Risks and Benefits of Hormone Therapy: An Overview of Findings From the Womens Health Initiative A...

Risks and Benefits of Hormone Therapy: An Overview

of Findings From the Women’s Health Initiative

A CME Slide Library From the

Council on Hormone Education

Risks and Benefits of Hormone Therapy: An Overview of Findings From the

Women’s Health Initiative

Section 1: Introduction

Section 2: Study Design and Methods

Section 3: Baseline Characteristics

Section 4: Overview of Clinical Outcomes

Section 5: Cardiovascular Events

Section 6: Breast Cancer

Section 7: Other Cancers

Section 8: Fractures

Section 9: Dementia and Mild Cognitive Impairment

Section 10: Mortality

Section 11: Summary and Conclusions

Section 1:

Introduction



HT = hormone therapy (estrogen alone [E-alone], estrogen plus a progestin [E+P]).The Women's Health Initiative Study Group. Control Clin Trials. 1998;19:61-109.

Women’s Health Initiative (WHI) Clinical Trials of HT

Large, parallel, NIH-sponsored, randomized, placebo-controlled, clinical trials

– Conjugated equine estrogen (CEE) alone

– CEE plus medroxyprogesterone acetate (MPA)

Purpose: Assess long-term risks and benefits of CEE alone and CEE/MPA in chronic disease prevention

Over 27,000 women aged 50 to 79 years (mean age, ~63 years) randomized between 1993 and 1998; originally scheduled to conclude in 2005

maybe a flow chart of the entire whi would be helpful here. observational study, ert and hrt.

Women’s Health Initiative (WHI) Clinical Trials of HT

CEE/MPA trial stopped in July 2002 after a mean follow-up of 5.2 years1

CEE-alone trial stopped in March 2004 after a mean follow-up of 6.8 years2

Trials originally designed for approximately 8 years of follow-up

1Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33. 2Women's Health Initiative Steering Committee. JAMA. 2004;291:1701-12.

maybe a flow chart of the entire whi would be helpful here. observational study, ert and hrt.

WHI: Data and Safety Monitoring Board Recommendations on 5/31/02

Terminate CEE/MPA Study Excess of breast cancer

– Crossed pre-specified monitoring boundary

Global index: trend towards greater risk than benefits

Continue CEE-only Study Uncertain benefit/risk ratio

Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33.

WHI: National Institutes of Health Decision on 2/2/04

Terminate CEE-alone Study Early Increased risk of stroke

– Did not cross predefined stopping boundary

– Deemed unacceptable in healthy women enrolled in 1° prevention trial

No increased risk of heart disease or breast cancer

Reduced risk of hip fracture

Women's Health Initiative Steering Committee. JAMA. 2004;291:1701-12.

Section 2:

Study Design and Methods



The WHI CEE/MPA Trial

373,092 Women Initiated Screening

18,845 Provided Consent and Reported No Hysterectomy

16,608 Randomized

8506Assigned to CEE/MPA

• 42% discontinued study drug

• 6% initiated HT through own HCP

• Unblinded: n = 3444

HCP = health care provider.Adapted from Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33. ©2002 American Medical Association. All rights reserved.

8102 Assigned to Placebo


• 11% initiated HT through own HCP


The WHI CEE-Only Trial

373,092 Women Initiated Screening

11,941 Provided Consent andReported Hysterectomy

10,739 Randomized

5310 Assigned to CEE


• 6% Initiated HT through own HCP


Adapted from Women's Health Initiative Steering Committee. JAMA. 2004;291:1701-12.

5429 Assigned to Placebo


• 9% Initiated HT through own HCP


The Women's Health Initiative Study Group. Control Clin Trials. 1998;19:61-109.

WHI HT Trials: Eligibility Criteria

Postmenopausal

– S/P hysterectomy (for CEE-alone)

– Intact uterus (for CEE/MPA) Age 50 to 79 years at initial screening Ability and willingness to provide written and

informed consent Resident in study area for 3 years following

enrollment

this could be more useful if;define postmenopausalwhat about prior hrt/ert useother disease stateshx/o dvt or PE?etc...

The Women's Health Initiative Study Group. Control Clin Trials. 1998;19:61-109.

WHI HT Trials: Exclusion Criteria

Exclusions Competing risks (conditions associated with survival

of <3 years) Safety reasons (eg, prior breast cancer within 10

years, low hematocrit or platelet counts) Adherence and retention concerns

– Alcoholism, dementia, transportation problems

Discouraged From Participating Women with moderate or severe menopausal

symptoms

this could be more useful if;define postmenopausalwhat about prior hrt/ert useother disease stateshx/o dvt or PE?etc...

WHI HT Trials: Regimens and Doses

CEE/MPA trial1

– CEE 0.625 mg/d + MPA 2.5 mg/d (n = 8506)

– Placebo (n = 8102) CEE-alone trial2

– CEE 0.625 mg/day (n = 5310)

– Placebo (n = 5429)

1Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33.2Women's Health Initiative Steering Committee. JAMA. 2004;291:1701-12.

