Pm 1.30 stefanick
Upcoming SlideShare
Loading in...5
×
 

Pm 1.30 stefanick

on

  • 308 views

 

Statistics

Views

Total Views
308
Views on SlideShare
308
Embed Views
0

Actions

Likes
0
Downloads
2
Comments
0

0 Embeds 0

No embeds

Accessibility

Categories

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment
  • 10: Cancer Prevention and Control

Pm 1.30 stefanick Pm 1.30 stefanick Presentation Transcript

  • The Vivian Pinn Womens Health Research Keynote Lecture - March 16, 2012 The Women’s Health Initiative (WHI) What Have We Learned? Marcia L. Stefanick, Ph.D. Professor of Medicine Stanford Prevention Research Center Professor of Obstetrics & Gynecology Stanford University School of Medicine
  • DISCLOSURE I have nothing to disclose Marcia L. Stefanick, Ph.D.Professor of Medicine, Stanford Prevention Research Center Professor of Obstetrics & Gynecology Stanford University School of Medicine
  • Women’s Health Initiative (WHI) Clinical Trials (Diet, Hormones, Calcium/Vit D) and Observational Study Postmenopausal Women aged 50-79 yrs (1993-1998) Residing in area (likely to survive) ≥ 3 yrs Conducted at 40 Clinical Centers + Clinical Coordinating Center www.whi.org (Fred Hutchinson Cancer Research Center)www.whiscience.org EXTENSIONS: 2005-2010, 2010-2015 Funded by National Institutes of Health National Heart, Lung, and Blood Institute
  • WHI Clinical TrialsPostmenopausal Women, aged 50-79; Not moving < 3 yrsDiet Modification (DM) Trial Design Primary Outcomes: ~ 9 years Breast & Colorectal Cancer Diet (DM) average follow-up Secondary Outcome: 48,836 Coronary Heart Disease (CHD) (40:60) 11.8%Hormone Trials Overlap Hormone Primary Outcome: CHD 27, 347 Secondary Outcomes: (50:50) Hip Fracture, Breast Cancer Ancillary Study: Memory (Dementia) Total CT = 68,133
  • WHI: Observational Study (OS) Women screened for the DM or HT trials could enroll in the OS, if ineligible for the CT, or chose not to join either DM or HT trials. Some women enrolled directly in the OS. Annual Questionnaires Purpose of OS: qsecular control for the CT qimprove risk prediction for primary outcomes OS qcase-control approach to study 93, 676sub-clinical markers for disease qassociations between genetic, biochemical,psychosocial, physiological factors and events qimpact of changes in risk factors on incident disease and mortality Total WHI Sample (CT + OS) = 161,809
  • WHI Clinical Trials and Observational Study Timeline: 1991 – 2011 Estrogen + Progestin (E+P) WHI Trial Stopped for Harm > Benefit EXTENSION 2 Diet and Calcium plus 2010-2015 Hormone Vitamin D JAMA 2002 BEGINS Clinical Trials Clinical Trial Begin Begins Diet and Estrogen only Hormone Trials DM Results . Trial: stopped JAMA 2006 Recruitment JAMA 2004 completed CaD Results NEJM 20061991 92 93 94 95 96 97 98 99 2000 2001 2002 03 2004 2005 06 07 08 09 2010 2011 DM, CaD Trials: E+P Post- Closeout visits stopping (2.4 yrs) Observational completed JAMA 2011 Study Begins Observational E only Study Post-stopping Observational Year 3 clinicWHI Begins Study visits complete WHI EXTENSION JAMA 2011 Recruitment 2005-2010 BEGINS completed
  • WHI Diet Trial: Sample Size, Key Outcomes; Criteria: Postmenopausal Women, aged 50-79; Not moving < 3 yrs Designq Excluded if ~ 9 years q % Energy from Fat Diet (DM) average < 32% by Food Frequency follow-up Questionnaire (FFQ) 48,836 (40:60) q History of Breast or Intervention: Colorectal Cancer N = 19,541 Comparison:Dietary Change Goals N = 29,294q 20% energy from fat q ≥ 5 vegetable & fruit servings per day q ≥ 6 grain servings daily q NO Weight Change Goals
