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Hormone Replacement Therapy and Associated Risk of Stroke in Postmenopausal Women Rozenn N. Lemaitre, PhD, MPH; Susan R. Heckbert, MD, PhD; Bruce M. Psaty, MD, PhD; Nicholas L. Smith, PhD; Robert C. Kaplan, PhD; W. T. Longstreth, Jr, MD, MPH

Background: There is little information about the risk of stroke in relation to time since initiation of hormone therapy and in relation to estrogen dose.

Methods: We conducted a population-based case- control study at Group Health Cooperative (GHC), a health maintenance organization in the greater Seattle (Wash) area, to assess the association of hormone replacement therapy with the risks of incident ischemic and hemorrhagic stroke. Cases were all postmenopausal women with incident stroke at GHC during July 1989 through December 1998 (726 is- chemic strokes and 213 hemorrhagic strokes). Controls were randomly selected from GHC enrollees and fre- quency matched to cases on age and calendar year (n = 2525). Hormone use was assessed from computer- ized pharmacy data. We reviewed the medical record to con- firm eligibility and assess other risk factors.

Results: After risk factor adjustment, ischemic stroke

was not associated with current use of estrogen with pro- gestin (odds ratio [95% confidence interval]: 0.97 [0.69- 1.37]) or without (0.94 [0.72-1.23]) compared with never use. Similarly, hemorrhagic stroke was not associated with current use of estrogen with progestin (0.74 [0.43- 1.28]) or without (1.06 [0.71-1.56]). However, the risks of ischemic stroke and hemorrhagic stroke were in- creased 2-fold during the first 6 months of hormone use (ischemic stroke: 2.16 [1.04-4.49], hemorrhagic stroke: 2.20 [0.83-5.81]). Risk of ischemic stroke also in- creased with estrogen dose (P for trend = .03).

Conclusion: The transitory increase in risks of ische- mic stroke and hemorrhagic stroke associated with ini- tiation of hormone replacement therapy merits further investigation.

Arch Intern Med. 2002;162:1954-1960

T HE POSSIBILITY that initia- tion of hormone replace- ment therapy (HRT) might be associated with a transi- tory increase in risk of stroke

was raised by a recent report from the Women’s Estrogen for Stroke Trial (WEST).1 In the WEST trial, therapy with 17-�-estradiol did not prevent strokes among postmenopausal women with pre- vious stroke or transient ischemic at- tack.1,2 Furthermore, estrogen therapy ap- peared to actually increase stroke risk during the first 6 months of therapy. Early harm from HRT has been observed previ- ously in another secondary prevention trial. In the Heart and Estrogen/progestin Re- placement Study (HERS), HRT appeared to increase the risk of coronary events in the first year of therapy.3 While the HERS study investigators did not report an early in- crease in stroke, only a small number of stroke events were observed in HERS.4

Primary prevention trials of HRT and cardiovascular disease among healthy women have yet to be reported. Observa-

tional studies provide conflicting evi- dence on the overall association of HRT and stroke.5-16 These studies relied largely on the self-report of hormone use, and the only study that addressed the possibility of early harm from HRT could not assess HRT use of less than 1 year’s duration.5

Furthermore, whether stroke risk varies with the dose of estrogen used or with other characteristics of HRT has re- ceived limited attention, although a dose-related hazard has been hypoth- esized17 and was suggested by a pro- spective study.5

We investigated the possible associa- tion of HRT with the risk of incident is- chemic stroke and incident hemorrhagic stroke in a population-based case-con- trol study using detailed computerized in- formation on hormone use. Our objec- tive was to investigate the association of current use of estrogen and estrogen plus progestin with the risks of incident ische- mic stroke and incident hemorrhagic stroke among postmenopausal women. In addition, the detailed assessment of HRT

ORIGINAL INVESTIGATION

From the Departments of Medicine (Drs Lemaitre, Psaty, and Smith) and Epidemiology (Drs Heckbert, Psaty, Smith, and Longstreth), Cardiovascular Health Research Unit, and the Department of Neurology (Dr Longstreth), University of Washington, Seattle; and the Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, New York, NY (Dr Kaplan).

