Is coronary artery disease (CAD) a contraindication to hormone replacement therapy (HRT) in menopausal women?

Coronary Artery Disease as a Contraindication to Hormone Replacement Therapy in Menopausal Women

Coronary artery disease (CAD) is a contraindication to hormone replacement therapy (HRT) in menopausal women due to increased cardiovascular risks, including a significant 52% increase in cardiovascular events during the first year of therapy. 1

Evidence Against HRT in Women with CAD

• The American College of Cardiology and American Heart Association recommend that HRT should not be initiated for secondary prevention of cardiovascular disease in women with established CAD, as it provides no cardiovascular benefit and may increase early risk of cardiovascular events 1, 2
• The Heart and Estrogen/progestin Replacement Study (HERS) demonstrated no overall reduction in coronary heart disease events among postmenopausal women with CAD despite 4.1 years of follow-up 3
• A post-hoc time-trend analysis revealed a significant 52% increase in cardiovascular events in the first year of HRT use compared to placebo (42.5/1000 person-years versus 28.0/1000 person-years) 3
• The HERS II follow-up study extended observations to 6.8 years and confirmed no reduction in cardiovascular events with continued HRT use (RH 0.99; 95% CI 0.84-1.17) 4
• The Women's Angiographic Vitamin and Estrogen (WAVE) Trial showed that coronary progression worsened with HRT compared to placebo, and when patients with intercurrent death or MI were included, there was an increased risk for women in the active HRT group (P=0.045) 5

Mechanisms of Increased Risk

• HRT increases the risk of venous thromboembolism nearly 3-fold compared to placebo, with a 5-fold increased risk in the first 90 days after myocardial infarction 1
• Women randomized to estrogen in clinical trials showed increased risk of fatal stroke and more severe neurological impairments after stroke 1
• The Estrogen Replacement and Atherosclerosis (ERA) Trial showed no benefit of estrogen therapy (with or without progestin) on angiographic progression of disease in women with documented coronary stenosis 3, 1

Management Recommendations for Women with CAD and Menopausal Symptoms

• For women who develop an acute coronary event while on HRT, it is prudent to discontinue the therapy immediately 2, 6
• For women with CAD who have been on long-term HRT, the decision to continue or stop should be based on the severity of menopausal symptoms, established non-coronary benefits/risks, and patient preference after informed discussion 2
• If discontinuation is not possible during hospitalization for an acute cardiovascular event, appropriate VTE prophylaxis should be used during immobilization 1

Alternative Approaches for Managing Menopausal Symptoms in Women with CAD

• Non-hormonal pharmacological options should be considered first-line therapy for vasomotor symptoms 2:
  • Selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) at low doses, such as paroxetine 7.5-10 mg daily or venlafaxine 37.5-75 mg daily 6
• Locally applied vaginal estrogen may be considered for genitourinary symptoms as there is minimal systemic absorption 2
• Lifestyle modifications remain cornerstone therapy, including smoking cessation, regular physical activity, optimal weight management, and heart-healthy diet 2, 6

Historical Context and Evolving Evidence

• Earlier observational studies suggested estrogen might have a cardioprotective role, noting decreased CHD risk in postmenopausal women on HRT 7
• By 1996, estrogen (specifically Premarin) was one of the most dispensed medications in the United States, widely endorsed for CHD risk reduction 7
• However, subsequent randomized controlled trials contradicted these observational findings, demonstrating no benefit and potential harm 4, 5, 7
• The discrepancy between observational studies and randomized trials may be attributed to selection bias, prevention bias, compliance bias, and survivor bias in observational studies 3

Common Pitfalls in Clinical Decision-Making

• Relying on surrogate markers (like lipid profiles) rather than clinical outcomes - HRT improves lipid profiles but doesn't reduce cardiovascular events 1
• Assuming that the timing of HRT initiation relative to menopause onset (the "timing hypothesis") negates the contraindication - no controlled data support this hypothesis in women with established CAD 3
• Continuing HRT during hospitalization for acute cardiovascular events without appropriate VTE prophylaxis 1
• Using HRT for presumed cardioprotection based on outdated observational studies rather than more recent randomized controlled trials 7