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Women’s Health Initiative (WHI) Estrogen plus Progestin Trial Design, Primary Results (JAMA 2002) 2003 Updates - Sele

Women’s Health Initiative (WHI) Estrogen plus Progestin Trial Design, Primary Results (JAMA 2002) 2003 Updates - Selected Outcomes. Marcia L. Stefanick, Ph.D. Associate Professor of Medicine and of Gynecology and Obstetrics, Stanford University PrincipaI Investigator, Stanford

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Women’s Health Initiative (WHI) Estrogen plus Progestin Trial Design, Primary Results (JAMA 2002) 2003 Updates - Sele

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  1. Women’s Health Initiative (WHI) Estrogen plus Progestin TrialDesign, Primary Results (JAMA 2002) 2003 Updates - Selected Outcomes Marcia L. Stefanick, Ph.D. Associate Professor of Medicine and of Gynecology and Obstetrics, Stanford University PrincipaI Investigator, Stanford Chair, WHI Steering Committee

  2. WHI Hormone Trials: Specific Aims To test whether Estrogen + Progestin(E+P)- or- Estrogen Only (E-Alone) • reduces the risk of CHD or other CVD, e.g. Stroke • increases the risk of Breast Cancer • reduces the risk of Hip and other Fractures To determine the overall balance of health risks and benefits of E+P and E-alone

  3. WHI Hormone Program Design YES CEE (Conjugated equine estrogens) 0.625 mg/d N= 10,739 = Premarin® Placebo Hysterectomy CEE 0.625 mg/d + medroxyprogesterone acetate (MPA) 2.5 mg/d * NO N= 16,608 = Prempro® Placebo * Initially: CEE only (N=331), CEE+MPA, or Placebo

  4. Outcomes Monitored by DSMB • Cardiovascular disease • Coronary Heart Disease (CHD) • Strokes • Pulmonary Emboli(PE) • Invasive Breast Cancer • Colorectal cancer • Endometrial cancer • Hip Fractures • Deaths from other causes • Global Index*:provides overall balance of benefits and risks*earliest occurrence of CHD, stroke, PE, breast cancer, colorectal cancer, endometrial cancer, hip fracture or death from other causes

  5. April 2000: WHI Data Safety Monitoring Board (DSMB) requested that HT Participants be informed that: • There was a small increase in the number of heart attacks, strokes, and blood clots in the lungs and legs in women receiving active hormones, compared to women taking placebo. • 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 June 2001: WHI DSMB required that all HT (E+P and E alone) Participants be informed that:

  6. May 2002: NHLBI accepted DSMB recommendation to stop WHI Estrogen + Progestin (E+P) Trial After an average of 5.2 years: • Women in E+P trial were told to stop study pills because the risks exceeded the benefits. • Participants in the E+P trial continue to be monitored, to determine how long risks or benefits persist, over time • Women in E-Alone study were asked to continue study pills: balance of benefits and risks is unclear. • No increased risk of breast cancer had been seen in women taking estrogen only vs placebo by this time. • E-Alone participants will continue to be closely monitored.

  7. 0.5 1.0 2.0 5.0 WHI: Preliminary Results With CEE/MPA Event nHR CHD 1.29 Stroke 1.41 Breast Cancer 1.26 VTE 2.11 Colon Cancer 0.63 Hip Fracture 0.66 Total Fracture 0.76 Death 0.98 Nominal 95% CI Adjusted 95% CI Hazard Ratio Writing Group for WHI Investigators: JAMA 2002; 288: 321-333

  8. Kaplan-Meier Estimates of Cumulative Hazards for the Global Index The number of women at risk are presented below the horizontal axis for each treatment arm.

  9. WHI E+P Trial: Annualized Event Rates Placebo E + P Risks* Neutral 60 50 40 30 20 10 0 Additional Events Reduced Events 7 8 8 8 Number of Casesper 10,000 Women per Year 6 5 CHD* Stroke* EndometrialCancer Deaths BreastCancer* PE* ColorectalCancer* HipFracture* *Statistically significant based on 95% nominal CI on Hazard Ratios Adapted from: Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333

  10. Estrogen+Progestin Study Results Summary • 19 more health problems per 10,000 women assigned to E+P compared to placebo • Over 5 years, a net 1 per 100 women in E+P group had a harmful outcome. • Treatment with estrogen + progestin for up to 5 years is not beneficial to overall health.