WHI: Outcomes

Primary outcome: coronary heart disease (CHD) events (nonfatal myocardial infarction [MI] and CHD death)

Primary adverse outcome: invasive breast cancer

Global index: an untested summary measure of the effects of HT on major disease outcomes recorded during the trial

– Menopausal symptoms, quality of life (QOL), venous thromboembolism (VTE), and cognitive function not included


WHI: Factors Included in the Global Index

CHD event (nonfatal MI, CHD death) Breast cancer Stroke Pulmonary embolism (PE) Endometrial cancer Colorectal cancer Hip fracture Death due to other causes


Interpreting the Global Index From WHI Data

QOL was not included in the global index, therefore not considered in the risk-benefit profile for HT

Global index was created for this study and has not been tested for validity

Significance of assigning equal weights to various conditions has not been examined

WHI: Statistical Analyses Outcome comparisons presented as hazard

ratios (HR) with nominal and adjusted 95% confidence intervals (CI)

Nominal CI (nCI): describes variability in risk estimates that would result from a trial with a single outcome– Most appropriate for primary outcomes

(CHD, breast cancer) and global index Adjusted CI (aCI): variability of risk estimates

corrected for multiple comparisons– Most appropriate for all other outcomes


Section 3:

Baseline Characteristics



CEE/MPA Trial: Baseline Characteristics

*Black, Hispanic, American Indian, Asian/Pacific Islander, or unknown.Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33.

CharacteristicCEE/MPA (n = 8506)

Placebo (n = 8102)

Mean age at screening, y (SD) 63.2 (7.1) 63.3 (7.1)Age group at screening, n (%)

50–59 years 2839 (33.4) 2683 (33.1)60–69 years 3853 (45.3) 3657 (45.1)70–79 years 1814 (21.3) 1762 (21.7)

Race/ethnicity, n (%)

White 7140 (83.9) 6805 (84.0)Minority* 1366 (16.1) 1297 (16.0)

Hormone use, n (%)

Never 6280 (73.9) 6204 (74.4)Past 1674 (19.7) 1588 (19.6)Current 548 (6.4) 487 (6.0)

CharacteristicCEE/MPA (n = 8506)

Placebo (n = 8102)

Body mass index, kg/m2* 28.5 (5.8) 28.5 (5.9)

Never smokers, % 49.6 50.0

Current smokers, % 10.5 10.5

Diabetes, % 4.4 4.4

Hypertension, % 35.7 36.4

Statin use at baseline, % 6.9 6.8

History of MI, %† 1.6 1.9

History of CABG/PTCA, %† 1.1 1.5‡

Family history breast cancer, % 16.0 15.3

CABG/PTCA = coronary artery bypass grafting/percutaneous transluminal coronary angioplasty.*Values are means (SD); ††Overall incidence of prior cardiovascular disease = 7.7%; ‡P = .04 vs CEE/MPA.Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33.

CEE/MPA Trial: Baseline Characteristics

CEE-Alone Trial: Baseline Characteristics

*Black, Hispanic, American Indian, Asian/Pacific Islander, or unknown.†Required a 3-month washout prior to randomization.Women's Health Initiative Steering Committee. JAMA. 2004;291:1701-12.

CharacteristicCEE

(n = 5310)Placebo (n = 5429)

Mean age at screening, y (SD) 63.6 (7.3) 63.6 (7.3)Age group at screening, n (%)

50–59 years 1637 (30.8) 1673 (30.8)60–69 years 2387 (45.0) 2465 (45.4)70–79 years 1286 (24.2) 1291 (23.8)

Race/ethnicity, n (%)

White 4007 (75.5) 4075 (75.1)Minority* 1303 (24.5) 1354 (24.9)

Hormone use, n (%)

Never 2769 (52.2) 2770 (51.1)Past 1871 (35.2) 1948 (35.9)Current† 669 (12.6) 708 (13.0)

CharacteristicCEE

(n = 5310)Placebo (n = 5429)

Body mass index, kg/m2* 30.1 (6.1) 30.1 (6.2)

Never smokers, % 51.9 50.4

Current smokers, % 10.3 10.6

Diabetes, % 7.7 7.6

Hypertension, % 48.0 47.4

Statin use at baseline, % 7.4 7.9

History of MI, % 3.1 3.2

History of CABG/PTCA, % 2.3 2.1

Family history breast cancer, % 18.0 17.1

CABG/PTCA = coronary artery bypass grafting/percutaneous transluminal coronary angioplasty.*Data available for 5281 CEE and 5391 placebo participants; values are means (SD).Women's Health Initiative Steering Committee. JAMA. 2004;291:1701-12.

CEE-Alone Trial: Baseline Characteristics

Section 4:

Overview of Clinical

Outcomes



WHI CEE/MPA: Preliminary Results

*VTE includes deep vein thrombosis and PE.Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33.

CHD

Breast Cancer

Stroke

VTE*

Endometrial Cancer

Colorectal Cancer

Hip Fracture

Total Fracture

Death

Hazard Ratio0.5 1.0 5.02.0

95% nCI

95% aCI

Primary Outcomes

Additional Outcomes

0

10

20

30

40

50

60

ColorectalCancer

EndometrialCancer

WHI CEE/MPA Results: Number of Cases/Year in 10,000 Women

Nu

mb

er p

er Y

ear

per

10,

000

Wo

men

Adapted from National Institutes of Health. National Heart, Lung, and Blood Institute. WHI HRT Update—2002. Available at: http://www.nhlbi.nih.gov/health/women/upd2002.htm. Accessed 6/22/02.

