An Epidemiologic Evaluation of Adverse Events of 5-Alpha-Reductase Inhibitors

描述(由申请人提供)：我们建议对5-阿尔法还原酶抑制剂(5ARIs)进行一项有害流行病学研究，以解决使用这些上市药物出现的安全问题(永久性副作用，抑郁症)，目前正考虑将这些药物扩大用于健康男性，作为前列腺癌化学预防的药物。为了经济高效地提供所需的安全信息，这项研究将通过分析大型电子病历数据库-英国的临床实践研究数据链(CPRD)来检查不良事件(AEs)的发生。CPRD是世界上使用最广泛的药物流行病学研究资源。在对这个非常大的数据库(1100万患者，4500万患者年)的初步分析中，我们确定了超过5.8万名有问题的药物类别的使用者，平均随访时间约为10年。除了研究事件的风险，这项拟议的研究将是第一次研究与两种药物(非那雄胺和度他雄胺)有关的症状持久性，并且将是最大的 迄今为止此类流行病学研究。我们建议研究AEs的4个主题组的发生：1)勃起功能障碍(ED)；2)非ED性功能障碍(射精和性心理功能障碍、性欲低下、Peyronie病)；3)乳房结局(良性/恶性乳腺疾病)；以及4)抑郁症，采用纵向流行病学方法。除了专注于事件事件的回顾性队列研究外，我们还将检验性功能障碍结局和停药后抑郁的持久性/持久性，以及持久性的危险因素。我们的分析旨在对接受不同药物治疗的良性前列腺增生症(BPH)患者进行比较(非那雄胺、度他雄胺和α-受体阻滞剂)，以说明BPH对预后的潜在影响。我们将在我们的分析中使用CPRD提供的各种医疗和行为因素来检查潜在的混淆，包括使用新的方法，如高维倾向评分分析。我们的研究团队由男性衰老流行病学、与性功能和下尿路症状相关的药物流行病学以及前列腺增生症的临床治疗方面的专家组成。在CPRD的药物流行病学应用方面，PI可以立即获得并拥有25年的经验。我们建议的研究的其他优势包括其庞大的规模、使用医疗记录(避免需要依赖于患者回忆处方和避免使用医疗索赔的问题)、纵向设计、能够将5ARI与其他治疗进行比较的能力，以及用于混淆控制的丰富的基础数据集。这项研究对公共卫生的贡献是，在进一步扩大到健康男性进行化学预防之前，迅速告知5ARI类别目前批准的适应症的安全概况。

DESCRIPTION (provided by applicant): We propose a harmacoepidemiologic study of 5-alpha-reductase inhibitors (5ARIs) to address emerging safety concerns (permanent sexual side effects, depression) with use of these marketed drugs, presently being considered for expanded use in healthy men as agents of prostate cancer chemoprevention. In order to cost- efficiently deliver needed safety information, this research will examine the occurrence of adverse events (AEs) via analysis of a large electronic medical records database, the UK-based Clinical Practice Research Datalink (CPRD). The CPRD is the most widely-used resource for pharmacoepidemiologic research in the world. In preliminary analyses of this very large database (11M patients, 45M patient-years), we have identified over 58,000 users of the drug class in question with on average approximately 10 years of follow-up time. In addition to studying risk of events, the proposed study will be the first to study symptom persistence in relation to both types of drugs in the class (finasteride and dutasteride), and will be the largest epidemiologic study of its kind to date. We propose to examine the occurrence of 4 thematic groups of AEs: 1) erectile dysfunction (ED); 2) non- ED sexual dysfunction (ejaculatory and psychosexual dysfunction, low libido, Peyronie's disease); 3) breast outcomes (benign/malignant breast diseases), and 4) depression, using longitudinal epidemiologic approaches. In addition to a retrospective cohort study focused on incident events, we will examine the persistence/permanency of sexual dysfunction outcomes and depression following drug cessation, and risk factors for permanency. Our analyses are designed such that men under various drug treatments for benign prostatic hyperplasia (BPH) are compared (finasteride, dutasteride, and alpha-blockers) to account for the underlying influence of BPH on outcomes. We will examine potential confounding in our analysis using the wide variety of medical and behavioral factors available in CPRD, including use of novel methods such as high-dimensional propensity score analysis. Our research team is comprised of experts in the epidemiology of male aging, pharmacoepidemiology relating to sexual function and lower urinary tract symptoms, and clinical treatment of BPH. The PI has immediate access and >25 years of experience in pharmacoepidemiologic utilization of the CPRD. Other strengths of our proposed study include its large size, use of medical records (avoiding the need to rely on patient recall o prescriptions and avoidance of problems with use of medical claims), longitudinal design, the ability to compare 5ARIs to other treatments, and the richness of the underlying dataset for confounder control. The public health contribution of the study is to quickly to inform the safety profile of the 5ARI class for currently-approved indications before further expansion to healthy men for chemoprevention.