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Study Question: Does the use of post-menopausal vaginal estradiol (VE) affect the mortality risk for coronary heart disease (CHD) and stroke., Summary Answer: The use of VE reduces the risk for cardiovascular mortality., What Is Known Already: A growing number of women use VE for post-menopausal genitourinary symptoms. Although this therapy is intended to have only local effects, estrogen is absorbed into the blood circulation and thus VE use may also have systemic effects., Study Design, Size, Duration: We studied a nationwide cohort in Finland 1994-2009 during which post-menopausal women (n = 195 756) initiated the use of VE (age [mean ± SD] 65.7 ± 10.9 years). Follow-up data gathered 1.4 million women-years and we assessed the mortality risk due to CHD (n= 9656) or stroke (n = 4294)., Participants/materials, Setting, Methods: The mortality risk in VE users was compared with that in the age-matched background population (standardized mortality ratio; [SMR]; 95% confidence interval) and related to various durations of exposure to VE (1 to ≤3, >3 to ≤5, >5 to ≤10 and >10 years)., Main Results and the Role of Chance: The use of VE was accompanied by decreases in the risk for CHD and stroke death. The risk reduction for CHD death was highest for >3 to ≤5 years exposure (SMR 0.64; 0.57-0.70) and for stroke for >5 to ≤10 years exposure (SMR 0.64; 0.57-0.72). The risk reductions for both CHD and stroke mortality were detected in all age groups with the highest risk reduction being in women aged 50-59 years (SMR 0.43; 0.19-0.88 and SMR 0.21; 0.06-0.58, respectively)., Limitations, Reasons for Caution: Our series lack a placebo arm and thus, may harbor a healthy woman bias. Moreover, data on clinical variables such as weight, smoking, blood pressure and family background were unobtainable for this study. Women using both VE and systemic hormone therapy (HT) were included in the comparator background population. This should not cause any significant error because the proportion of women using VE or other HT was modest (<10% in age-matched population) and because the use of systemic HT also reduces death risks in the same population. Our data cannot be directly applied for local regimens containing conjugated equine estrogens, because they are absorbed differently and may show effects that differ from those of estradiol., Wider Implications of the Findings: In 1000 women using VE for up to 10 years, a maximum of 24 fewer CHD deaths and 18 fewer stroke deaths is likely to occur., Study Funding/competing Interests: This work was supported by unrestricted grants from the Päivikki and Sakari Sohlberg Foundation, the Emil Aaltonen Foundation, the Finnish Medical Foundation, Finska Läkaresällskapet, the Orion Farmos Research Foundation, the Paavo Nurmi Foundation and a special governmental grant for health sciences research. The funding sources had no role in the study design, data handling or manuscript preparation. EPID Research is a company that performs financially supported studies for several pharmaceutical companies. Dr Korhonen, Dr Hoti and MSc Vattulainen, employed by Epid Research, report financial activities from several other pharmaceutical companies outside the submitted work. Dr Mikkola has been a speaker and/or received consulting fees from Mylan and Novo Nordisk. Dr Tuomikoski has been a speaker and/or received consulting fees from Orion and Mylan. The remaining authors report no conflict of interest., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: To assess whether coronary heart disease mortality in Finnish hormone therapy (HT) users differed before and after 2002 when the Women's Health Initiative study was published., Methods: The risks of coronary heart disease death in HT users in relation to the age-matched background population were compared between the pre- (1995-2001) and post- (2002-2009) Women's Health Initiative eras. We used a nationwide register on HT (ie, estradiol with or without progestin) reimbursement and linked them to causes of death in 290,272 women aged 40 years or older., Results: Exposure to HT for 1 year or less was accompanied by a 29% reduction (0.71; 0.63-0.80; three per 10,000 fewer deaths) and an exposure of 1-8 years with a 43% reduction (0.57; 0.48-0.66; three per 10,000 fewer deaths) in the risk of coronary heart disease death in the pre-Women's Health Initiative era. In the post-Women's Health Initiative era, HT use of 1 year or less was associated with an 18% reduction (0.82; 0.76-1.00; one per 10,000 fewer deaths) and an exposure of 1-8 years with a 54% reduction (0.46; 0.32-0.64; two per 10,000 fewer deaths) in coronary heart disease mortality. Discontinuation of HT was associated with an increased risk of cardiac death of 42% (1.42; 1.17-1.71; seven per 10,000 extra deaths) in the pre-Women's Health Initiative era and 31% (1.31; 0.92-1.82; two per 10,000 extra deaths) in the post-Women's Health Initiative era during the first posttreatment year. This risk increase vanished in further follow-up during both eras., Conclusion: Changes in HT use after the Women's Health Initiative failed to affect coronary heart disease mortality of HT users in this nationwide study.