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Hormone Replacement 2009: Seven years after WHI

David Barad, MD CHR Grand Rounds April 14, 2009. Hormone Replacement 2009: Seven years after WHI. History. 1940: DES used for “healthy pregnancy” 1966: Feminine Forever published by Dr. Wilson 1976: Unopposed estrogen linked to endometrial cancer 1980s: Estrogen and Progestin given

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Hormone Replacement 2009: Seven years after WHI

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  1. David Barad, MD CHR Grand Rounds April 14, 2009 Hormone Replacement 2009:Seven years after WHI

  2. History • 1940: DES used for “healthy pregnancy” • 1966: Feminine Forever published by Dr. Wilson • 1976: Unopposed estrogen linked to endometrial cancer • 1980s: Estrogen and Progestin given • 1993 to Present: WHI

  3. Vasomotor Symptoms • Occur in 60 - 80% • Severe in 15% • Worse in iatrogenic menopause • Primary reason for starting or restarting HRT • Primary SE of stopping HRT

  4. Mood Swings • Multifactorial: Stress, empty nesters, fatigue • The gamut of tears, laughter, depression • Estrogen/ Serotonin receptor association • Often reported by significant others

  5. Genitourinary Atrophy • Vaginal dryness and burning • Thinned mucosa • May complain of pain with intercourse • Increased microhematuria

  6. After menopause, cardiac risk approaches that of men Cardiac disease is #1 killer of women Cardiovascular Disease

  7. CHD Mortality in Men and Women by Age Myth and paradox of coronary risk and menopause Tunstall-Pedoe, Lancet 1998; 351: 1425-27

  8. The Evidence Estrogen+ Progestin Estrogen Only Cohort StudiesFalkeborn, 1992Wolf, 1991Henderson, 1991Sullivan, 1990Avila, 1990Criqui, 1988Petitti, 1987LRC Prevalence Study: Bush, 1987 Framingham:Wilson, 1985 Nurses Health Sutdy: Stampfer, 1985Angiographic StudiesMcFarland, 1989Sullivan, 1988Gruchow, 1988Case-Control StudiesMann, 1994Rosenberg, 1993Croft, 1989Beard, 1989Szklo, 1984Ross, 1981Bain, 1981Adam, 1981Rosenberg, 1980Pfeffer, 1978Talbott, 1977Rosenberg, 1976 Summary Relative Risk Cohort Studies Falkeborn, 1992 Case-Control Studies Psaty, 1994 Mann, 1994 Rosenberg, 1993 Thompson, 1989 Clinical Trial 0.1 1 0.01 0.1 1 0.01 10 Barrett-Connor. Annu Rev Public Health. 1998;19:55-72

  9. WHI 1993-2005: Objectives and Design • Addressed etiology and prevention of major causes of morbidity and mortality in • Postmenopausal Women • aged 50-59 enrolled 1993-1996 • aged 60-79 enrolled 1993-1998 • Three clinical trials (N=68,133) • Hormone Therapy (HT) to prevent CHD • Diet Modification (DM) to prevent cancer • Calcium/Vitamin D (CaD) to prevent hip fractures • Large observational study (N=93, 676) • Planned duration 8.4 years (average) www.whi.org www.whiscience.org

  10. Health Promotion Acute care Rehabilitation Prevention Trials Secondary Tertiary Primary Event

  11. Health Promotion Acute care Rehabilitation Prevention Trials Secondary Tertiary Primary Event Disease

  12. CHD Mortality in Men and Women by Age Myth and paradox of coronary risk and menopause BMJ. 2002 August 10; 325(7359): 311–312.

  13. CHD Mortality in Men and Women by Age Myth and paradox of coronary risk and menopause BMJ. 2002 August 10; 325(7359): 311–312.

  14. “HRT” PUZZLE TO BE SOLVED, (1998) NOT KNOWN: Postmenopausal Hormone Therapy for Aging Heart Disease - Not for Secondary Prevention AHA Position (HERS) Primary Prevention - believed favorable Stroke - NOT for 2ndary Prevention; primary, unknown VTE (blood clots: lungs, PE; legs, DVT)- unfavorable Breast Cancer - believed unfavorable Hip Fractures - believed favorable Vertebral Fractures - favorable? Memory, AD - believed favorable Gallbladder Disease - unfavorable? Urinary Incontinence - favorable?

