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Hormone replacement therapy increases the risk of stroke - meta-analysis
ARTICLE IN PRESS MENOPAUSE
Hormone replacement therapy increases the risk of stroke ^ meta-analysis Bath PMW,Gray LJ. Association between hormone replacement therapy and subsequent stroke: a meta-analysis. BMJ 2005; 330:342^5.
OBJECTIVE To determine the e¡ect of hormone replacement therapy on the risk of stroke.
DESIGN Meta-analysis of randomized, controlled trials. DATA SOURCES Computerized searches of MEDLINE, EMBASE, and the Cochrane Library to May 2004, and hand searches of the reference lists of previous reviews and included studies. STUDY SELECTION Published articles in English of completed randomized, controlled trials that compared HRT (estrogen alone or combined with progesterone) with a control group (in men or women) and provided data on stroke events (separately from transient ischemic attack). Studies were assessed for methodological quality. DATA EXTRACTION Data independently by two reviewers.
were
extracted
MAIN OUTCOME MEASURES Odds ratio (OR, 95% CI) for stroke overall and by type (ischemic or
0021-9290/$ - see front matter r 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.ebobgyn.2005.09.011
hemorrhagic) and outcome (non-fatal, fatal, death or dependency). MAIN RESULTS Twenty-eight trials, published between 1965 and 2004 (all but 4 since 1993), were included in the meta-analysis. Three early trials included men. Mean age of subjects ranged from 50 to 82 years. Fifteen trials, representing 88% of subjects, had the maximum score for quality.The overall control event rate was 2%; the use of HRT increased the odds of stroke by 29% (number needed to harm is 147). The results of the meta-analysis are shown in Table 1. There was no signi¢cant statistical heterogeneity for any outcome. CONCLUSION The use of hormone replacement therapy is associated with an increased risk of stroke, especially ischemic stroke and severe stroke. The increase in risk is similar, regardless of type of HRTor type of estrogen.
Overall study quality (out of 10) Topic importance Methodological quality Practical relevance
8 8 8
Evidence-based Obstetrics and Gynecology (2005) 7, 217^218
217
ARTICLE IN PRESS Table 1
Results of the meta-analysis of the e¡ect of HRTon stroke Stroke outcome/subgroup
No. of subjects
Odds ratio (95% CI)
Overall Women only
39,769 38,926
1.3 (1.1^1.5) 1.3 (1.1^1.5)
23,426 23,690
1.3 (1.1^1.6) 1.1(0.7^1.8)
36,430 36,230 20,445
1.3 (0.9^1.9) 1.2 (1.1^1.4) 1.6 (1.1^2.2)
14,256 25,513
1.2 (0.9^1.7) 1.3 (1.1^1.6)
4,569 33,194
1.2 (0.8^1.7) 1.3 (1.1^1.5)
Type of stroke:
ischemic hemorrhagic Outcome:
fatal non-fatal death or dependency Type of HRT:
estrogen only estrogen plus progesterone Type of estrogen:
estradiol conjugated equine estrogens Commentary This meta-analysis of clinical trials of hormone therapy (HT) indicated an approximate 30% excess risk for ischemic stroke.The authors used systematic criteria for trial selection and contemporary statistical analysis methods that lend considerable credibility to their f|ndings. Not surprisingly, the results were dominated by the two Women’s Health Initiative trials that accounted for approximately 70% of the 40,000 subjects enrolled in the various trials. However, the f|nding of excess risk for stroke was supported by nine other trials, in which the rate of stroke was higher in the HT arm than in the control arm, and also several observational studies that observed an association between HTuse and risk of stroke.1 The fact that ischemic stroke, like venous thromboembolic events, appears to be elevated in women using either unopposed or opposed estrogen regimens suggests that the effect may be related to a thrombophilic effect of estrogen. Two trials of tamoxifen have also observed increased rates of stroke with treatment, further implicating estrogen agonists for stroke risk.2,3 Unfortunately, the data to date have failed to identify a subgroup of women that is uniquely predisposed to HT-associated stroke, making it diff|cult to offer more than general advice to
218
Evidence-based Obstetrics and Gynecology (2005) 7, 217^218
individual women contemplating use of HT for relief of perimenopausal symptoms. Hopefully, ongoing research will reveal the mechanisms involved in this adverse effect of HTand lead to safer alternatives for perimenopausal symptom relief. David M. Herrington, MD,MHS Wake Forest University School of Medicine, Winston-Salem, NC, USA
Literature cited 1. Nelson HD, Humphrey LL, Hygren P, Teutsch SM, Allan JD. Postmenopausal hormone replacement therapy. Scientif|c review. JAMA 2002; 288:872^ 81. 2. Fisher B,Costantino JP,Wickerham DL, et al.Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1Study. J Natl Cancer Inst 1998; 90:1371^ 88. 3. Dignam JJ, Fisher B. Occurrence of stroke with tamoxifen in NSABP B-24. Lancet 2000; 355:848 ^9.
