Menopause and Cardiovascular Risk

• Menopause and Cardiovascular Risk are linked

Objectives

• Define how reduced estrogen levels impact cardiovascular risk.
• Explain the pros and cons of menopausal hormone therapy (MHT) concerning cardiovascular health.
• Give an overview of methods to lower cardiovascular risk.

CV Changes with Menopause

• Total cholesterol, LDL-C, triglycerides, and apolipoprotein B increase
• Lipoprotein(a) increases around age 50 in women.
• Visceral fat increases, with the SWAN study noting a non-linear increase in abdominal visceral fat accelerating 2 years before menopause; this is related to increased carotid intima-media thickness (CIMT), a significant indicator of cardiovascular risk.
• Insulin resistance increases.
• Endothelial dysfunction occurs.
• Blood pressure and sympathetic tone increase.

Lipids and CV Risk

• Lipoprotein (a) levels > 40 mg/dL in women > 50 increase the risk of myocardial infarction, aortic valve stenosis, and ischemic heart disease.
• LDL-C acts as a causal agent in atherosclerotic cardiovascular disease pathogenesis, with a 39 mg/dL increase in LDL:
  • Triples Myocardial infarction
  • Doubles ischemic heart disease
  • Multiplies CV death by five times
  • Increases all-cause mortality fourfold
• LDL-C goals are based on CV risk profile; lower levels achieved faster and maintained longer are preferable.

Age at Menopause and CV Risk

• Earlier menopause increases the risk of coronary heart disease, heart failure, cardiovascular mortality, and all-cause mortality.
• There is a bidirectional relationship where a worse CV risk profile before menopause is associated with earlier menopause (Framingham Heart Study).
• Bilateral salpingo-oophorectomy (BSO) before natural menopause is associated with increased CV risk and mortality.
  • The Nurses' Health Study indicated that hormone therapy use is linked to reduced cardiovascular disease risk after surgical premature menopause.

Vasomotor Symptoms and CV Risk

• The SWAN study of 3,038 women aged 42–52 at baseline, followed for 22 years, showed a dose-dependent relationship between vasomotor symptom frequency, severity, and cardiovascular risk

Early Data on MHT and CV Risk

• The Women's Health Initiative (WHI, primary prevention trial) and the Heart and Estrogen/progestin Replacement Study (HERS, secondary prevention trial) found no benefit of MHT on CVD risk.
  • WHI: CVD events in older women increased when randomized to hormone therapy.
  • HERS: CVD events increased during the first year of hormone therapy use versus placebo.

Timing Hypothesis

• Re-analysis of the WHI study showed no excess CV risk for those receiving MHT at age 50–59 or within 10 years of entering menopause.
• A Cochrane review in 2015 found less CHD in women who started hormone therapy less than 10 years after menopause (RR 0.52, 95% CI 0.29-0.96).
• The "timing hypothesis" suggests that women starting hormone therapy closer to menopause experience neutral or reduced CVD risk patients starting it more than 10 years post-menopause, might have an increased CVD risk.

Additional Supporting Data

• Kronos Early Estrogen Prevention Study (KEEPS) randomized women within 3 years of their final menstrual period to oral conjugated estrogen, transdermal estradiol patch, or placebo with cyclic oral progesterone.
  • After 4 years of hormone therapy, no difference in CIMT was observed between hormone therapy and placebo at 10 years.
• The Early versus Late Intervention Trial with Estradiol compared oral estradiol with vaginal progesterone gel versus placebo in women within 6 years (early cohort, median age 55.4 years) or >10 years since menopause (late cohort, median age 63.6 years).
  • After 5 years, the early cohort randomized to oral estradiol had lower progression of subclinical atherosclerosis as measured by CIMT (p=0.008).