  15. WHI Hormone Trials Conjugated equine estrogens (CEE) 0.625 mg/d Placebo E Alone N = 10,739 YES Hysterectomy NO CEE 0.625 mg/d + medroxyprogesterone acetate (MPA) 2.5 mg/d E + P N=16,608 Placebo

  16. WHI Hormone Trials: Baseline Hypotheses Anticipated Risk Expected Benefit Coronary Artery Disease (Heart Attacks) Stroke? Breast Cancer Threshold LevelEarly STOPPING for HARM Threshold LevelEarly STOPPING for BENEFIT • Additional Risks: • Blood Clots, VTE • Lungs=PE; Legs=DVT • Additional Benefits: • Hip (Bone) Fractures • Overall Mortality Plan to follow to 2005 (average 8.5 years) • Colon Cancer • Global Index:overall balance of benefits and risks • Earliest occurrence of CHD, Stroke, PE, Breast Cancer, Hip Fracture, Colorectal Cancer, Death from other causes, Endometrial Cancer

  17. WHI E+P Trial: Findings, July 2002 Risks Benefits 26% Increase Breast Cancer Threshold Level STOPPED Early, Clear Harm Stopped 3.3 yrs early * had 0.4 more yrs of data Other Fractures Also: DVTs *Adapted from: Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333

  18. WHI E+P Trial: Findings, July 2002 Risks 29% IncreaseCHD (Coronary Heart Disease) Benefits 41% Increase Stroke 33% Decrease Hip Fracture Decreased Colorectal Cancer 113% Increase Pulmonary Emboli 26% Increase Breast Cancer Threshold Level STOPPED Early, Clear Harm Stopped 3.3 yrs early * had 0.4 more yrs of data Other Fractures Also: DVTs *Adapted from: Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333

  19. WHI: Absolute (Annualized) Risk Benefits Risks

  20. Total: 52.9/10,000 E+P vs 52.3/10,000 • Breast Cancer: Increase in E+P arm reason for stopping trial • Not statistically significant, but exceeded preset threshold by DSMB • Colon Cancer: Decrease in E+P arm • Endometrial Cancer: No difference WHI E+P: Cancer

  21. No increased risk for breast cancer during the first 2 years of combined estrogen and progesterone (E+P) • potentially identifying a "safe" period. • Marked drop in the risk for breast cancer 2 years after postmenopausal women stopped taking the hormones. • Cancer. Published online before print January 20, 2009. AbstractN Engl J Med. 2009 :360:573-587. WHI E+P: Cancer

  22. CAD: Overall 29% higher rate in E+P • Equal number of revascularization procedures and cardiac deaths • Excess events in non-fatal MI group • Stroke: • Equal number of fatal strokes • DVT/PE: • 10 x number reported by USPSTF WHI E+P: Cardiovascular

  23. Osteoporosis • T score > 2.5 SD below young adults • 10 million Americans • 1.5 million fractures annually • Hip fractures • 1 out of 6 women • 1/2 can not walk without assist • 1/4 die within one year of fracture

  24. Hip fractures reduced by 34% • Vertebral fractures reduced • Only 40% symptomatic • No routine radiographs to screen for vertebral fractues • Patients with osteoporosis excluded from enrollment WHI E+P: Fractures

  25. Dementia/ Memory Loss

  26. Enrolled 4500 women 65 – 79 • Participants memory and cognitive functions were tested yearly • Tested rate of memory decline and for presence of dementia • Outcomes: • E+P does not protect from normal decline • E+P showed increase in dementia WHIMS E+P

  27. WHIMS E+P: Probable Dementia Hazard Ratio 4532 women, aged 65-79; followed for 4.1 years E+P Placebo HR, 2.05 95% CI, 1.21__3.48 Cumulative Hazard 0 1 2 3 4 5 Years Since Randomization No. at Risk E+P Placebo 2229 2112 2026 1915 1325 401 2303 2200 2125 1984 1392 477

