Luc Missault, MD, DSc Cardiology St Jan Hospital Bruges Dyslipidemia in Postmenopausal Women
Luc Missault, MD, DScCardiology
St Jan Hospital Bruges
Dyslipidemiain
Postmenopausal Women
Sint Jan Bruges
! Atrial fibrillation !Largest centrum for Belgium
European accredited center for fellowship ASD/PFO/LAA closure
Transcatheter closurelocal anesthesia/one day clinic
Aim: °insight into:
• CV disease, dyslipidemia & other risk factors• CV disease in women• CV disease and menopause• Dyslipidemia management in women
normal fatty fibrous athero- complicatedinfiltration plaque sclerotic plaque
plaque
Atherosclerotic coronary stenosis
Cobalt-Chromium stent
normal fatty fibrous athero- complicatedinfiltration plaque sclerotic plaque
plaque
Ruptured coronary plaque,thrombolysed anterior infarction
Revascularisation
Desocclusion and stenting of occluded right coronary artery
♂
♀
Recent Declines in Hospitalizationsfor Acute Myocardial Infarction
the annual AMI hospitalization rate in the Medicare fee-for-service population fell by 265 per 100 000 beneficiary-years from 2002 to 2007, a relative decline of 23.4%
Chen et al., Circulation. 2010;121:1322-1328
Causes of Death 2006“Vlaams gewest”
32%
12%
25%
31%
Cancer cardiovascularrespiratory other
24%
11%
28%
37%
cancer cardiovascularrespiratory other
Men Women
Cardiovascular disease in women
Women presenting with cardiac symptomsare on average 10 years older than men
Underestimation of “own” complaints More often atypical presentation Less often presentation of acute infarction More often presentation as chronic angina Hormonal influence: estrogens …
1984
0
25
50
75
100
125
150
Gotto AM Jr, et al. Circulation. 1990;81:1721-1733.Castelli WP. Am J Med. 1984;76:4-12.
Relationship Between Cholesterol and CHD Risk: Epidemiologic Trials
10-y
ear C
HD
dea
th ra
te
(Dea
ths/1
000)
Serum cholesterol (mg/dL)1% reduction in total cholesterol resulted in a 2% decrease in CHD risk
CH
D in
dica
tions
per
100
0Each 1% increase in total cholesterol level is associated with a 2% increase in CHD risk
Serum cholesterol (mg/100 mL)
Framingham Study (n=5209)Multiple Risk Factor Intervention Trial (MRFIT) (n=361,662)
204
205-234
235-264 265-294
295
150 200 250 3000
50
40
30
20
10
POSCHProgram On the Surgical Control of the Hyperlipidemias
00
2 4 6 8 10
39
77
116
155
193
232
271
Years
mg/
dL
SurgeryControl
Buchwald et al. N Engl J Med. 1990;323:946
0
0.5
0.6
0.7
0.8
0.9
1.0
Proportion Without Event (combined end point of nonfatal
MI or CHD death)Total Cholesterol
0 2 4 6 8 10 12Years
35% Relative
Risk Reduction
417 384 352 320 213 3692
421 383 368 357 247 49116
Control
Surgery
Prop
ortio
n
4S (secondary prevention)Primary Endpoint: Overall Survival
4S (secondary prevention)4S (secondary prevention)Primary Endpoint: Overall SurvivalPrimary Endpoint: Overall Survival
80828486889092949698
100
0 1 2 3 4 5 6
SimvastatinPlacebo
Years since randomizationYears since randomization
% S
urvi
ving
% S
urvi
ving
30% risk reduction
p = 0.0003
The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
001010
20203030
404000
4040 8080REDUCTION IN PLASMA CHOLESTEROLREDUCTION IN PLASMA CHOLESTEROL
(mg/dL)(mg/dL)
4S4SWOSWOS
CARECAREPOSCHPOSCH
LIPIDLIPIDLRCLRC
REL
ATI
VE R
EDU
CTI
ON
IN C
HD
EVE
NTS
(%
)R
ELA
TIVE
RED
UC
TIO
N IN
CH
D E
VEN
TS (
%)
AFCAPSAFCAPS
5050
HPSHPS
ASCOTASCOT
ALLHATALLHAT
MAJOR INTERVENTION TRIALSMAJOR INTERVENTION TRIALS
Statin vs PlaceboStatin vs Placebo
PROCAM (Münster Heart Study):LDL-Cholesterol and Lp (a) According to
Age in Women
75
95
115
135
155
175
195
20-24
25-29
30-34
35-39
40-44
45-49
50-54
55-59
60-64
4
5
6
7
8
9
10
Age (years)
LDL-Cholesterol (mg/dl) Lp(a) mg/dl)
LDL-Chol. (n=5,961)
Lp(a) (n=1,386)
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 < 0.001LDL-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
Hormones & Menopause
Estrogens decrease “bad” LDL-cholesterol.
