An observational study combined data on HT use in 5 population-based Swedish cohort studies, with baseline investigations performed during the period 1987-2002. In total, 88 914 postmenopausal women who 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. 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 (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 percentile difference (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 precentilie difference (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.
A systematic review and meta-analysis including 28 studies with a total of 39 769 subjects reviewed completed randomised controlled trials assessing effect of hormone replacement therapy on subsequent risk of stroke.
Hormone replacement therapy (HT) was associated with significant increases in total stroke (OR 1.29; 95% confidence interval 1.13 to 1.47, n = 28), non-fatal stroke (1.23; 95% CI 1.06 to 1.44, n = 21), stroke leading to death or disability (1.56; 95% CI 1.11 to 2.20, n = 14), ischaemic stroke (1.29; 95% CI 1.06 to 1.56, n = 16), and a trend to more fatal stroke (1.28; 95% CI 0.87 to 1.88, n = 22). It was not associated with haemorrhagic stroke (1.07; 95% CI 0.65 to 1.75, n = 17) or transient ischaemic attack (1.02; 95% CI 0.78 to 1.34, n = 22). Statistical heterogeneity was not present in any analysis. In conclusion, hormone replacement therapy was associated with an increased risk of stroke, particularly of ischaemic type. Among subjects who had a stroke, those taking hormone replacement therapy seemed to have a worse outcome. HT cannot be recommended for the primary or secondary prevention of stroke.
A Cochrane review included 22 studies involving 43 637 women. Nearly 70% of the data was derived from two studies (HERS 1998; WHI 1998). Most participants were postmenopausal American women with at least some degree of comorbidity, and mean participant age in most studies was over 60 years. None of the studies focused on perimenopausal women. Combined continuous HT increased the risk of stroke (after 3 years' use: from 6 per 1000 to between 6 and 12 per 1000; RR 1.46, )5% CI 1.02 to 2.09; 2 trials, n=17 585). Oestrogen-only HT increased the risk of stroke (after 7 years' use: from 24 per 1000 to between 25 and 40 per 1000; RR 1.33, 95% CI 1.06 to 1.67; 1 trial, n=10 739).