  28. Enrolled 10,739 women, aged 50 -79, and treated with estrogen or placebo • Average follow-up of 6.8 years • Tested primary prevention/safety estrogen • Outcomes: • Increased risk in stroke, decreased hip fx • No change in breast CA, CAD, colon CA WHI Estrogen Only

  29. WHI E only Trial: Findings, March 2004 Risks Benefits 37% Increase Stroke (55% Increase Ischemic Stroke) 33% Decrease Hip Fracture Threshold Level STOPPED - Increased Stroke No CHD Benefit Stopped 1.5 yrs early * had 0.3 more yrs of data Other Fractures No Effect onCHD No Increase Breast Cancer No Effect on Colorectal Cancer N.S. 37% Increase Pulmonary Emboli 47% increase DVTs *Adapted from: Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333

  30. Summary: WHI E+P* vs. E-Alone** Trialpublished: *July 2002 **April 2004 • Concordant results • Heart Disease – no benefit (for E+P, early harm) • Strokes, Blood Clots – harmful • Fractures – beneficial • Dementia (if ≥ 65 yrs of age) – harmful • Disparate Results • Breast Cancer • Increased in E+P Trial (women with a uterus) • Not increased in E-Alone Trial (women with prior hysterectomy) • Increased breast cancer risk in women with highest baseline risk • Global Index • Increased in E+P (CEE + MPA) Trial • Neutral in E-Alone (CEE) Trial

  31. WHIMS : Probable Dementia & MCI N=4,532; 4.1 yrs follow-up N=2,947; 5.2 yrs follow-up 34% (NS) 105% 49% (NS) JAMA 2003; 289:2651-2662 JAMA 2004; 291:2947-2958

  32. WHI: Absolute (Annualized) Risk Risk Benefit Risk? Benefit? Benefits Risks

  33. US Prescriptions for HT 1995 - Aug 2003 WHI E+P HERS WHI E only Hersh AL, Stefanick ML, Stafford RS JAMA 291: 2004; 291: 47-53

  34. WHI E+P Trial 12,304 74.1% Mean =28.5 kg/m2 Mean =63.3 yrs N 5522 33.3% 7510 45.2% 3576 21.5% 5058 30.6% 5826 35.3% 5636 34.1% 3262 19.6% 1035 6.2% % of Enrolled Population Prior HT Use Age (yrs) Body Mass Index JAMA. 2002;288: 321-333

  35. WHI E-alone Trial Mean =63.6 yrs Mean =30.1 kg/m2 5539 51.6% N 3310 30.8% 4852 45.2% 2577 24.0% 2206 20.7% 3707 34.7% 4759 44.6% 3819 35.6% 1377 12.8% % of Enrolled Population Prior HT Use Age (yrs) Body Mass Index JAMA. 2004;291: 1701-1712

  36. WHI HT : Ethnic Distribution By Baseline Age PercentMinority E-alone (32.7%) E+P (21.5%) E-alone (22.0%) E+P (12.5%) E-alone (13.9%)E+P ( 8.6%) 25 20 Percent 15 10 5 0 Black Black Hispanic Black Hispanic Hispanic 50-59 60-69 70-79 Hysterectomy (75.3% White) Uterus (84.0 % White ) Ann Epidemiol 2003; 13: S78-S86

  37. Age 60-69 y Age 70-79 y Age 50-59 y CHD and AGE: ? Interaction With CEE P for interaction=0.07 Arch Intern Med. 2006;166:357-365

  38. Atherosclerosis And Calcification

  39. Women aged 50-59 at time of randomization into E-Alone trial (with prior hysterectomy) at 28 (of 40) WHI sites • After mean 7.4 years of treatment; 1.3 yrs after trial was completed - Did not study older women in E-only trial or women in E+P trial Baseline Characteristics (N=1064: 537 CEE, 527 Placebo) • Age: Mean 55 years (50-54, 39.5%; 55-59, 60.5%) • Age at Menopause: Mean 43.5 years • Age at Hysterectomy: < 35 (28%); 35-39 (25%); 40-44 (22.5%); ≥ 45 (23%) • Ethnicity: White, ~ 75% Black, 16.5% Hispanic, 6% Asian/PI, 0.3% American Indian, <1% • Body Mass Index: 30.5 kg/m2; Hypertension: 35.5%; Diabetes: 6.3% WHI Coronary Artery Calcium Study (CACS) Manson et al,NEJM 2007; 356: 2591-2602

