What is the largest randomized placebo-controlled trial on Hormone Replacement Therapy (HRT)?

The Women's Health Initiative (WHI) is the Largest Randomized Placebo-Controlled Trial on HRT

The correct answer is C. WHI (Women's Health Initiative), which represents the largest randomized placebo-controlled trial on hormone replacement therapy with the longest duration of follow-up 1.

Evidence Supporting WHI as the Largest HRT Trial

The Women's Health Initiative (WHI) enrolled 161,809 postmenopausal women aged 50-79 years into a set of clinical trials from 1993 to 1998 1. The hormone therapy component included:

• 16,608 women with intact uteri randomized to receive estrogen plus progestin or placebo 1, 2
• 10,739 women with prior hysterectomy randomized to receive estrogen alone or placebo 1, 3

The WHI was specifically designed to evaluate the effectiveness of hormone therapy for the primary prevention of multiple chronic conditions 1. It compared:

• Oral conjugated equine estrogen (CEE), 0.625 mg/day, plus medroxyprogesterone acetate (MPA), 2.5 mg/day versus placebo in women with intact uteri
• Oral conjugated equine estrogen (CEE), 0.625 mg/day, alone versus placebo in women with hysterectomy

Comparison to Other HRT Trials

When comparing the major HRT trials mentioned in the question:

1. WHI: Over 27,000 women total (16,608 in estrogen+progestin arm, 10,739 in estrogen-alone arm) 1
2. HERS I & II: 2,763 women with established coronary heart disease 1, 4
3. E3N-EPIC: An observational cohort study, not a randomized controlled trial
4. KEEPS: A smaller randomized controlled trial not mentioned in the provided evidence

Significance of the WHI Trial

The WHI represents the most comprehensive evidence on HRT because:

• It was the only trial powered to evaluate the effectiveness of hormone therapy for primary prevention of multiple chronic conditions 1
• It had the longest duration of follow-up (median 5.6 years for estrogen+progestin arm and 7.2 years for estrogen-alone arm, with subsequent follow-up extending to 18 years) 3
• It is most applicable to the target population of average-risk postmenopausal women living in the United States 1

Key Findings from WHI

The WHI produced several landmark findings that dramatically changed HRT prescribing practices:

• Combined estrogen and progestin therapy showed a trend toward increased risk for coronary heart disease (HR, 1.22 [CI, 0.99 to 1.50]) 1
• Increased risk of invasive breast cancer (HR, 1.26 [CI, 1.00-1.59]) 2
• Increased risk of stroke (HR, 1.41 [CI, 1.07-1.85]) 2
• Increased risk of pulmonary embolism (HR, 2.13 [CI, 1.39-3.25]) 2
• Decreased risk of colorectal cancer (HR, 0.63 [CI, 0.43-0.92]) 2
• Decreased risk of hip fracture (HR, 0.66 [CI, 0.45-0.98]) 2

The trial was stopped early after a mean of 5.2 years of follow-up because the risks exceeded benefits 2.

Clinical Implications

The WHI findings fundamentally changed clinical practice regarding HRT, establishing that combined estrogen-progestin therapy should not be used for primary prevention of chronic diseases in postmenopausal women 1, 2. Subsequent analyses have suggested that timing of HRT initiation influences its risk-benefit profile, with potentially more favorable effects in younger women or those recently menopausal 3.