Menopause: decrease in estrogens.
So at menopause this “protection” stops.
What follows then is a slow catch-up fenomenon in incidence of CVD decreasing the differences between genders.
Reflex?
Menopause lipid treatment?
• Lipid Profile • High total cholesterol• High LDL-C• High triglycerids• Low HDL-C
• High Blood Pressure• Obesity• Diabetes• Sedentary lifestyle• Smoking
• Age• >55 year (men)• >65 jaar (women)
• Gender
Risk factors for cardiovascular disease
Changeable Unchangeable
WHO. The Atlas of Heart Disease and Stroke 2004.
• De accumulatie van risicofactoren verhoogt het cardiovasculaire risico insterk mate
• Een mannelijke roker met een TC en een SBD in het bovenste quintiel heeft een CV mortaliteitsrisico dat 20 maal groter is dan dat van een mannelijke niet-roker met een TC en een SBD in het laagste quintiel
Risico van CV mortaliteit x20 indien accumulatie van 3 risicofactoren
BLOEDDRUK
SBD ≥110 mmHg
CHOLESTEROL
TC ≥180 mg/dl
ROKEN
Meerdere risicofactoren = Cumulatieve stijging van het cardiovasculaire risico
Voor elke patiënt is de behandeling van het globaal CV risico belangrijk
1. Neaton JD, et al. Arch Intern Med. 1992 Jan; 152(1):56-64.
2. AHA. Heart Disease and Stroke Statistics-2005 Update.
SCORE België:10-jaar risico op CV overlijden in primaire preventiebij patienten zonder diabetes noch nierinsufficientie
1. European Journal of Cardiovascular Prevention and Rehabilitation 2007;4(Suppl.2):S1-S113. 2. Journal of Hypertension 2007;25:1105-1187.
8 10 13 166 7 9 114 5 6 83 3 4 5
5 6 8 93 4 5 72 3 4 52 2 3 3
3 4 4 52 2 3 41 2 2 31 1 1 2
2 2 3 31 1 2 21 1 1 21 1 1 1
1 1 2 21 1 1 10 1 1 10 0 1 1
0 0 1 10 0 0 00 0 0 00 0 0 0
16 20 24 3012 14 18 228 10 13 156 7 9 11
10 12 15 187 8 10 135 6 7 93 4 5 6
6 7 9 114 5 6 83 3 4 52 2 3 4
3 4 5 72 3 4 52 2 3 31 1 2 2
2 2 3 41 2 2 31 1 2 21 1 1 1
1 1 1 11 1 1 10 0 1 10 0 0 0
15 18 22 2710 13 16 207 9 11 145 6 8 10
10 12 15 187 8 11 135 6 7 93 4 5 6
6 8 10 124 5 7 83 4 5 62 3 3 4
4 5 6 83 3 4 52 2 3 41 2 2 3
2 3 4 52 2 3 31 1 2 21 1 1 2
1 1 1 21 1 1 10 1 1 10 0 0 1
28 34 41 4820 25 30 3615 18 22 2710 13 16 19
19 23 28 3413 17 20 259 12 15 187 8 10 13
12 15 19 239 11 13 176 8 9 124 5 7 8
8 10 12 156 7 9 114 5 6 83 3 4 5
5 6 8 103 4 5 72 3 4 52 2 2 3
2 2 3 41 2 2 21 1 1 21 1 1 1
Vrouwen MannenNiet-rokers RokersNiet-rooksters Rooksters
Syst
olis
che
bloe
ddru
k (m
mH
g)
≥170≥150≥130<130
≥170≥150≥130<130
≥170≥150≥130<130
≥170≥150≥130<130
≥170≥150≥130<130
≥170≥150≥130<130
Leeftijd
≥68 j
≥63 j
≥58 j
≥53 j
≥48 j
<45 j
Totaal cholesterol (mg/dl)
SCORE België
10-jaar risico op CV overlijden
≥10%
5-9%
2-4%
<2%
<175 ≥275≥225≥175 <175 ≥275≥225≥175 <175 ≥275≥225≥175 <175 ≥275≥225≥175
Different clinical situationsIndividualisation
• Primary versus Secondary Prevention