  40. Odds Ratios for Elevation in Coronary Artery Calcium Intent-to-Treat Analyses Adherent Analyses Multivariate P=0.03Multivariate P=0.004 CAC Categories Manson et al,NEJM 2007; 356: 2591-2602

  41. Summary & Conclusions • Among women aged 50-59 in E-alone Trial calcified plaque burden in coronary arteries was lower in CEE group than placebo 1.3 yrs after 7.4 yrs of treatment.Did not study older women or E+P trial • WHI data do not suggest CHD harm for short-term therapy to relieve menopausal symptoms. HRT and the Young at Heart: Mendelssohn ME, Karas RH. NEJM 2007; 356: 2639-2641

  42. Timing Hypothesis • Timing Hypothesis: The beneficial effects of HRT in preventing atherosclerosis occur only when the therapy is initiated before advanced atherosclerosis develops. • Predicts that HRT is NOT beneficial when given to older women, because the underlying biologic characteristics of the vessel wall and vascular response to HRT are altered in older, more atherosclerotic vessels. • Age is a powerful risk factor for atherosclerosis; risk is low for majority of women aged 50-59.

  43. Women starting hormones close to the menopause may have fewer heart attacks and deaths due to HT compared to increases in women distant from the menopause Provides some reassurance that younger women using hormones for the short term for relief of hot flashes and night sweats are not at increased risk of heart disease Stroke increased irrespective of age or years since menopause (Breast cancer also increased in E+P only) Secondary Analyses of Combined WHI Trials (2007) Rossouw et al JAMA 2007;297:1465-1477

  44. Older women with moderate/severe hot flashes or night sweats appear to be at high risk if they start hormone therapy In part explained by higher prevalence of risk factors (obesity, high blood pressure, high blood cholesterol, diabetes) in women with vasomotor symptoms Secondary Analyses of Combined WHI Trials (2007) Rossouw et al JAMA 2007;297:1465-1477

  45. “one estrogen and one estrogen/progestin” • Most commonly prescribed HT • “Women with moderate to severe menopausal symptoms discouraged” • Not a study of symptoms… symptomatic women were considered to have greater noncompliance • QOL measurement tools • Standardized and highly reliable, no QOL tool for menopause existed at the initiation of the WHI WHI Critiques

  46. “Women with osteoporosis were excluded” • WHI was a prevention trial and osteporosis was one outcome • “Over 1200 women with previous cardiovascular events were included” • Prevention of repeat MI was a part of the hypothesis being tested • “No routine colonoscopy or bone density” • Bone density was performed routinely on a subset of participatnts WHI Critiques II

  47. Estrogens and progestins should not be used for the prevention of cardiovascular disease. • Other doses of CEE and MPA and other combinations of estrogens and progestins were not studied in the WHI and, in the absence of comparable data, these risks should be assumed to be similar The FDA Black Box

  48. HRT is not recommended for prevention of CAD HRT is approved for treatment of moderate to severe menopausal sx HRT is approved for osteoporosis prevention in certain patients For approved conditions HRT should be used in the low dose for short duration Summary

  49. Treatment of moderate to severe symptoms associated with menopause Treatment of moderate to severe symptoms associated with vaginal and vulvar atrophy assoc. with menopause Prevention of postmenopausal osteoporosis in women at significant risk, after considering non-hormonal rx Current Labeling

  50. www.menopause.org: NAMS http://www.cme.wisc.edu/online/menopause/sld001.htm: UW menopause review www.4women.gov/owh: DHHS Office of Women’s Health www.nhlbi.nih.gov/health/women/index.htm: WHI website Helpful Websites

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