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Postmenopausal hormone therapy and risk of stroke: A pooled analysis of data from population-based cohort studies
PLOS Medicine ( IF 15.8 ) Pub Date : 2017-11-17 , DOI: 10.1371/journal.pmed.1002445
Germán D. Carrasquilla , Paolo Frumento , Anita Berglund , Christer Borgfeldt , Matteo Bottai , Chiara Chiavenna , Mats Eliasson , Gunnar Engström , Göran Hallmans , Jan-Håkan Jansson , Patrik K. Magnusson , Peter M. Nilsson , Nancy L. Pedersen , Alicja Wolk , Karin Leander

Background

Recent research indicates a favourable influence of postmenopausal hormone therapy (HT) if initiated early, but not late, on subclinical atherosclerosis. However, the clinical relevance of timing of HT initiation for hard end points such as stroke remains to be determined. Further, no previous research has considered the timing of initiation of HT in relation to haemorrhagic stroke risk. The importance of the route of administration, type, active ingredient, and duration of HT for stroke risk is also unclear. We aimed to assess the association between HT and risk of stroke, considering the timing of initiation, route of administration, type, active ingredient, and duration of HT.

Methods and findings

Data on HT use reported by the participants in 5 population-based Swedish cohort studies, with baseline investigations performed during the period 1987–2002, were combined in this observational study. In total, 88,914 postmenopausal women who reported data on HT use and had no previous cardiovascular disease diagnosis were included. Incident events of stroke (ischaemic, haemorrhagic, or unspecified) and haemorrhagic stroke were identified from national population registers. Laplace regression was employed to assess crude and multivariable-adjusted associations between HT and stroke risk by estimating percentile differences (PDs) with 95% confidence intervals (CIs). The fifth and first PDs were calculated for stroke and haemorrhagic stroke, respectively. Crude models were adjusted for age at baseline only. The final adjusted models included age at baseline, level of education, smoking status, body mass index, level of physical activity, and age at menopause onset. Additional variables evaluated for potential confounding were type of menopause, parity, use of oral contraceptives, alcohol consumption, hypertension, dyslipidaemia, diabetes, family history of cardiovascular disease, and cohort. During a median follow-up of 14.3 years, 6,371 first-time stroke events were recorded; of these, 1,080 were haemorrhagic. Following multivariable adjustment, early initiation (<5 years since menopause onset) of HT was associated with a longer stroke-free period than never use (fifth PD, 1.00 years; 95% CI 0.42 to 1.57), but there was no significant extension to the time period free of haemorrhagic stroke (first PD, 1.52 years; 95% CI −0.32 to 3.37). When considering timing as a continuous variable, the stroke-free and the haemorrhagic stroke-free periods were maximal if HT was initiated approximately 0–5 years from the onset of menopause. If single conjugated equine oestrogen HT was used, late initiation of HT was associated with a shorter stroke-free (fifth PD, −4.41 years; 95% CI −7.14 to −1.68) and haemorrhagic stroke-free (first PD, −9.51 years; 95% CI −12.77 to −6.24) period than never use. Combined HT when initiated late was significantly associated with a shorter haemorrhagic stroke-free period (first PD, −1.97 years; 95% CI −3.81 to −0.13), but not with a shorter stroke-free period (fifth PD, −1.21 years; 95% CI −3.11 to 0.68) than never use. Given the observational nature of this study, the possibility of uncontrolled confounding cannot be excluded. Further, immortal time bias, also related to the observational design, cannot be ruled out.

Conclusions

When initiated early in relation to menopause onset, HT was not associated with increased risk of incident stroke, regardless of the route of administration, type of HT, active ingredient, and duration. Generally, these findings held also for haemorrhagic stroke. Our results suggest that the initiation of HT 0–5 years after menopause onset, as compared to never use, is associated with a decreased risk of stroke and haemorrhagic stroke. Late initiation was associated with elevated risks of stroke and haemorrhagic stroke when conjugated equine oestrogen was used as single therapy. Late initiation of combined HT was associated with haemorrhagic stroke risk.



中文翻译:

绝经后激素治疗和中风风险:基于人群的队列研究数据的汇总分析

背景

最近的研究表明,如果尽早而不是晚开始绝经后激素治疗(HT),则会对亚临床动脉粥样硬化产生有利影响。但是,对于中风等硬性终点,HT起始时间的临床相关性尚待确定。此外,以前没有研究考虑与出血性中风风险相关的HT起始时间。尚不清楚中风风险的给药途径,类型,有效成分和HT持续时间的重要性。我们旨在评估HT与中风风险之间的相关性,考虑开始时间,给药途径,类型,有效成分和HT持续时间。

方法和发现

在这项观察性研究中,结合了5项基于人群的瑞典队列研究中参与者报告的HT使用数据,并在1987-2002年期间进行了基线研究。总共包括88,914名报告了HT使用数据且以前没有心血管疾病诊断的绝经后妇女。从国家人口登记册中识别出中风(缺血性,出血性或非特定性)和出血性中风的事件。通过估计具有95%置信区间(CI)的百分位数差异(PD),采用拉普拉斯回归来评估HT和中风风险之间的粗略和多变量调整关联。分别计算卒中和出血性卒中的第五和第一PD。粗模型仅针对基线年龄进行了调整。最终调整后的模型包括基线年龄,受教育水平,吸烟状况,体重指数,体育活动水平和更年期开始年龄。评估潜在混杂因素的其他变量包括更年期类型,均等,口服避孕药的使用,饮酒,高血压,血脂异常,糖尿病,心血管疾病家族史和队列研究。在14。3年的中位随访期间,记录了6,371例首次中风事件;其中1,080例出血。经过多变量调整后,HT的早期开始(距绝经后<5年)与无卒中期相比从未使用更长(第五PD,1.00年; 95%CI 0.42至1.57),但没有明显延长。无出血性中风的时间段(首次PD,1.52年; 95%CI -0.32至3.37)。当考虑作为连续变量的时间时,如果从绝经开始大约0-5年开始HT,则无卒中和出血性无卒中的周期最大。如果使用单一共轭马雌激素HT,则HT的较晚开始与较短的无卒中发作(第五PD,−4.41年; 95%CI −7.14至−1.68)和无出血的卒中(第一PD,−9.51年)相关。 ; 95%CI -12.77至-6.24)期间比从未使用过。迟发的联合HT与出血性无卒中期较短(第一次PD,-1.97年; 95%CI -3.81至-0.13)显着相关,但与较短的无卒中期没有关系(第五PD,-1.21年) ; 95%CI −3.11至0.68)比从不使用。鉴于这项研究的观察性质,不能排除不受控制的混杂的可能性。此外,不朽的时间偏差,

结论

与绝经期发作有关的早期启动时,无论给药途径,HT类型,有效成分和持续时间如何,HT均与发生中风的风险增加无关。通常,这些发现也适用于出血性中风。我们的结果表明,绝经后0-5年开始HT的发生(与从不使用相比)与中风和出血性中风的风险降低相关。当使用结合的马雌激素作为单一疗法时,延迟开始与中风和出血性中风的风险升高相关。合并HT的较晚开始与出血性中风的风险有关。

更新日期:2017-12-01
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