cardiovascular health and menopause a cme slide library from the council on hormone education

Cardiovascular Health and Menopause

A CME Slide Library From the

Council on Hormone Education


Section 1: IntroductionSection 2: Cardiovascular Effects of EstrogenSection 3: Clinical Trials of Hormone Therapy (HT) and

Cardiovascular Outcomes3a. HERS3b. ERA3c. WAVE3d. ESPRIT3e. WELL-HART3f. PHASE3g. EPAT3h. WHI

Section 4: Timing of HT InitiationSection 5: Summary and Conclusions

Section 1:

Introduction


Impact of Cardiovascular Disease (CVD) in Women

Single largest killer of American women

– About 500,000 women die annually from CVD

More women than men die each year from CVD

In women, CVD-related deaths exceed the next 7 causes of death combined

One woman dies of CVD ~ every minute 2/3 of women who die had no prior symptoms

American Heart Association. Heart Disease and Stroke Statistics–2004 Update. 2004:1-50.

National Center for Health Statistics. 1999:164-7.

Mortality Rates in WomenAt Every Age, More Women Die of Heart Disease Than Breast Cancer

Coronary Artery Disease

Stroke

Lung Cancer

Breast Cancer

Colon Cancer

Endometrial Cancer

Age (years)

Mo

rtal

ity

Rat

e p

er 1

00,0

00

6500

4500

2500

1600

1200

800

400

075–7970–7465–6960–6455–5950–5445–49 80–84 85+

0.6 0.6

2.0

3.6

2.2

3.64.0

6.5

0

1

2

3

4

5

6

7

<40 40–44 45–49 50–54

Premenopausal

Postmenopausal

Incidence of CVD: Relation to Menopause Status

Inci

den

ce

(p

er

10

00

wo

men

)

Age (years)n = 2873.Kannel WB, et al. Ann Intern Med. 1976;85:447-52.

The Framingham Study

Observational Studies of CVD Risk: E Alone Compared With E+P

0.25 0.50 1.0 2.0 4.0

Grodstein et al, 1999Swedish cohort

Grodstein et al, 2000Nurses’ Health Study (NHS)

Varas-Lorenzo et al, 2000

Relative Risk (95% CI)

E Alone

E+P

Rosenberg et al, 1993

Mann et al, 1994

Psaty et al, 1994

Sidney et al, 1997

E alone = estrogen-only therapy; E+P = estrogen-plus-progestin therapy.

Section 2:Cardiovascular Effects

of Estrogen


*Data based on animal studies.HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; Lp(a) = lipoprotein(a).

Major Systemic and Direct Effects of Estrogens

Systemic Lipid

– HDL-C

– LDL-C

– Lp(a)

– Triglycerides Nonlipid

– Coagulation factors

– Carbohydrate metabolism

– Inflammation

– Homocysteine

Direct Short-term/rapid

– Vasodilation

– Nitric oxide availability

– LDL oxidation Long-term*

– Atherosclerosis

– Vascular injury response

– Endothelial and smooth muscle cell growth

Adapted from Mendelsohn ME, Karas RH. N Engl J Med. 1999;340:1801-11. ©1999 Massachusetts Medical Society. All rights reserved.

Endothelial cells

Smooth-musclecells

Estrogen

Rapid Effects Without alteration ofgene expression

Long-Term Effects

Related to alterationof gene expression

Direct Effects of Estrogen on Arterial Vessels

Section 3:Clinical Trials of Hormone

Therapy (HT) and Cardiovascular Outcomes


Section 3a:

Heart and Estrogen/progestin

Replacement Study

(HERS)

Heart and Estrogen/progestin Replacement Study (HERS)

Study Design:Randomized, double-blind, placebo- controlled, secondary prevention trial

Subjects:2763 postmenopausal women, <80 years old (mean age, 66.7 years) with CAD

Intervention:CEE 0.625 mg + MPA 2.5 mg daily or placebo

Follow-up:HERS I, 4.1 years HERS II, open-label 2.7 years

1° Endpoint:Nonfatal MI or CHD death

CAD = coronary artery disease; CEE = conjugated equine estrogen; MPA = medroxyprogesterone acetate; MI = myocardial infarction; CHD = coronary heart disease.Hulley S, et al. JAMA. 1998;280:605-13.Grady D, et al. JAMA. 2002;288:49-57.

HERS: CHD Events by Year

0

10

20

30

40

50

1 2 3 4 5 >5Year

Eve

nts

/100

0 P

erso

n-Y

ears

CEE/MPA

Placebo HERS I HERS II

Grady D, et al. JAMA. 2002;288:49-57.

0

5

10

15

20

0 1 2 3 4 5

HERS: Effects of Statins on Early CVD Events

Herrington DM, et al. Circulation. 2002;105:2962-7. Used with permission.

Inci

den

ce

(%

)

No Statin Use

Statin Use

With CEE/MPAWith Placebo

Follow-up (years)

HERS: Summary CEE/MPA in postmenopausal women with

established CHD did not reduce the overall risk of MI and CHD death

CEE/MPA significantly increased risk of events in the first year followed by a significant reduction in Years 4 and 5

In HERS II, the reduction in events did not continue

As previously shown, venous thrombo- embolic events were significantly increased with CEE/MPA

Hulley S, et al. JAMA. 1998;280:605-13.Grady D, et al. JAMA. 2002;288:49-57.Blumenthal RS, et al. Am J Cardiol. 2000;85:1015-7.

