Women’s Health Initiative: HRT TrialBaseline Data and Update on Follow-up

Marcia L. Stefanick, Ph.D. Marcia L. Stefanick, Ph.D.

Associate Professor of MedicineAssociate Professor of Medicine and of Obstetrics and Gynecologyand of Obstetrics and Gynecology

Stanford University School of Medicine, Stanford, CAStanford University School of Medicine, Stanford, CA

Principal Investigator of Stanford WHI Clinical CenterPrincipal Investigator of Stanford WHI Clinical Center

Chair of WHI Steering CommitteeChair of WHI Steering Committee

Women’s Health InitiativeBaseline Monograph: HRT Chapter

Marcia L. StefanickMarcia L. Stefanick, PhD , PhD (Stanford PI)

Barbara B. CochraneBarbara B. Cochrane, RN, PhD , RN, PhD (FHCRC)

Judith HsiaJudith Hsia, MD , MD (GWU PI)

David H. BaradDavid H. Barad, MD , MD (Einstein)

James H. LiuJames H. Liu, MD , MD (Cincinnati PI)

Susan J. JohnsonSusan J. Johnson, MD , MD (Iowa)

WHI CT Sample Size, Outcomes, Follow-upWHI CT Sample Size, Outcomes, Follow-up Women, aged 50-79 Women, aged 50-79 TotalTotal CT = 68,133 CT = 68,133

Diet Modification (DM) Trial Primary Outcomes: Breast & Colorectal Cancer Secondary Outcome: Coronary Heart Disease (CHD)

Hormone (HRT) Trial Primary Outcome: CHD Secondary Outcomes: Hip Fracture, Breast Cancer Ancillary Study: Memory

11.8% Overlap

Average Follow-up 8.5 years

Average 8.4 years

DM

48,836

HRT27, 347

Background for HRT/CHD hypothesisBackground for HRT/CHD hypothesis

LRC LRC Prevalence StudyPrevalence Study (‘83,’87)(‘83,’87) Nurses’ Health Study Nurses’ Health Study (‘85, ‘91)(‘85, ‘91) Framingham Study Framingham Study (‘85)-reversed(‘85)-reversed Nurses’ Nurses’ Health Study Health Study (‘97) (‘97) PERTPERT

Survival benefit diminishes with longer duration use; is lower for women at low risk for CHD - NEJM ‘97: 336; 1769

Many Observational Studies Many Observational Studies HRT users vs nonusers (generally): less likely to smoke, leaner, more physically active, healthier, more educated, higher SES, visit MDs more often, at lower CVD risk

WHI (2005)

PEPI PEPI (‘95)(‘95) healthyhealthy, aged 45-64, aged 45-64. . HRT improved HDL-C (ERT > PERT) HRT improved HDL-C (ERT > PERT) & LDL-C& LDL-C + + fibrinogenfibrinogen; ; incr TG, CRPincr TG, CRP..

HERS HERS (‘98) (‘98) prior CHD (+ uterus), prior CHD (+ uterus), aged<80.aged<80. PERTPERT for for MI: No benefit MI: No benefit @@ 4 yrs; 4 yrs; incr.incr. 1st yr, 1st yr, decr.decr. 4-5 yrs; 4-5 yrs; incr incr VTE (DVTVTE (DVT&&PE),Gallbladder D.PE),Gallbladder D.

ERAERA (‘00) (‘00) angiographicangiographic CHD. CHD. No No ERT or PERTERT or PERT benefitbenefit,aver 3.2 yr,aver 3.2 yr

PHASE(‘00); (‘00); [WAVE?; WELL-HART?][WAVE?; WELL-HART?] EPATEPAT LDL≥ 130;if >160,lipid-lowering--No WESTWEST(‘01)(‘01) recent stroke or TIA - recent stroke or TIA - NoNo WHI (2005) women aged 50-79 women aged 50-79

Observational Studies Clinical Trials

ERT10,739

WHI HRT Sample Size, Outcomes, Follow-upWHI HRT Sample Size, Outcomes, Follow-up Women, aged 50-79 Women, aged 50-79 TotalTotal HRT = 27,347 HRT = 27,347

Hormone (HRT) Trial Primary Outcome: Coronary Heart Disease Secondary Outcomes: Hip Fracture; Other Fractures Breast & Endometrial Cancers WHI Memory Study (WHIMS) - for women 65+ - Memory

