Clinical Implications of WHI or, what's a doctor to do?

Clinical Implications of WHI or, what's a doctor to do?

Menopause-Clinical Considerations Esther Eisenberg, M.D., M.P.H. Professor, Obstetrics and Gynecology Vanderbilt University Medical Center "The desire to take medicine is perhaps the greatest feature which distinguishes man from animals." Sir William Osler Learning objectives To discuss the role of HRT in the menopausal woman To compare findings of WHI study in women with natural vs. surgical menopause

To discuss alternatives for HRT in the treatment of menopausal problems MENOPAUSE Permanent cessation of menses Ovarian follicular depletion Marked by last menstrual period Clinical definition no menses x 1 year Age-related decrease in total number of primordial follicles

from birth to menopause. Lobo, RA, Clin Obstet Gynecol, 1998 Stages of Reproductive Aging ASRM Committee Opinion 2001 Signs of Menopause Menstrual cycle changes-Oligomenorrhea, amenorrhea Vasomotor symptoms-hot flashes, night sweats

Vaginal dryness Depression (if prone) Low libido Consequences of Estrogen Loss on Target Tissue Brain Eyes Vasomotor Vasomotor sx Hot flashes Sleep disturbance Urogenital atrophy

Vaginal dryness Bone Heart Breast Colon Urogenital Tract

Low libido Osteoporosis Skin changes ?CVD, ?Dementia Prevalence of Vasomotor Symptoms > 75% of women report hot flashes within the 2-year period surrounding their menopause Primary reason women seek medical treatment 25% remain symptomatic for > 5 years Prevalence of Hot Flashes Menopause Years Before

Years After 3 2 1 1 2 Kronenberg F. Ann N Y Acad Sci. 1990;592:52-86. 3

History Of HRT 1965 Dr. Robert A Wilson publishes Feminine Forever, ERT = fountain of youth 1975 ERT associated with risk of endometrial cancer 1980 Nachtigall & Gambrell pioneer HRT-add MPA 1980s Continuous combined HRT regimen developed to reduce uterine bleeding and increase adherence 1990s New and more HRT products developed 1992 ACP, ACFP and USPS Task Force endorse guidelines for Rx of HRT for prevention of heart disease and osteoporosis-WHI trial is conceived. History Of HRT 1998 HERS Trial - 2 prevention - no difference in fatal or nonfatal CHD

2001 AHA advises against prescription of HRT for secondary prevention of CHD 2002 HRT arm of WHI trial stopped; Global index - risks outweigh benefits. Events occurred in fewer than 1% of WHI women 2003 ACOG, NAMS, FDA, USPSTF revise recommendations for HRT 2004 WHI hysterectomy trial stopped. Increased risk of stroke. No effect on CHD risk. Decreased fracture risk. Breast Ca risk increase in HRT, not ERT. WHI Clinical Trial

Multi-center double-blind randomized placebo controlled trial --HRT Arm-mean age 63.3 years. Intact uterus Average follow-up = 5.2 years; Regimen: CEE 0.625 mg/d + MPA 2.5 mg/d (n = 8506) or placebo (n = 8102) --ERT Arm-All with hysterectomy -Average follow-up = 6.8 years - Regimen: CEE 0.625 mg/d (n = 5310) or placebo (n = 5429)

Primary outcome: Nonfatal MI and CHD death Primary adverse outcome: Invasive breast cancer Global index: Summary measure of risks and benefits Writing Group for the Womens Health Initiative Investigators. JAMA. 2002;288:321-333. WHI Combined HRT Baseline Characteristics Age at screening Prior hormone use BMI (kg/m2) Never smokers Diabetes Hypertension

Statin use at baseline Family Hx Breast Ca History of MI History of CABG/PTCA HRT n=8506 (%) 63.2 26.1 28.5 49.6 4.4 35.7 6.9 16.0