CHD Strokes BreastCancer

VTE HipFractures

Total Deaths

Risks Neutral Benefits

CEE/MPAPlacebo

PE

EventOverall

HR

Confidence Intervals

Attributable Risk per 10,000

Women/Year

Benefitper 10,000

Women/Year95%

Nominal95%

Adjusted

CHD 1.24 1.00–1.54 0.97–1.60 6

Breast cancer 1.24 1.01–1.54 0.97–1.59 8

Strokes 1.31 1.02–1.68 0.93–1.84 7

VTE 2.11 1.58–2.82 1.26–3.55 18

PE 2.13 1.39–3.25 0.99–4.56 8

Colorectal cancer 0.56 0.38–0.81 0.33–0.94 7

Hip fractures 0.67 0.47–0.96 0.41–1.10 5

Total fractures 0.76 0.69–0.83 -- 47

WHI CEE/MPA Results: Overall Relative and Attributable Risk

Women 50 to 79 Years of Age at Baseline

Cauley JA, et al. JAMA. 2003;290:1729-38; Chlebowski RT, et al. N Engl J Med. 2004;350:991-1004; Chlebowski RT, et al. JAMA. 2003;289:3243-53; Manson JE, et al. N Engl J Med. 2003;349:523-34; Wassertheil-Smoller S, et al. JAMA. 2003;289:2673-84; Writing Group for the WHI Investigators. JAMA. 2002;288:321-33.

WHI CEE Alone: Preliminary Results

VTE = venous thromboembolism (includes deep vein thrombosis and PE).Women's Health Initiative Steering Committee. JAMA. 2004;291:1701-12.

CHD

Breast Cancer

Stroke

VTE

Pulmonary Embolism

Colorectal Cancer

Hip Fracture

Total Fracture

Death

Hazard Ratio0.5 1.0 5.02.0

95% nCI

95% aCI

Primary Outcomes

Additional Outcomes

0

10

20

30

40

50

60

70

80

90

WHI CEE-Alone Results: Number of Cases/Year in 10,000 Women

Nu

mb

er p

er Y

ear

per

10,

000

Wo

men


Risks Neutral Benefits

CEEPlacebo

ColorectalCancer

CHDStrokes BreastCancer

VTE HipFractures

Total Deaths

PE

EventOverall

HR

Confidence Intervals

Attributable Risk per 10,000

Women/Year

Benefitper 10,000

Women/Year95%

Nominal95%

Adjusted

CHD 0.91 0.75–1.12 0.72–1.15 5

Breast cancer 0.77 0.59–1.01 0.57–1.06 7

Strokes 1.39 1.10–1.77 0.97–1.99 12

VTE 1.33 0.99–1.79 0.86–2.08 7

PE 1.34 0.87–2.06 0.70–2.55 3

Colorectal cancer 1.08 0.75–1.55 0.63–1.86 1

Hip fractures 0.61 0.41–0.91 0.33–1.11 6

Total fractures 0.70 0.63–0.79 0.59–0.83 56


WHI CEE-Alone Results: Overall Relative and Attributable Risk

Women 50 to 79 Years of Age at Baseline

Section 5:

Cardiovascular Events



0.00

0.01

0.02

0.03

0.04

0.05

0 1 2 3 4 5 6 7 8

Time (years)

Cu

mu

lati

ve H

azar

d

CEE

Placebo

WHI Results: Effect of CEE Alone on Risk of CHD

HR = 0.91

95% nCI = 0.75–1.12

95% aCI = 0.72–1.15

Kaplan-Meier Estimate


0.0 0.5 1.0 1.5 2.0 2.5 3.0

Hazard Ratio

WHI Results: Effect of CEE Alone on Risk of CHD by Age


Annualized Percentage of CHD

Subgroup CEE Placebo HR

Age (years)

50–59 0.14 0.24 0.56

60–69 0.54 0.59 0.92

70–79 0.88 0.84 1.04

CEE/MPA

Placebo

0

0.01

0.02

0.03

0.04

0 1 2 3 4 5 6 7

Years of Follow-up

Cu

mu

lati

ve H

azar

d f

or

CH

DWHI Results: Effect of CEE/MPA

on Risk of CHDKaplan-Meier Estimate

Manson JE, et al. N Engl J Med. 2003;349:523-34.

HR = 1.24

95% nCI = 1.00–1.54

95% aCI = 0.97–1.60

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

1 2 3 4 5 6+

Pe

rce

nt

CH

D E

ve

nts

*

CEE/MPA

Placebo

HazardYear Ratio 95% CI

1 1.81 (1.09-3.01)

2 1.34 (0.82-2.18)

3 1.27 (0.64-2.50)

4 1.25 (0.74-2.12)

5 1.45 (0.81-2.59)

6+ 0.70 (0.42-1.14)

WHI Results: Annualized Percent CHD Events by Year

Year

P = .02 for trend over time (z score = –2.36).

HR = 1.24

95% nCI = 1.00–1.54

95% aCI = 0.97–1.60

*Includes 9 silent MIs.Manson JE, et al. N Engl J Med. 2003;349:523-34.

