risicofactoren en cardiovasculaire preventie :

stand van zaken ?

J.Van Cleemput, MD, PhD,

dienst cardiologie,

KUL-UZ GHB

RISICO PREVENTIE

RR AR10 jaar ARR NNT10 jaar

side effects

50%

25%

1% 10% 50%

1%

10% 50%

0.5% 5% 25%

0.25% 2.5%

12.5%

200 20 4

400 40 8

2% 2% 2%

2% 2% 2%

RISICO PREVENTIE

“klassieke” risicomodellen

nieuwere risicofactoren

“beeldvorming”

genetisch onderzoek

(I)

gezonde levenswijze

risicofactormodificatie

medicatie

(II)

Lipid core

Adventitia

stabiele plaque

Lipid core

Adventitia

Thrombus

instabiele plaque

age-standardized mortality( males 1990/1991)

cancer : 21%other cvd : 10%ischemic cvd : 37%other : 32%

Atlas of Mortality in Europe

RISICO BEPALEN

(I)

high risk ? European guidelines

• established coronary heart disease, peripheral arte-ry disease or atherosclerotic cerebrovascular disease

• asymptomatic patients with : • diabetes type 2 or type 1 with microalbuminuria• total (LDL) cholesterol > 320 (240) mg/dl or BP > 180/110

mmhg• close relatives with early (men < 55 yrs and women < 65 yrs)

onset atherosclerotic cardiovascular disease• multiple risk factors resulting in a 5% 10-year risk of fatal

cardiovascular event

De Backer. EHJ.2003;24:1601

SCORE system

• 12 European cohort studies• 205.178 men and women 20 80 yrs. • gender, age, smoking, sbp and total cholesterol or

total/HDL cholesterol• 10 yr. risk of any fatal “atherosclerotic” endpoint

Conroy.EHJ 2003;24:987

SCORE system

. cumulative CVD death rate by age 65 (men)

cumulative CVD death rate by age 65 (women)

Finland Russia Norway UK Scotland Denmark Sweden Belgium Germany Italy France Spain

12.8% 11.91% 7.91% 7.11% 6.49% 6.44% 4.80% 4.79% 4.72% 4.01% 3.20% 2.81%

2.66%

1.95%

2.33% 2.37%

1.60% 1.15% 0.96%

0.94%

Conroy.EHJ 2003;24:987

Fig. 2. Ten-year risk of fatal cardiovascular disease in populations at low cardiovascular disease risk. Chart based on total cholesterol.

BelgiumFranceGreeceItaly LuxembourgSpain SwitzerlandPortugal

Fig. 1. Ten-year risk of fatal cardiovascular disease in populations at high cardiovascular disease risk. Chart based on total cholesterol.

DenmarkFinlandGermanyNorwayRussiaScotlandSwedenUK

“nieuwere” risicofactoren

• apolipoprotein B, small dense LDL cholesterol, oxLDL cholesterol, Lp(a)…

• hs-CRP, SAA, sICAM-1, IL-6,….

• homocysteine, fibrinogen, von Willebrand factor, tissue factor, PAI-1….

Figure 3. hs CRP provides prognostic information at all levels of LDL cholesterol and at all levels of the Framingham Risk Score. Data adapted from reference 6

Ridker et al.NEJM 2002;347:1557

27939 apparently healthy American women

“beeldvorming”

• carotid-intima media thickness

• electron beam computer tomography

• multi-slice CT

• MRI

• fluorodeoxyglucose-PET/CT

Fig. 3. (a and b) Two-dimensional "angiograms" derived from the three-dimensional reconstruction on the same patient. (a) The normal (large) circumflex artery and (b) the smaller left anterior descending artery, with a severe proximal stenosis (arrow). (c) The comparative invasive coronary angiogram (left anterior oblique, cranial angulation) confirming the severe proximal left anterior descending artery lesion.

Fig. 1. Multislice CT coronary angiography. (a) An axial section of the heart at the level of the aortic sinuses. The left ventricle (LV) and left atrium (LA) are marked and the right coronary artery is seen arising from the aorta (Ao). (b) The same patient but at the level of the left main stem. An area of calcification is noted in the left anterior descending artery and sequential axial sections suggested a significant lesion prior to the

calcification in the proximal vessel segment (arrow).

Fig. 2. Three-dimensional reconstructions of multislice CT coronary angiography (same patient as in Fig. 1). Volume-rendering techniques have been used to "remove" the pulmonary trunk, right ventricular outflow tract, both atrial appendages and part of the left atrium to allow visualization of the course of the coronary arteries (Cx, circumflex artery; RCA, right coronary artery). The appearance of the proximal left anterior descending artery (arrow) provides further evidence of a significant lesion.