1.6 1.1 Placebo n=8102 (%) 63.3 25.6 28.5 50.0 4.4 36.4 6.8 15.3 1.9 1.5

WHI CEE Alone Baseline Characteristics CEE (n=5310) Placebo (n=5429) < 40 2100 (39.8)

2149 (39.8) 40-49 2281 (43.2) 2275 (42.2) 50-54 501 (9.5) 566 (10.5) > 55

401 (7.6) 404 (7.5) BSO 1938 (39.5) 2111 (42.0) Fam hx/Breast ca 893 (18.0)

870 (17.1) Fracture age > 55 676 (14.0) 643 (13.2) Age at hysterectomy WHI CEE Alone Baseline Characteristics CEE

(n=5310) Hormone use Never 2769 (52.2) Past 1871 (35.2) Current* 669 (12.6) Duration of prior hormone** <5 1352 (53.2) 5 - < 10 469 (18.5) > 10 720 (28.3)

BMI 30.1 Smoking Never 2723 (51.9) Past 1986 (37.8) Current 542 (10.3) Placebo (n=5429) 2770 (51.1) 1948 (35.9) 708 (13.0)

1412 (53.1) 515 (19.4) 732 (27.5) 30.1 2705 (50.4) 2089 (38.9) 571 (10.6) *Required 3-month washout ** Among women reporting hormone use JAMA 2004; 291: 1704 Number of Cases per Year in 10,000 Women

WHI Disease Rates for Women on Combination HRT or Placebo 60 50 40 30 20 10 0 CHD Strokes

Breast Cancer VTEs Combination HRT Colorectal Hip Cancer Fractures Total Deaths Placebo

Adapted from WHI HRT Update, June 2002. WHI: Relative and Absolute Risk or Benefit of CEE plus MPA at 5.2 Yrs Cases Risk Ratio Changes/10,000 Outcome HRT Placebo Breast Ca MI/CVD Stroke VTE

PE Colon Ca Hip Fx Vertebral Fx Death 166 164 127 151 70 45 44 41 231

124 122 85 67 31 67 62 60 218 Women 1.26(1.0-1.59) 1.29(1.02-1.63) 1.41(1.07-1.85)

2.11(1.58-2.82) 2.14(1.39-3.25) 0.63(0.43-0.92) 0.66(0.45-0.98) 0.66(0.44-0.98) 0.988(0.82-1.18) +8 +7 +8 +18 +8 -6 -5 -5

WHI Results CEE Alone Health Event Risk Ratio vs. Placebo (6.8 yrs) CHD (nonfatal MI or death) Stroke VTE Breast Cancer Colorectal Cancer Hip Fracture Global Index

0 .91 1.39 1.33 0.77 1.08 0.61 1.01 Nominal CI 0.75-1.12 1.10-1.12 0.99-1.79 0.59-1.01 0.75-1.55 0.41-0.91

0.91-1.12 Kaplan-Meier Estimates of Cumulative Hazards for Selected Outcomes (JAMA 2004; 291:1707) Estrogen plus Progestin Increases Breast Cancer Risk in Postmenopausal Women EPT use increased breast cancer risk by 24% (p < .001) Invasive breast CA risk ( 24%, p = 0.003) Tumors were larger and at more advanced stage in EPT users EPT users were more likely to have abnormal mammograms (9.4% vs. 5.4%, p < 0.001) Higher Levels of Exercise Reduce Breast Cancer Risk JAMA 2003; 290: 1331-1336 Reduced risk of breast cancer was seen across all categories including women who took estrogen and progestin Greatest reduction in women with BMI < 24 Hazard Ratios from 3 Hormone Therapy Trials Hazard Ratio (95% C.I.) JAMA 2004; 291; 1770