WHI: Effect of CEE/MPA on Risk of CHD by Age and Years Since Menopause

The dotted vertical line indicates the overall CHD odds ratio (1.24). P-values for interaction were not significant.Manson JE, et al. N Engl J Med. 2003;349:523-34.

Subgroup

CEE/MPA Placebo

Number of Cases of CHD (annualized percentage)

Age (years)

50–59

60–69

70–79

37 (0.22)

75 (0.35)

76 (0.78)

27 (0.17)

68 (0.34)

52 (0.55)

Years Since Menopause

<10

10–19

20

31 (0.19)

63 (0.38)

74 (0.75)

34 (0.22)

51 (0.32)

44 (0.46)

0.5 1.0 1.5 2.0 2.5

Hazard Ratio for CHD

1.27

1.05

1.44

0.89

1.22

1.71


0.00

0.01

0.02

0.03

0.04

0.05

0 1 2 3 4 5 6 7 8

Time (years)

Cu

mu

lati

ve H

azar

d

CEE

Placebo


HR = 1.39

95% nCI = 1.10–1.77

95% aCI = 0.97–1.99

WHI Results: Effect of CEE Alone on Risk of Stroke

Annualized Percentage of Stroke

Subgroup CEE Placebo HR

Age (years)

50–59 0.16 0.16 1.08

60–69 0.49 0.30 1.65

70–79 0.71 0.57 1.25

0.0 0.5 1.0 1.5 2.0 2.5 3.0

Hazard Ratio

WHI Results: Effect of CEE Alone on Risk of Stroke by Age


0.000

0.005

0.010

0.015

0.020

0.025

0.030

0 1 2 3 4 5 6

Time (years)

Cu

mu

lati

ve H

azar

dWHI Results: Effect of CEE/MPA

on Risk of Stroke

Wassertheil-Smoller S, et al. JAMA. 2003;289:2673-84.

CEE/MPA

Placebo


HR = 1.31

95% nCI = 1.02–1.68

95% aCI = 0.93–1.84

0.00

0.01

0.02

0.03

0.04

0.05

0 1 2 3 4 5 6 7 8

Time (year)

Cu

mu

lati

ve H

azar

d

CEE

Placebo

Women’s Health Initiative Steering Committee. JAMA. 2004;291:1701-12.

WHI Results: Effect of CEE Alone on Risk of Pulmonary Embolism


HR = 1.34

95% nCI = 0.87–2.06

95% aCI = 0.70–2.55

0

0.01

0.02

0.03

0 1 2 3 4 5 6 7

Time (year)

Cu

mu

lati

ve H

azar

d

HR = 2.13

95% nCI = 1.39–3.25

95% aCI = 0.99–4.56

WHI Results: Effect of CEE/MPA on Risk of PE

Placebo

CEE/MPA


Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33. ©2002 American Medical Association. All rights reserved.

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

1 2 3 4 5 6+

Per

cen

t V

TE

Eve

nts

CEE/MPA

PlaceboHazardYear Ratio

1 3.60

2 2.26

3 1.67

4 1.84

5 2.49

6+ 0.90

WHI CEE/MPA Results: Annualized Percent VTE Events by Year

P < .05, significant fordecreasing risk over time.

Year

HR = 2.11

95% nCI = 1.58–2.82

95% aCI = 1.26–3.55


Section 6:

Breast Cancer



0.00

0.01

0.02

0.03

0.04

0.05

0 1 2 3 4 5 6 7 8

Time, y

Cu

mu

lati

ve H

azar

d

CEE

Placebo



HR = 0.77

95% nCI = 0.59–1.01

95% aCI = 0.57–1.06

WHI Results: Effect of CEE Alone on Risk of Invasive Breast Cancer

0

0.01

0.02

0.03

0.04

0 1 2 3 4 5 6 7

WHI Results: Effect of CEE/MPA on Risk of Invasive Breast Cancer

Cu

mu

lati

ve P

rop

ort

ion

Time (years)

Chlebowski RT, et al. JAMA. 2003;289:3243-53.

Placebo

CEE/MPAUnweighted HR = 1.24

95% CI, 1.01–1.54

WHI CEE/MPA Trial: Risk of Breast Cancer in Women With and Without Prior HT Use

Hazard Ratio (95% CI)

0.1 0.5 1.0 4.02.0

Prior HT Use

None

<5 Years

5 Years

Overall

% of Population

74.0

14.8

11.2

100

6.0


WHI CEE/MPA Trial: Characteristics of Invasive Breast Cancers

SEER = Surveillance, Epidemiology, and End Results.Chlebowski RT, et al. JAMA. 2003;289:3243-53.

E+P(n = 199)

Placebo(n = 150) P-Value

Tumor size, mean ± SD (cm) 1.7 ± 1.1 1.5 ± 0.9 .04

Positive lymph nodes, % 25.9 15.8 .03

SEER stage, %

Localized 74.6 82.7

Regional 24.4 14.0 .048

Metastatic 1.0 2.0

Morphology, grade, %

Well differentiated 25.0 20.3

Moderately differentiated 43.3 47.7 .61

Poorly differentiated/anaplastic 31.7 32.0

ER = estrogen receptor; PR = progesterone receptor.Chlebowski RT, et al. JAMA. 2003;289:3243-53.