HERS: Lessons Learned

Women were on average 18 years postmenopause, suggesting that years since menopause may have an important influence on the cardiovascular effects associated with initiation of E+P

Cardiovascular risks of E+P in this population were observed early and did not occur in individuals taking concomitant statin therapy

Section 3b:

Estrogen Replacement and

Atherosclerosis (ERA) Study

Postmenopausal women with >30% coronary artery stenosis

Mean follow-up, 3.2 years

Angiographic follow-up in 248 patients

Mean cholesterol, 216 mg/dL

Compliance: 86% placebo, 84% E+P, 74% E alone

CEE only(0.625 mg)

n = 100

CEE (0.625 mg)+

MPA (2.5 mg)n = 104

Placebon = 105

Estrogen Replacement and Atherosclerosis (ERA) Study

Herrington DM, et al. N Engl J Med. 2000;343:522-9.

randomization

309Women

With Documented Coronary Artery

Stenosis(mean age, 65 years)

P = .38-0.16

-0.14

-0.12

-0.10

-0.08

-0.06

-0.04

-0.02

0.00

Placebo CEE CEE + MPA

Pro

gre

ssio

no

f Ath

eros

clero

sis

ERA Study: Change in Minimal Lumen Diameter

*Adjusted for length of follow-up, location of segment, clinic, and use of lipid-lowering therapy.Herrington DM, et al. N Engl J Med. 2000;343:522-9.

Ad

just

ed

Ch

ang

e in

Min

ima

l L

um

en

Dia

me

ter

Fro

m B

ase

line

*

(n = 79) (n = 85) (n = 84)

P = .97

Herrington DM, et al. N Engl J Med. 2000;343:522-9.

ERA Study: Summary

Neither CEE alone nor CEE plus MPAaffected the progression of coronary atherosclerosis in women with angiographically documented coronary artery stenosis who were on average 23 years postmenopausal

These findings are consistent with those of HERS

Section 3c:

Women’s Angiographic

Vitamin and Estrogen

(WAVE) Trial

Study Design:Randomized, double-blind, placebo-controlled trial

Subjects:423 postmenopausal women with at least one 15% to 75% coronary stenosis; mean age, 65 years

Intervention:CEE 0.625 mg + MPA 2.5 mg daily, or placebo; or vitamins E and C, or placebo

Follow-up:2.8 years (average)

1° Endpoint:Annualized mean change in minimum lumen diameter by quantitative coronary angiography

Women’s Angiographic Vitamin and Estrogen (WAVE) Trial

Waters DD, et al. JAMA. 2002;288:2432-40.

Lack of Effect of CEE/MPA and Antioxidant Vitamin Supplements on Progression of Coronary

Artery Atherosclerosis: WAVE Results

-0.07

-0.06

-0.05

-0.04

-0.03

-0.02

-0.01

0

0.01

Ch

ang

e/Y

ear

in M

inim

um

Lu

men

D

iam

eter

(m

ean

± S

E,

mm

)

Placebo/Placebon = 87

E+P/Placebon = 77

Placebo/Vitamins

n = 71

E+P/Vitamins

n = 85

Pro

gressio

no

f Ath

erosclero

sis

Waters DD, et al. JAMA. 2002;288:2432-40.

P = .30

Section 3d:

Oestrogen in the Prevention of

Reinfarction Trial (ESPRIT)

Oestrogen in the Prevention of Reinfarction Trial (ESPRIT)

Study Design:Randomized, double-blind, placebo- controlled, secondary prevention trial

Subjects:1017 postmenopausal women,

50 to 69 years old (mean age, 62.6 years) with CAD

Intervention:Estradiol valerate 2 mg daily or placebo

Follow-up:2 years

1° Endpoint:Reinfarction or cardiac death and all-cause mortality

Cherry N, et al. Lancet. 2002;360:2001-8.


ESPRIT: Primary Outcomes

Estradiol Valerate(n = 513)

Placebo(n = 504)

Rate Ratio (95% CI) P-Value

Reinfarction or cardiac death

62 61 0.99 (0.70–1.41) 0.97

Cardiac death 21 30 0.68 (0.39–1.19) 0.17

Death from any cause

32 39 0.79 (0.50–1.27) 0.34

ESPRIT: Rate Ratio of Cardiac Death by Months of Follow-up


Time to Events (months)

Estradiol Valerate Placebo


3 4 12 0.33 (0.11–1.01) 0.052

6 9 18 0.49 (0.22–1.09) 0.079

12 14 25 0.54 (0.28–1.05) 0.059

18 19 30 0.61 (0.35–1.09) 0.096

24 21 30 0.68 (0.39–1.19) 0.17

Time to Events (months)

Estradiol Valerate Placebo


3 8 14 0.56 (0.29–1.33) 0.19

6 14 20 0.68 (0.34–1.35) 0.27

12 20 30 0.65 (0.37–1.14) 0.13

18 27 39 0.67 (0.41–1.10) 0.11

24 32 39 0.79 (0.50–1.27) 0.34

ESPRIT: Rate Ratio of Any Death by Months of Follow-up


Section 3e:

Women’s Estrogen-progestin

Lipid-Lowering Hormone

Atherosclerosis Regression Trial

(WELL-HART)

Hodis HN, et al. N Engl J Med. 2003;349:535-45.