Average Follow-up 8.4 years

Average 8.4 years

PERT16,608

WHI HRT Trial WHI HRT Trial (N=27,347):(N=27,347): Treatments TreatmentsAdherence < 80% activates Intensive Adherence ProgramAdherence < 80% activates Intensive Adherence Program

Estrogen with Progestin (50%)Conjugated Equine Estrogen (CEE) - 0.625 mg/day +

Medroxyprogesterone Acetate - 2.5 mg/day (daily MPA)or

Placebo (50%)

Women with a Uterus (55% by design): Actual = 60.7% (N=16,608)

Women with a Hysterectomy (45%): Actual = 39.3% (N=10,739)

Estrogen only (50%)Conjugated Equine Estrogen (CEE) - 0.625 mg/day

orPlacebo (50%)

Goal: 50-54 = 10%; 55-59=20%; 60-69=45%; 70-79=25%

12.5

19.822.9 22.3

15.7

6.8

05

101520253035

50-54 55-59 60-64 65-69 70-74 75-79

Perc

ent

HystX-ERT Uterus-PERT HRT total

WHI HRT: Baseline Age DistributionWHI HRT: Baseline Age DistributionMean Mean ±± SDSD: : HystX-ERT = 63.6HystX-ERT = 63.6 ± 7.3± 7.3; ; Uterus-PERT = 63.3Uterus-PERT = 63.3 ± 7.1± 7.1

60-69ERT=45%; PERT=45%

70-79 ERT=24%; PERT=22%

50-59ERT=31%; PERT=33%

WHI HRT: Minority Distribution HystX: 2657HystX: 2657/10,739/10,739 (24.7%)(24.7%) Uterus: N = 2663 Uterus: N = 2663/16,608/16,608 (16.0%)(16.0%)

Total HRT: N = 5320Total HRT: N = 5320/27,347/27,347 (19.5%) (19.5%)

10.0

5.6

1.90.5

1.4

0.0

2.04.0

6.08.0

10.0

12.014.0

16.018.0

20.0

Blacks Hispanic Asian/PI Native Am Other

Pe

rce

nt

HysterX(75.3% White) Uterus (84.0 % ) HRT total (80.5%)

BlacksN=2741

HispanicN=1543

Asian/PIN=527

Nat. Amer.N=131

Total Numbers of Minority Women in HRT Trial

Total HRT Goal: 50-59=30% 60-69=45% 70-79=25%

25

46

29

14

4244

9

38

54

22

4335

0

20

40

60

50-59 60-69 70-79

Per

cent

White Black Hispanic Asian/PI

WHI HRT: Mean WHI HRT: Mean (± SD)(± SD) Baseline Age DistributionBaseline Age DistributionWhiteWhite: : 63.963.9±7.1±7.1 BlackBlack: : 61.361.3±7.0 ±7.0 HispanicHispanic: : 59.759.7±6.4±6.4 Asian/PIAsian/PI: : 63.263.2±7.5±7.5

WHI HRT: Differences among Minority GroupsWhites, N=22,027; Black, N = 2741; Hispanics, N = 1543; Asian/PI, N = 527

39

61

37

6359

4142

58

31

69

0

10

20

30

40

50

60

70

HystX - ERT No HystX - PERT

Pe

rce

nt

Total . WhitesBlacks Hispanic Asian/PI

Total Percent with Hysterectomy by Ethnic Group

WHI HRT: Age by Uterine Status and EthnicityWhites, N=22,027; Black, N = 2741; Hispanics, N = 1543; Asian/PI, N = 527

63.6 64.3

61.663.2

59.7

63.2

59.660.9

63.763.3

5052545658606264666870

Total White Black Hispanic Asian/PI

Ag

e (

ye

ars

)

HystX - ERT No HystX - PERT

Mean Age by Ethnic Group and Uterine Status

WHI HRT: Body Mass Index (kg/m2) by Uterine StatusWhites, N=22,027; Black, N=2741; Hispanics, N=1543; Asian/PI, N=527

