Hormone Therapy for Preventing Cardiovascular Disease in Post-Menopausal Women

An observational follow-up of WHI studies 2 examined total and cause-specific cumulative during the cumulative 18-year follow-up with prespecified analyses by 10-year age group based on age at time of randomization. Among 27 347 women who were randomized (baseline mean [SD] age, 63.4 [7.2] years), mortality follow-up was available for more than 98%. All-cause mortality was 27.1% in the hormone therapy group vs 27.6% in the placebo group (hazard ratio [HR], 0.99, 95% CI 0.94 to 1.03]) in the overall pooled cohort; with CEE plus MPA, the HR was 1.02, 95% CI 0.96 to 1.08); and with CEE alone, the HR was 0.94, 95% CI 0.88 to 1.01). HR for cardiovascular mortality was 1.00 (95% CI 0.92 to 1.08 [8.9 % with hormone therapy vs 9.0% with placebo]); for total cancer mortality 1.03 (95% CI 0.95 to 1.12 [8.2 % with hormone therapy vs 8.0% with placebo]); and for other causes 0.95 (95% CI 0.88 to 1.02 [10.0% with hormone therapy vs 10.7% with placebo]), and results did not differ significantly between trials. When examined by 10-year age groups comparing younger women (aged 50-59 years) to older women (aged 70-79 years) in the pooled cohort, the ratio of nominal HRs for all-cause mortality was 0.61 (95% CI 0.43 to 0.87) during the intervention phase and the ratio was 0.87 (95% CI 0.76 to 1.00) during cumulative 18-year follow-up, without significant heterogeneity between trials.

A secondary analysis of the WHI studies 3 explored the effects of HRT on risk of cardiovascular disease by age or years since menopause began. For women with less than 10 years since menopause began, the HR for CHD was 0.76 (95% CI 0.50 to 1.16); 10 to 19 years, 1.10 (95% CI 0.84 to 1.45); and 20 or more years, 1.28 (95% CI 1.03 to 1.58) (P for trend = .02). The estimated absolute excess risk for CHD for women within 10 years of menopause was -6 per 10 000 person-years; for women 10 to 19 years since menopause began, 4 per 10 000 person-years; and for women 20 or more years from menopause onset, 17 per 10 000 person-years. For the age group of 50 to 59 years, the HR for CHD was 0.93 (95% CI 0.65 to 1.33) and the absolute excess risk was -2 per 10 000 person-years; 60 to 69 years, 0.98 (95% CI 0.79 to 1.21) and -1 per 10,000 person-years; and 70 to 79 years, 1.26 (95% CI 1.00 to 1.59) and 19 per 10 000 person-years (P for trend = .16). Hormone therapy increased the risk of stroke (HR 1.32; 95% CI 1.12 to 1.56). Risk did not vary significantly by age or time since menopause. There was a nonsignificant tendency for the effects of hormone therapy on total mortality to be more favorable in younger than older women (HR of 0.70 for 50-59 years; 1.05 for 60-69 years, and 1.14 for 70-79 years; P for trend = .06).

A Cochrane review [Abstract] 1 included 19 studies with a total of 40 410 post-menopausal women. The studies compared hormone therapy for 6 months or more (oestrogen, with or without progestogen) with placebo or no treatment. Most participants were post-menopausal American women, and the mean age in most studies was over 60 years. The length of time women were on treatment varied across the studies from 7 months to 10.1 years.

Hormone therapy in both primary and secondary prevention conferred no protective effects for death (RR 1.01, 95% CI 0.92 to 1.11; 14 studies, n=35 483), death from cardiovascular causes (RR 0.96, 95% CI 0.78 to 1.18; 9 studies, n=33 613), non-fatal myocardial infarction (RR 1.01, 95% CI 0.89 to 1.14; 14 studies, n=34 841), angina (RR 0.90, 95% CI 0.79 to 1.03; 5 studies, n=30 502), or revascularisation procedures (RR 0.95, 95% CI 0.85 to 1.05; 6 studies, n=30 724) compared to placebo. However, there was an increased risk of stroke in those in the hormone therapy arm for combined primary and secondary prevention (RR 1.24, 95% CI 1.10 to 1.41; 10 studies, n=34 672). Venous thromboembolic events were increased (RR 1.92, 95% CI 1.36 to 2.69; 10 studies, n=37 313), as were pulmonary emboli (RR 1.81, 95% CI 1.32 to 2.48; 7 studies, n=36 316) on hormone therapy relative to placebo. The associated numbers needed-to-harm (NNH) were 165, 118 and 242 for stroke, venous thromboembolism and pulmonary embolism respectively. Results for primary and secondary prevention separately are shown in tablesT1 and T2.

Those who started hormone therapy less than 10 years after the menopause had lower mortality (RR 0.70, 95% CI 0.52 to 0.95; 5 studies, n=9 088) and coronary heart disease risk (composite of death from cardiovascular causes and non-fatal myocardial infarction) (RR 0.52, 95% CI 0.29 to 0.96; 4 studies, n=8 311), though they were still at increased risk of venous thromboembolism (RR 1.74, 95% CI 1.11 to 2.73; 3 studies, n=9 838) compared to placebo or no treatment. In those who started treatment more than 10 years after the menopause it had little effect on death or coronary heart disease between groups but there was an increased risk of stroke (RR 1.21, 95% CI 1.06 to 1.38; 8 studies, n=22 722) and venous thromboembolism (RR 1.96, 95% CI 1.37 to 2.80; 9 studies, n=27 475).

The following decision support rules contain links to this evidence summary:

• Limiting the duration of hormone replacement therapy http://www.ebmeds.org/ebmeds/ebmeds_home.asp?mode=scripts&submode=view&id=scr00538&country=UK

References

• Boardman HM, Hartley L, Eisinga A et al. Hormone therapy for preventing cardiovascular disease in post-menopausal women. Cochrane Database Syst Rev 2015;(3):CD002229. [PubMed]
• Manson JE, Aragaki AK, Rossouw JE et al. Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women's Health Initiative Randomized Trials. JAMA 2017;318(10):927-938. [PubMed]
• Rossouw JE, Prentice RL, Manson JE et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007;297(13):1465-77.[PubMed]