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Hormone therapy and stroke: is it all about timing?

ABSTRACT: Although women have a lower incidence of stroke than men in most age groups, women have an overall increased lifetime risk of stroke. Women also have unique risk factors for stroke, including the menopausal transition, the existence of debilitating vasomotor symptoms for some women, and the issues related to hormonal treatment for those symptoms. Although the initial studies of hormone therapy (HT) use in postmenopausal women suggested significant protection against heart disease, there was no obvious protection against stroke. Randomized trials of HT for secondary prevention showed a lack of benefit for both heart disease and stroke, and the suggestion of some early risk after initiation. However, the Women's Health Initiative (WHI), a primary prevention study of the impact of HT on women aged 50 to 79 years, showed an increased risk of stroke, whether the HT was estrogen alone or estrogen combined with progestin. Therefore, HT is not recommended for stroke prevention, and it appears to cause harm. The reason for this increased stroke risk is not understood, but some have suggested that the initiation of HT closest to the time of menopausal transition should decrease the risk. Although there was a lower risk of heart disease when HT was initiated earlier, the risk appeared to be the same for stroke regardless of the timing. This was shown in both the WHI and the Nurses' Health Study cohorts. Therefore, more research is needed to understand the mechanisms for the increased stroke risk and to identify those who may be at risk because of HT for vasomotor symptoms, atrophic vaginitis, or osteoporosis, the three remaining indications for HT use in women. Trials are under way to assess the intermediate outcomes of HT on subclinical vascular disease in perimenopausal/early postmenopausal women.

SUBMITTER: Bushnell C

PROVIDER: S-EPMC3074540 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Hormone therapy and stroke: is it all about timing?

Bushnell Cheryl C

Current treatment options in cardiovascular medicine 20090601 3

Although women have a lower incidence of stroke than men in most age groups, women have an overall increased lifetime risk of stroke. Women also have unique risk factors for stroke, including the menopausal transition, the existence of debilitating vasomotor symptoms for some women, and the issues related to hormonal treatment for those symptoms. Although the initial studies of hormone therapy (HT) use in postmenopausal women suggested significant protection against heart disease, there was no o ...[more]

PMID: 19433019

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Project description:BackgroundThe 'Timing Hypothesis' states that the benefits and harms of hormone replacement therapy (HRT) are related to the proximity with which it is begun following the onset of menopause. The primary aim of this analysis was to test for heterogeneity of treatment effect for HRT using Chi2 and I2 tests for younger versus older initiators of HRT. The secondary aim was to perform a meta-regression with mean age at trial baseline as the covariate for various outcomes.MethodsYounger initiation trials were defined as those with mean age of participants <60 years and older initiation trials were those with mean age >60 years. The primary endpoints included all-cause mortality, cardiac mortality, coronary heart disease (CHD) events (a composite of cardiac mortality and nonfatal myocardial (MI)), and a composite of stroke, transient ischemic attack (TIA) and systemic embolism.ResultsThirty-one RCTs were identified comparing HRT users to nonusers (n = 40,521). There was significant heterogeneity of treatment effect between younger versus older HRT initiators for all-cause mortality (Chi2 = 9.74, p = 0.002, I2 = 89.7%), cardiac mortality (Chi2 = 4.04, p = 0.04, I2 = 75.2%), and CHD events (Chi2 = 3.06, p = 0.08, I2 = 67.3%). Both groups experienced an increase in stroke, TIA and systemic embolism (1112/18,774 in the HRT group versus 734/18,070 in the control group; OR = 1.52; 95% confidence interval (CI) = 1.38-1.67). When performing the meta-regression, as age increased the treatment effect of HRT was increased for stroke, TIA and systemic embolism (point estimate 0.006 with a standard error of 0.002) (p = 0.0003).ConclusionYounger initiation of HRT may be effective in reducing death and cardiac events. However, younger HRT initiators remained at an increased risk of stroke, TIA and systemic embolism and this risk increased as average age increased. Younger menopausal women using HRT to treat vasomotor symptoms do not appear to be at an increased risk of dying or experiencing CHD events.

