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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
Società Italiana per lo Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
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
Sez. Regionale Lombarda
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
Società Italiana per lo Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
Società Italiana per lo Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
EFFECTS OF ORAL ESTROGENS ON SERUM LIPOPROTEINS IN POSMENOPAUSAL WOMEN
BRANCHI A., 1998
0
50
100
150
200
250
mg
/dL
Total C LDL-C HDL-C TGL
Run-in Baseline 3 months
0
50
100
150
200
250
mg
/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
Società Italiana per lo Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
Società Italiana per lo Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
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
Società Italiana per lo Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
RELATIVE RISK AND 95% CI FROM STUDIES OF ESTROGEN USE TO PREVENT CHD
STAMPFER, NEJM, 1991
Società Italiana per lo Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
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
Sez. Regionale Lombarda
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.
Società Italiana per lo Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
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
Società Italiana per lo Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
HEART AND ESTROGEN/PROGESTIN REPLACEMENT STUDY (HERS)
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
Società Italiana per lo Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
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
15
0 1 2 3 4 5
0
5
10
15
0 1 2 3 4 5
0
5
10
15
0 1 2 3 4 5
0
5
10
15
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
HEART AND ESTROGEN/PROGESTIN REPLACEMENT STUDY (HERS)
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
Società Italiana per lo Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
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.
Società Italiana per lo Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
Società Italiana per lo Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
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
Società Italiana per lo Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
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
Società Italiana per lo Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
NON CHD OUTCOMES DURING 6.8 YEARS OF HORMONE THERAPY (HERS II) 1
Events HRT Placebo Relative Risk
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
Società Italiana per lo Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
NON CHD OUTCOMES DURING 6.8 YEARS OF HORMONE THERAPY (HERS II) 2
Events HRT Placebo Relative Risk
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
Società Italiana per lo Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
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
Società Italiana per lo Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
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
Società Italiana per lo Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
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
Società Italiana per lo Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
WHI: CLINICAL OUTCOMES 2
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
Società Italiana per lo Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
WHI: CLINICAL OUTCOMES 3
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
Società Italiana per lo Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
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
Società Italiana per lo Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
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
Società Italiana per lo Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
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
Società Italiana per lo Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
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
Società Italiana per lo Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
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
Società Italiana per lo Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
HORMONAL REPLACEMENT THERAPY (WHEN TO BE USED)
• Menopausal symptoms (vasomotor, urogenital or vaginal atrophy, mood disturbance)
• High risk of osteoporosis
• Early menopause