WHI CEE/MPA Trial: Characteristics of Invasive Breast Cancers (continued)

E+P(n = 199)

Placebo(n = 150) P-Value

ER status, %

Positive 86.8 88.2.72

Negative 13.2 11.8

PR status, %

Positive 75.0 69.9.33

Negative 25.0 30.0

Deaths attributed to breast cancer, no. (%) 4 (2.0) 4 (2.7)

WHI CEE/MPA Trial: Mammography Results

*Abnormal mammograms included those that were associated with recommendations for short-term follow-up, showed a suspicious abnormality, or were highly suggestive of malignancy.†P < .001 vs E+P.


% Abnormal*

E+P Placebo

Year 1Year 1 9.49.4 5.45.4††

OverallOverall 31.531.5 21.221.2††

Section 7:

Other Cancers



0.00

0.01

0.02

0.03

0.04

0.05

0 1 2 3 4 5 6 7 8

Time (year)

Cu

mu

lati

ve H

azar

d

CEE

Placebo



HR = 1.08

95% nCI = 0.75–1.55

95% aCI = 0.63–1.86

WHI Results: Effect of CEE Alone on Risk of Colorectal Cancer

0.000

0.005

0.010

0.015

0 1 2 3 4 5 6 7

Time (year)

Cu

mu

lati

ve H

azar

dWHI Results: Effect of CEE/MPA

on Risk of Colorectal Cancer

Placebo

E+P

Chlebowski RT, et al. N Engl J Med. 2004;350:991-1004.

HR = 0.56

95% nCI = 0.38–0.81

95% aCI = 0.33–0.94


WHI Results: Hazard Ratio for Invasive Ovarian Cancer With CEE/MPA

Incidence rate of invasive ovarian cancer for the total study population was 34 cases per 100,000 person-years.Anderson GL, et al. JAMA. 2003;290:1739-48.

Hazard Ratio

0.1 0.5 1.0 5.02.0

95% nCI

95% aCI

E+P

Placebo

WHI Results: Hazard Ratio for Endometrial Cancer With CEE/MPA

Incidence rate of endometrial cancer for the total study population was 62 cases per 100,000 person-years.Anderson GL, et al. JAMA. 2003;290:1739-48.

Hazard Ratio

E+P

0.1 0.5 1.0 5.02.0

95% nCI

95% aCI

Placebo

Section 8:

Fractures



HR = 0.61

95% nCI = 0.41–0.91

95% aCI = 0.33–1.11

0.00

0.01

0.02

0.03

0.04

0.05

0 1 2 3 4 5 6 7 8

Time (year)

Cu

mu

lati

ve H

azar

d

CEE

Placebo


WHI Results: Effect of CEE Alone on Risk of Hip Fracture


WHI: Baseline Prevalence of Osteoporosis (WHO) by DXA Femoral Neck T-scores

Normal(>–1.0)

Low Bone Mass(–1.0 to –2.4)

E+P Placebo

P = .29

Cauley JA. Available at: http://www.fda.gov/ohrms/dockets/ac/cder03.html#EndocrinologicMetabolicDrugs. Accessed 1/7/04.

In 6% of Participants (n = 1024)

32%

58%

10%

35%

53%

12%

Osteoporosis(–2.5 )

-1

0

1

2

3

4

5

6

7

0 1 2 3

-1

0

1

2

3

4

5

6

7

0 1 2 3

PlaceboHT

-1

0

1

2

3

4

5

6

7

0 1 2 3

WHI Results: Mean Change in BMD During 3 Years of E+P

Follow-up (years)

Cauley JA, et al. JAMA. 2003;290:1729-38.

Mea

n C

han

ge

in B

MD

F

rom

Bas

elin

e (%

)

Total Hip Spine

In 6% of Participants (n = 1024)

WHI Results: Fracture Outcomes

Hip

Vertebral

Lower Arm/Wrist

Total

Hazard Ratio

95% nCI

95% aCI

0.5 1.0 2.0

Adjusted confidence interval reported only for hip fracture.Cauley JA, et al. JAMA. 2003;290:1729-38.

0

50

100

150

200

Total Fractures

WHI Results: Effect of CEE/MPA in Preventing Fractures

0

20

40

60

80

Hip ClinicalVertebral

Wrist/LowerArm

Nu

mb

er o

f F

ract

ure

s/Y

ear

in 1

0,00

0 W

om

en

PlaceboCEE/MPA

Number of Fractures/Year in 10,000 Women

Type of FractureCauley JA, et al. JAMA. 2003;290:1729-38.

need to align bars...

0.00

0.01

0.02

0.03

0 1 2 3 4 5 6 7

HR = 0.6795% nCl = 0.47–0.9695% aCI = 0.41–1.10

WHI Results: Effect of CEE/MPAon Risk of Hip Fracture


Time (year)

Cu

mu

lati

ve H

azar

d

Placebo

E+P

Cauley JA, et al. JAMA. 2003;290:1729-38.

0.0

0.1

0.2

0.3

0.4

0.5

0 1 2 3 4 5 6 7

WHI Results: Effect of CEE/MPA on Risk of Lower Arm/Wrist Fracture

Adjusted confidence interval not reported.Cauley JA, et al. JAMA. 2003;290:1729-38.