Women’s Estrogen-progestin Lipid-Lowering Hormone Atherosclerosis Regression Trial

(WELL-HART)

Study Design

Randomized, double-blind, placebo-controlled trial

226 postmenopausal women with CAD (mean age, 63.5 years)

Oral 17-estradiol (1 mg/d), taken with or without 5 mg MPA administered 12 days/month, or usual care

Median follow-up = 3.3 years

LDL-C reduced to <130 mg/dL by diet and lipid-lowering therapy

Primary Outcome

Average change in percent stenosis measured by quantitative coronary angiography

0

1

2

3

Usual Care Estradiol Estradiol +Sequential MPA

Ch

ang

e in

% S

ten

osi

s ±

SE

WELL-HART: Change in Percent Stenosis

Pro

gre

ssio

n

P = NS

n = 76n = 76

n = 74


Ch

an

ge

in M

inim

al L

um

ina

l D

iam

ete

r (m

m)

± S

E

-0.2

-0.1

0

Usual Care Estradiol Estradiol +Sequential MPA

WELL-HART: Change in Minimal Luminal Diameter


Pro

gre

ssio

n

P = NS

n = 76 n = 76n = 74

Section 3f:

Papworth HRT

Atherosclerosis Study

(PHASE)

Papworth HRT Atherosclerosis Study (PHASE)

Study Design:Randomized, prospective trial

Subjects:Postmenopausal women with one or more coronary stenoses 50%; mean age, 66 to 67 years

Intervention:Transdermal estradiol 80 for 14 daysTransdermal estradiol 80/norethisterone 120 for 14 days(all doses g/patch/day) (n = 134)

Placebo control (n = 121)

Mean Follow-up:30.8 months

1° Outcome:Proven MI, cardiac death, or admission to hospital with unstable angina

Clarke SC, et al. Br J Obstet Gynecol. 2002;109:1056-62.

0.0

0.1

0.2

0.3

0.4

0 1 2 3 4 5

Incidence of Cardiac Events With Transdermal Estradiol and Norethisterone: PHASE Results

Event rate ratio: 1.29 (95% Cl, 0.84–1.95; P = .24)Clarke SC, et al. Br J Obstet Gynecol. 2002;109:1056-62. Used with permission from Blackwell Publishing.

Pro

po

rtio

n o

f P

ati

ents

W

ith

Ev

en

t

Time After Recruitment (years)

14%

19%

20%

27%29%

34%

E+P Group (n = 134)

Control Group (n = 121)

Intention-to-Treat Analysis

Section 3g:

Estrogen in the Prevention of

Atherosclerosis Trial

(EPAT)

IMT = intima-media thickness.Hodis HN, et al. Ann Intern Med. 2001;135:939-53.

Estrogen in the Prevention of Atherosclerosis Trial (EPAT)

Study Design Randomized, double-blind, placebo-controlled trial 222 apparently healthy postmenopausal women

(mean age, ~61 years) No pre-existing CVD and LDL-C levels 130 mg/dL Micronized 17-estradiol (1 mg/d) or placebo

for 2 years Lipid-lowering drugs given if LDL-C exceeded

160 mg/dLPrimary Outcome Rate of change in carotid artery IMT

-0.005

0

0.005

0.01

0.015

0.02

Rat

e o

f IM

T C

han

ge

(mm

/yea

r) PlaceboEstradiol

EPAT: Effect of Estrogens on Carotid IMT

All Subjects (n = 199)

No Lipid-LoweringMedications

(n = 77)

Lipid-LoweringMedications

(n = 122)

Hodis HN, et al. Ann Intern Med. 2001;135:939-53.

P = .045 P = .002 P = .92

EPAT: Summary

Primary finding: women randomized to unopposed micronized 17-estradiol had a significant reduction in the progression of subclinical atherosclerosis compared with women randomized to placebo

The results from EPAT are consistent with the more than 20 observational studies that indicate that postmenopausal women who use E alone have lower rates of CHD than postmenopausal women who do not use E alone

Hodis HN, et al. Ann Intern Med. 2001;135:939-53.

Section 3h:

Women’s Health Initiative

(WHI)

Women’s Health Initiative (WHI)

Study Design:Randomized, double-blind, placebo-controlled trial

Subjects:16,608 postmenopausal women without vasomotor symptoms 50 to 79 years old (mean age, 63.3 years)

Intervention:CEE 0.625 mg + MPA 2.5 mg daily or placebo

Follow-up:5.6 years (average)—terminated early (8.5 years planned)

1° Endpoint:Nonfatal MI or CHD death

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

CEE/MPA Arm

Definition of Endpoints for WHI Primary outcome: CHD events

(nonfatal MI and CHD death) Primary adverse outcome: invasive

breast cancer 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

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

WHI: Baseline Characteristics

*Values are means; †Overall incidence of prior CVD = 7.7%; ‡P = .04 vs CEE/MPA.BMI = body mass index; CABG/PTCA = coronary artery bypass graft/percutaneous transluminal coronary angioplasty.Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33.

CharacteristicCEE/MPA (n = 8506)

Placebo (n = 8102)

Age at screening, years* 63.2 63.3

Prior hormone use, % 26.1 25.6

BMI, kg/m2* 28.5 28.5

Never smokers, % 49.6 50.0

Diabetes, % 4.4 4.4

Hypertension, % 35.7 36.4

Statin use at baseline, % 6.9 6.8

Family history breast cancer, % 16.0 15.3

History of MI, %† 1.6 1.9

History of CABG/PTCA, %† 1.1 1.5‡

Age Groups

Data are number (%) of patients; CEE/MPA and placebo groups were similar.Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33.

