Does hormone replacement therapy (HRT) increase the risk of heart attack in postmenopausal women?

Does HRT Increase Risk for Heart Attack?

Yes, hormone replacement therapy (HRT) increases the risk of heart attack in postmenopausal women, particularly when started more than 10 years after menopause or in women over age 60. The Women's Health Initiative demonstrated a 29% increased risk of coronary heart disease events (fatal and nonfatal myocardial infarctions) with combined estrogen-progestin therapy, with this risk appearing shortly after starting treatment 1, 2.

Primary Evidence on Heart Attack Risk

The highest quality evidence comes from the Women's Health Initiative (WHI), which found:

• Combined estrogen-progestin therapy increases coronary heart disease by 29% (RH 1.29,95% CI 1.02-1.63) 1, 2
• The risk is highest in the first year of therapy, with a 52% increase in cardiovascular events (42.5 versus 28.0 per 1000 person-years) compared to placebo 2
• Coronary heart disease mortality was not significantly increased (RH 1.18,95% CI 0.70-1.97), though the trend was concerning 1

Critical Timing Considerations

The timing of HRT initiation relative to menopause dramatically affects cardiovascular risk:

Starting HRT <10 Years After Menopause

• Lower mortality (RR 0.70,95% CI 0.52-0.95) 3
• Reduced coronary heart disease (RR 0.52,95% CI 0.29-0.96) 3
• Still carries increased venous thromboembolism risk (RR 1.74,95% CI 1.11-2.73) 3
• No strong evidence of increased stroke risk in this subgroup 3

Starting HRT ≥10 Years After Menopause

• No benefit for death or coronary heart disease 3
• Increased stroke risk (RR 1.21,95% CI 1.06-1.38) 3
• Increased venous thromboembolism (RR 1.96,95% CI 1.37-2.80) 3
• Women in their late 60s represent a particularly high-risk population 2

Why Observational Studies Were Misleading

Earlier observational studies suggested HRT was protective against heart disease, but this was due to selection bias (healthier women chose to use HRT) 1:

• Meta-analyses of observational studies showed apparent CHD reduction (RR 0.80,95% CI 0.68-0.95) among current users 1
• However, when controlled for socioeconomic status, no benefit was seen (RH 0.97,95% CI 0.82-1.16) 1
• The USPSTF concluded that selection bias explains the apparent protective effect seen in observational data 1

Secondary Prevention Evidence

HRT should never be used for secondary prevention in women with established coronary disease:

• The HERS trial found no overall reduction in CHD events after 6.8 years of follow-up (RH 0.99,95% CI 0.84-1.17) 4
• There was a 50% increased risk of heart attacks within the first year of starting HRT in women with existing CHD 5
• ACC/AHA guidelines state hormone therapy should not be given de novo to postmenopausal women after acute coronary syndrome for secondary prevention (Class III, Level A) 1

Additional Cardiovascular Risks Beyond Heart Attack

HRT increases multiple cardiovascular risks that compound overall morbidity and mortality:

• Stroke increased by 41% (RH 1.41,95% CI 0.86-2.31) 1, 2
• Venous thromboembolism doubled (RH 2.11,95% CI 1.26-3.55), with highest risk in the first year (RR 3.49,95% CI 2.33-5.59) 1, 6
• Pulmonary embolism increased 81% (RR 1.81,95% CI 1.32-2.48) 3

Guideline Recommendations

Major medical societies uniformly recommend against HRT for cardiovascular prevention:

• The American Heart Association recommends HRT should not be initiated to prevent cardiovascular disease in postmenopausal women (Class III, Level A) 2
• The American College of Cardiology recommends HRT should not be continued to prevent cardiovascular disease (Class III, Level C) 2
• The USPSTF concluded that HRT does not decrease, and may in fact increase, the incidence of CHD 1

Common Pitfalls to Avoid

• Do not prescribe HRT for cardiovascular protection based on outdated observational data 1, 5
• Do not continue HRT in women who develop acute coronary syndrome while on therapy 1
• Do not assume all postmenopausal women face equal risk—timing relative to menopause matters critically 3
• Do not overlook the compounding thrombotic risks (stroke, VTE, PE) when counseling patients 2, 6

Clinical Bottom Line

HRT increases heart attack risk overall, with the magnitude depending on when therapy is initiated. Women starting HRT within 10 years of menopause may have reduced coronary risk, but those starting later face increased cardiovascular events without benefit 3. HRT should only be used for symptomatic relief of menopausal symptoms at the lowest effective dose for the shortest duration, never for cardiovascular prevention 5, 7.