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use up to the date of stroke events allowed us to inves- tigate the association of recency of HRT initiation, as well as dose of estrogen used, with the risk of stroke.

METHODS

DESIGN AND SETTING

This was a population-based case-control study conducted at Group Health Cooperative (GHC), a large health mainte- nance organization that serves approximately 570 000 enroll- ees in western Washington State.

STUDY SUBJECTS

Cases were all female GHC enrollees aged 30 to 79 years who experienced an incident fatal or nonfatal stroke between July 1, 1989, and December 31, 1998. Cases were identified from GHC hospitalization discharge diagnosis databases and from the results of a match between Washington State death rec- ords and the membership list of GHC. Controls were a ran- dom sample of GHC female enrollees, frequency matched to cases on calendar year and age (by decade). The ratio of con- trols to cases was at least 2 to 1. We excluded women who had a prior stroke and women who were not postmenopausal. In addition, we excluded women who had been a member at GHC for less than a year or who had fewer than 4 visits prior to their index date because we might not have found adequate risk fac- tor information in their records.

Classification of an event as an ischemic stroke required the rapid onset of a neurologic deficit that persisted at least 24 hours or evidence of infarction on brain imaging studies, at surgery, or at autopsy. Strokes were defined as hemorrhagic if there was evidence of blood in the subarachnoid space or ven- tricles or dense intraparenchymal blood on brain imaging studies. In the absence of test results, strokes were defined as hemorrhagic if there was rapid onset of neurologic deficit followed by death within 24 hours. We excluded stroke cases that could not be categorized as ischemic or hemor- rhagic due to insufficient information (64 of 1003 identified stokes).

INDEX DATES

The index date was the date of hospitalization for hospitalized cases or the date of death for out-of-hospital fatal cases. For controls, the index date was a randomly assigned date within the calendar year for which they were sampled as controls.

DATA COLLECTION

We reviewed the ambulatory medical record to determine eli- gibility and to collect information on key covariates for the pe- riod before the index date. We collected information on medi- cal history, including angina, hypertension, diabetes, congestive heart failure, myocardial infarction, transient ischemic attack, and peripheral vascular disease, and information on traditional risks factors such as blood pressure and smoking status. Angina was defined as probable or definite based on the notes of the pri- mary care physician and consultants and the results of diagnos- tic tests. Diabetes mellitus was defined as treatment with oral hy- poglycemic medication and/or insulin or a history of diabetes. Hypertension was defined as treatment with antihypertensive medications. Blood pressure was the blood pressure measured during the most recent visit before the index date. Cardiovas- cular disease was defined as any of following conditions: prior myocardial infarction, angina, angioplasty, coronary artery by-

pass, carotid endarterectomy, peripheral vascular disease pro- cedure, transient ischemic attack, claudication, congestive heart failure, or atrial fibrillation. We also performed a telephone in- terview of consenting survivors to assess risk factors such as smok- ing status, education, and race.

EXPOSURE ASSESSMENT

We used the GHC computerized pharmacy database to assess current and past use of estrogen and estrogen plus progestin as of the index date. Since 1976, the GHC pharmacy database includes a record of all prescriptions dispense to GHC enroll- ees. In a previous case-control study of HRT and myocardial infarction, we found that 97% of both myocardial infarction cases and controls filled all or almost all their prescriptions at a GHC pharmacy.18 Current users of hormone therapy were de- fined as women who received at least 1 estrogen prescription before the index date with enough estrogen pills to last until the index date, assuming at least 80% compliance with pre- scribing instructions.18 Past users of hormone therapy were de- fined as women who received at least 2 estrogen prescriptions before the index date and were not current users at the index date.