WHI: Baseline Characteristics

Age Group at Screening

CEE/MPA (n = 8506)

Placebo (n = 8102)

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)

WHI: Statistical Analyses

Primary analyses: time-to-event analyses based on intention to treat

Outcome comparisons presented as hazard ratios (HR) with nominal and adjusted 95% CIs

Nominal CI (nCI): describes variability in risk estimates that would result from a trial with a single outcome

– Used for primary outcomes (CHD, breast cancer) and global index

Adjusted CI (aCI): variability of risk estimates corrected for multiple comparisons

– Used for all other outcomes


EventOverall

HR

Confidence Intervals

Increased Absolute Risk

per 10,000 Women/Year

Increased Absolute Benefit


95% Nominal

95% Adjusted

CHD 1.29 1.02–1.63 0.85–1.97 7

Strokes 1.41 1.07–1.85 0.86–2.31 8

Breast cancer 1.26 1.00–1.59 0.83–1.92 8

VTE 2.11 1.58–2.82 1.26–3.55 18

Colorectal cancer 0.63 0.43–0.92 0.32–1.24 6

Hip fractures 0.66 0.45–0.98 0.33–1.33 5

Total fractures 0.76 0.69–0.85 0.63–0.92 44

Absolute and Relative Risk or Benefit of CEE/MPA

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

WHI: Statistical Analyses

Cauley JA, et al. JAMA. 2003;290:1729-38; 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 Women's Health Initiative Investigators. JAMA. 2002;288:321-33.

WHI: Revised ResultsAbsolute and Relative Risk or Benefit of CEE/MPA

EventOverall

HR

Confidence Intervals

Increased Absolute Risk


Increased Absolute Benefit


95% Nominal

95% Adjusted

CHD 1.24 1.00–1.54 0.97–1.60 6

Strokes 1.31 1.02–1.68 0.93–1.84 7

Breast cancer 1.24 1.01–1.54 0.97–1.59 8

VTE 2.11 1.58–2.82 1.26–3.55 18

Colorectal cancer 0.63 0.43–0.92 0.32–1.24 6

Hip fractures 0.67 0.47–0.96 0.41–1.10 5

Total fractures 0.76 0.69–0.83 — 47

Year HR 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)

Annualized Percent CHD Events by Year

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

WHI: Revised Results

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.

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: Revised Results

Effect of CEE/MPA on Risk of CHDKaplan-Meier Estimate


HR = 1.24

95% nCI = 1.00–1.54

95% aCI = 0.97–1.60

WHI: Cardiovascular Outcomes


Number of Cases (annualized percentage)

VariableCEE/MPA (n = 8506)

Placebo (n = 8102)

Adjusted HR 95% nCI 95% aCI

CHD 188 (0.39) 147 (0.33) 1.24 1.00–1.54 0.97–1.60

Nonfatal MI

Including silent MI 151 (0.31) 114 (0.25) 1.28 1.00–1.63 0.96–1.70

Excluding silent MI 147 (0.31) 109 (0.24) 1.30 1.01–1.67 0.97–1.74

Death due to CHD 39 (0.08) 34 (0.08) 1.10 0.70–1.75 0.65–1.89

CHD, revascularization, or angina 369 (0.77) 356 (0.79) 1.00 0.86–1.15 0.82–1.22

Congestive heart failure 113 (0.23) 109 (0.24) 0.99 0.76–1.29 0.69–1.42

WHI: Effect of CEE/MPA on Risk of CHD: No Effect of Age, But Possible Effect of 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.

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

Number of Cases of CHD (annualized percentage)

Subgroup CEE/MPA Placebo

Age (years)

50–59 37 (0.22) 27 (0.17)

60–69 75 (0.35) 68 (0.34)

70–79 76 (0.78) 52 (0.55)

Years Since Menopause

<10 31 (0.19) 34 (0.22)

10–19 63 (0.38) 51 (0.32)

20 74 (0.75) 44 (0.46)

WHI: Effect of CEE/MPA on Risk of CHD by Body Mass Index, Statin Use, and Aspirin Use

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.

0.5 1.0 1.5 2.0 2.5


0.99

1.27

1.14

1.27

1.23

1.38

Number of Cases of CHD (annualized percentage)

Subgroup CEE/MPA Placebo

Body mass index (kg/m2)

<25.0 53 (0.36) 37 (0.27)

25.0–29.9 64 (0.38) 53 (0.33)

≥30.0 71 (0.44) 57 (0.38)

Statin use

Yes 24 (0.78) 23 (0.80)

No 164 (0.36) 124 (0.29)

Aspirin use (≥80 mg/day)

Yes 48 (0.53) 41 (0.46)

No 140 (0.36) 106 (0.29)

1.16

WHI: Effect of CEE/MPA on Risk of CHD by Baseline Lipid Levels

The dotted vertical line indicates the overall CHD odds ratio.Manson JE, et al. N Engl J Med. 2003;349:523-34.

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0


0.76

1.28

2.03

1.43

0.86

1.68

1.86

1.50

0.88

Number of Cases of CHD

P-Value for InteractionBiomarker CEE/MPA Placebo

Total cholesterol .07

<208 mg/dL 22 25

208–242 mg/dL 49 25

>242 mg/dL 51 32

LDL cholesterol .01

<126 mg/dL 24 21

126–155 mg/dL 41 23

>155 mg/dL 51 34

HDL cholesterol .20

<47 mg/dL 60 40

47–58 mg/dL 36 21

>58 mg/dL 25 20

0.5 1.0 1.5 2.0 2.5 3.0

WHI: Effect of CEE/MPA on Risk of CHD by Baseline Triglycerides and C-Reactive Protein

The dotted vertical line indicates the overall CHD odds ratio. No interaction between subgroups was significant.Manson JE, et al. N Engl J Med. 2003;349:523-34.


