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

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(%

)R

ELA

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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