To determine the duration of estrogen use, we calculated the number of days that each prescription would last using pre- scribing instructions and assuming 80% compliance. If an es- trogen prescription was filled out before another one run out, we assumed that the extra pills were not taken. Duration of use was obtained by summing the duration of exposure for each estrogen prescription, with or without progestin, recorded in the GHC database since 1976. All estrogen prescriptions were counted whether they provided continuous or intermittent es- trogen exposure. As a measure of recency of HRT initiation, we calculated the time elapsed between the first estrogen pre- scription ever recorded in the GHC pharmacy database and the index date. This measure was computed for all current users, whether the exposure to estrogen between the initiation of HRT use and the index date was continuous or interrupted with pe- riods of nonuse. To determine the dose of estrogen used, we assumed that the following doses were equivalent: 0.625 mg of conjugated estrogens, 0.625 mg of esterified estrogens, 1 mg of estropipate, 1 mg of micronized estradiol, 1 mg of estradiol valerate, and 0.05 mg of ethinyl estradiol.19 All estrogen doses are given as equivalents of conjugated estrogens.

STATISTICAL ANALYSES

Statistical analyses were performed using STATA 7.0 (Stata Corp, College Station, Tex). We compared the risk factor distribu- tion in stroke cases and controls using descriptive analyses. We defined 4 mutually exclusive categories of hormone use as of the index date: current use of estrogen without progestin, cur- rent use of estrogen with progestin, past use of estrogen (with or without progestin), and never use of estrogen. To compare the distribution of risk factors across categories of hormone use among the controls, we used analyses of variance for the con- tinuous variables and �2 tests for categorical variables. Be- cause there were differences in age across the hormone use cat- egories, the analyses of variance and means and proportions across the categories were adjusted for age.

To investigate the association of hormone use with ische- mic and hemorrhagic stroke we performed unconditional logistic regression analyses. Using never users of estrogen as reference, we obtained odds ratios (ORs) and 95% confidence intervals (CIs) associated with the 3 categories of hormone use in logistic regression analyses with indicator variables for each category. The statistical significance associated with the addition of a variable to the models was based on the likeli-

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hood ratio test. The study had 83% power to detect an OR of ischemic stroke of 0.75 and 81% power to detect an OR of hemorrhagic stroke of 0.60 associated with current exposure to HRT. Multivariate ORs were adjusted for the matching fac- tors, age (linear term plus centered quadratic term), and index year, and the covariates diabetes, systolic blood pressure, cur- rent smoking, and cardiovascular disease. Covariates were retained in the final models if their addition changed the OR associated with current use of HRT by 5% or more in either the analyses of ischemic stroke or the analyses of hemorrhagic stroke. Goodness of fit of the models was validated with the Hosmer-Lemeshow goodness-of-fit test and could not be rejected for any of the estimated models shown.

For the analyses of estrogen dose and ischemic and hem- orrhagic stroke, we created 3 mutually exclusive categories of estrogen dose for the most recent HRT prescription of current HRT users: modal dose of estrogen (equivalent of 0.625 mg of conjugated estrogens daily), less than the modal dose (0.3 mg of conjugated estrogens daily), and more than modal dose (me- dian 1.25 mg of conjugated estrogen). Using current users of low estrogen dose as reference, we obtained ORs and 95% CIs associated with higher estrogen doses in logistic regression analy- ses with indicator variables for each category. To investigate the possibility of a transitory increase in risk of ischemic stroke or hemorrhagic stroke with initiation of hormone use, we cre- ated a priori categories of recency of HRT initiation from 6 months to 3 years or more, among current users of HRT. Odds

ratios were obtained for each category of recency in analyses with indicator variables for each category using never users of estrogen as reference.

RESULTS

We identified 726 incident ischemic stroke cases, 213 in- cident hemorrhagic stroke cases, and 2525 controls dur- ing the study period. Women in the study were on av- erage 68 years old and were long-time enrollees at GHC (Table 1). Ischemic stroke cases were older on average than hemorrhagic stroke cases. Further, as expected in this type of study, cardiovascular risk factors were more prevalent among cases than controls. Systolic blood pres- sure was higher and current smoking and cardiovascu- lar disease were more prevalent in both types of stroke cases than in controls. Ischemic stroke cases also had higher mean cholesterol levels and weight and higher prevalence of diabetes than controls.

