Mnster Heart Study PROCAM Change of Lipoproteina with Aging

1
DEATH DUE TO CHD IN THE USA IN 1986
BUSH, ANN NY ACAD SCI,1990
2
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 lt 0.001 BMI
(kg/m2) 25.8 4.3 26.4 4.5 lt
0.001 cholesterol (mg/dL) 221 39 239 41 lt
0.001 triglycerides (mg/dL) 88
99 lt 0.001 LDL-C (mg/dL) 143 36 158
38 lt 0.001 HDL-C (mg/dL) 59 15 59
16 n.s. chol./HDL-C ratio 4.02 1.25 4.31
1.32 lt 0.001 geometric mean, n.s. not
significant
3
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 lt 0.001 D-dimer (mg/l) 321
345 n.s. factor
VIIc (mg/dL) 108 26 120 34 lt
0.001 protein C () 111 19 120 24 lt
0.001 plasminogen () 104 14 106
14 lt 0.05 PAI-1 (U/l) 2.22
2.48 lt 0.05 vWF () 103
35 96 31 n.s. CRP (mg/dL)
0.32 0.28 lt 0.05 geometric mean
4
MAJOR RISK FACTORS FOR CHD

• AGE gt 45 Y MALES AND gt 55 Y FEMALES
• Family history of MI or sudden death lt 55 males
  lt 65 females
• Cigarettes smoke
• Elevated blood pressure
• HDL-C lt 35 mg/dL
• Diabetes mellitus
• HDL-C gt 60 mg/dL

NATIONAL CHOLESTEROL EDUCATION PROGRAM.CIRCULATIO
N 1994891329-445.
5
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 1995273199
6
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 1995273199
7
EFFECTS OF ORAL ESTROGENS ON SERUM LIPOPROTEINS
IN POSMENOPAUSAL WOMEN
BRANCHI A., 1998
8
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 1995273199
9
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

10
RELATIVE RISK AND 95 CI FROM STUDIES OF
ESTROGEN USE TO PREVENT CHD
STAMPFER, NEJM, 1991
11
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 1996335453
12
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.

13
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 1998280605-613
14
HEART AND ESTROGEN/PROGESTIN REPLACEMENT STUDY
(HERS) CHANGES IN LIPID LEVELS AT 1 YEAR
15
10
8
10
5
2
0
Mean change from baseline
-2
-3
-5
Placebo Estrogen/progestin
-10
-15
-14
-20
LDL-C
HDL-C
TG
P lt 0.001 HULLEY S ET AL. JAMA 1998280605613
15
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 280605-613
16
HEART AND ESTROGEN/PROGESTIN REPLACEMENT STUDY
(HERS)CUMULATIVE INCIDENCE OF PRIMARY CHD EVENTS
Estrogen/progestin Placebo
Hulley S et al. JAMA 1998280605613
17
SIDE-EFFECTS IN HERS STUDY
Side-effects confirmed venous thrombosis deep
vein thrombosis pulmonary embolus fatal
pulmonary Embolus gallbladder disease
oestrogen/ progestin (n1380) 34 25 11 2
84
placebo (n1383) 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
HULLEY ET AL. JAMA 1998 280605-613
18
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 1998280605-613
19
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
20
CHD OUTCOMES DURING 6.8 YEARS OF HORMONE THERAPY
(HERS II)
JAMA, 2002
21
NON CHD OUTCOMES DURING 6.8 YEARS OF HORMONE
THERAPY (HERS II) 1
JAMA, 2002
22
NON CHD OUTCOMES DURING 6.8 YEARS OF HORMONE
THERAPY (HERS II) 2
JAMA, 2002
23
RISK AND BENEFITS OF ESTROGEN PLUS PROGESTIN IN
HEALTHY POSTMENOPAUSAL WOMENPrincipal Results
from the Womens 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
24
PROFILE OF THE ESTROGENPROGESTIN COMPONENT OF
THE WOMENS HEALTH INITIATIVE
25
WHI CLINICAL OUTCOMES 1
JAMA, 2002
26
WHI CLINICAL OUTCOMES 2
JAMA, 2002
27
WHI CLINICAL OUTCOMES 3
JAMA, 2002
28
WHI CAUSE OF DEATH
JAMA, 2002
29
CONCLUSIONS

• Overall health risk exceeded benefits from use of
  combined estrogenprogestin 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

30
MENOPAUSAL HORMONE REPLACEMENT THERAPYAND 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
31
HORMONAL REPLACEMENT THERAPY AND OVARIAN CANCER
LACEY, JAMA 2002
32
INTERVENTION STUDIES AIMED AT THE PREVENTION OF
CORONARY HEART DISEASE (SUBGROUPS OF WOMEN)
4S The Lancet
19943441383-1389 Care
Sacks FM et al. N Engl J Med 19963351001-1009 AF
CAPS/TexCAPS Downs JR et al. JAMA
19982791615-1622
33
SIMVASTATIN SECONDARY ENDPOINT
VASCULAR EVENTS BY AGE AND GENDER
STATIN worse
34
HORMONAL REPLACEMENT THERAPY (WHEN TO BE USED)

• Menopausal symptoms (vasomotor, urogenital or
  vaginal atrophy, mood disturbance)
• High risk of osteoporosis
• Early menopause