Objective To assess the associations between statins and adverse events in primary prevention of cardiovascular disease and to examine how the associations vary by type and dosage of statins. Design Systematic review and meta-analysis. Data sources Studies were identified from previous systematic reviews and searched in Medline, Embase, and the Cochrane Central Register of Controlled Trials, up to August 2020. Review methods Randomised controlled trials in adults without a history of cardiovascular disease that compared statins with non-statin controls or compared different types or dosages of statins were included. Main outcome measures Primary outcomes were common adverse events: self-reported muscle symptoms, clinically confirmed muscle disorders, liver dysfunction, renal insufficiency, diabetes, and eye conditions. Secondary outcomes included myocardial infarction, stroke, and death from cardiovascular disease as measures of efficacy. Data synthesis A pairwise meta-analysis was conducted to calculate odds ratios and 95% confidence intervals for each outcome between statins and non-statin controls, and the absolute risk difference in the number of events per 10 000 patients treated for a year was estimated. A network meta-analysis was performed to compare the adverse effects of different types of statins. An Emax model based meta-analysis was used to examine the dose-response relationships of the adverse effects of each statin. Results 62 trials were included, with 120 456 participants followed up for an average of 3.9 years. Statins were associated with an increased risk of self-reported muscle symptoms (21 trials, odds ratio 1.06 (95% confidence interval 1.01 to 1.13); absolute risk difference 15 (95% confidence interval 1 to 29)), liver dysfunction (21 trials, odds ratio 1.33 (1.12 to 1.58); absolute risk difference 8 (3 to 14)), renal insufficiency (eight trials, odds ratio 1.14 (1.01 to 1.28); absolute risk difference 12 (1 to 24)), and eye conditions (six trials, odds ratio 1.23 (1.04 to 1.47); absolute risk difference 14 (2 to 29)) but were not associated with clinically confirmed muscle disorders or diabetes. The increased risks did not outweigh the reduction in the risk of major cardiovascular events. Atorvastatin, lovastatin, and rosuvastatin were individually associated with some adverse events, but few significant differences were found between types of statins. An Emax dose-response relationship was identified for the effect of atorvastatin on liver dysfunction, but the dose-response relationships for the other statins and adverse effects were inconclusive. Conclusions For primary prevention of cardiovascular disease, the risk of adverse events attributable to statins was low and did not outweigh their efficacy in preventing cardiovascular disease, suggesting that the benefit-to-harm balance of statins is generally favourable. Evidence to support tailoring the type or dosage of statins to account for safety concerns before starting treatment was limited. Systematic review registration PROSPERO CRD42020169955. Data sharing: Requests for data sharing should be sent to the corresponding author (james.sheppard@phc.ox.ac.uk).

中文翻译：

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他汀类药物与心血管疾病一级预防不良事件之间的关联：采用成对、网络和剂量反应荟萃分析的系统评价

目的 评估他汀类药物与心血管疾病一级预防不良事件之间的关联，并检查相关性如何因他汀类药物的类型和剂量而异。设计系统审查和荟萃分析。数据来源 研究从之前的系统评价中确定，并在 Medline、Embase 和 Cochrane Central Register of Controlled Trials 中检索，截至 2020 年 8 月。包括对照或比较不同类型或剂量的他汀类药物。主要结局指标主要结局是常见的不良事件：自我报告的肌肉症状、临床确诊的肌肉疾病、肝功能障碍、肾功能不全、糖尿病和眼部疾病。次要结局包括心肌梗塞、中风和心血管疾病导致的死亡，作为疗效的衡量标准。数据综合 进行配对荟萃分析以计算他汀类药物和非他汀类药物对照之间每个结果的优势比和 95% 置信区间，并估计每 10 000 名治疗一年的患者发生事件数量的绝对风险差异。进行网络荟萃分析以比较不同类型他汀类药物的不良反应。基于 Emax 模型的荟萃分析用于检查每种他汀类药物不良反应的剂量反应关系。结果 共纳入 62 项试验，120 456 名参与者平均随访 3.9 年。他汀类药物与自我报告的肌肉症状风险增加相关（21 项试验，优势比 1.06（95% 置信区间 1. 01 至 1.13)；绝对风险差异 15（95% 置信区间 1 至 29））、肝功能障碍（21 项试验，优势比 1.33（1.12 至 1.58）；绝对风险差异 8（3 至 14））、肾功能不全（八项试验，优势比 1.14） （1.01 至 1.28）；绝对风险差 12（1 至 24））和眼部状况（六项试验，优势比 1.23（1.04 至 1.47）；绝对风险差 14（2 至 29））但与临床证实的肌肉疾病或糖尿病。增加的风险并未超过主要心血管事件风险的降低。阿托伐他汀、洛伐他汀和瑞舒伐他汀分别与一些不良事件相关，但在他汀类药物之间几乎没有发现显着差异。确定了阿托伐他汀对肝功能障碍影响的 Emax 剂量反应关系，但其他他汀类药物和不良反应的剂量反应关系尚无定论。结论 对于心血管疾病的一级预防，他汀类药物引起的不良事件风险较低，且并未超过其预防心血管疾病的功效，表明他汀类药物的利弊平衡总体上是有利的。支持调整他汀类药物类型或剂量以在开始治疗前考虑安全问题的证据有限。系统审查注册 PROSPERO CRD42020169955。数据共享：数据共享请求应发送给通讯作者（james.sheppard@phc.ox.ac.uk）。归因于他汀类药物的不良事件风险较低，且并未超过其预防心血管疾病的功效，这表明他汀类药物的利弊平衡总体上是有利的。支持调整他汀类药物类型或剂量以在开始治疗前考虑安全问题的证据有限。系统审查注册 PROSPERO CRD42020169955。数据共享：数据共享请求应发送给通讯作者（james.sheppard@phc.ox.ac.uk）。归因于他汀类药物的不良事件风险较低，且并未超过其预防心血管疾病的功效，这表明他汀类药物的利弊平衡总体上是有利的。支持调整他汀类药物类型或剂量以在开始治疗前考虑安全问题的证据有限。系统审查注册 PROSPERO CRD42020169955。数据共享：数据共享请求应发送给通讯作者（james.sheppard@phc.ox.ac.uk）。