  • WHI Diet Trial: INVASIVE BREAST CANCER N=48,325; 8.1 yrs follow-up HR 0.91 (95% CI: 0.83-1.01) 1,727 total diagnoses (3.5% of all DM participants) Rates per 10,000/year CumulativeBreast Cancer Invasive Hazard Ratio HR, 0.91 0.04 (95% CI, 0.83-1.01) Comparison Intervention 9% (not significant) 0.03Cumulative Hazard 0.02 0.01 Time (years) 0.00 0 1 2 3 4 5 6 7 8 9 Events Intervention 47 79 92 80 72 94 89 46 33 Comparison 74 140 123 137 136 137 145 97 58 Number at Risk Intervention 19541 19328 19084 18798 18520 18263 17900 15507 10245 5075 Comparison 29294 28908 28536 28195 27806 27372 26977 23337 15373 7580 JAMA 2006; 295; 629-642
  • WHI Diet Trial: PRIMARY CANCER OUTCOMES N=48,325; 8.1 yrs follow-upINVASIVE BREAST CANCER COLORECTAL CANCER1,727 total diagnoses (3.5% ppts) 480 total diagnoses (1% of ppts)q HR 0.91 (95% CI: 0.83-1.01) q HR 1.08 (95% CI: 0.90-1.29) q Self-reported polyps & adenomasThere was a significant interaction of dietassignment with baseline % calories from HR 0.91 (95% CI: 0.87-0.95)fat, by quartile (p=0.04): JAMA 2006; 295; 643-654Women who consumed highest % Relative 1 Yr Hormone Changes (Subsample) Figure 3. Change* from Baseline to Year 1 in the Intervention Compared to the Comparison Group for Blood Hormone Concentrations Adjusted for Baselinefat at baseline (≥ 36.8%) had Differences E2 0.85 Estradiolsignificant 22% reduction in Estrone 0.98 E1invasive breast cancer if assigned Estrone-sulfate 0.96 Estrone Sulfateto DIET vs Control T 0.99 Testosterone (HR: 0.78; 95% CI: 0.64,0.95). Sex Hormone Binding Globulin 1.09 SHBG JAMA 2006; 295; 629-642 0.6 0.7 0.8 0.9 1 1.1 Change Estimate and 95% Confidence Interval 1.2 1.3 1.4 1.5 1.6 *Logarithm of change based on intervention minus control group average difference between year one and baseline log-biomarker values
  • WHI Calcium Vitamin D Trial: Relationship to CT Primary Outcome: Hip Fracture Secondary Outcomes: Diet (DM) Colorectal Cancer; Other Fractures 25,210 1000 mg calcium carbonate + of 48,836 (52%) 53.3% of CT CaD 400 IU vitamin D* at 1st (or 2nd) 36,282 Placebo Hormone Annual Visit 16,089 of 27,347 (59%) * 1/2 (i.e. 500 mg Ca + 200 IU Vit D) AM, 1/2 PM Choice: Chewable or Swallowable Pills Hip Fracture: 12% decrease (not significant)  21% significant decrease for ages 60-80 Colorectal Cancer: no benefit Kidney Stones: increased 17% (significant)
  • Women’s Health Initiative (WHI) Hormone Therapy (HT) TrialsGenerally Healthy E+P TrialPostmenopausal NO CEE + MPA (medroxy- Women N= 16,608 progesterone acetate, 2.5 mg/d) aged 50-79 years = Prempro® Placebo Hysterectomy E-alone Trial CEE (Conjugated equine YES estrogens, 0.625 mg/d) N= 10,739 Placebo = Premarin®*Initially: CEE only (N=331), CEE+MPA, or Placebo (Post-PEPI: CEE only were converted to CEE+MPA) Current HT required 3-month wash-out before baseline testing.
  • WHI HT Trials: Sample Size, Outcomes, Follow-up Women, aged 50-79 Total HT trials = 27,347Hormone Trials Primary Outcome: Average E+P Coronary Heart Disease Follow-up 16,608 Secondary Outcomes: 5.6 years* Stroke, Blood Clots q Lungs (PE, pulmonary emboli) E-Alone Average q Legs (DVT, deep vein thrombosis) 10,739 7.1 years* Breast, Colorectal, Uterine Cancers Hip Fracture; Other DeathsWHI Memory Study (WHIMS) *design ~ 8.5 years - for women aged ≥ 65: Dementia
  • WHI Hormone Trials: Baseline Hypotheses Anticipated Risk Expected Benefit Coronary Artery Disease (Heart Attacks) Stroke? Breast Cancer Threshold Level Threshold Level Early STOPPING Early STOPPING for HARM for BENEFIT Additional Risks: Additional Benefits: • Blood Clots, VTE Plan to follow to 2005 • Hip (Bone) FracturesLungs=PE; Legs=DVT (average 8.5 years) • Overall Mortality • 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