Complexity of WHI Trial 1. Participants - healthy postmenopausal women - asymptomatic Some participants have relative contraindications to HRT - smokers (10.5%), history of MI (7.7%), Stroke, DVT, PE or BMI > 30 Kg/m2 Trial is applicable to general population more generalizable and external validity Complexity of WHI Trial 2. High drop out rate in treatment (42%) and placebo groups (38%) - unanticipated 3. Unblinding in 40.5% of treatment group compared with 6.8% in placebo group 4. Adjusted confidence intervals are more valid

when making multiple comparisons; but in WHI study, there are seven variables - very conservative CI after adjustment. Level of uncertainly, probably somewhere in between Age is an Effect Modifier NEJM 2003; 348:1836 WHI Summary 1. WHI combined EPT risks outweigh benefits for prevention 2. WHI ET risks and benefits are balanced 3. When quality of life and menopausal

symptoms are issues EPT and ET are most effective treatment and risks are low 4. Age is an effect modifier; the younger the woman , the lower the absolute risk JAMA 2003; 289:3241 Number of and Percentage Change in US Prescriptions for Hormone Therapy Between January-Jane 2002 and January-June 2003 by Formulation Hersh AL, et al. JAMA, 2004; 291: 51. Predictors of Inability to Stop HRT

377 women; Kaiser Health Plan; age 50-69 All tried to discontinue HRT 74% successfully stopped; 26% resumed HT Predictors-Troublesome sxs (OR: 8.8; CI: 4.9, 16) Flushes (88%)

Excessive sweating (54%) Difficulty sleeping (54%) Fatigue (39%) Depression (38%) Vaginal dryness (38%) Grady D, et al. Obstet Gynecol 2003;102: 1233-9. Predictors of Inability to Discontinue PMP Hormone Therapy Troublesome symptoms Grady D, et al. Obstet Gynecol 2003; 102: 1233-9.

Predictors of Inability to Stop PMP Hormone Therapy Predictors (cont.) Hysterectomy (OR: 1.9; CI: 1.1, 3.6) HRT prescribed by nongynecologist (OR: 2.2; CI: 1.2,4.0) High risk for fracture (OR: 1.4; CI: 1.1, 1.8) Grady D. Obstet Gynecol 2003; 102: 1233-9 Menopausal Hormone Therapy Other Issues EPT Route of delivery Transdermal patch

Drops/Oil/Gel Vaginal ring Choice of estrogen Progesterone vs progestin ?Androgen ESTHER Trial Scarabin PY, Oger E, Ply-Bureau G ESTHER Study Group Lancet 2003; 362: 428-32.

Oral and transdermal EPT have different effects on risk of thromboembolism 155 Women Age 45-70 Cases Diagnosed with VTE 318 Women Matched controls ESTHER Case Control Study of Estrogen & VTE RX Cases

Control OR CT Oral EPT 21% 7% 3.5

1.8-6.8 Transdermal EPT 19% 24% 0.9 0.5-1.6 Menopausal Sexual Concerns Lack of desire (low libido)

?Androgen deficiency ?Other relationship issues; Life stress Vaginal dryness ?Estrogen deficiency Source of Androgens in Naturally Postmenopausal Women Adapted from: Simon JA. Fert Steril. Menopausal TherapyOther Considerations

Prevention and treatment of osteoporosis BMD testing-timing Adequate calcium (1200 mg/d) and Vitamin D (800 IU/d) Anti-resorptive Rx Prescribing HRT HRT is best treatment for menopausal symptoms and quality of life issues HRT should not be continued or started to prevent heart disease For osteoporosis prevention, the benefits should be weighed vs. individualized risks for MI, stroke, VTE, and breast cancer. Other anti-resorptive

agents should be considered. National Institutes of Health. National Heart, Lung, and Blood Institute. New Facts About: Estrogen/Progestin Hormone Therapy. July 9, 2002. Clinical Considerations for HRT *Approximately 25% of women who discontinue HRT are unsuccessful most common reason for restarts is menopausal symptoms *If a woman successfully discontinues hormone therapy, consider her risk for osteoporosis use other agents for prevention

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