Thirty-eight percent of ischemic stroke cases, 45% of hemorrhagic stroke cases, and 47% of controls had used estrogen at some time, alone or in combination with pro- gestin, while 22% of ischemic stroke cases, 27% of hem- orrhagic stroke cases and 28% of controls were current users (Table 1). Among controls, never users were older than estrogen users, and current users of estrogen with progestin were younger than other users (Table 2). Af- ter adjustment for age, current HRT users were less likely to have diabetes, while current users of estrogen with pro- gestin were less likely to be current smokers and had lower average systolic and diastolic blood pressure, weight, and total cholesterol levels (Table 2).

In unadjusted analyses, ever use of estrogen was as- sociated with a decreased risk of incident ischemic stroke (OR, 0.71; 95% CI, 0.60-0.84). However, after adjust- ment for age, index year, diabetes, systolic blood pres- sure, cardiovascular disease, and current smoking, the association was weak (OR, 0.93; 95% CI, 0.76-1.12). Like- wise, current use of estrogen, current use of estrogen in combination with progestin, and past use of HRT were not associated with ischemic stroke after adjustment for potential confounders (Table 3). In addition, we found no evidence that diabetes, cardiovascular disease, cur- rent smoking, treated hypertension, or age modified the association of HRT with ischemic stroke. Use of HRT was not associated with the risk of incident hemorrhagic stroke in both unadjusted and adjusted analyses (Table 4).

The median duration of HRT use among ever users was 3.7 years for controls, 3.3 years for ischemic stroke cases, and 3.1 years for hemorrhagic stroke cases. Du- ration of estrogen use was not associated with incident ischemic stroke (ORs, adjusted for risk factors, corre- sponding to quartiles of increasing duration: 1.0, 0.9, 0.9, and 0.8; P for trend = .27) and was not associated with incident hemorrhagic stroke (ORs corresponding to quar- tiles of increasing duration: 1.0, 1.1, 0.9, and 0.7; P for trend = .26).

We explored the possibility that recent HRT initia- tion might be associated with an increased risk of inci- dent stroke. Compared with never use of HRT, current use initiated within 6 months of the index date ap- peared associated with about 1.8-fold increase in risk of

Table 1. Characteristics of Cases and Controls*

Characteristic

Ischemic Stroke Cases

(n = 726)

Hemorrhagic Stroke Cases

(n = 213) Controls

(n = 2525)

Age, y 70.3 (7.4)† 67.9 (9.2) 68.1 (8.1) White race, % 89.1† 87.1‡ 91.1 Time in GHC, y 19.3 (12.1) 18.4 (12.0) 19.9 (11.5) No. of physician visits

in last year 8.7 (7.8)† 6.6 (6.1) 5.9 (5.6)

Hypertension, % 61.9† 43.7‡ 35.1 Systolic blood pressure,

mm Hg 148.0 (22.7)† 143.9 (22.5)‡ 136.8 (19.8)

Diastolic blood pressure, mm Hg

81.4 (11.1)† 83.2 (12.2)‡ 79.1 (10.1)

Cholesterol, mg/dL§ 243.6 (47.7)† 236.9 (50.8) 234.6 (41.1) Weight, kg 73.0 (17.5) 68.0 (15.8) 71.4 (16.3) Diabetes, % 31.3† 10.8 9.3 Cardiovascular disease, % 52.5† 32.9‡ 22.0 Angina, % 20.7† 12.7 9.9 Transient ischemic attack, % 15.2† 13.2‡ 3.3 Myocardial infarction, % 20.1† 13.2‡ 8.5 Congestive heart failure, % 12.8† 4.7 3.5 Current smoking, % 18.7† 24.4‡ 13.9 Ever use of hormone

replacement therapy, % 38.2† 45.1 46.5

Current use of hormone replacement therapy at index date, %

22.2† 27.2 27.8

*Numbers are mean (SD) unless indicated otherwise. Information was missing on time in Group Health Cooperative (GHC) (9 controls, 8 ischemic strokes, 1 hemorrhagic stroke); number of visits (6 controls, 1 hemorrhagic stroke); history of myocardial infarction (1 ischemic stroke, 1 hemorrhagic stroke); cholesterol levels (182 controls, 57 ischemic strokes, 23 hemorrhagic strokes), weight (4 controls), and race (310 controls, 63 ischemic strokes, 19 hemorrhagic strokes).