1.24

1.63

1.36

1.44

1.56

1.08

Number of Cases of CHD

Biomarker CEE/MPA Placebo

Triglycerides

<109 mg/dL 28 17

109–168 mg/dL 46 31

>168 mg/dL 48 34

C-reactive protein

<1.28 mg/L 25 16

1.28–3.57 mg/L 50 26

>3.57 mg/L 45 37

Timing of Initiation

WHI: Effect of CEE/MPA on CHD in Postmenopausal Women


0 1.0 2.5

Yes

No

Hazard Ratio (95% CI)

0.5 1.5 2.0

Hot Flushes in Women 50–59 Years Old

0.95

1.98

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: Estimates of Cumulative Hazard

for Strokes

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

CEE/MPA

Placebo

0

0.1

0.2

0.3

0.4

0.5

1 2 3 4 5 6+

Str

ok

e E

ve

nts

(a

nn

ua

lize

d %

)

CEE/MPA

Placebo

WHI: Effect of CEE/MPA on Annualized Percent of Stroke Events

Year of Follow-Up


HR = 1.3195% nCI = 1.02–1.6895% aCI = 0.93–1.84

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

0.1 0.5 1.0 5.02.0

WHI: Effect of CEE/MPA on Hemorrhagic Stroke and Ischemic Stroke

Hemorrhagic Stroke

Ischemic Stroke

Hazard Ratio

WHI: Study Considerations

Average age at screening was 63 years

Study stopped when two thirds of patients were 68 years or older

High rates of discontinuation in the CEE/MPA group (42%) and crossover to active treatment in the placebo group (10.7%)

Women with moderate or severe menopausal symptoms were discouraged from participating

Results do not necessarily relate to lower dosages of these drugs or other formulations or routes of administration

0

5

10

15

20

25

40–44 45–49 50–54 55–59 60–64 65–69 70–74 75+

E Alone E+P

Prevalence of Current Use of HT Among Women 40 Years of Age With No History

of Hysterectomy

Cu

rre

nt

Us

er (

%)

Age (years)n = 9400.Brett KM, Reuben CA. Obstet Gynecol. 2003;102:1240-9.

United States, 1999

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

22 24 27 >29

RH

fo

r C

VD

BMI (kg/m2)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

WHI*

RH

for C

VD

The Effect of Body Mass on the Risk of CHD: Putting the WHI Results in Perspective

RH = relative hazard.*Mean BMI 28.5 kg/m2.BMI data from Willett WC, et al. JAMA. 1995;273:461-5.WHI data from Manson JE, et al. N Engl J Med. 2003;349:523-34.

WHI: Surprises?

None except for CHD

No surprise for CHD if WHI is considered a secondary prevention trial (consistent with HERS and other data)

All-Cause Mortality Was Not Affected by E+P in WHI or HERS

0

0.05

0.1

0.15

0 1 2 3 4 5 6 7

Time (years)

Cu

mu

lati

ve H

azar

d

E+P Placebo

HR = 0.98P = NS

WHI (cumulative hazard)

0

5

10

15

0 1 2 3 4 5

Follow-up, Years (number at risk)

Inci

den

ce (

%)

E+P Placebo

HERS (incidence %)

P = NS

Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33. ©2002 American Medical Association. All rights reserved.Hulley S, et al. JAMA. 1998;280:605-13. ©1998 American Medical Association. All rights reserved.

Relative Risk of CHD: Nurses’ Health Study (NHS) Versus WHI

wy = woman-years.Grodstein F, et al. Ann Intern Med. 2000;133:933-41; Manson JE, et al. N Engl J Med. 2003;349:523-34.

NHS

Never-Users(358,125 wy)

E Alone(175,140 wy)

E+P(90,063 wy)

WHI

Placebo(42,130 wy)

E+P(42,312 wy)

0.5 1.0 5.02.0

95% aCI

Risk Estimate

95% nCI

Relative Risks in the NHS and the WHI

*HT vs placebo; †Current use vs never use.Manson JE, et al. N Engl J Med. 2003;349:523-34; Grodstein F, et al. Ann Intern Med. 2000;133:933-41; Colditz GA, et al. N Engl J Med. 1995;332:1589-93; Kiel DP, et al. N Engl J Med. 1987;317:1169-74; Grodstein F, et al. Ann Intern Med. 1998;128:705-12; Torgerson DJ, Bell-Syer SEM. JAMA. 2001;285:2891-7; Grodstein F, et al. N Engl J Med. 1997;336:1769-75; Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321-33.

CHD

Risk Estimate0.5 1.0 5.02.0

NHS†

Hip Fractures

Stroke

Pulmonary Embolism

WHI*

Breast Cancer

Colon Cancer

Meta-analysis

Disease Incidence* Among Women Not Using HT in Recent Studies

*Incidence rates are expressed as events per 10,000 person-years. 1Manson JE, et al. N Engl J Med. 2003;349:523-34; 2Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33; 3Wassertheil-Smoller S, et al. JAMA. 2003;289:2673-84; 4Grodstein F, et al. Ann Intern Med. 2000;133:933-41; 5Grodstein F, et al. Lancet. 1996;348:983-7.