Estrogen Risks

• Oral estrogens should be avoided in women with:
  • History of CVD
  • Blood clots
  • High triglycerides
  • Gallbladder disease
  • Migraine with aura
  • Prior breast or endometrial cancer, including transdermal use

Transdermal vs. Oral Estrogen

• Transdermal estradiol results in lower VTE and possibly lower stroke risk compared to oral estrogen (Endocrine Society Guidelines).
• Meta-analysis (oral versus transdermal ET):
  • VTE risk (9 studies): RR 1.63 (1.40-1.90)
  • Stroke risk (1 study): RR 1.23 (1.03-1.48)
• More data is needed on hormone therapy dosage, formulation, delivery route, and duration of use regarding its impact on CVD risk.

ASCVD Risk Factors

• HLD (Hyperlipidemia), HTN (Hypertension), DM (Diabetes Mellitus)
• Family history of early CVD (men < 55, women < 65)
• Obesity
• Physical inactivity
• Smoking
• Coronary calcification (moderate risk: CAC 1-99; high risk: CAC > 100)
• Pregnancy events: pre-eclampsia, preterm delivery, gestational diabetes mellitus, intrauterine growth restriction
• Systemic autoimmune collagen vascular disease (SLE, RA)

ASCVD Risk Calculator

• Can estimate 10 year ASCVD risk: https://tools.acc.org/ascvd-risk-estimator-plus/#!/calculate/estimate/
  • Factors considered: age, race, blood pressure, lipids, diabetes mellitus, smoking, hypertension treatment, statin use, and aspirin use.
• it is not to be used for patients with ASCVD
• Risk stratification:
  • Low-risk: <5%
  • Borderline risk: 5% to 7.4%
  • Intermediate risk: 7.5% to 19.9%
  • High risk: ≥20%

CV Risk Assessment Prior to MHT

• Evaluate age, time since menopause, and symptoms: women less than 10 years from their final menstrual cycle, younger than 60 years old, and experiencing bothersome vasomotor symptoms.
• Perform ASCVD risk assessment and exclude any hormone therapy contraindications.
  • ASCVD risk factors to consider include: hyperlipidemia, hypertension, diabetes, family history of premature CVD in first-degree relatives (men < 55 or women < 65 years), obesity (BMI > 30 kg/m²), physical inactivity, cigarette smoking, coronary calcification (moderate risk: CAC 1-99; high risk: CAC > 100), history of preeclampsia, and history of systemic autoimmune collagen-vascular disease.
  • Contraindications to systemic hormone therapy: coronary heart disease, stroke, TIA, breast or endometrial cancer, history of pulmonary embolus, venous thrombosis or clotting disorder, active liver disease, and undiagnosed abnormal vaginal bleeding.
• Evaluate risk category, Hormone therapy use is not recommended for:
  • May consider Hormone therapy if: ASCVD risk <5% (low risk) and <1 CVD risk factor
  • May consider hormone therapy, transdermal formulation if: ASCVD risk 5-10% or ASCVD risk <5% but ≥2 CVD risk factors.
  • Age ≥60 or >10 years since menopause onset or ASCVD risk >10%
• Ensure routine follow-up with re-evaluation of risks and benefits.

What Else About Age?

• According to the Menopause Society in 2022, initiating hormone therapy more than 10 years after menopause onset or after age 60 shows a less favorable benefit-risk ratio, with higher absolute risks of CHD, stroke, VTE, and dementia.
• The WHI indicates the greatest risk when initiating MHT at age > 70.
• Use an appropriate dose for the necessary duration to manage symptoms
• Longer therapy durations are acceptable for indications like persistent vasomotor symptoms, with shared decision-making and periodic re-evaluation.
• There is no arbitrary age-based stopping rule.

Lifestyle Factors to Modify CV Risk

• Diet:
  • Avoid high glycemic index/load foods, sugar-sweetened beverages, red meat, and trans fats. Consume more fruits and vegetables
• Exercise:
  • Even moderate exercise protects against CHD and all-cause mortality. It also increases serum HDL, reduces blood pressure and insulin resistance, and aids in weight loss.
• Weight loss:
  • Obesity is associated with hypertension, insulin resistance, glucose intolerance, and high TG. There is a continuous linear relationship between BMI and CVD risk and weight loss > 5% can decrease cardiovascular risk factors like hypertension, hyperlipidemia, and diabetes mellitus.