†P�.05 for the ischemic stroke/control comparison. ‡P�.05 for the hemorrhagic stroke/control comparison. §To convert to millimoles per liter, multiply by 0.02586.

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both incident ischemic stroke (OR, 1.86; 95% CI, 0.91- 3.79) and hemorrhagic stroke (OR, 1.70; 95% CI, 0.66- 4.40) (Table 5, top). There was no increase in risk as- sociated with current HRT use initiated earlier (Table 5, top). Since current HRT users appeared healthier than never users (Table 2), we also performed analyses con- fined to current users. When current users of HRT ini- tiated within 6 months were compared with other cur- rent users, the stroke risk increases were slightly more pronounced (Table 5, bottom). Current HRT use initi- ated within 6 months was associated with a 2-fold increase in risk of ischemic stroke (OR, 2.16; 95% CI, 1.04-4.49), and hemorrhagic stroke (OR, 2.20; 95% CI, 0.83-5.81), compared with current use initiated earlier.

Among current users who had initiated HRT use within 6 months of their index date, 7 ischemic stroke cases (50%) and 25 controls (68%) used estrogen in combination with progestin. Current HRT use initiated within 6 months appeared associated with increased risk of ischemic stroke among both users of estrogen alone (OR, 3.31; 95% CI, 1.16-9.43) and users of estrogen combined with progestin (OR, 1.55; 95% CI, 0.51-4.69) with the difference in the point estimates well within chance (P for interaction = .22). Of the 6 hemorrhagic stroke cases who were recent current HRT users, 5 used

progestin in combination with estrogen and 1 used estrogen alone. Owing to small numbers, we could not meaningfully investigate if progestin use modified the association of recently initiated current HRT use with hemorrhagic stroke.

Among current HRT users, 78% of controls, 76% of ischemic stroke cases and 74% of hemorrhagic stroke cases used a modal dose of estrogen (equivalent to 0.625 mg of conjugated estrogen). Dose of estrogen used was as- sociated with the risk of incident ischemic stroke among current users. Compared with use of low-dose estrogen (equivalent to 0.3 mg of conjugated estrogen), use of the modal estrogen dose was associated with an OR of 1.44 (95% CI, 0.81-2.61) and use of higher doses (median 1.25 mg of conjugated estrogen) was associated with an OR of 2.41 (95% CI, 1.09-5.35) (P for trend = .03) (Table 6). Exclusion of women who had initiated HRT within 6 months of the index date did not change the point esti- mates. In contrast to the association with ischemic stroke, dose of estrogen was not associated with hemorrhagic stroke (P for trend = .89).

We could not investigate whether recent initiation of HRT with low-dose (0.3 mg) estrogen was also associated with increased risk of stroke because 88% of ischemic stroke cases and 100% of hemorrhagic stroke cases who initiated

Table 2. Characteristics of Controls According to Estrogen Use*

Current Use

Past Use, Estrogen ± Progestin (n = 470)

Never Use

(n = 1352) P

Value

Estrogen and

Progestin (n = 290)

Estrogen Only

(n = 413)