  • WHI HT: Baseline Age Distribution Mean (SD): E+P Trial = 63.3(7.1) E-Alone Trial = 63.6 (7.3) Goal: 50-54: 10% 60-69: 45% 70-79: 25% 55-59: 20% 50-59 60-69 70-79 35 E+P 33% E+P 45% E+P 22% 30 E-alone 31% E-alone 45% E-alone 24% 25 20 15Percent 10 5 0 50-54 55-59 60-64 65-69 70-74 75-79 Intact Uterus:E+P Hysterectomy: CEE onlyStefanick, Cochrane, Hsia, Barad, Liu, Johnson Ann Epidemiol 2003; 13: S78-S86
  • WHI Hormone Trials: Ethnic Distribution by Age 50-59 60-69 70-79 25 E+P 21.5% E+P 12.5% E+P 8.6% E-Alone 32.7% 20 E-Alone 22.0% E-Alone 13.9% 20 14 15 10 10 10 10 9 Percent 6 5 4 5 4 2 2 0 Black Hispanic Black Hispanic Black Hispanic Uterus - E+P (84.0 % White ) Hysterectomy- E only (75.3% White)Stefanick, Cochrane, Hsia, Barad, Liu, Johnson Ann Epidemiol 2003; 13: S78-S86
  • WHI E+P Trial: Preliminary* Findings, July 2002 (*aver. 5.2 yrs) Risks Benefits 26% Increase Breast Cancer Threshold Level STOPPED Early, Clear Harm Stopped 3.3 yrs early Also: DVTs * had 0.4 more yrs of data Other Fractures *Adapted from: Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333
  • WHI E+P Trial: Preliminary* Findings, July 2002 (*aver. 5.2 yrs) Risks 29% Increase CHD (Coronary Heart Disease) Benefits 41% Increase 33% Decrease Hip Fracture Stroke Fewer Colorectal Cancers 113% Increase Pulmonary Emboli 26% Increase Breast Cancer Threshold Level STOPPED Early, Clear Harm Stopped 3.3 yrs early Also: DVTs * had 0.4 more yrs of data Other Fractures *Adapted from: Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333
  • WHI E+P Trial: Absolute (annualized) Risk (5.2 Yrs*)*Preliminary Findings per 10,000 Women per Year E+P Placebo Risks* Number of Cases 60 Additional Events Reduced Neutral 50 7 8 8 8 Events 40 30 6 5 20 10 0 CHD* Stroke* Breast PE* Colorectal Hip Endometrial Deaths Cancer Cancer* Fracture* Cancer *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
  • WHI Memory Study (WHIMS) - ancillary study (Postmenopausal Women, aged ≥ 65 yrs) WHIMS E+P and E-only trials = 7,479Primary Outcome: E+P Average q Probable Dementia (PD) (women with Follow-up a uterus) 4.1 years* Secondary Outcomes: 4532 q Combined PD & Mild Cognitive E-Alone Average Impairment (MCI) (post-hystX) 5.2 years* - Supporting Data: 2947 Global Cognitive Function (by annual Modified Mini-mental *design ~ 7 years State Examination, 3MSE))
  • WHIMS E+P: Probable Dementia Hazard Ratio4532 women, aged 65-80; followed for 4.1 years E+P Placebo Cumulative Hazard HR, 2.05 95% CI, 1.21__3.48 Years Since Randomization No. at Risk E+P 2229 2112 2026 1915 1325 401 Placebo 2303 2200 2125 1984 1392 477
  • Annual Number of US Prescriptions for HT 1995 - Aug 2003 Oral E Oral E/P Trnd/Vag 60 50 40 WHI 30 HERS E+P WHI E-only 20 ?? 10 0 Annual Prescriptions by Formulation (millions) 1995 1996 1997 1998 1999 2000 2001 2002 2003 Source: IMS Health NPA Plus Hersh AL, Stefanick ML, Stafford RS JAMA 291: 2004; 291: 47-53
  • WHI E only Trial: Preliminary Findings, March 2004 (aver. 6.8 yrs) Risks Benefits 37% Increase Stroke (55% Increase Ischemic Stroke) 33% Decrease Hip Fracture STOPPED - Threshold Level Increased Stroke Stopped 1.5 yrs early No CHD Benefit * had 0.3 more yrs of data Other Fractures N.S. 37% Increase No Effect on CHD Pulmonary Emboli No Increase Breast Cancer 47% increase DVTs No Effect on Colorectal Cancer *Adapted from: Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333
