Objective To assess the effect of contemporary menopausal hormone therapy on the risk of cardiovascular disease according to the route of administration and combination of hormones. Design Nationwide register based emulated target trial. Setting Swedish national registries. Participants 919 614 women aged 50-58 between 2007 and 2020 without hormone therapy use in the previous two years, identified from the Swedish population. Interventions 138 nested trials were designed, starting each month from July 2007 until December 2018. Using the prescription registry data for that specific month, women who had not used hormone therapy in the previous two years were assigned to one of eight treatment groups: oral combined continuous, oral combined sequential, oral unopposed oestrogen, oral oestrogen with local progestin, tibolone, transdermal combined, transdermal unopposed oestrogen, or non-initiators of menopausal hormone therapy. Main outcome measures Hazard ratios with 95% confidence intervals were estimated for venous thromboembolism, as well as for ischaemic heart disease, cerebral infarction, and myocardial infarction separately and as a composite cardiovascular disease outcome. Treatment effects were estimated by contrasting initiators and non-initiators in observational analogues to “intention-to-treat” analyses and continuous users versus never users in “per protocol” analyses. Results A total of 77 512 women were initiators of any menopausal hormone therapy and 842 102 women were non-initiators. 24 089 women had an event recorded during the follow-up: 10 360 (43.0%) had an ischaemic heart disease event, 4098 (17.0%) had a cerebral infarction event, 4312 (17.9%) had a myocardial infarction event, and 9196 (38.2%) had a venous thromboembolic event. In intention-to-treat analyses, tibolone was associated with an increased risk of cardiovascular disease (hazard ratio 1.52, 95% confidence interval 1.11 to 2.08) compared with non-initiators. Initiators of tibolone or oral oestrogen-progestin therapy had a higher risk of ischaemic heart disease (1.46 (1.00 to 2.14) and 1.21 (1.00 to 1.46), respectively). A higher risk of venous thromboembolism was observed for oral continuous oestrogen-progestin therapy (1.61, 1.35 to 1.92), sequential therapy (2.00, 1.61 to 2.49), and oestrogen-only therapy (1.57, 1.02 to 2.44). Additional results in per protocol analyses showed that use of tibolone was associated with a higher risk of cerebral infarction (1.97, 1.02 to 3.78) and myocardial infarction (1.94, 1.01 to 3.73). Conclusions Use of oral oestrogen-progestin therapy was associated with an increased risk of heart disease and venous thromboembolism, whereas the use of tibolone was associated with an increased risk of ischaemic heart disease, cerebral infarction, and myocardial infarction but not venous thromboembolism. These findings highlight the diverse effects of different hormone combinations and administration methods on the risk of cardiovascular disease. The analyses were based on data from different registries (Statistics Sweden and the National Board of Health and Welfare), and the data can be made available on reasonable request to each of the registry managers after an ethical approval from the Swedish Ethical Review Authority. The underlying code will be freely available at .

中文翻译：

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当代更年期激素治疗和心血管疾病风险：基于瑞典全国注册的模拟靶点试验


目的 根据给药途径和激素组合，评估现代绝经期激素治疗对心血管疾病风险的影响。设计 Nationwide 基于注册的模拟目标试验。设置 Swedish 国家注册处。参与者 919 614 名 50 年至 58 年间 2007-2020 岁女性在过去两年中没有使用激素治疗，从瑞典人群中确定。干预措施 设计了 138 项嵌套试验，从 2007 年 7 月到 2018 年 12 月每月开始。使用该特定月份的处方登记数据，将过去两年内未使用激素治疗的女性被分配到八个治疗组之一：口服联合连续、口服联合序贯、口服无拮抗雌激素、口服雌激素联合局部孕激素、替勃龙、透皮联合、透皮无拮抗雌激素或更年期激素治疗的非启动者。主要结局指标 分别估计静脉血栓栓塞以及缺血性心脏病、脑梗死和心肌梗死的风险比和 95% 置信区间，并作为复合心血管疾病结局。通过在观察类似物中对比发起者和非发起者来估计治疗效果，在“根据方案”分析中对比连续使用者与从未使用者。结果 共有 77 512 名女性是任何更年期激素治疗的启动者，842 102 名女性是非开始者。24 089 例女性在随访期间记录了事件： 10 360 例 （43.0%） 发生缺血性心脏病事件，4098 例 （17.0%） 发生脑梗死事件，4312 例 （17.9%） 发生心肌梗死事件，9196 例 （38.2%） 发生静脉血栓栓塞事件。 在意向治疗分析中，与非启动者相比，替勃龙与心血管疾病风险增加相关 （风险比 1.52,95% 置信区间 1.11 至 2.08）。替勃龙或口服雌激素-孕激素治疗的启动者患缺血性心脏病的风险更高 （分别为 1.46 （1.00 至 2.14） 和 1.21 （1.00 至 1.46）。口服连续雌激素-孕激素治疗 （1.61， 1.35 至 1.92）、序贯治疗 （2.00， 1.61 至 2.49） 和单纯雌激素治疗 （1.57， 1.02 至 2.44） 观察到静脉血栓栓塞的风险更高。根据方案分析的其他结果表明，使用替勃龙与脑梗塞 （1.97， 1.02 至 3.78） 和心肌梗塞 （1.94， 1.01 至 3.73） 的风险较高相关。结论 使用口服雌激素-孕激素治疗与心脏病和静脉血栓栓塞风险增加相关，而使用替勃龙与缺血性心脏病、脑梗死和心肌梗死风险增加相关，但与静脉血栓栓塞无关。这些发现强调了不同激素组合和给药方法对心血管疾病风险的不同影响。这些分析基于来自不同登记处（瑞典统计局和国家卫生与福利委员会）的数据，在获得瑞典道德审查局的道德批准后，可以向每个登记管理机构合理要求提供数据。底层代码将在.