• Risk Classification in Primary Prevention– Diabetes? / T1 or T2? / OD?– CKD?– Markedly elevated cholesterol as a single risk factor?– Systematic COronary Risk Evaluation (SCORE) in others
Total cardiovascular risk estimationvery individualised
Overview Guidelines
ESC-EAS 2011 SCORE and/or type of patient Target LDL VERY HIGH risk Event/Diabetes/CKD 70 mg/dl
SCORE > 10% and/or > 50% reductionHIGH risk Individual elevated risk factor 100 mg/dl
SCORE 5% - 10 %MODERATE risk Family History 115 mg/dl
SCORE 1% - 5 %ESC 2007 SCORE and/or type of patient Target LDL
INCREASED risk Event/Diabetes/Markedly raised lipid levels 100 mg/dl - 80 mg/dl if feasibleSCORE > 5 %
ESC-EASD 2007 SCORE and/or type of patient Target LDL HIGH risk Event/Diabetes 100 mg/dl
VERY HIGH risk Event AND Diabetes 70 mg/dl
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 (g/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
Estrogens # Lipids alone!
CV risk/menopause/treatment
Specifically after menopause the age related risk for cardiovascular disease increases at higher pace
Estrogens probably related, considering changes in lipids accompanying menopausal years
How to intervene? Hormone replacement therapy?...HERS…
Cholesterol lowering drugs?...Prosper & Jupiter…some conflicting results…
PROSPER(The HERS equivalent for Statins in women)
• Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial
Shepherd et al Lancet 2002;360: 1623-30
PROSPER
• 3000 women aged 70-82 years• History or at risk vascular disease• Pravastatin 40mg/day or placebo• N = Prav 1495, Plac 1505 • treatment for 3.2 years• Coronary death, non-fatal MI
Lancet 2002; 360:1623
Slide 35
PROSPER - Major Cardiovascular Outcomes According to Sex
0 0.25 0.75 1 1.25 1.75 2
Men
Statin better Statin worseHazard ratio
TIA
CHD death, non-fatal and fatal non-fatal stroke
Fatal and non-fatal strokeCHD death, non-fatal MI
Women
0.5 1.5
TIA
CHD death, non-fatal and fatal non-fatal stroke
Fatal and non-fatal strokeCHD death, non-fatal MI
Pravasatin Placebo
222(n=1369) (n=1408)
167
6538
279
219
5370
186
125
7039
194
137
4961
(n=1495) (n=1505)
Shepherd et al Lancet 2002;360:1623-30
Women’s Health Initiative (E):HR in CHD & STARTING AGE
• 10,739 “healthy” postmenopausal women
• age 50 - 79 years
• CEE 0.625 mg• duration 6.8 years (planned 8.5 years)• primary benefit: CHD events
• primary adverse event: breast cancer
• overall benefits exceeded risks
0
0,2
0,4
0,6
0,8
1
1,2
50-59 60-69 70-79
CHD events
The Women’s Health Initiative Steering Committee. JAMA 2004; 291: 1701-12
HR
Placebo
Rosuvastatin 20 mg
JUPITER - Primary EndpointTime to first occurrence of a CV death, non-fatal stroke, non-fatal
MI, unstable angina or arterial revascularization
Ridker P et al. N Eng J Med 2008;359: 2195-2207
NNT for 2y = 955y* = 25