0

5

10

15

20

25

30

35

Acute MI Stroke

Inci

den

ce R

ate

WHI

NHS

1–3

4,5

Baseline Characteristics: NHS Versus WHI

*34.1% had BMI 30 kg/m2.1Grodstein F, et al. Ann Intern Med. 2000;133:933-41; 2Grodstein F, et al. N Engl J Med. 1996;335:453-61; 3Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321-33.

NHS1,2 WHI3

Mean age or age range at enrollment (years) 30–55 63

Smokers (past and current) 6.9% 49.9%

BMI (mean) 25.1 kg/m2 28.5 kg/m2*

Aspirin users 43.9% 19.1%

HT regimenunopposed or

sequentialcontinuous-combined

Menopausal symptoms (flushing) predominant uncommon

Summary of Differences Between Observational and Clinical Trial Participants

Observational Clinical Trials

Menopausal symptoms

Most users have symptoms

Few with symptoms

Age started HT 30–55 years 63 years (WHI)67 years (HERS)

Time since menopause

<5 years ~14 years (WHI)~18 years (HERS)

Stage of atherosclerosis

Fatty streaks and plaques

Advanced plaques

Section 4:Timing of HT Initiation


The Challenge How can we integrate the findings of all of the

published studies into one consistent concept?

A Hypothesis The timing of initiation of HT in relation to the

development of atherosclerosis has a major impact on its potential efficacy

What Do Recent Randomized Studies Have in Common?

They all involve the initiation of HT in older women (age 64 to 67 years)

They have not tested whether HT has primary cardiovascular prevention effects as defined by vascular biologists

1Clarkson TB, et al. J Clin Endocrinol Metab. 1998;83:721-6; 2Adams MR, et al. Arterioscler Thromb Vasc Biol. 1997;17:217-21; 3Clarkson TB, et al. J Clin Endocrinol Metab. 2001;86:41-7; 4Williams JK, et al. Arterioscler Thromb Vas Biol. 1995;15:827-36.

Effect of E Alone on Coronary Atherosclerosis in Monkeys: Timing of Initiation

Premenopausal Years Postmenopausal YearsOvariectomy

Plaque Area (% of placebo)

Time

Healthy diet CEE + atherogenic diet1. 70%1,2

Atherogenic diet CEE + atherogenic diet2. 50%3

Healthy dietAtherogenic

dietHealthy diet

+ CEE3. 0%4

~ 6 Year Human Equivalent

Placebo CEE

Co

ron

ary

Art

ery

Pla

qu

e S

ize

(m

m2)

0.10

0.20

0.30

0.40

0Baseline Placebo CEE CEE+MPA

A. Early Intervention B. Late Intervention*

P < .05

P = NS

Effect of HT on Coronary Atherosclerosis in Monkeys: Timing of Initiation of HT

*Comparable to approximately 6 patient-years after menopause.Karas RH, Clarkson TB. Menopausal Med. 2003;10:8-12.

Effect of the Extent of Preexisting Atherosclerosis on Effectiveness of CEE Treatment of Surgically

Postmenopausal Cynomolgus Monkeys

-0.30

-0.25

-0.20

-0.15

-0.10

-0.05

0.00

Pla

qu

e S

ize

Co

mp

are

d

Wit

h P

lace

bo

(m

m2)

High Moderate Low

P = .71

P = .33

P = .0001

Tertile of Initial Plaque Burden

Karas RH, Clarkson TB. Menopausal Med. 2003;10:8-12.

0123456789

10

4 10 16 22 28 34 40

Weeks

Nu

mb

er

of

Mic

e W

ith

Le

sio

ns

Iliac –EstradiolIliac +Estradiol

New Lesions Established Lesions

Estrogen Inhibits Initiation but not Progression of Established Lesions in Mice

Rosenfeld ME, et al. Atherosclerosis. 2002;164:251-9.

0123456789

10

4 10 16 22 28 34 40

Weeks

Nu

mb

er

of

Mic

e W

ith

Le

sio

ns

Carotid –EstradiolCarotid +Estradiol

2.0

2.5

3.0

3.5

4.0

4.5

5.0 No HT

Any HT

HT Vasodilates Only in Women Without Cardiovascular Risk Factors

RFs = risk factors; Ds = diseases; Meds = medications.Herrington DM, et al. Arterioscler Thromb Vasc Biol. 2001;21:1955-61.

Ch

ang

e in

Dia

met

er (

%)

No CV RFs, Ds, or Meds

Any CV RFs,Ds, or Meds

P = .01

P = .44

Importance of Intima-Media Thickness (IMT) on the Effect of HT

-0.006

-0.004

-0.002

0.000

0.002

0.004

0.006

0.008

0.010

0.012

0.014

IMT

Ch

ang

e (m

m/y

r)

-0.004

-0.002

0.000

0.002

0.004

0.006

0.008

0.010

0.012

0.014

IMT

Ch

ang

e (m

m/y

r)

P = .32P < .05

Estradiol(n = 97)

CEE+MPA(n = 177)

Placebo(n = 102)

Placebo(n = 185)

Byington RP, et al. Arterioscler Thromb Vasc Biol. 2002;22:1692-7.Hodis HN, et al. Ann Intern Med. 2001;135:939-53.

