Münster Heart Study (PROCAM) Change of Lipoprotein(a) with Aging

DEATH DUE TO CHD IN THE USA IN 1986
40
45
50
55
60
65
70
75
80
85
0
000,01 rep shtaeD
1000
2000
3000
4000
5000
6000
Women
Men
Società Italiana per lo
Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
BUSH, ANN NY ACAD SCI,1990
PROCAM (MÜNSTER HEART STUDY):
MENOPAUSE AND LIPID RISK FACTORS
IN 45 TO 55 YEARS OLD WOMEN
Pre-Menopause
(n = 1537)
Menopause
(n = 2456)
P
age (years)
48.3 ± 2.8
BMI (kg/m2)
25.8 ± 4.3
cholesterol (mg/dL)
221 ± 39
triglycerides (mg/dL)*
88
51.0 ± 3.0
26.4 ± 4.5
239 ± 41
99
<
<
<
<
LDL-C (mg/dL)
HDL-C (mg/dL)
chol./HDL-C ratio
158 ± 38
59 ± 16
4.31 ± 1.32
< 0.001
n.s.
< 0.001
143 ± 36
59 ± 15
4.02 ± 1.25
*: geometric mean, n.s.: not significant
0.001
0.001
0.001
0.001
PROCAM (MÜNSTER HEART STUDY):
MENOPAUSE AND HEMOSTATIC RISK FACTORS
IN 45 TO 55 YEARS OLD WOMEN
Pre-Menopause
(n = 229)
fibrinogen (mg/dL)
D-dimer (mg/l)*
factor VIIc (mg/dL)
protein C (%)
plasminogen (%)
PAI-1 (U/l) *
vWF (%)
CRP (mg/dL)*
*: geometric mean
265 ± 50
321
108 ± 26
111 ± 19
104 ± 14
2.22
103 ± 35
0.32
Menopause
(n = 307)
276 ± 56
345
120 ± 34
120 ± 24
106 ± 14
2.48
96 ± 31
0.28
P
< 0.001
n.s.
< 0.001
< 0.001
< 0.05
< 0.05
n.s.
< 0.05
MAJOR RISK FACTORS FOR CHD
AGE > 45 Y MALES AND > 55 Y FEMALES
Family history of MI or sudden death: < 55 males < 65 females
Cigarettes smoke
Elevated blood pressure
HDL-C < 35 mg/dL
Diabetes mellitus
HDL-C > 60 mg/dL
NATIONAL CHOLESTEROL EDUCATION PROGRAM.
CIRCULATION 1994;89:1329-445.
Società Italiana per lo
Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
POSTMENOPAUSAL ESTROGEN/PROGESTIN
INTERVENTIONS TRIAL (PEPI)
• 875 HEALTHY POST-MENOPAUSAL WOMEN AGE 45-64
• PARALLEL INTERVENTION GROUPS:
Placebo
CEE 0.625 mg/d
CEE 0.625 mg/d + MPA 10 mg/d x 12 d/mo
CEE 0.625 mg/d + MPA 2.5 mg/d
CEE 0.625 mg/d + MP 200 mg/d x 12 d/mo
• ENDPOINTS:
HDL-C
Systolic blood pressure
Fibrinogen
Insulin
JAMA 1995;273:199
Società 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
Società Italiana per lo
Studio dell’ Aterosclerosi
JAMA 1995;273:199
Sez. Regionale Lombarda
EFFECTS OF ORAL ESTROGENS ON SERUM LIPOPROTEINS
IN POSMENOPAUSAL WOMEN
Run-in
Run-in
3 months
Oral
250
250
200
200
-15%
+37%
150
100
50
0
Baseline
3 months
Transdermal
mg/dL
mg/dL
-5%
Baseline
150
100
50
Total C
LDL-C
HDL-C
TGL
0
Total C
LDL-C
HDL-C
TGL
Società Italiana per lo
Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
BRANCHI A., 1998
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
Società Italiana per lo
Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
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
Società Italiana per lo
Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
RELATIVE RISK AND 95% CI FROM STUDIES
OF ESTROGEN USE TO PREVENT CHD
Società Italiana per lo
Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
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;335:453
Società 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;