Time (year)

Cu

mu

lati

ve H

azar

d HR = 0.7195% nCl = 0.59–0.85

Placebo

E+P

0.0

0.1

0.2

0.3

0 1 2 3 4 5 6 7

WHI Results: Effect of CEE/MPA on Risk of Vertebral Fracture



Time (year)

Cu

mu

lati

ve H

azar

d HR = 0.6595% nCl = 0.46–0.92

Placebo

E+P

0.00

0.05

0.10

0.15

0 1 2 3 4 5 6 7

Cu

mu

lati

ve H

azar

d

Time (year)

WHI Results: Effect of CEE/MPAon Risk of Total Fracture



HR = 0.7695% nCl = 0.69–0.83

Placebo

E+P

1Cauley JA, et al. JAMA. 2003;290:1729-38.2Black DM, et al. Osteoporosis Int. 2001;12:519-28.

WHI: Summary Fracture Risk Score

WHI Investigators1 developed a summary fracture risk score guided by the methods used to develop the FRACTURE Index2

Predictive validity of FRACTURE Index has been shown2

Validity of WHI fracture risk score not established

– WHI reported fracture risk score showed moderate predictive strength for hip fracture1

1Cauley JA, et al. JAMA. 2003;290:1729-38.2Black DM, et al. Osteoporosis Int. 2001;12:519-28.

WHI: Summary Fracture Risk Score

Differences between FRACTURE Index and WHI risk score1,2:

– WHI score includes age, prior fracture after age 55 years, current smoking, and BMI 22.4 kg/m2

– FRACTURE Index includes age, prior fracture after age 50 years, maternal hip fracture after age 50 years, weight 125 lbs, current smoking, use of arms to stand from a chair, and total hip BMD (if available)2

HR for Global Index: Stratified by Fracture Risk Scores

Highest

Middle

Lowest

Hazard Ratio (95% nCI)

Fracture Risk*

0.5 1.0 2.0

*Stratified by tertiles of summary fracture risk scores; the WHI Global Index measure and WHI Fracture Risk Score have not been validated.Cauley JA, et al. JAMA. 2003;290:1729-38.

Summary: WHI Results and Considerations

CEE/MPA significantly decreased the risk of hip fractures, vertebral fractures, and all other fractures in a population not specifically selected for being at increased risk of fracture1

This benefit has not been demonstrated in a similarly low-risk population with any other osteoporosis therapy

1Cauley JA, et al. JAMA. 2003;290:1729-38.

Section 9:

Dementia and Mild Cognitive

Impairment



Women’s Health Initiative Memory Study (WHIMS)

1Shumaker SA, et al. JAMA. 2003;289:2651-62.2Rapp SR, et al. JAMA. 2003;289:2663-72.

Ancillary study to the WHI, a randomized, multicenter study of CEE alone and CEE plus MPA

Primary outcome measure: probable dementia

Two studies from WHIMS have been published

– Effect of CEE/MPA on probable dementia and mild cognitive impairment1

– Effect of CEE/MPA on global cognitive function2

WHIMS: Dementia and Mild Cognitive Impairment

1Shumaker SA, et al. JAMA. 2003;289:2651-62.

4532 postmenopausal women with a uterus and free of probable dementia, aged 65 years, were recruited from WHI centers and enrolled in the E+P arm of the WHIMS1

Study drug administration was stopped early

– Mean time between randomization and last 3MSE in WHIMS was 4.05 years

The ending of the CEE-only component of WHI and WHIMS ~1 year before its planned completion was announced by the NIH on March 2, 2004

OutcomeE+P

(n = 2229)Placebo

(n = 2303) HR (95% CI)

Probable dementia, n 40 21 2.05 (1.21–3.48)

Follow-up, mean (SD), years 4.01 (1.21) 4.06 (1.18)

Rate per 10,000 person-years 45 22

Mild cognitive impairment, n 56 55 1.07 (0.74–1.55)

Follow-up, mean (SD), years 3.99 (1.23) 4.04 (1.20)

Rate per 10,000 person-years 63 59

Cases of Probable Dementia and Mild Cognitive Impairment

Shumaker SA, et al. JAMA. 2003;289:2651-62.

0

0.01

0.02

0.03

0.04

0 1 2 3 4 5

Years Since Randomization

Cu

mu

lati

ve H

azar

dCumulative HR for a Diagnosis of

Mild Cognitive Impairment


HR, 1.0795% CI, 0.74–1.55

CEE/MPA

Placebo

Number of Events

CEE/MPA 5 18 18 11 4

Placebo 7 8 18 12 6

Cumulative HR for a Diagnosis of Probable Dementia


0

0.01

0.02

0.03

0 1 2 3 4 5

Years Since Randomization

Cu

mu

lati

ve H

azar

d

HR, 2.0595% CI, 1.21–3.48

CEE/MPA

Placebo

Number of Events

CEE/MPA 5 7 8 11 4

Placebo 3 2 3 3 9

Classification of Probable Dementia Cases by Treatment Assignment


Number (%) of Cases

Dementia Type CEE/MPA (n = 40) Placebo (n = 21)