HERS (baseline IMT, 1.193 mm)

EPAT (baseline IMT, 0.764 mm)

-4

-2

0

2

4

6

8

<100 100–400 >400

Pe

rce

nt

Dif

fere

nc

e*

(95

% C

I)Percent Difference in Distribution

of the Coronary Artery Calcium Score in HT Versus Non-HT Groups

Coronary Artery Calcium Score*Percent difference in distribution of the coronary artery calcium score in HT versus non-HT groups.Odds ratio for a coronary artery calcium score >400: 0.5; P = .02.Akhrass F, et al. J Clin Endocrinol Metab. 2003;88:5611-4.

Odds Ratio for Coronary Artery Calcium Score >400

Non-HT

Hazard Ratio

0.1 0.5 1.0 5.02.0

HT

P = .02Akhrass F, et al. J Clin Endocrinol Metab. 2003;88:5611-4.

Incidence of Carotid Artery Plaque by Menopausal Status and Duration

0

10

20

30

40

50

60

Ag

e-S

tan

dar

diz

ed I

nci

den

ce R

ate

(per

100

0 p

erso

n-y

ears

)

>10 Men1–5 5–10Postmenopausal (years)

Premenopausal

Kiechl S, Willeit J. Arterioscler Thromb Vasc Biol. 1999;19:1484-90.

The Bruneck Study

Relation of Years Since Menopause to Stage of Progression of Coronary Artery Atherosclerosis

Adventitia

Media

Fatty Streak/Plaque

InternalElastic

Lamina

Necrotic Core

Plaque

FibrousCap

FibrousCap

Plaque Necrotic Core

Plaque

FibrousCap

MMP-9

Years Postmenopause: 0–5 5–15 >15

No HTHypothetical Pathogenetic Sequence

Adventitia

Media

Fatty Streak/Plaque

InternalElastic

Lamina

Necrotic Core

Plaque

FibrousCap

FibrousCap

Plaque Necrotic Core

Plaque

FibrousCap

MMP-9

HT Early & Continued

HT Late

HT

Age 35–45 years Age 45–55 years Age 55–65 years Age >65 years

HT

Mural Thrombus

Relation of Years Since Menopause in WHI to Stage of Progression of Coronary Artery Atherosclerosis

Adventitia

Media

InternalElastic

Lamina Plaque

FibrousCap

FibrousCap

Plaque

FibrousCap

MMP-9

5 to <1019%Years Postmenopause 10 to <15

21%≥1543%

<517%

Fatty Streak/Plaque

Necrotic CorePlaque Necrotic Core

Estrogen Effects on the Natural History of AtherosclerosisAdventitia

Media

InternalElastic

Lamina Plaque

FibrousCap

FibrousCap

Plaque

FibrousCap

MMP-9

Estrogen Effects in AtherogenesisLDL oxidation LDL atherogenicityLDL binding/accum lesion

progressionCAMs monocyte adhesion/

macrophage accumulation

SMC proliferation lesion progressionEndothelial function vasodilation

Estrogen Effects in Established PlaquesInflammation PQ instability

lesion progressionMMP expression PQ instability/ruptureNeovascularization PQ hemorrhage

Loss of Estrogen Benefits Expression of estrogen receptors Vascular responsivity

Benefits of estrogen on atherosclerosis prevention

Potentially adverse effects ofestrogen on atherosclerosis/CHD

PlaqueFatty Streak/Plaque

Necrotic Core Necrotic Core

Mea

n C

han

ge

Fro

m B

asel

ine

in %

CR

P C

on

cen

trat

ion

s

-20

0

20

40

60

80

100

Oral CEE TransdermalEstradiol

Oral CEE TransdermalEstradiol

Comparison of CRP Increases in Postmenopausal Women Treated With

Oral CEE or Transdermal Estradiol

6 Months 12 MonthsCRP = C-reactive protein.Decensi A, et al. Circulation. 2002;106:1224-8.

Relative Risk of Future Cardiovascular Events According to Baseline CRP in

the Women’s Health Study

0

1

2

3

4

5

6

1 2 3 4 5

Rel

ativ

e R

isk

of

Fir

st

Car

dio

vasc

ula

r E

ven

t

HT Nonusers HT Users

Baseline Quintile of CRP

Ridker PM, et al. N Engl J Med. 2002;347:1557-65.

90

100

110

120

130

140

150

0.0

0.1

0.2

0.3

0.4

0.5

0.6

Pla

sm

a C

RP

(n

g/m

L)

Control CEE Control CEE

Co

ron

ary A

rtery A

the

rosc

leros

isP

laqu

e S

ize (mm

2)

P = .028 P < .05

Lack of Effect of Increased CRP on the Coronary Artery Atheroprotective Effect of CEE in Surgically

Postmenopausal Micropigs

Goodrich JA, et al. Fertil Steril. 2003;79:779-88.

The Pathophysiology of Plaque Rupture

Heistad DD. N Engl J Med. 2003;349:2285-7.

Metalloproteinase Staining and Gelatinolytic Activity of Human Coronary

Artery Atherosclerotic Plaques

Galis ZS, et al. J Clin Invest. 1994;94:2493-503. Used with permission.

0

200

400

600

800

0

500

1000

1500

2000

MM

P-9

(n

g/m

L)

Placebo E+P Placebo E+P

Ge

latino

lytic A

ctivity

(de

ns

itom

etric

un

its)

P = .02 P = .036

Plasma Expression of Matrix Metalloproteinase-9 (MMP-9) and Gelatinolytic Activity of Postmenopausal Women (Average Age,

66 Years) Treated With Either Placebo or E+P*

*0.625 mg CEE and 2.5 mg MPA per day.Zanger D, et al. J Am Coll Cardiol. 2000;36:1797-802.

