ABSTRACT
Estrogen-containing oral contraceptive pills have long been recognized to carry an excess risk of VTE.1,2 HRT, however, was not,3-6 until recently, considered to be a risk factor for VTE. However, many of the initial studies assessing the risk had limited statistical power or methodological limitations. Recently, a series of case control studies have shown a modest increase in the relative risk of VTE in women using estrogen-containing HRT (Table 25.1). A North American population-based nested case control study reported that women with idiopathic VTE had a relative risk of 3.6 [95% confidence interval (CI) 1.67.8] for VTE with current use of estrogen compared to non-users.7 The absolute risk was estimated at 9 per 100,000 women per year in non-users compared to 32 per 100,000 women per year in users. A UK hospital-based case control study8 assessed 45-64 year old women with idiopathic VTE. This study found an odds ratio for current HRT use, compared to non-users, of 3.5 (95% CI 1.8-7.0). Furthermore, the risk appeared to be highest among short-term current users. The estimate of absolute risk was 11 per 100,000 women per year for non-users and 27 per 100,000 women per year for current users. The Nurses Health Cohort study estimated the adjusted relative risk of primary pulmonary embolism to be 2.1 (95% CI 1.2-3.8) for current HRT users.9 The General Practice Research Database in the UK was used to conduct a population-based case control study and found an adjusted odds ratio of VTE for current users of 2.1 (95% CI 1.4-3.2) relative to non-users.10 In this study, the increase in risk was restricted to the first year of use with an odds ratio of 4.6 (2.5-8.4) during the first 6 months. An Italian case control study reported that there was a 2.3 times (95% CI 1.0-5.3) increase in risk with the effect
restricted to the first year of use.11 The Heart and Estrogen/progestin Replacement Study (HERS), a large randomized controlled trial on the secondary prevention of coronary artery disease using HRT (containing equine
Authors (ref)
Study design Relative risk
conjugated estrogens and medroxyprogesterone acetate), reported an increase in risk of coronary events in women in the first 4 months of use followed by a reduction in risk over the last 2 years of this trial, which was conducted over 4.1 years. An increase in relative risk of VTE of 2.7 (95% CI 1.4-5.5.1) was also reported.12 A Scandinavian population-based case control study reported that HRT preparations containing only estradiol had no overall association with VTE with an adjusted odds ratio of 1.22 (95% CI 0.76-1.94).13 However, stratification by duration of exposure found that there was a significantly increased risk in the first year (odds ratio 3.54; 95% CI 1.54-8.2) reducing after the first year of use (odds ratio 0.66; 95% CI 0.39-1.10). This study differed from the others in several respects. It studied only estradiol-containing HRT and, in contrast with other studies that had excluded cases with presumed risk factors such as surgery, previous VTE and bed rest. It did not select the women except for excluding cancerrelated VTE. While this study differed from the others with regard to the overall risk of VTE, it was consistent with regard to an excess risk occurring in the first year of use (Table 25.2).
