Primary Prevention of Cardiovascular Disease With HRT

Kate Maclaran; John C Stevenson


Women's Health. 2012;8(1):63-74. 

In This Article


CVD not only incorporates CHD, but also disorders of both the arterial and venous blood vessels. It is important, therefore, to also consider the impact of HRT on two important clinical outcomes: VTE and stroke.

The WHI estrogen alone arm terminated 8 months early after almost 7 years due to an apparent increased risk of stroke (HR: 1.39, estimated at an excess of 12 cases per 10,000 patient years) with 0.625 mg CEE;[29] although, surprisingly, this termination was not at the behest of the Data Safety and Monitoring Board. However, data remain conflicting regarding the exact risk of stroke with HRT. In the NHS, use of estrogen plus progestin (RR: 1.45, 95% CI: 1.10–1.92) and higher doses of CEE alone were associated with increased risk of ischemic stroke.[27] A recent meta-analysis found that oral HRT was associated with a 32% increased risk of stroke (OR: 1.32, 95% CI: 1.14–1.53).[57]

Risk of stroke appears to vary by dose and route of administration. A recent case–control study found that, consistent with previous results, there was approximately a 30% increased risk of stroke in users of oral HRT (RR: 1.28, 95% CI: 1.15–1.42).[58] The authors estimated that this would amount to an attributable risk of 0.8 additional strokes per 1000 women per year. Overall, transdermal therapy was not associated with increased stroke risk (RR: 0.95, 95% CI: 0.75–1.20), but high-dose transdermal therapy alone (doses >50 µcg) was associated with increased risk (RR: 1.89, 95% CI: 1.15–3.11).

Unlike CHD, the timing hypothesis does not appear to apply to the risk of stroke, most likely because the risk of stroke is probably due to thrombotic rather than atherosclerotic mechanisms.[59] Therefore, although the literature is suggestive of an increased risk of stroke with oral HRT, there is a dose dependent relationship and the event rate is extremely low, especially in younger women.


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