Can estradiol and progesterone (hormone replacement therapy, HRT) contribute to a heart attack in a hypertensive postmenopausal woman?

Hormone Replacement Therapy Significantly Increases Heart Attack Risk in Hypertensive Women in Their Late 60s

Yes, estradiol and progesterone (combined hormone replacement therapy) can contribute to heart attack in a hypertensive woman in her late 60s, and should not be used for cardiovascular protection in this population. 1, 2

Primary Cardiovascular Risks

Coronary Heart Disease

• Combined estrogen-progestin therapy increases coronary heart disease events by 29% (RH 1.29; 95% CI 1.02-1.63), with risk evident shortly after starting therapy 1, 3, 2
• The Women's Health Initiative demonstrated 41 versus 34 CHD events per 10,000 women-years in the treatment versus placebo groups 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 1
• In women with established coronary disease (average age 66.7 years), HRT showed no cardiovascular benefit and increased early risk 1, 2

Stroke Risk

• Combined HRT increases stroke risk by 41% (RH 1.41; 95% CI 0.86-2.31) 1, 3
• The absolute risk translates to 33 versus 25 strokes per 10,000 women-years in treated versus placebo groups 2
• The increase in stroke risk appears after the first year and persists throughout treatment 2

Thrombotic Events

• Venous thromboembolism risk increases 2-fold (RH 2.11; 95% CI 1.26-3.55) with combined estrogen-progestin therapy 1, 3, 4, 2
• Meta-analysis of 12 studies confirms more than doubled VTE risk (RR 2.14; 95% CI 1.64-2.81) 1, 3, 4
• Risk is highest in the first year, with a 3.5-fold increase (RR 3.49; 95% CI 2.33-5.59) during initial 12 months 1, 3
• Deep vein thrombosis specifically increases from 13 to 26 per 10,000 women-years 2
• Pulmonary embolism increases from 8 to 18 per 10,000 women-years 2

Specific Concerns for Hypertensive Women

Blood Pressure Effects

• The Women's Health Initiative found an average 1 mm Hg increase in systolic blood pressure over 5.6 years in women on combined HRT 1
• Current hormone users have a 25% greater likelihood of having hypertension compared to non-users 1
• While the blood pressure increase is modest, it compounds existing cardiovascular risk in hypertensive patients 1

Age-Related Considerations

• Women in their late 60s represent a particularly high-risk population for HRT-related cardiovascular events 1
• The average age in HERS (66.7 years) and ERA (65.8 years) trials showed no cardiovascular benefit and possible harm 1
• The hypothesis that women "too old to benefit" (average age 66.7 years) may explain null or harmful effects 1

Guideline Recommendations

Definitive Contraindications

• Combined estrogen-progestin therapy should NOT be initiated to prevent cardiovascular disease in postmenopausal women (Class III, Level A) 1
• Combined estrogen-progestin therapy should NOT be continued to prevent cardiovascular disease in postmenopausal women (Class III, Level C) 1
• The FDA black box warning explicitly states that estrogen plus progestin therapy should not be used for cardiovascular disease prevention 2

Secondary Prevention

• HRT should NOT be initiated for secondary prevention of cardiovascular disease 1
• In women with established atherosclerosis, there is no overall cardiovascular benefit and possible early increased risk 1

Clinical Decision Algorithm

For a hypertensive woman in her late 60s considering HRT:

1. If considering for cardiovascular protection: Absolutely contraindicated 1, 2

2. If considering for menopausal symptoms:

   • Weigh thrombotic and cardiovascular mortality risks against quality-of-life benefits 3
   • The mortality risks from blood clots and stroke outweigh symptom relief benefits in most scenarios 3
   • If symptoms are severe and no alternatives work, use the lowest effective dose for the shortest duration 2

3. If already on HRT:

   • Consider discontinuation based on cardiovascular risk profile 1
   • If acute cardiovascular event occurs, discontinue immediately or ensure VTE prophylaxis during hospitalization 1, 2

4. Blood pressure monitoring:

   • Monitor BP closely initially, then at 6-month intervals if HRT is continued 1

Critical Pitfalls to Avoid

• Do not extrapolate observational study benefits to clinical practice: Observational studies showing cardiovascular benefit were confounded by socioeconomic status and healthy-user bias; when controlled for these factors, no benefit was seen (RH 0.97; 95% CI 0.82-1.16) 1
• Do not assume transdermal routes are safer for cardiovascular events: While oral estrogen increases hypertension risk more than transdermal 5, the cardiovascular event data from WHI applies to all routes until proven otherwise 3
• Do not continue HRT based on "time since menopause" theory: The hypothesis that early initiation prevents disease better than late initiation has no controlled data to support it 1

Mechanistic Understanding

The prothrombotic effects occur through multiple pathways 4:

• Increased factor VII activity and D-dimer
• Increased prothrombin F1.2
• Decreased antithrombin III
• Decreased tissue factor pathway inhibitor
• Decreased tissue plasminogen activator

These hemostatic changes create a hypercoagulable state that compounds existing cardiovascular risk in hypertensive patients 4.