società italiana per lo studio dell aterosclerosi sez. regionale lombarda death due to chd in the...

Società Italiana per lo Studio dell’ Aterosclerosi

Sez. Regionale Lombarda

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WomenMenDEATH DUE TO CHD IN THE USA IN 1986

BUSH, ANN NY ACAD SCI,1990

PROCAM (MÜNSTER HEART STUDY): MENOPAUSE AND LIPID RISK FACTORS

IN 45 TO 55 YEARS OLD WOMEN

Pre-Menopause Menopause P

(n = 1537) (n = 2456)

age (years) 48.3 ± 2.8 51.0 ± 3.0 < 0.001BMI (kg/m2) 25.8 ± 4.3 26.4 ± 4.5 < 0.001cholesterol (mg/dL) 221 ± 39 239 ± 41 < 0.001triglycerides (mg/dL)* 88 99 < 0.001

LDL-C (mg/dL) 143 ± 36 158 ± 38 < 0.001HDL-C (mg/dL) 59 ± 15 59 ± 16 n.s.chol./HDL-C ratio 4.02 ± 1.25 4.31 ± 1.32 < 0.001 *: geometric mean, n.s.: not significant

PROCAM (MÜNSTER HEART STUDY): MENOPAUSE AND HEMOSTATIC RISK FACTORS

IN 45 TO 55 YEARS OLD WOMEN

Pre-Menopause Menopause P (n = 229) (n = 307)

fibrinogen (mg/dL) 265 ± 50 276 ± 56 < 0.001D-dimer (mg/l)* 321 345 n.s.factor VIIc (mg/dL) 108 ± 26 120 ± 34 < 0.001protein C (%) 111 ± 19 120 ± 24 < 0.001plasminogen (%) 104 ± 14 106 ± 14 < 0.05PAI-1 (U/l) * 2.22 2.48 < 0.05vWF (%) 103 ± 35 96 ± 31 n.s.CRP (mg/dL)* 0.32 0.28 < 0.05

*: geometric mean



MAJOR RISK FACTORS FOR CHD

AGE > 45 Y MALES AND > 55 Y FEMALESFamily history of MI or sudden death: < 55 males < 65

femalesCigarettes smokeElevated blood pressureHDL-C < 35 mg/dLDiabetes mellitus

HDL-C > 60 mg/dL

NATIONAL CHOLESTEROL EDUCATION PROGRAM.CIRCULATION 1994;89:1329-445.

POSTMENOPAUSAL ESTROGEN/PROGESTIN INTERVENTIONS TRIAL (PEPI)

• 875 HEALTHY POST-MENOPAUSAL WOMEN AGE 45-64• PARALLEL INTERVENTION GROUPS:

PlaceboCEE 0.625 mg/dCEE 0.625 mg/d + MPA 10 mg/d x 12 d/moCEE 0.625 mg/d + MPA 2.5 mg/dCEE 0.625 mg/d + MP 200 mg/d x 12 d/mo

• ENDPOINTS:HDL-CSystolic blood pressureFibrinogenInsulin

JAMA 1995;273:199Società Italiana per lo Studio dell’ Aterosclerosi


PEPI TRIAL RESULTS

• LIPOPROTEINS:– HDL-C increased in all active treatments (Greatest with CEE

and CEE + MP)– LDL-C decreased equally in all treatment groups– Triglycerides increased equally in all treatment groups

• SYSTOLIC BLOOD PRESSURE: increased similarly in all treatment groups

• INSULIN: no difference in fasting or 2-hour insulin among all treatment groups

• FIBRINOGEN: no difference among active treatment groups

JAMA 1995;273:199





EFFECTS OF ORAL ESTROGENS ON SERUM LIPOPROTEINS IN POSMENOPAUSAL WOMEN

BRANCHI A., 1998

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/dL

Total C LDL-C HDL-C TGL

Run-in Baseline 3 months

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100

150

200

250

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/dL

Total C LDL-C HDL-C TGL

Oral Transdermal-5%

-15% +37%

Run-in Baseline 3 months

PEPI Trial Results

• LIPOPROTEINS:– HDL-C increased in all active treatments (Greatest with CEE

and CEE + MP)– LDL-C decreased equally in all treatment groups– Triglycerides increased equally in all treatment groups

