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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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slide1

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

slide2

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

slide3

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

slide4

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
slide5

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:

slide6

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.
slide7

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

slide8

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.

slide9

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

slide10

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.
slide11

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
slide12

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

slide13

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

slide14

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

slide15

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

slide16

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

slide17

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

slide18

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

slide19

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

slide20

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)
slide21

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

slide22

Discontinuation and “Drop-in” Rates by Randomization Assignment and Follow-up Time

Writing Group for WHI Investigators: JAMA 2002; 288: 321-333

Percent

slide23

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

slide24

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)

slide25

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)

slide26

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

slide27

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)

slide28

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.