*Extrapolated figure based on Altman and Andersen method
0 1 2 3 4
0.00
0.02
0.04
0.06
0.08
Cum
ulat
ive
Inci
denc
e
Follow-up (years)Number at RiskRosuvastatinPlacebo
8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 1578,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174
HR 0.56 (95% CI 0.46-0.69)P<0.0001
-Selection of pts based on hsCRP elevation
-Rosuvastatin = powerful statin
JUPITER – Subgroup analysisRosuvastatin better Placebo better
N P- value*
Age 0.32≤ 65 years 8,541>65 yrs 9,261Gender 0.80Males 11,001Females 6,801Race 0.57White 12,683Non-white 5,117Hypertension 0.53Yes 10,208No 7,586Region 0.51US or Canada 6,041Other 11,761Metabolic syndrome 0.14Yes 7,375No 10,296Family history of CHD 0.07Yes 2,045No 15,684
Framingham risk score 0.99≤10% 8,882>10% 8,895
0 0.2
0.4
0.6
0.8 1
1.2
Ridker P et al. N Eng J Med 2008;359: 2195-2207
Hazard ratio (95% CI)
Baseline characteristics
JUPITER – Elderly Subgroup DataAge ≥70 Subgroup Analysis
0.250.25 0.50.5 1.01.0 2.02.0 4.04.0
Rosuvastatin SuperiorRosuvastatin Superior
Rosuvastatin InferiorRosuvastatin Inferior
MenMenWomenWomen
CaucasianCaucasianNon-CaucasianNon-Caucasian
Metabolic syndromeMetabolic syndromeNo met. syndromeNo met. syndrome
HypertensionHypertensionNo hypertensionNo hypertension
SmokerSmokerNon smokerNon smoker
Framingham ≤ 10%Framingham ≤ 10%Framingham > 10%Framingham > 10%
All ParticipantsAll Participants
2,7642,7642,9312,931
3,9833,9831,7111,711
2,2572,2573,3973,397
3,7323,7321,9601,960
4774775,2155,215
1,7531,7533,9323,932
5,6955,695
1221227272
1561563838
7474119119
1321326262
2727167167
3535159159
194194
2.462.461.541.54
2.162.161.511.51
1.731.732.172.17
2.242.241.551.55
3.083.081.891.89
1.151.152.392.39
1.991.99
n Placeborate
events
Rosuva Placebo
No. (Rate)* No. (Rate)* HR 95% CI P Value
Women 39 (0.57) 70 (1.04) 0.54 0.37-0.80 P=0.002
Men 103 (0.88) 181 (1.54) 0.58 0.45-0.73 P<0.0001* Rates are per 100 person-years
JUPITER JUPITER –– Women Subgroup DataWomen Subgroup DataPrimary Endpoint: Primary Endpoint: Time to first occurrence of a CV death, non fatal stroke, nonTime to first occurrence of a CV death, non fatal stroke, non--fatal MI, unstable angina or arterial revascularizationfatal MI, unstable angina or arterial revascularization
Mora S et al. Circulation 2009; 120 (Suppl): S500-S501; Abs 1426
Dyslipidemia in womenESC guidelines 2011
Dyslipidemia in postmenopausal womenconflicting data but:
• Although menopause does seem to induce changes in lipids due to estrogen decrease,
• Systematic treatment of dyslipidemia is not the way to go.
• If systematic treatment– high NNT to prevent an event if anything– budget restrictions!
• Therefore treatment should not be based on menopausal status
• But targeted to the high “risk status” independent of menopause