Hormone Replacement Therapy, Prothrombotic Mutations, and the Risk of Incident Nonfatal Ischemic Stroke in Postmenopausal Women
To the Editor:
In secondary-prevention clinical trials, hormone replacement therapy (HRT) has not decreased the risk of coronary events1 or the risk of stroke2 in postmenopausal women. In fact, post hoc analyses in both trials suggested early harm from HRT use.1,3⇓ We recently reported that HRT use was associated with the risk of first nonfatal myocardial infarction in hypertensive postmenopausal women with the prothrombin 20210G→A variant but not in women without the variant.4 We now report the possibility of a similar interaction on the risk of first nonfatal ischemic stroke in the same study population.
We conducted a population-based case-control study at Group Health Cooperative (GHC), a Seattle-based health maintenance organization. Cases were 130 postmenopausal women, 30 to 79 years old, with a first nonfatal ischemic stroke between 1995 and 1998. Controls were a random sample of 692 postmenopausal women without stroke, frequency matched to cases by age, calendar year, and hypertension. We identified study subjects from GHC databases and reviewed the medical record to establish their eligibility. We used the GHC pharmacy database to assess HRT use. A woman was classified as a current user if she received enough pills to last until the date of admission for stroke cases or until a random date within their calendar year for controls. Presence of factor V Leiden (factor V 1691G→A) and the prothrombin 20210G→A variant in subjects’ blood specimens was assessed as previously described.4
Prevalence of factor V Leiden and prothrombin variant among controls was 5.5% and 2.3%, respectively. Considered individually, neither use of HRT nor the factor V and prothrombin variants was associated with the risk of ischemic stroke. Among women with the wild-type genotype, HRT use was not associated with ischemic stroke, but among subjects with either prothrombotic variant, HRT use was associated with a doubling of stroke risk (Table).
Adjustment for age, calendar year, systolic blood pressure and presence of cardiovascular disease had little effect on the results. Results appeared similar in analyses stratified on hypertension and for separate analyses of factor V Leiden and prothrombin variant.
Study results suggest that in women with a prothrombotic mutation, HRT use may be associated with a higher risk of first nonfatal ischemic stroke. A larger study is needed to confirm this association. Although testing women on HRT for these mutations would be premature, the possibility that women with prothrombotic mutations may be more susceptible to adverse effects of estrogen warrants further investigation.
- ↵Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women: Heart and Estrogen/progestin Replacement Study (HERS) Research GroupJAMA. 1998; 280: 605–613.
- ↵Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Horwitz RI. Estrogen after ischemic stroke: Effect of estrogen replacement on risk of recurrent stroke and death in the Women’s Estrogen for Stroke Trial (WEST).Stroke. 2001; 32: 329.
- ↵WEST study confirms no benefit of ERT in preventing recurrent stroke: Heartwire.