Società Italiana per lo
Studio dell’ Aterosclerosi
JAMA 1998;280:605-613
Sez. Regionale Lombarda
HEART AND ESTROGEN/PROGESTIN REPLACEMENT
STUDY (HERS)
Mean % change from baseline
CHANGES IN LIPID LEVELS AT 1 YEAR
15
10*
8*
10
5
2
0
-5
-2
-3
-10
Placebo
-15
Estrogen/progestin
-20
-14*
LDL-C
*P < 0.001
HULLEY S ET AL. JAMA 1998;280:605–613
HDL-C
TG
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
15
CHD Death +
Nonfatal MI
10
Incidence (%)
15
CHD Death
10
RH = 0.99
p = 0.91
5
RH = 1.24
p = 0.23
5
0
Placebo (n=1383)
Estrogen/Progestin
(N=1380)
0
0
15
1
2
3
4
5
0
20
10
15
10
RH = 0.99
p = 0.46
5
2
3
4
5
Coronary
Revascularisation
or Unstable
Angina
25
Nonfatal MI
1
RH = 0.88
p = 0.15
5
0
0
0
1
2
3
4
5
0
1
2
3
4
Follow-up (years)
HULLEY ET AL. JAMA 1998; 280:605-613
5
HEART AND ESTROGEN/PROGESTIN REPLACEMENT STUDY
(HERS)
CUMULATIVE INCIDENCE OF PRIMARY CHD EVENTS
Incidence (%)
15
10
Estrogen/progestin
5
0
Placebo
5
3
4
0
1
2
(2,763)(2,631) (2,506) (2,392) (1,435) (113)
Follow-up, y (No. at risk)
Società Italiana per lo
Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
Hulley S et al. JAMA 1998;280:605–613
SIDE-EFFECTS IN HERS STUDY
Side-effects
confirmed venous thrombosis
oestrogen/
progestin
(n=1380)
placebo
(n=1383)
34
12
relative
risk
P value
2.3
0.002
3.1
0.004
2.8
0.08
deep vein thrombosis
25
pulmonary embolus
11
8
4
2
0
-
-
84
62
1.4
0.05
fatal pulmonary
Embolus
gallbladder disease
HULLEY ET AL. 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.
JAMA 1998;280:605-613
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.
Società Italiana per lo
Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
GRADY ET AL., JAMA 2002
CHD OUTCOMES DURING 6.8 YEARS OF HORMONE
THERAPY (HERS II)
Events
CHD
HERS
HERS II
CHD death
HERS
HERS II
CHD non fatal
HERS
HERS II
JAMA, 2002
HRT
Placebo
Relative
Risk
95% CI
179
111
182
111
0.99
1.00
0.81-1.22
0.77-1.29
70
62
59
63
1.20
0.99
0.85-1.69
0.70-1.41
122
61
134
62
0.92
0.98
0.72-1.17
0.69-1.40
Società Italiana per lo
Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
NON CHD OUTCOMES DURING 6.8 YEARS OF HORMONE
THERAPY (HERS II) 1
Events
Thromboembolic events
HERS
HERS II
Breast cancer
HERS
HERS II
All tumors
HERS
HERS II
JAMA, 2002
HRT
Placebo
Relative
Risk
95% CI
34
15
13
11
2.66
1.40
1.41-5.04
0.64-3.05
34
15
25
14
1.38
1.08
0.82-2.31
0.52-2.24
101
58
91
44
1.13
1.34
0.85-1.49
0.90-1.98
Società Italiana per lo
Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
NON CHD OUTCOMES DURING 6.8 YEARS OF HORMONE
THERAPY (HERS II) 2
Events
Biliary surgry
HERS
HERS II
Hip fracture
HERS
HERS II
All fractures
HERS
HERS II
HRT
Placebo
Relative
Risk
95% CI
85
40
62
24
1.39
1.70
1.00-1.93
1.03-2.83
15
25
13
12
1.16
2.11
0.55-2.44
1.06-4.19
140
90
148
74
0.96
1.22
0.76-1.20
0.89-1.65
Società Italiana per lo
Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
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
Società Italiana per lo
Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