Age, mean, y 62.8 66.0 67.7 70.0 �.001 Time in GHC,

mean, y 22.1 18.7 21.5 19.3 �.001

Cardiovascular disease, %

19.8 24.5 22.0 21.7 .46

Angina, % 8.3 12.2 9.8 9.5 .30 Myocardial

infarction, % 8.3 6.6 8.2 9.1 .47

Congestive heart failure, %

2.8 3.6 2.0 4.1 .19

Transient ischemic attack, %

2.6 3.9 3.7 3.0 .70

Claudication, % 2.0 2.8 2.0 2.5 .84 Diabetes, % 6.7 6.1 9.6 10.7 .02 History of

hypertension, % 31.6 42.7 35.6 33.3 .003

Systolic blood pressure, mean, mm Hg

133.1 137.8 135.6 137.6 .002

Diastolic blood pressure, mean, mm Hg

77.3 79.0 79.4 79.5 .01

Cholesterol, mean, mg/dL†

226.1 234.6 236.3 236.0 .004

Weight, mean, kg 67.9 71.9 72.0 71.9 .002 Current smoker, % 8.6 11.5 14.1 16.0 .006

*Except for values of age, the values shown in the table are age adjusted. GHC indicates Group Health Cooperative.

†To convert to micromoles per liter, multiply by 0.02586.

Table 3. Association of Ischemic Stroke With Estrogen Use

Estrogen Use

No. (%) Odds Ratio

(95% Confidence Interval)

Controls Cases Unadjusted Adjusted*

Never use 1352 (54) 449 (62) 1.0 (Reference) 1.0 (Reference) Current use of

estrogen with progestin

290 (12) 59 (8) 0.61 (0.45-0.83) 0.97 (0.69-1.37)

Current use of estrogen only

413 (16) 102 (14) 0.74 (0.58-0.95) 0.94 (0.72-1.23)

Past use of estrogen ± progestin

470 (19) 116 (16) 0.74 (0.59-0.93) 0.90 (0.70-1.16)

*Adjusted for age, index year, diabetes, systolic blood pressure, presence of cardiovascular disease, and current smoking.

Table 4. Association of Hemorrhagic Stroke With Estrogen Use

Estrogen Use

No. (%) Odds Ratio

(95% Confidence Interval)

Controls Cases Unadjusted Adjusted*

Never use 1352 (54) 117 (55) 1.0 (Reference) 1.0 (Reference) Current use of

estrogen with progestin

290 (11) 18 (8) 0.72 (0.43-1.20) 0.74 (0.43-1.28)

Current use of estrogen only

413 (16) 40 (19) 1.12 (0.77-1.63) 1.06 (0.71-1.56)

Past use of estrogen ± progestin

470 (19) 38 (18) 0.93 (0.64-1.37) 0.95 (0.64-1.40)

*Adjusted for age, index year, diabetes, systolic blood pressure, presence of cardiovascular disease, and current smoking.

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HRT within 6 months of index date used the modal dose equivalent to 0.625 mg of conjugated estrogen.

Further adjustment for body weight, angina or myo- cardial infarction, history of transient ischemic attack, atrial fibrillation, hypertension, total cholesterol and glu- cose levels, added one at a time to the models, did not change any of the results.

COMMENT

Overall, among the postmenopausal women in this case- control study, ever use of estrogen, past use of estrogen, current use of estrogen alone, and current use of estro- gen plus progestin were not associated with the risk of incident ischemic stroke or the risk of incident hemor- rhagic stroke after adjustment for cardiovascular risk fac- tors. Nonetheless, the risk of both types of stroke ap- peared to be transiently increased after initiation of HRT. Compared with current HRT use of longer duration, there was a 2-fold increase in risk of first ischemic stroke and a 2-fold increase in risk of first hemorrhagic stroke dur- ing the first 6 months after initiating HRT use. In addi- tion, the association between current HRT and ischemic stroke differed depending on the dose of estrogen used. Compared with use of 0.3 mg of estrogen, use of 0.625 mg of estrogen was associated with a 1.4-fold increase in risk of incident ischemic stroke and use of higher estrogen doses was associated with a 2.4-fold increase in risk.

The strengths of our study include the population- based study design, the objective assessment of hor- mone use, and control for many potential confounders of the association of estrogen with stroke. While cases were identified after their event, the assessment of HRT exposure and other stroke risk factors was based on in- formation accrued prospectively in a computerized da- tabase and in the medical record, thereby avoiding all pos- sibility of recall bias. In addition, the computerized pharmacy records on HRT use provided detailed infor- mation on combination therapy, timing of HRT use and dose of estrogen.