  • WHI E-Alone (CEE) Trial: Absolute (annualized) Risk (6.8 Yrs*)*Preliminary Findings Effects of CEE and Placebo on Disease Rates 90 Risk Benefit 80 12 6 70 P=.007 3 PE: ns P=.06 P=0.01 60 6 DVT 50 CEE P=.03 40 Placebo 30 20 in 10,000 women 10 0 Number of cases per year clots Blood Heart Strokes attacks cancer Deaths Breast Hip cancer Colorectal fractures The Women’s Health Initiative Steering Committee: JAMA 2004; 291: 1701-1712
  • Summary: WHI E+P* vs. E-Alone** Trial published: *July 2002 **April 2004 Concordant results s Heart Disease – no benefit (for E+P, early harm) s Strokes, Blood Clots – harmful s Fractures – beneficial s Dementia (if ≥ 65 yrs of age) – harmful *Brain MRI Disparate Results s Breast Cancer s Increased in E+P Trial (women with a uterus) s Not increased in E-Alone Trial (women with prior hysterectomy) s Colorectal Cancer s Decreased in E+P Trial (women with a uterus) s No difference in E-Alone Trial s Global Index (Overall Risk/Benefit) s Increased in E+P (CEE + MPA) Trial s Neutral in E-Alone (CEE) Trial
  • WHI E-alone: CORONARY HEART DISEASE (CHD) Total and by Age (Rates per 10,000/year) p = 0.07 for interactionN=10,739; 7.1 yrs follow-up HR: 0.63 HR: 0.94 1.11 HR= 0.95 (95%CI: 0.79-1.16) (0.36-1.08) (0.71-1.24) (0.82-1.52) 100 96 100 86 80 53 56 80 57 61 60 60 40 40 27 17 20 20 0 0 CHD 50-59 60-69 70-79 CEE only Placebo CEE only Placebo Hsia et al Arch Intern Med 2006; 166:357-365.
  • WHI Hormone Trials: Percent Obese (BMI ≥30 kg/m2) E+P Trial (Women with a Uterus) E-Alone Trial (Hysterectomy) Mean BMI = 28.5 kg/m2 Mean BMI = 30.1 kg/m2 34.1% Obese 70 44.6% ObesePERCENT OF AGE GROUP (30.6% Normal Wt.) 60 (20.7% Normal Wt.) 51.0 50 50 45.8 36.6 40 35.2 40 34.1 27.7 30 30 20 20 10 10 0 0 50-59 60-69 70-79 50-59 60-69 70-79 BMI: 28.9 28.6 27.5 BMI: 31.2 30.2 28.6 Stefanick, et al Ann Epidemiol 2003; 13: S78-S86
  • Prior HT Use by Age at Baseline CEE +MPA CEE only 80 70 60 50 40 50-59 y 60-69 y 30Percentage 70-79 y 20 10 0 Intact Bilat Ooph No Bilat Uterus Ooph (36.5%) (56%) Hysterectomy Rossouw JAMA 2007;297:1465-1477
  • WHI E+P: Post-Intervention Follow-upAfter E+P trial was stopped early (mean 5.6 yrs ofintervention), WHI followed study participants through theplanned termination of the trial (March 31, 2005)Except for stopping the intervention and unmasking, thesame trial protocol was followed, e.g. semi-annualmonitoring to identify and classify study outcomesPost-intervention information (July 8, 2002 to March 31, 2005)available on 15,730 (95% of eligible) participants:mean of 2.4 years of post-trial follow-upWHI has continued follow-up since 2005 Heiss et al, JAMA 2008; 299: 1036-1045
  • WHI E+P: Post-Intervention Follow-up Cardiovascular risks disappeared s CHD, Stroke*, Blood Clots – no longer increased Fracture benefits disappeared s Hip Fracture - no longer decreased Cancer s Breast Cancer - 27% (ns) more diagnosed post-Int. s Colorectal Cancer - no longer decreased s TOTAL CANCER - increased 1.24 (1.04-1.48) s Due to increase in variety of cancers, incl. Lung Cancer All-cause Mortality -15% (ns) higher s Most due to Cancer (E+P: 101 vs placebo: 69) s only 27 (E+P) and 16 (placebo) due to pre-specified CA Heiss et al, JAMA 2008; 299: 1036-1045
  • N Engl J Med 2007; 356:16Number of Prescriptions of Menopausal Hormone Therapy in U.S. by Year
  • Breast Cancer Incidence: Initiating (CT) or Using (OS), then Stopping, Menopausal Estrogen + Progestin in WHI During Intervention (Trial) After Stopping Study PillsWHI Clinical Trial (CT) HR = 1.26 (1.02, 1.53) HR = 1.27 (0.91, 1.72)Estrogen + Progestin vs.PlaceboBlack Line = Sensitivity Analysis*Intervention Phase HR =1.62 (1.02, 2.39)Postintervention HR =1.26 (0.73, 2.20)*censored 6 months after changing pillsWHIObservational Study (OS)Estrogen+Progestin Usersvs. Non-users - at Entry Serial E+P UseN Engl J Med 2009;360(6): 573-87Chlebowski et al (Stefanick)
