What are the cardiovascular and thrombo‑embolic risks of hormone replacement therapy in a postmenopausal woman who smokes?

Hormone Replacement Therapy in Postmenopausal Smokers: Cardiovascular and Thromboembolic Risks

Smoking is an independent risk factor for venous thromboembolism and pulmonary embolism, and when combined with hormone replacement therapy, the thrombotic risks are compounded—making HRT particularly hazardous in smokers despite any potential vascular benefits. 1

Baseline Thrombotic Risk with HRT

HRT substantially increases thromboembolic risk regardless of smoking status:

• Venous thromboembolism (VTE) risk increases more than 2-fold with combined estrogen-progestin therapy (RR 2.14,95% CI 1.64-2.81) and approximately 2-fold with estrogen alone (RR 1.92,95% CI 1.36-2.69) 2, 3, 4
• The highest VTE risk occurs in the first year of treatment (RR 3.49), with risk remaining elevated throughout therapy 5, 6
• Pulmonary embolism risk nearly doubles (RR 1.81-2.15) on HRT compared to placebo 1, 3, 4
• Stroke risk increases by 24-44% (RR 1.24-1.44) with systemic HRT 1, 3, 4

The absolute risk translates to 8 additional VTE events per 1,000 women treated (NNTH = 118), 4 additional pulmonary emboli per 1,000 women (NNTH = 242), and 6 additional strokes per 1,000 women (NNTH = 165) over approximately 4-6 years of treatment 4.

Smoking as an Independent Risk Factor

Smoking independently increases pulmonary embolism risk, as demonstrated in the Nurses' Health Study, and is classified as a secondary risk factor for venous thromboembolism in European Society of Cardiology guidelines 1. When a postmenopausal woman who smokes initiates HRT, she faces the additive thrombotic burden of both risk factors simultaneously.

Mechanistic Considerations

The prothrombotic effects of HRT are well-established:

• Estrogen (with or without progestin) increases factor VII activity, D-dimer, and prothrombin F1.2 while decreasing antithrombin III, tissue factor pathway inhibitor, and tissue plasminogen activator 6, 2
• Oral estrogen undergoes first-pass hepatic metabolism, which amplifies clotting factor production—a process that contributes to the elevated VTE risk 6
• Combined estrogen-progestin regimens carry higher thrombotic risk than estrogen alone, with the progestin component adding additional prothrombotic effects 5, 2

Clinical Recommendation for Smokers

For postmenopausal smokers, systemic HRT (oral or transdermal) should be avoided for cardiovascular disease prevention. 1, 3 The U.S. Preventive Services Task Force and American Heart Association both conclude that the harms of HRT—including increased VTE, stroke, and coronary events—outweigh chronic disease prevention benefits in most women, and this risk-benefit ratio is even more unfavorable in smokers 1.

If Menopausal Symptoms Require Treatment:

• For vasomotor symptoms (hot flashes): Use non-hormonal alternatives such as selective serotonin reuptake inhibitors rather than systemic HRT in smokers 6
• For genitourinary symptoms (vaginal dryness, dyspareunia): Switch to low-dose vaginal estradiol 0.01% cream, which provides local relief without systemic absorption and does not increase VTE or stroke risk 5, 6
• If systemic HRT is already prescribed: Strongly consider discontinuation in smokers unless there are compelling, documented indications with shared decision-making, given the compounded thrombotic risk 5

Age-Specific Considerations:

Women who start HRT less than 10 years after menopause have lower mortality (RR 0.70) and coronary heart disease (RR 0.52) but remain at increased VTE risk (RR 1.74) 4. However, in smokers, the baseline thrombotic risk from smoking negates any potential cardiovascular benefit, making even early initiation inadvisable 1, 4.

Women who start HRT more than 10 years after menopause or over age 65 face substantially elevated stroke risk (RR 1.21-1.36), VTE risk (RR 1.96), and doubled dementia risk with no cardiovascular benefit 5, 4. Systemic HRT should be discontinued in this population, particularly in smokers 5.

Absolute Contraindications

Any woman with a history of stroke, VTE, or cardiovascular disease—whether she smokes or not—should have systemic HRT discontinued immediately 5. Smoking adds to this contraindication by further elevating baseline thrombotic risk 1.

Common Pitfalls to Avoid

• Do not assume transdermal estrogen is safe in smokers. While transdermal formulations have lower VTE risk than oral (OR 0.9 vs. 4.2), they are not risk-free and should still be avoided in smokers with other thrombotic risk factors 6
• Do not confuse low-dose vaginal estrogen with systemic HRT. Vaginal estradiol 0.01% delivers local effects with minimal systemic absorption and does not carry the cardiovascular risks of systemic therapy, making it the preferred option for genitourinary symptoms in smokers 5, 6
• Do not rely on observational data suggesting cardiovascular benefits of HRT. Randomized controlled trials (Women's Health Initiative, HERS) have definitively shown no protective effect for cardiovascular death, myocardial infarction, or all-cause mortality, with increased harm from VTE and stroke 1, 3, 4