Vascular dementia 5 (12.5) 1 (4.8)

Alzheimer’s disease 20 (50.0) 12 (57.1)

Other dementia types

Mixed type 5 (12.5) 3 (14.3)

Normal pressure hydrocephalus 2 (5.0) 0

Parkinson 0 1 (4.8)

Frontal lobe type 2 (5.0) 0

Alcohol related 1 (2.5) 0

Other dementia 3 (7.5) 2 (9.5)

Etiology unknown 2 (5.0) 2 (9.5)

Patient Adherence in WHIMS

2534 participants (55.9%) were nonadherent at some point during the trial

Nonadherent patients stopped study medication, took less than 80% of pills, or started HT outside of the trial

When nonadherent participants were censored 6 months after first becoming nonadherent, the number of probable dementia cases that occurred before censoring was reduced from 41 to 21 in the E+P group and from 20 to 6 in the placebo group (HR, 3.22; 95% CI, 1.25–8.29; P = .02)



WHI: Effect of E+P on Stroke IncidenceE

ven

ts (

per

10,

000

per

son

-yea

rs)

0

10

20

30

40

1 2 3 4 5 6

CEE/MPAPlacebo

Year of Follow-up

Related Study

WHISCA – Women’s Health Initiative Study on Cognitive Aging

Ancillary study to WHIMS

Designed to determine if estrogen or E+P reduces the rate of cognitive decline in women 65 years of age

Planned 6-year follow-up

What WHIMS and WHISCA Cannot Address

Whether there is a critical period of initiation of HT for prevention of

– Cognitive aging

– AD Whether dose, types of HT, or duration of

treatment may have different effects

Observational vs Randomized Studies

Observational Prospective Studies

Typical patterns of HT use (age, treatment)

Mostly E alone Risk for AD

Women’s Health Initiative Memory Study (WHIMS)

Only women 65 years of age

CEE + MPA Risk of all-cause

dementia

HT and AD

Section 10:

Quality of Life



WHI Quality of Life (QOL) Study

Health and functional status—RAND-36

Depression — CES-D

Sleep quality — WHI Insomnia Rating Scale

Satisfaction with sexual functioning — 1 item with 4-point response scale

Cognitive functioning — mMMSE

Menopausal symptoms — 5-item checklist

CES-D = Center for Epidemiological Studies-Depression; mMMSE = modified Mini-Mental State Examination.Hays J, et al. N Engl J Med. 2003;348:1839-54.

QOL-Related Assessments

One-Year Change in RAND-36 Scores

-3 -2 -1 0 1 2 3

Mental Health

Social Functioning

Energy and Fatigue

Bodily Pain

Physical Functioning

General Health

Physical Role Limitations

Emotional Role Limitations

CEE/MPA

Placebo

Change From Baseline at Year 1

*

For all parameters except depression, higher numbers indicate a positive effect and lower numbers indicate a negative effect.*P < .01 compared with placebo at Year 1.Hays J, et al. N Engl J Med. 2003;348:1839-54.

0

*

For all parameters except depression, higher numbers indicate a positive effect and lower numbers indicate a negative effect.*P < .01 compared with placebo at Year 1.Hays J, et al. N Engl J Med. 2003;348:1839-54.

One-Year Change in Other QOL-Related Measures

-1 0 1 2

CEE/MPA

Placebo

Change From Baseline at Year 1

*

0

0

Depression

Sleep Disturbance

Satisfaction With Sex

mMMSE

WHI QOL: Summary of Findings

The WHI1 found

– No significant clinical QOL benefit on any of the outcomes, including general health, vitality, mental health, or sexual satisfaction

– A statistically—but not clinically—significant benefit in sleep disturbance, physical functioning, and body pain at 1 year

Findings were similar to HERS2

– No improvement in QOL was seen with E+P use in older, asymptomatic, postmenopausal women

1Hays J, et al. N Engl J Med. 2003;348:1839-54.2Hlatky MA, et al. JAMA. 2002;287:591-7.

WHI QOL: Study Considerations

Only 12% of participants reported moderate or severe vasomotor symptoms

Unclear how “moderate” and “severe” vasomotor symptoms were defined

Vaginal symptoms were not evaluated Outcome scores were high at baseline, limiting

potential for therapy to increase them further 63% of the participants were ≥10 years

postmenopausal No validated menopausal QOL tools used

Hays J, et al. N Engl J Med. 2003;348:1839-54.

Section 10:

Mortality



0.00

0.05

0.10

0.15

0.20

0 1 2 3 4 5 6 7 8

Time (year)

Cu

mu

lati

ve H

azar

d

CEE

Placebo


WHI Results: Effect of CEE-Alone on Total MortalityKaplan-Meier Estimate

HR = 1.04

95% nCI = 0.88–1.22

95% aCI = 0.81–1.32

WHI Results: Causes of Death* in the CEE/MPA Trial

*Causes of death for placebo versus CEE/MPA were not statistically different.n = number of patients; % = annualized % calculated from average exposure over 60 months.Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33.