  • WHI E-only: Post-Intervention Follow-upAfter E-only trial was stopped early (mean 7.1 yrs intervention),WHI continued to follow study participants through the plannedtermination of the trial (March 31, 2005)By this time 54% of participants had stopped study medication.Median time on treatment: 5.9 or 5.8 years in active vs.placebo Median adherent time on treatment was 3.5 yearsPostintervention follow-up: 47.2 (20.7) mo. ( thru August 14, 2099)Consent obtained for annual mail and telephone follow-up foroutcomes ascertainment in 78% of surviving eligible women 81% had at least 1 mammogram; 4.7% of active & 2.7% of placebo reported use of E alone after stoppingIntention-to-treat analysis, time-to-event methods LaCroix, et al. JAMA 2011;305(13):1305-1314
  • Estrogen Alone Results All Participants by Intervention Period Intervention Post-intervention Overall FUCHD/Total MI 0 0 0Stroke 0 0DVT/PE 0Breast cancerColorectal cancer 0 0 0Hip fracture 0All-cause mortality 0 0 0Global index 0 0 0 LaCroix, et al. JAMA 2011;305(13):1305-1314
  • Estrogen Alone: Age Specific Results 50-59 years 60-69 years 70-79 yearsCHD/Total MI 0Stroke 0DVT/PE 0 0Breast cancerColorectal cancer 0 0Hip fracture 0 0 0All-cause mortality 0Global index 0 LaCroix, et al. JAMA 2011;305(13):1305-1314
  • WHI E-only: Post-Intervention Follow-up Cardiovascular: Stroke & VTE no longer elevated s CHD: aged 50-59baseline: HR 0.59 (0.38-0.90); age, pinteraction=0.05 s MI: aged 50-59: HR 0.54 (0.34-0.86); 60-69,HR 1.05; 70-79,HR 1.23 age pinteraction=0.007 All CVD events: HR 1.06 (0.98-1.15) Fracture: benefits disappeared Cancer: Breast Cancer significantly lower in CEE (HR 0.77), all ages (Not high risk, e.g. family history, benign breast disease; Lancet Oncology, E March 2012) s Colorectal Cancer: women aged 70-79, 2-fold higher in CEE All-cause Mortality AGE, p for interaction = 0.04 s Women aged 50-59 @ baseline: HR 0.73 (0.53-1.00) s No increase for women 60-69; slight increase for women 70-79 Global Index AGE, p for interaction = 0.009 s aged 50-59: HR 0.85 (0.70-1.03) – possible benefit JAMA 2011;305):1305-1314
  • U.S. MHT Trends by Routes of Administration 9,000 Oral ET 62% WHI E+P 8,000 June 2002 Oral EPT 76% 7,000 WHI E alone April 2004 Vaginal 32% 6,000 Transdermal 5,000 Intramuscular 58% 4,000 3,000 2,000 1,000 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 Year Tsai, Stefanick, Stafford. Menopause 2011; 18(4): 385-392
  • WHI Extension Study (ES) - 2005- 2010 Diet CT 48,836 OS Eligible: 45,560 93,676 Eligible: 86,744 ES: 37,844 ES: 63,207 (83.1%) (72.9%) Hormone 27,347 Eligible:25,193 Total WHI (CT + OS) = 161,809 ES:20,425 Eligible:150,075 (81.1%) Extension Study = 115,363 (77% of Eligible) Ages 57-91SHARe – Genome–wide Association Study (NHLBI): African-American & Hispanic PptsAdded rest of Hormone Trial Cohort, Core Biomarkers, e.g. lipids, glucose, creatinineCMS (Medicare) linkage, Medication Inventory
  • WHI Extension 2010-2015Total CT Eligible: 107,706 2010-15 Cohortconsented: 93,544 (87%) Mean Age = 78 yrs Baseline* Number % of Age Group Eligible 50-54 14,470 91.2 55-59 21,527 90.7 Diet OS 60-69 43,352 87.1(86.2%) (88.2%) 70-79 14,195 77.4 *Baseline 60-79: 1993-1998 nH White, 88% nH Black, 79% Hispanic, 77% Asian/PI, 83% Hormone Native American/Alaskan, 84% (82.9%) Regional Centers: Ongoing Outcomes Collection In-Person Visit: 8000 women aged ≥72 yrs Ancillary Studies, e.g. WHIMS-Y, OPACH, NPAAS - currently working on a WHI Physical Activity Trial Proposal