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QUESTION: In women with coronary artery disease, does hormone replacement therapy (HRT) (oestrogen plus progestin) increase the risk for venous thromboembolism (VTE)?
Randomised (unclear allocation concealment*), blinded (patients, investigators, and outcome assessors),* placebo controlled trial with a mean follow up of 4.1 years (Heart and Estrogen/progestin Replacement Study [HERS]).
20 US outpatient and community settings.
2763 postmenopausal women between 44 and 79 years of age (mean age 67 y, 89% white) who had established coronary artery disease and who had not had a hysterectomy. Exclusion criteria were recent coronary events; recent use of hormone therapy; history of VTE, breast cancer, or endometrial cancer; uncontrolled hypertension; diabetes; or other life threatening disease. Follow up was 100% for mortality and 98% for other outcomes.
1380 women were allocated to HRT (conjugated equine oestrogen, 0.625 mg/d plus medroxyprogesterone acetate, 2.5 mg/d) and 1383 to placebo. Data on risk factors were collected (fractures, non-fatal myocardial infarction, stroke, congestive heart failure, and transient ischaemic attack).
Main outcome measures
Documented and suspected VTE events.
During follow up, more women in the HRT group had VTE and deep venous thrombosis than women in the placebo group (table) (p=0.003 and 0.008, respectively). The groups did not differ for pulmonary embolism (p=0.08) (table), although few pulmonary embolisms occurred (11 in the HRT group v 4 in the placebo group). Subgroup analyses showed a trend towardincreased risk for idiopathic VTE (relative hazard 3.1, 95% CI 0.8 to 11.3) and increased nonidiopathic VTE (relative hazard 2.5, CI 1.2 to 5.3).
In older women with coronary artery disease, HRT increased the risk for VTE and deep venous thrombosis.
Decisions about HRT seem to get harder every day. Firstly, HERS raised doubts about benefits for heart disease,1 and now the report by Grady et al indicates that HRT increases the risk for VTE. Although this finding was not seen in an earlier randomised controlled trial (RCT) in healthy women (only 4 cases of VTE occurred),2 comparable risks have been reported in observational studies,3 as well as in RCTs of selective oestrogen receptor modifiers like raloxifene.4 Thus, the finding is probably real, but is it important? For the average menopausal woman, the risk for VTE is small (smaller than in the HERS participants) and probably less important than other benefits (relief of symptoms and prevention of osteoporosis) or risks (possible increase in breast cancer) of HRT. However, women who have a lower extremity fracture, recent surgery or other admission to hospital, cancer, congestive heart failure, myocardial infarction, or stroke should probably avoid HRT. These factors increase the risk for VTE 2-30-fold, and they accounted for 75% of all cases of VTE in HERS. In these patients, clinicians should consider bone specific agents for osteoporosis and alternatives to HRT for menopausal symptoms.
An important question is whether topical HRT, which avoids the first pass effects on the liver, carries the same risk. An Italian study, where 80% of HRT use was with transdermal oestrogen, reported a 2-fold increased risk for VTE but had only 6 exposed cases.5