The main limitation of the study is the small num- ber of study subjects who recently initiated HRT use and the small number of users of estrogen doses other than the modal dose. For this reason, we were not able to in- vestigate if initiation of low estrogen dose was also as- sociated with increased risk of incident stroke in the first 6 months after initiating HRT. Another limitation was the observational study design from which cause and effect cannot be concluded. We did not know if the study subjects took the estrogen pills prescribed to them. Although we took into account many potential risk factors, residual confounding by unmeasured par- ticipant characteristics, such as compliance,20 cannot be eliminated.

The study results are similar to those of the WEST trial, a randomized trial of estrogen therapy among postmenopausal women with a history of stroke or

Table 5. Ischemic Stroke, Hemorrhagic Stroke, and Initiation of Hormone Replacement Therapy (HRT)

No. of Controls

No. of Cases Adjusted* Odds Ratio of Stroke

(95% Confidence Interval)

Ischemic Hemorrhagic Ischemic Stroke Hemorrhagic Stroke

Among Current Users, Using Never Users as Reference Time since initiation of HRT, y

Never users 1352 449 117 1.0 (Reference) 1.0 (Reference) �0.5 36 14 6 1.86 (0.91-3.79) 1.70 (0.66-4.40) 0.5-1 29 6 1 0.84 (0.32-2.22) 0.34 (0.04-2.64) 1-2 41 8 5 0.72 (0.31-1.68) 1.21 (0.45-3.28) 2-3 56 11 3 0.86 (0.42-1.77) 0.55 (0.16-1.82) �3 541 122 43 0.92 (0.72-1.19) 0.94 (0.64-1.37)

Among Current Users, Using Current Longer-term Users as Reference Time since initiation of HRT, y

�0.5 36 14 6 2.16 (1.04-4.49) 2.20 (0.83-5.81) �0.5 667 147 52 1.0 (Reference) 1.0 (Reference)

*Adjusted for age, index year, diabetes, systolic blood pressure, presence of cardiovascular disease, and current smoking.

Table 6. Association of Ischemic Stroke With Dose of Estrogen Used Among Current Users

Dose of Estrogen, mg

Mean Duration of Use Among Controls, y

No. of Controls

No. of Cases

Odds Ratio (95% Confidence Interval)

Unadjusted Adjusted*

0.3 7.3 93 19 1.0 (Reference) 1.0 (Reference) 0.625 6.3 546 122 1.09 (0.64-1.86) 1.44 (0.81-2.61)

�0.625 6.4 64 20 1.53 (0.76-3.1) 2.41 (1.09-5.35)

*Adjusted for age, index year, diabetes, systolic blood pressure, presence of cardiovascular disease, and current smoking. P for trend = .03.

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transient ischemic attack. In WEST, therapy with 1 mg/d of 17-�-estradiol did not prevent strokes (relative risk of stroke compared with placebo, 1.1; 95% CI, 0.8-1.6).1,2 However, post hoc analysis suggested an in- creased risk of stroke in the first 6 months of estradiol therapy (relative risk, 2.3; 95% CI, 1.1-5.0).1 In the HERS trial, a secondary prevention trial conducted among postmenopausal women with coronary heart disease,3 treatment with 0.625 mg of conjugated estro- gens and 2.5 mg of medroxyprogesterone did not prevent strokes either (relative risk, 1.23; 95% CI, 0.89-1.70).4 Furthermore, early harm from HRT was also suggested in the HERS trial. In post hoc analyses, an increased risk of coronary events was observed dur- ing the first year of HRT therapy.3 In HERS, the risk of stroke did not appear to increase with the initiation of HRT4; however, the power to find an early risk of stroke may have been limited.

