Does hormone replacement therapy (HRT) improve or increase the risk of cardiovascular (CV) disease in postmenopausal women?

Does HRT Increase or Improve Cardiovascular Disease Risk?

HRT should not be initiated for cardiovascular disease prevention and increases CV risk, particularly in women with established heart disease or those over 60 years old or more than 10 years past menopause. 1, 2, 3, 4

Critical Distinction: Secondary vs. Primary Prevention and Timing

Secondary Prevention (Women with Established CVD)

Do not initiate HRT for secondary prevention of cardiovascular disease. 1

• The HERS trial demonstrated a 52% increase in cardiovascular events in the first year of HRT (42.5 vs 28.0 per 1000 person-years) compared to placebo in women with established coronary disease 1
• The ERA trial showed no benefit of HRT on angiographic progression of atherosclerosis in women with documented coronary stenosis 1
• Both estrogen-alone and estrogen-plus-progestin regimens failed to prevent recurrent cardiovascular events 1
• Women who develop acute coronary events while on HRT should consider discontinuation or ensure appropriate VTE prophylaxis during hospitalization 1

Primary Prevention: The "10-Year Window" Rule

The cardiovascular effects of HRT depend critically on timing of initiation relative to menopause onset. 3, 5

Favorable Window (Lower Risk):

• Women under 60 years old AND within 10 years of menopause onset have the most favorable benefit-risk profile 3, 5
• In this window, HRT does not appear to increase cardiovascular mortality and may have neutral or slightly beneficial effects 6

Unfavorable Window (Increased Risk):

• Women over 60 years old OR more than 10 years past menopause face excess cardiovascular and stroke risk 2, 3, 4
• Oral estrogen-containing HRT in this population carries excess stroke risk and should be avoided 2, 3
• For every 10,000 women taking estrogen-progestin for 1 year beyond the favorable window, there are 7 additional CHD events, 8 more strokes, and 8 more pulmonary emboli 3

Specific Cardiovascular Risks by Event Type

Venous Thromboembolism

• HRT increases VTE risk nearly 3-fold overall 1
• Relative risk of venous thromboembolic events: 2.15 (95% CI 1.61-2.86) 7
• Pulmonary embolus risk: RR 2.15 (95% CI 1.41-3.28) 7
• Risk is highest in the first 90 days after myocardial infarction, increasing 5-fold even after adjustment for hospitalization 1

Stroke

• Stroke risk increases with HRT: RR 1.44 (95% CI 1.10-1.89) 7
• The WHI estrogen-alone substudy showed increased stroke risk during 7.1 years of treatment 4
• A nonsignificant increase in fatal stroke risk was observed (relative hazard 1.61,95% CI 0.97-3.55) 1

Coronary Heart Disease

• No protective effect of HRT was found for cardiovascular death or non-fatal MI in meta-analysis 7
• The WHI estrogen-plus-progestin substudy reported increased risks of MI in postmenopausal women aged 50-79 during 5.6 years of treatment 4

Absolute Contraindications to HRT

Do not prescribe HRT in women with: 2, 3

• History of breast cancer or hormone-sensitive malignancies
• Active or history of venous thromboembolism or stroke
• Coronary heart disease or prior MI
• Active liver disease
• Antiphospholipid syndrome or positive antiphospholipid antibodies
• Unexplained abnormal vaginal bleeding
• History of spontaneous coronary artery dissection (SCAD) 2

Clinical Decision Algorithm

Step 1: Determine Indication

• If seeking HRT solely for cardiovascular or osteoporosis prevention: Do not prescribe 1, 3, 4
• If treating severe vasomotor symptoms: Proceed to Step 2 3

Step 2: Screen for Absolute Contraindications

• If any absolute contraindication present: Do not prescribe HRT; use non-hormonal alternatives 2, 3
• If no contraindications: Proceed to Step 3 2

Step 3: Assess Timing Window

• If age ≥60 OR >10 years past menopause: Avoid oral estrogen; consider transdermal at lowest dose only if severe symptoms persist despite non-hormonal options 2, 3
• If age <60 AND ≤10 years past menopause: HRT is appropriate for symptom management 3, 5

Step 4: Assess Cardiovascular Risk

• Women with elevated cardiovascular risk require symptoms that lower quality of life by at least 12% to justify HRT 8
• Women at low cardiovascular risk may benefit from HRT if symptoms lower quality of life by as little as 4% 8

Important Caveats and Pitfalls

The "Healthy User" Bias

• Observational studies showing cardiovascular benefit from HRT likely overestimated benefits due to selection bias, where healthier women were more likely to receive HRT 1
• Randomized controlled trials consistently fail to show cardiovascular benefit, contradicting earlier observational data 1, 7

Route of Administration Matters

• The WHI studies used only oral conjugated equine estrogen (0.625 mg) with or without medroxyprogesterone acetate (2.5 mg) 4
• The relevance of these findings to transdermal preparations, lower doses, or other formulations remains uncertain 1
• Transdermal estradiol may have lower thrombotic risk than oral preparations, though definitive data are limited 6

Duration Considerations

• Use HRT at the lowest effective dose for the shortest duration consistent with treatment goals 4
• The FDA boxed warning emphasizes not using HRT for cardiovascular disease or dementia prevention 4
• Prolonged use beyond symptom control increases risks without additional cardiovascular benefit 3

Early vs. Late Initiation Paradox

• There is a hypothesis that early initiation of HRT (close to menopause) might prevent CHD development more effectively than treating established disease 1
• However, no controlled data currently support timing of initiation affecting cardiovascular disease rates 1