WHI Clinical Trials and Observational Study

National Institutes of Health National Heart, Lung, and Blood Institute Women’s Health Initiative (WHI) Clinical Trials and Observational Study Presentations by WHI Principal Investigators WHI Clinical Centers (40) Seattle, WA Portland, OR Clinical Center Minority Clinical Center Minneapolis, MN Milwaukee, WI Detroit, MI Buffalo, NY Worcester, MA Madison, WI Boston, MA Bronx, NY Iowa City, IA Pawtucket, RI Chicago, IL Pittsburgh, PA Stony Brook, NY Columbus, OH Newark, NJ Reno, NV Cincinnati, OH Sacramento, CA Oakland, CA Washington, DC Stanford, CA Winston-Salem, NC Memphis, TN Los Angeles, CA Chapel Hill, NC Torrance, CA Orange, Atlanta, GA San Diego, CA CA Tucson, AZ Birmingham, AL San Antonio, TX Honolulu, HI Gainesville, FL Houston, TX Miami, FL WHI CT Sample Size, Outcomes, Follow-up Women, aged 50-79 Total CT = 68,133 Diet Modification (DM) Trial Primary Outcomes: Average 8.5 year Follow-up Breast & Colorectal Cancer Secondary Outcome: DM 48,836 Coronary Heart Disease (CHD) 11.8% Overlap Hormone Trials Primary Outcome: CHD Secondary Outcomes: Hormone 27, 347 Hip Fracture, Breast Cancer Ancillary Study: Memory Average 8.5 year Follow-up WHI CaD: Outcomes, Relationship to CT Total CT = 68,133 Calcium + Vitamin D (CaD) DM 48,836 Primary Outcome: Hip Fracture Secondary Outcomes: Other Fractures, Colorectal Cancer Hormone 27, 347 at 1st (or 2nd) Annual Visit CaD 36,282 53.3% of CT WHI: Relationship of OS to CT The Observational Study (OS) is a complement to the Clinical Trial Women screened for the DM or HT trials could enroll in the OS, if they were ineligible for the CT, or chose not to join either DM or HT trials . Purpose of OS  To improve risk prediction of cardiovascular disease, cancers, fractures, and all-cause mortality (death) in postmenopausal women  To create a resource of data and biological samples which can be used to identify new risk factors and/or disease biomarkers  To examine impact of changes in lifestyle and risk factors on disease and mortality OS 93, 676 Total WHI Sample (CT+ OS) = 161,809 The Women’s Health Initiative (WHI) Postmenopausal Hormone Program: Background and Rationale Marcia L. Stefanick, Ph.D. Associate Professor of Medicine and of Gynecology and Obstetrics, Stanford University PrincipaI Investigator, Stanford Chair, WHI Steering Committee A Brief History of Hormone Therapy Observational Studies suggest Benefits > Risks 1942: FDA approved Estrogen for treatment of menopausal symptoms E associated with fewer fractures; higher BMD OCs associated with E associated with lower CHD blood clots, heart attacks E associated with E associated with “Feminine higher breast cancer uterine cancer forever” E+P 2000: Br CA Progestins CEE in men: blood lower E+P > E only protect uterus clots, heart attacks CHD 1995: PEPI E vs E+P 40 30 Prescriptions (Millions) 20 ESTROGEN 10 0 1960 PROGESTIN 1997: HERS- E+P blood clots 1998: HERS 1st yr = heart attacks; no 4yr benefit 1980 1985 1990 1995 1965 1970 1975 2001: AHA position Observational Studies are Biased  Women who use Hormones over an extended time differ from those who don’t, in many ways besides HT use. Compared to non-users, estrogen users are generally:       less obese less likely to smoke more physically active more highly educated more likely to go to doctors regularly more likely to check cholesterol, BP, etc. (& have mammograms & other screening)  less likely to consume high fat diet and salt  Literature is based mostly on estrogen without progestin Differences could explain why hormone users have a lower CHD WHI Hormone Trials: Specific Aims To test whether Estrogen + Progestin (E+P) - or- Estrogen Only (E-Alone) • reduce the incidence of Coronary Heart Disease and other Cardiovascular Disease • reduce the incidence of all osteoporosisrelated fractures and hip fractures, separately • increase the risk of breast cancer To determine the balance of risks and benefits of menopausal hormones on the overall health of postmenopausal women. WHI Hormone Program Study Population: Inclusion criteria • Age 50-79 at baseline • Post menopausal, defined as: – No uterine bleeding for >6 months (>12 mo, if aged 50-54) – Current/prior use of menopausal hormones – Post hysterectomy with symptoms • Likely to reside in the clinic area for 3 years • Willing to provide written informed consent WHI Estrogen+Progestin Trial Background circa 1992 Suspected benefits of hormones: •  risk of Coronary Heart Disease (CHD) •  risk of Osteoporotic (hip/other) Fracture • ( risk of colorectal cancer, suspected later) Suspected risks of hormones: •  risk of Breast Cancer •  risk of Blood Clots: Pulmonary Emboli (lungs), Deep Vein Thromboses (legs) (based on Oral Contraceptive literature, later, HERS) WHI Hormone Program Design YES N= 10,739 Hysterectomy CEE (Conjugated equine estrogens) 0.625 mg/d Placebo NO N= 16,608 * CEE 0.625 mg/d + medroxyprogesterone acetate (MPA) 2.5 mg/d Placebo * Initially: CEE only (N=331), CEE+ MPA, or Placebo WHI Hormone Sample Size, Outcomes, Follow-up Women, aged 50-79 Total HT trials = 27,347 Hormone Trials Primary Outcome: Average Follow-up 5.2 years Coronary Heart Disease Secondary Outcomes: Hip Fracture; Other Fractures Breast & Endometrial Cancers WHI Memory Study (WHIMS) - for women 65+ - Memory E+P 16,608 E only 10,739 Average 8.5 years WHI HRT: Baseline Age Distribution Mean ± SD: HystX-E only = 63.6 ± 7.3; Uterus-E+P = 63.3 ± 7.1 50-59 E=31%; E+P=33% 60-69 E=45%; E+P=45% 70-79 E=24%; E+P=22% WHI HRT: Minority Distribution HystX: 2657/10,739 (24.7%) Uterus: N = 2663/16,608 (16.0%) Total HRT: N = 5320/27,347 (19.5%) Estrogen+Progestin Study Participants • 16,608 women joined this part of the study. • The E + P trial was for women who still had a uterus when they joined WHI Hormone Study • Participants were assigned by chance to take active E+P or inactive (placebo) pills. • The estrogen plus progestin combination we studied is identical to Prempro® (The estrogen is identical to the most common dose of Premarin®) Outcomes Monitored by DSMB • Cardiovascular disease – Heart attacks (Coronary Heart Disease, CHD) – Strokes – Blood Clots in the Lungs (Pulmonary Emboli) Breast Cancer Colorectal cancer Endometrial (uterine) cancer Hip Fractures Deaths from other causes provide index of overall balance of benefits and risks • • • • • • Global Index (includes all of the above) - Defined to Trial monitoring for benefit Early stopping considerations required: • Evidence of Coronary Heart Disease benefit – Statistical rules based on O’Brien-Fleming (OBF) procedures using a 0.025-level, one-sided test AND • Global index supportive of benefit – Statistical rules based on OBF procedures using a 0.05level, one-sided test OBF = O’Brien PC, Fleming TR. Biometrics. 1979;35:549-556. Trial monitoring for risk Early stopping considerations required: • Evidence of increased breast cancer – OBF procedure using a 0.05-level one-sided test. OR • Evidence of increases in CHD, stroke, PE, hip fracture, colorectal cancer, endometrial cancer, or death from other causes – OBF procedure using a 0.05-level one-sided test, with Bonferroni correction. AND • Global index supportive of overall harm (Z < -1.0) Freedman, et al. Control Clin Trials. 1996;17:509-525. At the request of WHI Data Safety Monitoring Board, HT Participants were informed (April 2000) that:  There was a small increase in the number of heart attacks, strokes, and blood clots in the legs and lungs, in women receiving active hormones, compared to women taking placebo.  It was believed that this difference was reduced and may disappear after 2 years (as in HERS). WHI Data Safety Monitoring Board required that HT Participants be informed (June 2001) that:  After an average of 4 years of follow-up, there were more heart attacks, more strokes, and more PE and DVT, in active hormone group (E+P + E-Alone combined) vs placebo Fewer than 1% of women had any one of these events per year in either active or placebo group Case-Control Biomarker Study was Initiated: Factor V Leiden, Prothrombin (G20210A) mutation, Selected Coagulation & Inflammation factors, etc.    NHLBI accepted DSMB recommendation to stop WHI Estrogen + Progestin Trial (May 2002) After an average of 5.2 years: • Women in Estrogen + Progestin trial told to stop study pills: risks of E+P exceed the benefits. – Participants in the E+P trial continue to be monitored, to determine how long risks or benefits persist, over time • Women in Estrogen-Alone study asked to continue study pills: balance of benefits and risks is unclear. – At this time, no increased risk of breast cancer has been seen in women taking estrogen only, vs placebo. – E-Alone participants will continue to be closely monitored. Results of Estrogen plus Progestin Use in Health Postmenopausal Women: Implications for Clinical Practice Risk of Cardiovascular Disease and Stroke — Marian C. Limacher, M.D. (Gainesville) Risk of Fracture — Rebecca D. Jackson, M.D. (Columbus) Risk of Cancer — Rowan T. Chlebowski, M.D., Ph.D. (Harbor-UCLA)