Project description:BackgroundGenome-wide association studies have identified several genomic regions that are associated with stroke risk, but these provide an explanation for only a small fraction of familial stroke aggregation. Genotype by environment interactions may contribute further to such an explanation. The Women's Health Initiative (WHI) clinical trial found increased stroke risk with postmenopausal hormone therapy (HT) and provides an efficient setting for evaluating genotype-HT interaction on stroke risk.MethodsWe examined HT by genotype interactions for 392 SNPs selected from candidate gene studies, and 2,371 SNPs associated with changes in blood protein concentrations after hormone therapy, in analyses that included 2,045 postmenopausal women who developed stroke during WHI clinical trial and observational study follow-up and one-to-one matched controls. A two-stage procedure was implemented where SNPs passing the first stage screening based on marginal association with stroke risk were tested in the second stage for interaction with HT using case-only analysis.ResultsThe two-stage procedure identified two SNPs, rs2154299 and rs12194855, in the coagulation factor XIII subunit A (F13A1) region and two SNPs, rs630431 and rs560892, in the proprotein convertase subtilisin kexin 9 (PCSK9) region, with an estimated false discovery rate <0.05 based on interaction tests. Further analyses showed significant stroke risk interaction between these F13A1 SNPs and estrogen plus progestin (E+P) treatment for ischemic stroke and for ischemic and hemorrhagic stroke combined, and suggested interactions between PCSK9 SNPs with either E+P or estrogen-alone treatment.ConclusionsGenotype by environment interaction information may help to define genomic regions relevant to stroke risk. Two-stage analysis among postmenopausal women generates novel hypotheses concerning the F13A1 and PCSK9 genomic regions and the effects of hormonal exposures on postmenopausal stroke risk for subsequent independent validation.

Project description:OBJECTIVE:To characterize risk and timing of postpartum stroke readmission after delivery hospitalization discharge. METHODS:The Healthcare Cost and Utilization Project's Nationwide Readmissions Database for calendar years 2013 and 2014 was used to perform a retrospective cohort study evaluating risk of readmission for stroke within 60 days of discharge from a delivery hospitalization. Risk was characterized as odds ratios (ORs) with 95% CIs based on whether patients had hypertensive diseases of pregnancy (gestational hypertension or preeclampsia), or chronic hypertension, or neither disorder during the index hospitalization. Adjusted models for stroke readmission risk were created. RESULTS:From January 1, 2013, to October 31, 2013, and January 1, 2014, to October 31, 2014, 6,272,136 delivery hospitalizations were included in the analysis. One thousand five hundred five cases of readmission for postpartum stroke were identified. Two hundred fourteen (14.2%) cases of stroke occurred among patients with hypertensive diseases of pregnancy, 66 (4.4%) with chronic hypertension, and 1,225 (81.4%) without hypertension. The majority of stroke readmissions occurred within 10 days of hospital discharge (58.4%), including 53.2% of patients with hypertensive diseases of pregnancy during the index hospitalization, 66.7% with chronic hypertension, and 58.9% with no hypertension. Hypertensive diseases of pregnancy and chronic hypertension were associated with increased risk of stroke readmission compared with no hypertension (OR 1.74, 95% CI 1.33-2.27 and OR 1.88, 95% CI 1.19-2.96, respectively). Median times to readmission were 8.9 days for hypertensive diseases of pregnancy, 7.8 days for chronic hypertension, and 8.3 days without either condition. CONCLUSION:Although patients with chronic hypertension and hypertensive diseases of pregnancy are at higher risk of postpartum stroke, they account for a minority of such strokes. The majority of readmissions for postpartum stroke occur within 10 days of discharge; optimal blood pressure management may be particularly important during this period.

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Hormone therapy and stroke: is it all about timing?

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Hormone therapy and stroke: is it all about timing?

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