30.126.8

32.229.7

30.5

25.228.5 28.3

31.0 29.5

0

5

10

15

20

25

30

35

Total White Black Hispanic Asian/PI

kg/m

2

HystX - ERT No HystX - PERT

Mean BMI by Ethnic Group and Uterine Status

2.6 5.4

20.8

40.7

30.6

05

101520253035404550

Perc

ent

HysterX-ERT Uterus-PERT HRT Total

WHI HRT: Education LevelWHI HRT: Education Level

Some College67.4% ERT; 73.8% PERT

< H.S. Diploma Equiv.9.9% ERT; 6.8% PERT

Percent Normal Weight, Overweight and Obese

0.6

22.7

10.35.2

35.126.1

05

10152025303540

<19 19-24.9 25-29.9 30-34.9 35.39.9 ≥40

Per

cent

Hyst-ERT Uterus-PERT HRT Total

WHI HRT: Baseline Body Mass Index (kg/mWHI HRT: Baseline Body Mass Index (kg/m22)) Mean BMIMean BMI: : ERT = 30.1ERT = 30.1 ± 6.2;± 6.2; PERT = 28.5PERT = 28.5 ± 5.9± 5.9;; HRT = 29.1HRT = 29.1 ± 6.1± 6.1

Normal Overweight Obese I Obese II Obese III

% Overwt+Obese ERT: 79.3 % PERT: 69.4 % HRT: 73.3 %

19.615.3

44.1

21.0

05

10152025303540455055

No Activity Some 2- <4/wkModerate

≥4X/wk

Perc

ent

HystX-ERT Uterus-PERT HRT Total

WHI HRT:Moderate & Strenuous ExerciseWHI HRT:Moderate & Strenuous Exercise(≥ 20 minutes/bout)(≥ 20 minutes/bout)

No Activity or ≤1X/wkNo Activity or ≤1X/wk63.7% of HRT63.7% of HRT

RecommendedRecommended

by CDCby CDC: 21% : 21%

32.1 33.523.1

11.2

50.339.2

10.5

01020304050607080

Perc

ent

HystX-ERT Uterus-PERT Total HRT

WHI HRT:Alcohol Intake and SmokingWHI HRT:Alcohol Intake and Smoking

Alcohol Intake Smoking Status

6.7

16.8

28.3

20.416.4

11.4

05

101520253035

Perc

ent

HysterX-ERT Uterus-PERT Total HRT

WHI HRT: Family IncomeWHI HRT: Family Income

< $20,00028.2% ERT20.5% PERT

> $50,00022.9% ERT30.9% PERT

3.8

17.7 20

58.5

0

10

20

30

40

50

60

70

80

Never married DivorcedSeparated

Widowed Marriage (likeRelationship)

Perc

ent

HystX-ERT Uterus-PERT Total HRT

WHI HRTWHI HRT:Marital Status:Marital Status

Divorced or Separated Widowed

Never Married

Marriage-like

WHI CaD: Outcomes, Relationship to CTWHI CaD: Outcomes, Relationship to CT

Calcium + Vitamin D (CaD) Primary Outcome: Hip Fracture Secondary Outcomes: Other Fractures, Colorectal Cancer

CaD36,282

at 1st (or 2nd) Annual Visit

Total CT = Total CT = 68,133

Total HRT = Total HRT = 27,347(40.1% of CT)

53.3% of CT

DM48,836

ERT10,739

PERT16,608

WHI Clinical Trials: Percent OverlapWHI Clinical Trials: Percent Overlap Total CT = 68,133 (53.3 % are in CaD)Total CT = 68,133 (53.3 % are in CaD)

29.4 % of HRT are in DM

CaD 36,282

59.7 %*

57.5 %*

19.5% ERT are in DM + CaD

17.6% PERT are in DM + CaD

44.3%CaD are

in HRT Trial

DM48,836

PERT16,608

ERT10,739

28.1% of PERT are in DM

31.6 % of ERT are in DM

58.8% HRT are in CaD

18.4% HRT are in DM + CaD

WHI HRT (N=27,347) & CaD (N=36,282): Follow-up Clinic Visits

Percent of Annual Visits Due for HRT and CaD

58.1

28.0

10.5

90.6

12

31

62

9291

0102030405060708090

100

AV1 AV2 AV3 AV4 AV5 AV6

Per

cent

Total HRT HystX-ERT Uterus-PERT CaD

WHI HRT & CaD: Follow-up Clinic Visits

Percent (of Due) Annual Visits Conducted in HRT & CaD

97 95 94 92 92 9198 97 95 94 94

0102030405060708090

100

AV1 AV2 AV3 AV4 AV5 AV6

Per

cent

Total HRT HystX-ERT Uterus-PERT CaD

WHI HRT: Follow-up

Percent Stopped HRT During Interval

109

76

54

02468

1012

AV1 AV2 AV3 AV4 AV5 AV6

Pe

rce

nt

Total HRT HystX-ERT Uterus-PERT

Cumulative, as of 2/01 = 33.5%

WHI HRT: Follow-up Clinic VisitsPercent of Women with Pill Counts taking > 80% Pills