  11. Updated Results: WHI Estrogen + Progestin Randomized, Placebo-controlled Clinical Trial • Coronary Heart Disease (CHD) • Manson J et al.N Engl J Med 2003; 349: 523-534 • Stroke • Wassertheil-Smoller S et al. JAMA 2003; 289: 2673-2684 • Breast Cancer (and Mammograms) • Chlebowski, Rowan T et al.JAMA 2003; 289: 3243-3253 • Fractures and Bone Mineral Density • Cauley, Jane A. et al.JAMA 2003; 290: 1729-1738

  12. CHD Update: Manson JE, et alN Engl J Med 2003; 349: 523-34 • CHD outcomes through July 7, 2002 • mean 5.6 yr follow-up (vs. 5.2 in 1st report) • 335 CHD cases (vs. 286 in first report) • centrally-adjudicated by cardiologists • Additional CHDendpoints: angina, acute coronary syndrome, and CHF • Analyses of subgroupsdefined by clinical characteristics and biomarkers

  13. CHD*: Overall HR and HR Year of Follow-Up CHD: N (Annualized %)*acute MI + silent MI+ CHD death (stratified, adjusted) E+P: 188 (0.39%) Placebo: 147 (0.33%)HR=1.24(1.00-1.54) HR=1.81 1.34 1.27 1.25 1.45 0.70 CHD Update: Manson JE, et alN Engl J Med 2003; 349: 523-34

  14. Legend Yr 1 - baseline (95% CI) *p<0.05 *-5.4 Total cholesterol LDL-cholesterol HDL-cholesterol Triglycerides Glucose Insulin Systolic BP Diastolic BP Weight Waist Circumference Waist-to-Hip Ratio *-12.7 7.3* 6.9* *-2.5 -7.1 0.9* -0.1 *-0.4 *-0.9 -0.2 -15 -14 -13 -12 -11 -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 11 %Change at One-Year (E+P - Placebo) WHI E+P: Intermediate Outcomes at Year 1 (% change, E+P minus Placebo) CHD Update: Manson JE, et alN Engl J Med 2003; 349: 523-34

  15. WHI E+P CHD Update: Analyses by Subgroups • Age(yrs):50-59,60-69,70-79p = 0.36 • Yearssince Menopause:< 10,10-19,≥ 20p = 0.33 • Hot Flashes (in women aged 50-59):Yes, Nop = 0.16 • Hot Flashes + Night Sweats (50-59):Yes, Nop = 0.61 • BMI(kg/m2):< 25.0, 25-29.9, ≥ 30p = 0.60 • Race/Ethnic Group:non-HspWhite,non-HspBlack, Hispanicp = 0.41 • Education Level:≤ H.S. or GED, > H.S. p = 0.86 CHD Update: Manson JE, et alN Engl J Med 2003; 349: 523-34

  16. WHI E+P CHD Update: Analyses by Subgroups • LDL-C (mg/dl): < 126, 126-155, >155p = 0.01 • HDL-C; Triglycerides; Total Cholesterol (p = 0.07)NS • Lp(a); Fibrinogen; Factor VIII:C; C-reactive Protein NS • Cigarette Smoking:Never or former, Currentp = 0.64 • Hypertension (140/90 or treated): No, Yes p = 0.49 • Diabetes: No, Yes - treated, Yes - all cases p = 0.51 • Number of Risk Factors0, 1-2, 3 (smoking, hypertension, p = 0.96 diabetes, high cholesterol, parental history-father<55 yrs; mother < 65 yrs) • Aspirin Use: Yes, Nop = 0.71 • Statin Use: Yes, Nop = 0.44 CHD Update: Manson JE, et alN Engl J Med 2003; 349: 523-34

  17. Adjusted P-value forSubgroup (Annualized %) Hazard Ratio* (95% CI) Interaction† Prevalent CVD at Baseline‡ 0.64No(E+P:0.34Pbo:0.28)1.23 (0.97-1.56)Yes(E+P:1.64Pbo:1.19)1.45 (0.84-2.49) Prevalent CHD at Baseline§ 0.66No(E+P:0.35Pbo:0.29)1.23 (0.97-1.55)Yes(E+P:2.18Pbo:1.65)1.44 (0.77-2.70) E + P and Risk of CHD: Additional Analyses of Subgroups * adjusted for age and prior CHD † between subgroup and treatment variables ‡ includes history of MI, CABG, PTCA, stroke, or transient cerebral ischemia. § includes history of MI, CABG, or PTCA. CHD Update: Manson JE, et alN Engl J Med 2003; 349: 523-34

  18. Clinical Outcomes (Annualized Percentage) by Randomization Assignment Estrogen+Progestin Placebo Hazard Ratio 95% CI Nominal Stroke151 (0.31%)107 (0.24%) 1.31 (1.02,1.08) Ischemic 125 (0.26%)81 (0.18%)1.44(1.09, 1.90) Hemorrhagic 18 (0.04%) 20 (0.04%) 0.82 (0.43, 1.56) Stroke Update: Wassertheil-Smoller et al. JAMA 2003; 289:2673-2684