OutcomeCEE/MPA (n = 8506)

n (%)Placebo (n = 8102)

n (%)

Total deaths 231 (0.52) 218 (0.53)

Adjudicated deaths 215 (0.49) 201 (0.49)

Cardiovascular 65 (0.15) 55 (0.13)

Breast cancer 3 (0.01) 2 (<0.01)

Other cancer 104 (0.24) 86 (0.21)

Other known cause 34 (0.08) 41 (0.10)

Unknown cause 9 (0.02) 17 (0.04)

0.00.10.20.30.40.50.60.70.80.91.01.1

1 2 3 4 5 6+

Per

cen

t A

ll-C

ause

Dea

ths

CEE/MPA

Placebo

Year

WHI CEE/MPA Trial: Annualized Percent of All-Cause Deaths by Year

P = NS for trend over time.

HR = 0.98

95% nCI = 0.82–1.18

95% aCI = 0.70–1.37


HazardYear Ratio

1 1.24

2 0.96

3 1.06

4 1.09

5 0.87

6+ 0.83

Section 11:

Summary and Conclusions



Summary of CEE/MPA Study

The overall risks of CEE 0.625 mg/d plus MPA 2.5 mg/d exceeded the benefits after an average of 5.2 years of follow-up in asymptomatic women ages 50 to 79 years at initial screening

Results from WHI indicate that CEE 0.625 mg/d plus MPA 2.5 mg/d should not be initiated or continued for the primary prevention of CHD

Risks for cardiovascular disease and breast cancer must be weighed against the benefit for fracture and colon cancer

Conclusions of the WHI Writing Group


Summary of CEE-Alone Study

In women with prior hysterectomy, the use of CEE-alone

– increases the risk of stroke

– decreases the risk of hip fracture

– does not affect the incidence of CHD A possible reduction in breast cancer with

use of CEE alone requires further study CEE alone not recommended for chronic

disease prevention

Conclusions of the WHI Writing Group


Interpretation of the Results from the WHI HT Trials

Average age at screening was 63 years; studies stopped when two-thirds or more of patients were 68 years

Results cannot be extrapolated to the typical population using HT

– Majority of women initiate HT to alleviate menopausal symptoms

– Women with moderate-to-severe menopausal symptoms were discouraged from participating

– 75% of HT users initiate therapy within 5 years of menopause; mean age of menopause, 51 years

Women’s Health Initiative Steering Committee. JAMA. 2004;291:1701-12; Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33; Newton KM, et al. J Womens Health. 1997;6:459-65; The Women's Health Initiative Study Group. Control Clin Trials. 1998;19:61-109; McKinlay SM, et al. Maturitas. 1992;14:103-15; Brett KM, Chong Y. Hormone Replacement Therapy: Knowledge and Use in the United States. Hyattsville, Md: National Center for Health Statistics; 2001:1-29.

Interpretation of the Results from the WHI HT Trials

Results may not relate to lower doses of these drugs or other estrogens or progestins, or other formulations or routes of administration

In the absence of clinical trial data, one cannot assume greater safety of other estrogens and/or progestins

Other Considerations

Treatment Discontinuation & Crossover

Interpretation of the CEE/MPA Results

Rates of discontinuation were high

– CEE/MPA = 42%

– Placebo = 38%

A number of women initiated HT with their own clinicians

– CEE/MPA = 6.2%

– Placebo = 10.7%

Unblinding

Interpretation of the CEE/MPA Results

Clinic gynecologists were unblinded to treatment assignment at higher rate in CEE/MPA group

– 41% unblinded in CEE/MPA

– 7% unblinded in placebo Effects of unblinding in CEE/MPA group

unclear; could influence patient monitoring for breast cancer and other conditions in the global index

National Institutes of Health. National Heart, Lung, and Blood Institute. New Facts About: Estrogen/Progestin Hormone Therapy. July 9, 2002. Available at: http://www.nhlbi.nih.gov/whi/hrtupd/ep_facts.htm. Accessed 7/15/02.

WHI: NIH Recommendations HT should not be continued or started to prevent

heart disease For osteoporosis prevention, women should consult

their doctor and weigh the benefits of HT against their personal risks; alternate treatments are available

While short-term use was not studied, women taking HT for relief of menopausal symptoms may reap more benefits than risks

Risk/benefit profiles must be individualized for each patient

Women should talk with their doctor about their personal risks and benefits

American College of Obstetricians and Gynecologists. Statement on the Estrogen Plus Progestin Trial of the Women’s Health Initiative. July 9, 2002. Available at: http://www.acog.org/from_home/publications/press_releases/nr07-09-02.cfm. Accessed 7/15/02.

WHI: American College of Obstetrics and Gynecology (ACOG) Advisory

Women who have been taking HT for a number of years should not panic, but discuss their individual situation with their physician

With respect to women’s short-term use of HT for relief of menopausal symptoms, it may be reasonable for women to continue use for this purpose, since the benefits are likely to outweigh the risks

Regarding a women’s short-term use of HT for relief of menopausal symptoms, ACOG continues to recommend that this be a personal, individualized decision, made after consultations between a woman and her physician—taking into account a woman’s individual benefits and risks from such use

Date post:	26-Mar-2015
Category:	Documents
Upload:	joshua-nichols
View:	220 times
Download:	0 times

Risks and Benefits of Hormone Therapy: An Overview of Findings From the Womens Health Initiative A...

Documents