• SYSTOLIC BLOOD PRESSURE: increased similarly in all treatment groups

• INSULIN: No difference in fasting or 2-hour insulin among all treatment groups

• FIBRINOGEN: No difference among active treatment groups

JAMA 1995;273:199





ANTIATHEROGENE PROPERTILE OF ESTROGENS

• Reduced proliferation of SMC and neo intima formation

• Reduced production of collagen and elastin

• Modulation of vasomotor response

• Increased coronary responsed to vasodilatory stimuli

• Increased prostacyclyn production by SMC

• Reduction of plasma homocysteine levels



RELATIVE RISK AND 95% CI FROM STUDIES OF ESTROGEN USE TO PREVENT CHD

STAMPFER, NEJM, 1991



THE NURSES HEALTH STUDY: CHD RISK AND POSTMENOPAUSAL ESTROGEN + PROGESTIN USE

• 59,337 women, age 30-55, followed for 16 years

• Relative risk for CHD events in current estrogen users was 0.60, and current estrogen + progestin users was 0.39

• Length of HRT did not change risk reduction

• Estrogen doses of 0.3 and 0.625 mg had the greatest benefit

• Women 60-71 years old had as much benefit as younger women

NEJM 1996;335:453Società Italiana per lo Studio dell’ Aterosclerosi


ESTROGEN REPLACEMENT IN POSTMENOPAUSAL WOMEN: NCEP RECOMMENDATIONS

• Observational information suggests lower CHD risk in women on HRT

• Experimental data suggests estrogen has beneficial effects on endothelial function

• Oral estrogen can lower LDL-C and increase HDL-C

• NCEP recommends that estrogen replacement can be used as alternative or adjunctive treatment to manage hypercholesterolemia in postmenopausal women.



HEART AND ESTROGEN/PROGESTIN REPLACEMENT STUDY (HERS)

• Randomized, placebo-controlled trial of E/P therapy vs. placebo in 2,763 women with CHD; average age 67 years

• Treatment was 0.625 mg CEE* + 2.5 mg medroxyprogesterone daily for 4 years

• Primary endpoint: nonfatal MI and CHD death

• Secondary endpoints: CABG, PTCA, unstable angina, CHF, PVD, TIA

*CEE = conjugated equine estrogen;

JAMA 1998;280:605-613




CHANGES IN LIPID LEVELS AT 1 YEAR

-20

-15

-10

-5

0

5

10

15

LDL-C HDL-C TG

Mean

% c

han

ge f

rom

baselin

e

Placebo

Estrogen/progestin

*P < 0.001HULLEY S ET AL. JAMA 1998;280:605–613

-3

-14*

-2

8*10*

2



THE HEART AND ESTROGEN/PROGESTIN REPLACEMENT STUDY (HERS) INCIDENCE OF CHD

EVENTS IN TREATMENT AND PLACEBO GROUPS

Follow-up (years)HULLEY ET AL. JAMA 1998; 280:605-613

0

5

10

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0 1 2 3 4 5

0

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0 1 2 3 4 5

0

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0 1 2 3 4 5

0

5

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20

25

0 1 2 3 4 5

Placebo (n=1383)Estrogen/Progestin(N=1380)

CHD Death +Nonfatal MI

Nonfatal MI

CHD Death

Coronary Revascularisation or Unstable Angina

Incid

en

ce (

%)

RH = 0.99p = 0.91

RH = 0.99p = 0.46

RH = 1.24p = 0.23

RH = 0.88p = 0.15


CUMULATIVE INCIDENCE OF PRIMARY CHD EVENTS

15

10

5

00

(2,763)1

(2,631)2

(2,506)3

(2,392)4

(1,435)5

(113)