There have been no clinical trials of HRT for the pre- vention of stroke in healthy women. Results from obser- vational studies have been inconsistent, in part due to differences in outcome, exposure, and study design.5-16

A healthy user bias might explain the decreased risk of stroke associated with HRT in some of the observa- tional studies.21,22 In our study, the apparent association of HRT use (ever, current, past, with or without proges- tin) with decreased risk of ischemic stroke appeared to be explained by other cardiovascular risk factors. The lack of benefits of current use of estrogen and current use of estrogen with progestin with respect to ischemic stroke is in agreement with studies that have looked at this out- come.5-7,9,15,23 A lack of association of HRT use with hem- orrhagic stroke was also reported in the most recent, and largest studies.5,6

Two observational studies have addressed the pos- sibility of early risk of incident stroke with HRT use. In a case-control study of HRT and ischemic stroke, re- ported HRT use of less than 1 year among current users was not associated with the risk of ischemic stroke (OR, 0.75; 95% CI, 0.23-2.42). These analyses included 90 cases and 102 controls who were current users and the num- ber of recent users was not shown but likely small. In recent analyses from the Nurses Health Study, current use of HRT of less than 1 year was not associated with increased risk of ischemic stroke (OR, 1.07; 95% CI, 0.44- 2.61) or with increased risk of hemorrhagic stroke (OR, 1.56; 95% CI, 0.63-3.90).5 However, the duration of HRT use in that study was reportedly underestimated by an average of 1 year due to the biannual self-report assess- ment of HRT use.5 Given the imprecision of the infor- mation on time of HRT initiation and the large 95% CIs, a lack of association with early HRT use in these studies remains inconclusive.

Our finding of decreased risk of ischemic stroke with lower estrogen doses is in agreement with the report from the Nurses Health Study: using never users as reference, the relative risk (95% CI) of ischemic stroke associated with 0.3 mg of estrogen was 0.43 (0.16-1.16); with 0.625 mg of estrogen, 1.44 (1.07-1.93); and with 1.25 mg or more, 2.00 (1.32-3.05).5 However, there were only 4 is- chemic stroke cases who used 0.3-mg estrogen. The pos- sibility that low-dose estrogen might lower the risk of is-

chemic stroke compared with higher doses needs to be investigated in a clinical trial.

The mechanisms by which HRT might increase the risk of stroke are not known. The higher risk of ischemic stroke associated with higher estrogen doses might be due to pro- thrombotic effects of estrogen.17 On the other hand, the simi- lar levels of the associations of current HRT use initiated recently with both ischemic stroke and hemorrhagic stroke do not support such a mechanism of action.

We recently reported that in the same population of postmenopausal women, current HRT use was asso- ciated with an 8-fold increase in risk of myocardial in- farction among hypertensive women with the prothrom- bin 20210 G→A variant, while there was no association of HRT use with myocardial infarction among hyperten- sive women without the variant.24 Whether this poly- morphism or other prothrombotic mutations also modify the association of HRT with stroke needs to be investi- gated as well.

In summary, we observed an increased risk of inci- dent ischemic stroke and an increased risk of incident hem- orrhagic stroke in the first 6 months after initiation of HRT among postmenopausal women. Further research is needed to confirm these findings and to investigate the reasons for the transitory increase in risk. We also found that the risk of ischemic stroke was inversely related to estrogen dose among current users of HRT. Until better evidence is avail- able to guide such decisions, these findings suggest that the lowest possible dose of estrogen should be used when women receive HRT for symptoms of the menopause.

Accepted for publication January 31, 2002. This research was supported by grants from the Na-

tional Heart, Lung, and Blood Institute (HL 40628, HL 43201) and the Merck/Society for Epidemiologic Research Clinical Epidemiology Fellowships (Dr Psaty).

We wish to thank Shannon Ryan and Marian Harper for their help with the project.

Corresponding author and reprints: Rozenn N. Le- maitre, PhD, MPH, University of Washington, Cardiovas- cular Health Research Unit, Metropolitan Park, East Tower, Suite 1360, 1730 Minor Ave, Seattle, WA 98101 (e-mail: [email protected]).

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