Hormone replacement therapy increases the risk of stroke ^ meta-analysis Bath PMW,Gray LJ. Association between hormone replacement therapy and subsequent stroke: a meta-analysis. BMJ 2005; 330:342^5.
OBJECTIVE To determine the e¡ect of hormone replacement therapy on the risk of stroke.
DESIGN Meta-analysis of randomized, controlled trials. DATA SOURCES Computerized searches of MEDLINE, EMBASE, and the Cochrane Library to May 2004, and hand searches of the reference lists of previous reviews and included studies. STUDY SELECTION Published articles in English of completed randomized, controlled trials that compared HRT (estrogen alone or combined with progesterone) with a control group (in men or women) and provided data on stroke events (separately from transient ischemic attack). Studies were assessed for methodological quality. DATA EXTRACTION Data independently by two reviewers.
were
extracted
MAIN OUTCOME MEASURES Odds ratio (OR, 95% CI) for stroke overall and by type (ischemic or
0021-9290/$ - see front matter r 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.ebobgyn.2005.09.011
hemorrhagic) and outcome (non-fatal, fatal, death or dependency). MAIN RESULTS Twenty-eight trials, published between 1965 and 2004 (all but 4 since 1993), were included in the meta-analysis. Three early trials included men. Mean age of subjects ranged from 50 to 82 years. Fifteen trials, representing 88% of subjects, had the maximum score for quality.The overall control event rate was 2%; the use of HRT increased the odds of stroke by 29% (number needed to harm is 147). The results of the meta-analysis are shown in Table 1. There was no signi¢cant statistical heterogeneity for any outcome. CONCLUSION The use of hormone replacement therapy is associated with an increased risk of stroke, especially ischemic stroke and severe stroke. The increase in risk is similar, regardless of type of HRTor type of estrogen.
Overall study quality (out of 10) Topic importance Methodological quality Practical relevance
8 8 8
Evidence-based Obstetrics and Gynecology (2005) 7, 217^218
217
ARTICLE IN PRESS Table 1
Results of the meta-analysis of the e¡ect of HRTon stroke Stroke outcome/subgroup
No. of subjects
Odds ratio (95% CI)
Overall Women only
39,769 38,926
1.3 (1.1^1.5) 1.3 (1.1^1.5)
23,426 23,690
1.3 (1.1^1.6) 1.1(0.7^1.8)
36,430 36,230 20,445
1.3 (0.9^1.9) 1.2 (1.1^1.4) 1.6 (1.1^2.2)
14,256 25,513
1.2 (0.9^1.7) 1.3 (1.1^1.6)
4,569 33,194
1.2 (0.8^1.7) 1.3 (1.1^1.5)
Type of stroke:
ischemic hemorrhagic Outcome:
fatal non-fatal death or dependency Type of HRT:
estrogen only estrogen plus progesterone Type of estrogen:
estradiol conjugated equine estrogens Commentary This meta-analysis of clinical trials of hormone therapy (HT) indicated an approximate 30% excess risk for ischemic stroke.The authors used systematic criteria for trial selection and contemporary statistical analysis methods that lend considerable credibility to their f|ndings. Not surprisingly, the results were dominated by the two Women’s Health Initiative trials that accounted for approximately 70% of the 40,000 subjects enrolled in the various trials. However, the f|nding of excess risk for stroke was supported by nine other trials, in which the rate of stroke was higher in the HT arm than in the control arm, and also several observational studies that observed an association between HTuse and risk of stroke.1 The fact that ischemic stroke, like venous thromboembolic events, appears to be elevated in women using either unopposed or opposed estrogen regimens suggests that the effect may be related to a thrombophilic effect of estrogen. Two trials of tamoxifen have also observed increased rates of stroke with treatment, further implicating estrogen agonists for stroke risk.2,3 Unfortunately, the data to date have failed to identify a subgroup of women that is uniquely predisposed to HT-associated stroke, making it diff|cult to offer more than general advice to
218
Evidence-based Obstetrics and Gynecology (2005) 7, 217^218
individual women contemplating use of HT for relief of perimenopausal symptoms. Hopefully, ongoing research will reveal the mechanisms involved in this adverse effect of HTand lead to safer alternatives for perimenopausal symptom relief. David M. Herrington, MD,MHS Wake Forest University School of Medicine, Winston-Salem, NC, USA
Literature cited 1. Nelson HD, Humphrey LL, Hygren P, Teutsch SM, Allan JD. Postmenopausal hormone replacement therapy. Scientif|c review. JAMA 2002; 288:872^ 81. 2. Fisher B,Costantino JP,Wickerham DL, et al.Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1Study. J Natl Cancer Inst 1998; 90:1371^ 88. 3. Dignam JJ, Fisher B. Occurrence of stroke with tamoxifen in NSABP B-24. Lancet 2000; 355:848 ^9.