Incid

en

ce (

%)

Follow-up, y (No. at risk)

Estrogen/progestin

Placebo

Hulley S et al. JAMA 1998;280:605–613



SIDE-EFFECTS IN HERS STUDY

HULLEY ET AL. JAMA 1998; 280:605-613

Side-effects

confirmed venous thrombosis

deep vein thrombosis

pulmonary embolus

fatal pulmonary

Embolus

gallbladder disease

oestrogen/

progestin(n=1380)

34

25

11

2

84

placebo

(n=1383)

12

8 4

0

62

relative

risk

2.3

3.1

2.8

-

1.4

P value

0.002

0.004

0.08

-

0.05

JAMA 1998;280:605-613

HERS RESULTS

• No statistically significant difference between HRT • and placebo in both primary and secondary endpoints after

4 years.• Within first year, greater incidence in CHD events in HRT

group. In years 3 and 4, lower CHD events in HRT group compared to placebo.

• HRT lowered LDL 11% and increased HDL 10% compared to placebo.

• Approximately 50% of randomized women were on lipid-lowering drugs.

• Higher incidence of VTE and cholelithiasis in HRT group.





CHD OUTCOMES DURING 6.8 YEARS OF HORMONE THERAPY (HERS II)

• The higher risk of developing CHD in HERS was in the first two years of therapy. A decline occured between year 3 and 5.

• HERS II was designed to verify whether the tendency to a reduction of CHD in HERS persisted in a longer follow up.

• The HERS II study recruited 2.321 women (average 67 yearsof age) who gave their informed consent to continue therapy with the active drug or placebo.

GRADY ET AL., JAMA 2002



CHD OUTCOMES DURING 6.8 YEARS OF HORMONE THERAPY (HERS II)

Events HRT Placebo Relative Risk

95% CI

CHD HERS HERS II

179 111

182 111

0.99 1.00

0.81-1.22 0.77-1.29

CHD death HERS HERS II

70 62

59 63

1.20 0.99

0.85-1.69 0.70-1.41

CHD non fatal HERS HERS II

122 61

134 62

0.92 0.98

0.72-1.17 0.69-1.40

JAMA, 2002



NON CHD OUTCOMES DURING 6.8 YEARS OF HORMONE THERAPY (HERS II) 1


95% CI

Thromboembolic events HERS HERS II

34 15

13 11

2.66 1.40

1.41-5.04 0.64-3.05

Breast cancer HERS HERS II

34 15

25 14

1.38 1.08

0.82-2.31 0.52-2.24

All tumors HERS HERS II

101 58

91 44

1.13 1.34

0.85-1.49 0.90-1.98

JAMA, 2002



NON CHD OUTCOMES DURING 6.8 YEARS OF HORMONE THERAPY (HERS II) 2


95% CI

Biliary surgry HERS HERS II

85 40

62 24

1.39 1.70

1.00-1.93 1.03-2.83

Hip fracture HERS HERS II

15 25

13 12

1.16 2.11

0.55-2.44 1.06-4.19

All fractures HERS HERS II

140 90

148 74

0.96 1.22

0.76-1.20 0.89-1.65

JAMA, 2002



RISK AND BENEFITS OF ESTROGEN PLUS PROGESTIN IN HEALTHY POSTMENOPAUSAL WOMEN

Principal Results from the Women’s Health Initiative Randomized Controlled Trial

• A randomized controlled primary prevention trial (planned duration 8.5 years) in which 16,608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998

• Participants received conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d or placebo

