Prospective controlled cohort study on the safety of a monophasic oral contraceptive containing nomegestrol acetate (2.5mg) and 17β-oestradiol (1.5mg) (PRO-E2 study): risk of venous and arterial thromboembolism

To assess and compare the risk of venous thromboembolism (VTE) and arterial thromboembolism (ATE) in NOMAC-E2 users with levonorgestrel-containing combined oral contraceptive (COCLNG) users. This large, prospective, observational active surveillance study used a non-inferiority design. New users of NOMAC-E2 and COCLNG were recruited in 12 countries in Australia, Europe, and Latin America. Women were followed up directly and self-reported outcomes of interest were validated via treating physicians. The main outcome of interest was VTE, specifically deep venous thrombosis of the lower extremities (DVT) and pulmonary embolism (PE). Secondary outcomes included all VTE and ATE. Data on confounders were captured and independent blinded adjudication assessed the classification of events. Incidence rates, crude (HRcrude), and adjusted (HRadj) hazard ratios were calculated. A total of 101,498 women (49,598 NOMAC-E2 users and 51,900 COCLNG users) were enrolled and followed for up to 2 years (144,901 WY of observation). NOMAC-E2 users had a higher mean age (31.0 ± 8.63 years) than COCLNG users (29.3 ± 8.53 years) but other baseline characteristics were similar between the cohorts. The main analysis comparing the risk of DVT of the lower extremities and PE in NOMAC-E2 users versus COCLNG users yielded an HRadj of 0.59 (95% CI, 0.25–1.35) (adjusted for age, BMI, family history of VTE, and current duration of use). The risk of all VTE and ATE was not higher in NOMAC-E2 users compared with COCLNG users. NOMAC-E2 use was not associated with a higher risk of VTE or ATE compared with COCLNG.

本研究旨在评估并比较使用NOMAC-E2与含左炔诺孕酮复方口服避孕药（levonorgestrel-containing combined oral contraceptive, COCLNG）人群的静脉血栓栓塞症（venous thromboembolism, VTE）与动脉血栓栓塞症（arterial thromboembolism, ATE）发病风险。本项大规模前瞻性观察性主动监测研究采用非劣效性研究设计。研究于澳大利亚、欧洲及拉丁美洲共12个国家招募NOMAC-E2与COCLNG的初始使用者。研究对象接受直接随访，受试者自行报告的目标结局由接诊医师进行验证。本次研究的主要目标结局为VTE，具体包括下肢深静脉血栓形成（deep venous thrombosis of the lower extremities, DVT）与肺栓塞（pulmonary embolism, PE）。次要结局涵盖所有VTE与ATE事件。研究收集了混杂因素相关数据，并由独立盲法评审团队对事件分类进行评估。研究计算了发病率、粗危险比（crude hazard ratio, HRcrude）与校正后危险比（adjusted hazard ratio, HRadj）。最终共有101498名女性纳入研究并接受最长2年的随访（总观察人年数为144901人年）。NOMAC-E2使用者的平均年龄（31.0±8.63岁）高于COCLNG使用者（29.3±8.53岁），但两组队列的其他基线特征均相似。针对NOMAC-E2使用者与COCLNG使用者的下肢深静脉血栓形成及肺栓塞发病风险进行比较的主要分析结果显示，校正后危险比（HRadj）为0.59（95%置信区间：0.25~1.35），校正因素包括年龄、体质量指数（body mass index, BMI）、VTE家族史及当前用药时长。与COCLNG使用者相比，NOMAC-E2使用者的全量VTE与ATE发病风险并未升高。与COCLNG相比，使用NOMAC-E2并未伴随更高的VTE或ATE发病风险。