HT and Plaque Rupture Susceptible Substrate

Incitant

PlaqueRupture

+

Early

Complicated Plaque

MMPHT +

MMPHT

ReactionCatalyst Substrate

Effect of HT on Risk of Nonfatal Acute MI

HT Never-User

HT Ever-User

Chilvers CE, et al. Eur Heart J. 2003;24:2197-205.

Odds Ratio

0.1 0.5 1.0 5.02.0

Effect of Duration of HT Use on Risk of Nonfatal Acute MI

Never Use

Odds Ratio

0.1 0.5 1.0 5.02.0

<12 Months

13–60 Months

>60 Months

HT Use

Chilvers CE, et al. Eur Heart J. 2003;24:2197-205.

Association Between Estrogen Receptor Gene Variation and MI in Men

CT or TT Genotype

Hazard Ratio

0.5 1.0 5.02.0

CC Genotype

P < .001.CC = ESR1 c.454-397CC homozygous.CT = ESR1 c.454-397CT heterozygous.TT = ESR1 c.454-397TT homozygous.Shearman AM, et al. JAMA. 2003;290:2263-70.

Northern California Kaiser Permanente Diabetes Registry (1995-1998) Study

Study Design:Observational cohort study

Subjects:25,000 diabetic women 50 years of age identified by the Northern California Kaiser Permanente Diabetes Registry

Follow-up:3 years (1995–1998)

Outcome:Risk of acute MI associated with current use of different HT regimens, estrogen doses, and time since initiation of hormonesFerrara A, et al. Circulation. 2003;107:43-8.

0.1 1.0 10.0

Northern CaliforniaKaiser Permanente Diabetes Registry

*Analyses adjusted for age, ethnicity, education, obesity, diabetes duration, hypoglycemic therapy, HbA 1c, hypertension, lipid-lowering medications, smoking, alcohol, and exercise.Ferrara A, et al. Circulation. 2003;107:43-8.

Association of Current Hormone Use With Risk of MI in Diabetic Women

Women Not Currently Using HT

Women Without Recent MI

Women With Recent MI

Relative Risk* (95% CI)

0.1 1.0 10.0

Relative Risk† (95% CI)

Effect of Estrogen Dose on Risk of MI in Diabetic Women Without A Recent MI

*CEE 0.625 mg/d or estradiol 0.5 mg/d.†Analyses adjusted for age, ethnicity, education, obesity, diabetes duration, hypoglycemic therapy, HbA 1c, hypertension, lipid-lowering medications, smoking, alcohol, and exercise.Ferrara A, et al. Circulation. 2003;107:43-8.


Low Dose

Most Commonly Prescribed Dose*

High Dose

0.1 1.0 10.0

Effect of Time Since Initiation of HT on Risk of MI in Diabetic Women

RH based on comparisons to women with no prior HT and no current HT exposure

Women Without Recent MI<1 Year Since Initiation1 Year Since Initiation

Women With Recent MI<1 Year Since Initiation1 Year Since Initiation


Relative Risk* (95% CI)

*Analyses adjusted for age, ethnicity, education, obesity, diabetes duration, hypoglycemic therapy, HbA 1c, hypertension, lipid-lowering medications, smoking, alcohol, and exercise.Ferrara A, et al. Circulation. 2003;107:43-8.

Glycemic Effects of HT: Results From HERS

2029 HERS participants with coronary disease who were not diabetic at enrollment were followed for incident diabetes and fasting glucose levels

Fasting glucose levels did not change among the E+P group but increased significantly among women assigned to placebo

The risk for incident diabetes was significantly reduced by 35% in the E+P group (RH, 0.65; 95% CI, 0.48–0.89)

Kanaya AM, et al. Ann Intern Med. 2003;138:1-9.

Recommended Therapies for Cardiovascular Treatment in Women

Statins

Aspirin

Angiotensin-converting enzyme inhibitors

Beta-blockers

Therapeutic lifestyle change

Section 5:Summary and Conclusions


Mosca L, et al. Circulation. 2001;104:499-503; Mendelsohn ME, Karas R. Circulation. 2001;104:2256-9.

Summary of Cardiovascular Effects of HT in Women

Large deficit in public awareness that heart disease is leading cause of mortality in women

More than 20 observational studies in younger postmenopausal women support the conclusion that HT has cardiovascular benefit in postmenopausal women

Data from the randomized controlled trials of older postmenopausal women have not supported the observational data

Current Perspectives on HT in Women

Potential of cardiovascular benefits may be decreased by

– Time since menopause

– Presence of diabetes and other risk factors

– Presence of subclinical atherosclerosis

– Concomitant event reducing therapies

Initiation and continuation of HT should be based on approved indications (ie, treatment of hot flushes and osteoporosis prevention)

Mosca L, et al. Circulation. 2001;104:499-503; Mendelsohn ME, Karas R. Circulation. 2001;104:2256-9.

Major Unresolved Issues

What is the effect of early initiation of HT on CVD endpoints?

Why haven’t recent clinical studies demonstrated cardiovascular benefit despite improvements in surrogate endpoints?

What are the differences between different formulations of E+P or E alone?

Are there particular patient populations who are likely to benefit or who are prone to harm?

cardiovascular health and menopause a cme slide library from the council on hormone education

Documents

menopause slide

menopause section

framingham study slide

postmenopausal women

hormone education slide

introduction section

cme slide library

women age years n