JAMA, 2002



8,506 assigned to Estrogen+Progestin

8,102 assigned to placebo

Status on April 30, 2002•7,968 alive

•307 unknown vital status•231 deceased

Status on April 30, 2002•7,608 alive•276 unknown vital status•218 deceased

PROFILE OF THE ESTROGEN+PROGESTIN COMPONENT OF THE WOMEN’S HEALTH INITIATIVE

373,092 women initiated screening

18,845 provided consent and reported no isterectomy

16,608 randomized



WHI: CLINICAL OUTCOMES 1

Cardiovascular diseases HRT Placebo Hazard ratio

95% CI

CHD 164 122 1.29 1.02-1.63

CABG/ PTCA 183 171 1.04 0.84-1.28

Stroke 127 85 1.41 1.07-1.85

Venous Thromboembolic disease

151

67

2.11

1.58-2.82

Total cardiovascular disease

694

546

1.22

1.09-1.36

JAMA, 2002




Cancer HRT Placebo Hazard ratio

95% CI

Invasive breast 166 124 1.26 1.00-1.59

Endometrial 22 25 0.83 0.47-1.47

Colorectal 45 67 0.63 0.43-0.92

Total 502 458 1.03 0.90-1.17

JAMA, 2002




Fractures

HRT Placebo Hazard ratio

95% CI

Hip 44 62 0.66 0.45-0.98

Vertebral 41 60 0.66 0.44-0.98

Other osteoporotic 579 701 0.77 0.69-0.86

Total 650 788 0.76 0.69-0.85

JAMA, 2002



WHI: CAUSE OF DEATH

HRT Placebo

Cardiovascular 215 201

Breast cancer 3 2

Other cancer 104 86

Other known cause 34 41

Unknown cause 34 41

Total 231 218

JAMA, 2002



CONCLUSIONS

• Overall health risk exceeded benefits from use of combined estrogen+progestin for an average 5.2 year follow-up among healthy postmenopausal women

• Risk for CHD was largely limited to the 1° year of therapy, whereas risk for Stroke and Venous Thromboembolism continued throughout the 5 years of therapy and may reflect prothrombotic and proinflammatory effects of progestins

• Risk for breast cancer was associated with the duration of treatment

• The risk-benefit profile of combined HRT is not consistent with the requirements for primary prevention of chronic diseases



MENOPAUSAL HORMONE REPLACEMENT THERAPY

AND RISK OF OVARIAN CANCER

Study Design: cohort study on 44.241 post menopausas women

Aim: to address whether the estrogen + progestin treatment

could modify the risk of developping ovary cancer

LACEY, JAMA 2002



HORMONAL REPLACEMENT THERAPY AND OVARIAN CANCER

No therapy EstrogensEstrogens+Progestins

Years-person 270.520 179.065 42.400

N° of ovarian cancer

120 116 18

RelativeRisk

1.01.6

(1.2-2.0)1.1

(0.64-1.7)

LACEY, JAMA 2002

INTERVENTION STUDIES AIMED AT THE PREVENTION OF CORONARY HEART DISEASE

(SUBGROUPS OF WOMEN)

4S: The Lancet 1994;344:1383-1389Care: Sacks FM et al. N Engl J Med 1996;335:1001-1009AFCAPS/TexCAPS: Downs JR et al. JAMA 1998;279:1615-1622



SIMVASTATIN: SECONDARY ENDPOINTSTATIN worse

Relative Risk IC 95%SIMVA PLACEBOGROUPS(10269) (10267) SIMVA better Placebo better

AGE (YEAR)

Het 23 = 4.4

< 65 838 1093

65 - 69 516 677

70-74 550 628

>75 138 208

GENDER

Het 21= 0.4

Male 1676 2148

Female 366 458

All patients 2042 2606(19.9%) (25.4%)

24%SE 2.6

(2P<0.00001)0.4 0.6 0.8 1.0 1.2 1.4

VASCULAR EVENTS BY AGE AND GENDER



HORMONAL REPLACEMENT THERAPY (WHEN TO BE USED)

• Menopausal symptoms (vasomotor, urogenital or vaginal atrophy, mood disturbance)

• High risk of osteoporosis

• Early menopause

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