Note: % with pill counts noted above columns

0102030405060708090

100

AV1 AV2 AV3 AV4 AV5 AV6

Pe

rce

nt

HystX-ERT Uterus-PERT

94% 90% 92% 92% 91% 92%

WHI HRT: Follow-up Clinic Visits

Percent < 50% & 50-80% Pill-taking Rate in Interval

0

2

4

6

8

10

12

AV1 AV2 AV3 AV4 AV5 AV5

Pe

rce

nt

HystX-ERT < 50% Uterus-PERT < 50%HystX 50-80% Uterus 50-80%

WHI HRT: Treated Hypertension by Ethnicity and Uterine Status

05

101520253035404550

Total White Black Hispanic Asian/PI

Perc

ent

Hysterectomy No HystX

Treated Hypertension by Uterine Status

HRT: High Blood Pressure* by Ethnicity and Uterine Status

* (Systolic BP>140 mmHg; Diastolic BP>90 mmHg)

0

5

10

15

20

25

30

35

40

Total White Black Hispanic Asian/PI

Perc

ent

HystX- High SBP No HystX- High SBP

HystX- High DBP No HystX- High DBP

High SBP and DBP (Baseline Clinic Visit) by Uterine Status

WHI HRT: Treated Diabetes by Ethnicity and Uterine Status

0

2

4

6

8

10

12

14

Total White Black Hispanic Asian/PI

Pe

rce

nt

Hysterectomy No HystX

Treated Diabetes (per Questionnaire)

WHI HRT: High Cholesterol requiring Pills by Ethnicity and Uterine Status

0

5

10

15

20

25

30

Total White Black Hispanic Asian/PI

Pe

rce

nt

Hysterectomy No HystX

High Blood Cholesterol requiring Pills

WHI HRT: History of MI or CABG/PTCAby Uterine Status and Ethnicity

00.5

11.5

22.5

33.5

44.5

5

Total White Black Hispanic Asian/PI

Pe

rce

nt

HystX-prior MI No HystX-prior MI

HystX-prior CABG/PTCA No HystX-prior CABG/PTCA

Positive Response to MI or CABG/PTCA Ever

WHI HRT: History of Stroke by Uterine Status and Ethnicity

0

0.5

1

1.5

2

2.5

3

Total White Black Hispanic Asian/PI

Pe

rce

nt

Hysterectomy No HystX

Positive Response to Stroke Ever

WHI HRT: Age at First Birth (%) by Uterine Status and Ethnicity

05

101520253035404550

Total White Black Hispanic Asian/PI

Pe

rce

nt

HystX 1st Birth < 20 yrs old No HystX 1st Birth < 20 yrs old

HystX-1st Birth ≥ 30 yrs old No HystX-1st Birth ≥ 30 yrs old

First Birth < 20 Yrs Age or ≥ 30 Yrs of age

WHI HRT: No Live Births by Uterine Status and Ethnicity

0123456789

10

Total White Black Hispanic Asian/PI

Pe

rce

nt

Hysterectomy No HystX

No Live Births (No term pregnancy)

WHI HRT: Oral Contraceptive Use and Duration by Ethnicity and Uterine Status

0

5

10

15

20

25

Total White Black Hispanic Asian/PI

Pe

rce

nt

HystX Used OC < 5 yrs No HystX Used OC < 5 yrsHystX Used OC 5-10 yrs No HystX Used OC 5-10 yrsHystX Used OC ≥ 10 yrs No HystX Used OC ≥ 10 yrs

Percent Using OC for <5, 5-<10 or ≥ 10 yrs

HRT Use at Baseline and Time Since last used (%) by Ethnicity and Uterine Status

02468

101214161820

Total White Black Hispanic Asian/PI

Pe

rce

nt

HystX- Current No HystX- Current

HystX- Used < 5 yrs ago No HystX- Used < 5 yrs ago

Percent Using HRT Currently or < 5 yrs ago

HRT Use at Baseline and Time Since last used (%) by Ethnicity and Uterus Status

0

5

10

15

20

25

Total White Black Hispanic Asian/PI

Pe

rce

nt

HystX Used 5-<10 yrs ago No HystX Used 5-<10 yrs ago

HystX Used ≥ 10 yrs ago No HystX Used ≥ 10 yrs ago

Percent Using HRT 5 -<10 or ≥ 10 yrs ago