A total of 502 women were randomly allocated to receive HT and 504 to receive no treatment (control; Table 9). Importantly, this study had an open-label design, and the patients in the control arm did not receive placebo, which could have influ- enced compliance in the HT arm. After 11 years, the trial was stopped secondary to concerns of potentially harmful effects of HT that had been seen in other trials, such as the WHI. Women were followed up as an observational cohort for an additional 5 years. There was no increase in stroke, VTE, or breast cancer in treated women. HT initiated in these recently postmenopausal, younger women significantly reduced the risk of the combined end point of mortality, MI, or heart fail- ure. Stroke rates did not differ between groups.258 Transdermal estradiol may represent a safer alterna- tive than oral estrogens, because treatment does not appear to increase the risk of VTE and stroke and may reduce the risk of MI compared with nonusers. In a nested case-control study examining patients in general practices in the United Kingdom that included 15710 cases of stroke and almost 60000 randomly selected, matched control subjects from women aged 50 to79 years, transdermal estradiol was not associated with an increased risk of stroke, whereas oral estro- gens significantly increased stroke risk.272 Importantly, dose effects, even from transdermal use, were seen in this popu- lation, because low-dose products that contained 50 g of estrogen did not increase stroke risk (rate ratio, 0.81; 95% CI, 0.62 1.05) compared with no use, but high-dose patches that contained >50 g did increase risk (rate ratio, 1.89; 95% CI, 1.15 3.11). 