分析的结果之间并无明显的差异。网络meta-分析显示,与使用安慰剂对照相比,使用所有PDE5-Is均可显著增加GAQ-1阳性应答。与西地那非(73%vs46%; RR:0.63;95%CI:0.35-0.92)、他达拉非(75%vs46%；RR：0.61；95%CI：0.33～0.90)、伐地那非(73%vs46%; RR:0.63;95%CI:0.35-0.92)、及乌地那非(69%vs46%；RR：0.67；95%CI：0.37～0.99)相比,使用阿伐那非的GAQ-1阳性应答显著较低。在所有有效性观察终点中,绝对效应及相对排序分析结果显示,他达拉非和伐地那非为最有效的两种药物。在对治疗剂量进行校正后,该结果仍保持不变。不同种类PDE5-Is的安全性分析结果显示无太大差异。PDE5-Is引起的不良反应总体来说都比较轻微,最主要的不良反应包括：面红、头痛、消化不良等。除了他达拉非引起肌痛发生率比西地那非高外(RR：4.69；95%CI：1.39～14.21),各种PDE-5抑制剂的安全性特征均类似。用配对meta-分析对异质性进行检验,结果显示异质性为中等或较低。在所有观察终点中,将所有直接和间接数据进行合并分析后,有27个配对比较合并了直接证据及间接证据。其中有两对比较研究(即西地那非与伐地那非对GAQ-1影响的比较[P=0.0004],和他达拉非与西地那非对面红的影响[P=0.0007])经Bucher扩展检验分析后显示出不一致性。按纳入研究的药物剂量及方法学质量进行敏感性分析后显示各研究对GAQ-1和IIEF-EF的效应值并无大的影响。对漏斗图进行观察后,发现西地那非、伐地那非、和他达拉非对GAQ-1影响的漏斗图存在不对称,而其他观察终点的效力均未见不对称。共计93项临床试验研究(26139例患者)纳入疗效和安全性影响因素meta-回归分析。当所有的PDE5-Is被作为一个整体分析时,单变量neta-回归分析结果显示,相比于亚裔人种,白种人GAQ-1的RR值增加了23.061%(95%CI：7.104%～41.396%),而在治疗后IIEF-EF的MD增加了1.880(95%CI：1.071～2.689)。IIEF-EF的基线水平每增加一个单位,则GAQ-1值的RR减少5.138%(95%CI：-8.021%～-2.166%),同时,治疗后IIEF-EF的MD减少0.329(95%CI：-0.536--0.121)。勃起功能障碍病程与GAQ-1的RR显著相关(RR减少6.885%,95%CI：1.196%～12.895%),但与治疗后IIEF-EF的MD没有显著相关(MD变化为0.086,95%CI：-0.291～0.463)。其他因素,如年龄、体重、体质指数、身高、吸烟者的比例、饮酒者的比例和勃起功能障碍病因等因素与治疗效果没有显著关联。当所有的PDE5-Is被作为一个整体分析时,多变量meta-回归分析结果显示,种族和IIEF-EF的基线水平与GAQ-1的RR密切相关,与治疗后IIEF-EF水平的MD显著相关,这一点与单变量meta-回归分析的结果一致。具体来说,相比于亚裔,白种人GAQ-1的RR增加了15.636%(95%CI：0.858%～32.579%),而在治疗后IIEF-EF的MD增加了1.473(95%CI：0.406～2.338)。IIEF-EF的基线水平每增加一个单位,则GAQ-1值的RR减少5.635%(95%CI：-9.120%～-2.017%),同时,治疗后IIEF-EF的MD减少0.229(95%CI：-0.425～-0.042)。就整体而言,白种人的疗效优于亚裔人种,且IIEF-EF基线水平与疗效呈负相关。然而,就西地那非而言,不同种族治疗后IIEF-EF水平的疗效差异有统计学意义(MD变化为2.231,95%CI：0.173～-4.289)；就伐地那非而言,GAQ-1与IIEF-EF的基线水平相关(RR变化为-5.809%,95%CI:-10.943%～-0.379%)。按纳入研究的药物剂量及方法学质量进行敏感性分析后显示,各研究对GAQ-1和IIEF-EF的估计值并无大的影响。对漏斗图进行观察后,发现西地那非、伐地那非、和他达拉非对GAQ-1影响的漏斗图存在不对称,但治疗后IIEF-EF则不存在不对称。这一点也和Egger’s试验结果相符(GAQ-1值：P=0.001；治疗后HEF-EF: P=0.354)。结论在推荐剂量下,口服PDE5-Is在治疗ED上比安慰剂更为有效,而他达那非有效性似乎最高,其次为伐地那非。总体来说,PDE5-Is的安全性及耐受性均较好,且各具体PDE5-Is在安全性方面无太大差异。PDE5-Is对于白种人比亚裔更有效。同时,PDE5-Is对严重的勃起功能障碍患者比对病情较轻患者更有效。年龄、体重、体质指数、身高、合并症(糖尿病、高血压、前列腺增生和高脂血症)、吸烟、饮酒和勃起功能障碍的病因等因素与PDE5-Is的疗效相关性无统计学意义。更多还原

【Abstract】 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.更多还原