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
8,506 assigned to
Estrogen+Progestin
Status on April 30, 2002
•7,968 alive
•307 unknown vital status
•231 deceased
8,102 assigned to placebo
Status on April 30, 2002
•7,608 alive
•276 unknown vital status
•218 deceased
Società Italiana per lo
Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
WHI: CLINICAL OUTCOMES 1
Cardiovascular diseases
HRT
Placebo
CHD
164
CABG/PTCA
Stroke
Venous Thromboembolic
disease
Total cardiovascular
disease
JAMA, 2002
122
Hazard
ratio
1.29
95% CI
1.02-1.63
183
171
1.04
0.84-1.28
127
85
1.41
1.07-1.85
151
67
2.11
1.58-2.82
694
546
1.22
1.09-1.36
Società Italiana per lo
Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
WHI: CLINICAL OUTCOMES 2
Cancer
HRT
Placebo
Invasive breast
166
Endometrial
Colorectal
Total
JAMA, 2002
124
Hazard
ratio
1.26
95% CI
1.00-1.59
22
25
0.83
0.47-1.47
45
67
0.63
0.43-0.92
502
458
1.03
0.90-1.17
Società Italiana per lo
Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
WHI: CLINICAL OUTCOMES 3
Fractures
HRT
Placebo
62
Hazard
ratio
0.66
Hip
44
Vertebral
0.45-0.98
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
95% CI
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
231
218
Total
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
Società Italiana per lo
Studio dell’ Aterosclerosi
LACEY, JAMA 2002
Sez. Regionale Lombarda
HORMONAL REPLACEMENT THERAPY
AND OVARIAN CANCER
No therapy
Estrogens
Estrogens+
Progestins
Years-person
270.520
179.065
42.400
N° of ovarian
cancer
120
116
18
Relative
Risk
1.0
1.6
(1.2-2.0)
1.1
(0.64-1.7)
Società Italiana per lo
Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
LACEY, JAMA 2002
INTERVENTION STUDIES AIMED AT THE
PREVENTION OF CORONARY HEART DISEASE
(SUBGROUPS OF WOMEN)
4S
(simvastatin)
CARE
(pravastatin)
CHD
Yes
Yes
No
Number of women
827
576
997
35-69
21-75
55 – 73
Average follow-up (years)
5.4
5.0
5.2
Mean LDL-C (mg/dl)
at baseline
188
139
150
Mean lowering of LDL-C in
the verum group
38%
32%
25%
Mean CHD risk reduction
(95% confidence interval)
35 (9-53)%
46 (22-62)%
46%
Age (years)
4S:
The Lancet 1994;344:1383-1389
Care:
Sacks FM et al. N Engl J Med 1996;335:1001-1009
AFCAPS/TexCAPS: Downs JR et al. JAMA 1998;279:1615-1622
AFCAPS/
TexCAPS
(lovastatin)
SIMVASTATIN: SECONDARY ENDPOINT
STATIN worse
VASCULAR EVENTS BY AGE AND GENDER
GROUPS
SIMVA
(10269)
Relative Risk IC 95%
PLACEBO
(10267)
SIMVA better
Placebo better
AGE (YEAR)
< 65
838
1093
65 - 69
516
677
70-74
550
628
>75
138
208
GENDER
Male
1676
2148
366
458
2042
(19.9%)
2606
(25.4%)
Female
All patients
Het 
2
3
= 4.4
Het 
2
1
= 0.4
24%SE 2.6
(2P<0.00001)
0.4
0.6
0.8
1.0
1.2
1.4
Società Italiana per lo
Studio dell’ Aterosclerosi
Sez. Regionale Lombarda
HORMONAL REPLACEMENT THERAPY
(WHEN TO BE USED)
• Menopausal symptoms (vasomotor,
atrophy, mood disturbance)
urogenital
or
vaginal
• High risk of osteoporosis
• Early menopause
Società Italiana per lo
Studio dell’ Aterosclerosi
Sez. Regionale Lombarda