  19. Summary and Implications of Stroke Data • E+P increases risk ofischemic stroke Excess strokes:7 per 10,000 women per year • Excess risk is: • not explained by blood pressure increase • apparent in hypertensives and normotensives • apparent in all subgroups examined • No significant interaction with any biomarker studied Wassertheil-Smoller S et al.JAMA 2003; 289: 2673-2684

  20. Updated Results: WHI Estrogen + Progestin Randomized, Placebo-controlled Clinical Trial • Gynecological Cancers • Anderson GL S et al. JAMA 2003; 290: 1739-1748 • Colorectal Cancer • Chlebowski RT. (Submitted to NEJM) • Diabetes • Margolis K et al. (Submitted to JAMA) • Venous Thromboembolism(in preparation)

  21. WHI E+P Trial Findings for Gynecological Cancers (Average 5.6 years of follow-up) • Invasive Ovarian Cancer Risk (32 cases)HR = 1.58; CI: 0.77-3.24 • Endometrial Cancer (58 cases) HR = 0.81; CI: 0.48-1.36 • No appreciable differences in distributions of tumor histology, stage, or grade for either. • Cervical Cancer (13 cases) Data too limited. Anderson GL S et al. JAMA 2003; 290: 1739-1748

  22. Discontinuation and “Drop-in” Rates by Randomization Assignment and Follow-up Time Writing Group for WHI Investigators: JAMA 2002; 288: 321-333 Percent

  23. WHI E+P Trial: Primary EndpointsPercent Event Rates Based on Analysis TypeFinal centrally-adjudicated outcomes - 2003 (average 5.6 yrs of follow-up) Intention to treat 80 60 % Increase Over Placebo 40 31% 20 24% 24% 0 CHD1 Stroke2 Breast Cancer3 1 Manson JE et al N Engl J Med 2003; 349: 523-534 2 Wassertheil-Smoller S et al JAMA 2003; 289: 2673-2684 3 Chlebowski RT et al. JAMA 2003; 289: 3243-3253

  24. 50% 50% 49% WHI E+P Trial: Primary EndpointsPercent Event Rates Based on Analysis TypeFinal centrally-adjudicated outcomes - 2003 (average 5.6 yrs of follow-up) Intention to treat 80 Compliant: taking ≥80% study pills; censored 6 mo. after becoming non adherent 60 % Increase Over Placebo 40 31% 20 24% 24% 0 CHD1 Stroke2 Breast Cancer3 1 Manson JE et al N Engl J Med 2003; 349: 523-534 HR: 1.50 (1.14-1.97) 2 Wassertheil-Smoller S et al JAMA 2003; 289: 2673-2684 HR: 1.50 (1.08-2.08) 3 Chlebowski RT et al. JAMA 2003; 289: 3243-3253 HR: 1.49 (1.13-1.96)

  25. Updated Results: WHI E + P Trial • Quality of Life • Hays J et al. N Engl J Med 2003; 348:1839-1854 • Gynecological Symptoms(in preparation) • Dementia • Shumaker S et al JAMA 2003: 289: 2651-2662 • Global Cognitive Function • Rapp S et al JAMA 2003: 289: 2663-2672 - - - - - - - - - - WHIMemory Study (WHIMS) - - - - - - - - - E+P Trial Participants (n=4532) aged ≥ 65 yrs (baseline)

  26. E+P N = 2,229 Placebo N = 2,303 Hazard Ratio (95% CI) Probable dementia Rate per 10,000 person-years 40 45 21 22 2.05 (1.21-3.48) WHIMS: Frequencies of Probable Dementia and Mild Cognitive Impairment Over 4.1 Years • Dementia - 23 excess cases per 10,000 person-yrs • MCI - No differences Shumaker et alJAMA 2003; 289:2651-2662

  27. Attributable Risk Summary • Excess risk per 10,000 women per year on E+P • 8* more women with breast cancer • 6* more women with CHD • 7* more women with strokes • 8 more women with PE • Risk reduction per 10,000 women per year • 6fewer colorectal cancer • 5* fewer hip fractures Writing Group for WHI Investigators: JAMA 2002; 288: 321-333 *2003UPDATES: CHD (Manson); Stroke (Wassertheil-Smoller); Breast Cancer (Chlebowski); Hip Fractures (Cauley)

  28. WHI Estrogen+Progestin TrialImplications • The overall risks of estrogen+progestin outweigh the benefits when taken to prevent chronic diseases in postmenopausal women. • Estrogen + progestin should not be initiated or continued for the primary prevention of CHD. • Risk for CHD, stroke, PE and breast cancer must be weighed against benefit for fracture in selecting from available agents to prevent osteoporosis.

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