Clin Radiol.2003;58:378

Rudd. Circulation.2002;105:2708

genetica

looking for polymorphisms in genes coding for :LIPIDS :

apolipoprotein-A-I,-B,-C-III,-E, hepatic lipase, lipoproteinlipase,LDL receptor–related protein, Lp(a),…

INFLAMMATION :Il-1,-1,-6,-10, P-selectin,CD-14 receptor,TNFlipoxygenase

THROMBOSIS :-fibrinogen, coagulation factor V, VII, XII, XIIIA, prothrombin, vWf, TFPI, PAI type1,

PAF, platelet endothelial cell adhesion molecule,…

MISCELLANEOUS :ace, AT-II receptor type1, angiotensinogen, ANP, 2 adrenergic receptor, metalloproteinase-

1 and 12…

Yamada et al. NEJM.2002;347:1916

Dwyer et al. NEJM 2004;350:29

Means were adjusted for age, sex, height, racial or ethnic group, smoking status, level of physical activity, dietary intake of saturated fat, and intake of alcohol by analysis of covariance. D denotes deletion alleles, A addition alleles, and W common allele (five tandem Sp1 binding motifs). P values are for the differences between indicated genotype groups.

Dwyer et al. NEJM 2004;350:29

470 healthy middle-aged

men and women from theLA atherosclerosis study

RISICOREDUCTIE

(II)

“gezonde levenswijze”(I)

risicofactormodificatie (II)

medicatie (III)

“gezonde levenswijze”(I)

• “gezonde” voeding

• rookstop

• 4 tot 5 maal per week 20 tot 30 minuten fysieke activiteit

De Backer. EHJ.2003;24:1601

Future ForumFuture ForumDEFINING GLOBAL STANDARDS IN VASCULAR DISEASEDEFINING GLOBAL STANDARDS IN VASCULAR DISEASE

Men participating in the NiMen participating in the Ni--HonHon--San study*San study*

Age (years)Age (years) 5757 5454 5252

Weight (kg)Weight (kg) 5555 6363 6666

Serum cholesterol (mg/dL)Serum cholesterol (mg/dL) 181181 218218 228228

Dietary fat (% of calories) Dietary fat (% of calories) 1515 3333 3838

Dietary protein (%)Dietary protein (%) 1414 1717 1616

Dietary carbohydrate (%)Dietary carbohydrate (%) 6363 4646 4444

Alcohol (%)Alcohol (%) 99 44 33

55--yr CHD mortality rateyr CHD mortality rate 1.31.3 2.22.2 3.73.7(per 1,000)(per 1,000)

ResidenceResidence

JapanJapan HawaiiHawaii CaliforniaCalifornia

*Data from Kato et al. Am J Epidemiol 1973;97:372. CHD, coronary heart disease.

Lyon Diet Heart Study

• meer brood• meer wortel- en bladgroenten foliumzuur)

• meer fruit• meer vis -poly-onverzadigde vetzuren)

• runds-, varkens en lamsvlees gevogelte• boter en margarine olijfolie en koolzaadolie linoleenzuur)

de Lorgeril. Circulation 1999;99:779

Lyon Diet Heart Study

diet (n=302)

control (n=303)

RR p

27 months ° - cardiac death - non-fatal mi - combined

3 5 8

16 17 34

73 (41-88)

0.001

46 months.* - cardiac death - non-fatal mi - combined

14

44

0.0001

° M. de Lorgeril. Lancet 1994;343:1454.* M. de Lorgeril. Circulation 1999;99:779.

nurses’ health study

• 7.401 women with type 2 diabetes

• never smokers past smokers current smokers : 114, 15 34 and >35 cigarettes/day

• 20 yrs of follow-up

• 724 all-cause mortality (I) 289 cardiovascular mortality (I) 237 cancer mortality

Al-Delaimy WK. Diabetes Care 2001;24:2043

smoking never past 1-14/d 15-34/d >35/d p

n n cv mort. age-adjusted RR multivariate*RR

1593 130

1 1

1240 111 1.18

(0.9-1.5)

1.30 (1.0-1.7)

196 10

1.08 (0.6-2.1)

1.58 (0.8-3.1)

418 33

1.89 (1.3-2.8)

2.56 (1.7-3.9)

95 5

1.44 (0.6-3.6)

1.85 (0.8-4.6)

0.001

0.0005

*adjusted for age, HRT, hypertension, cholesterol, family history, physical activity

women’s health initiative observational study

• 73.743 postmenopausal women 50 to 79 years free of diagnosed cv disease and cancer

• physical activity questionaires : walking + exercise => MET (hr/week)

• 3.2 yrs of follow-up

• 287 nonfatal mi and 58 coronary death (I) 1521 cardiovascular events (I)

Manson JE. NEJM 2002;347:716

nurses’ health study

• 84.129 women 34 to 59 years free of diagnosed cv disease, cancer and diabetes

• >15, 114, stopped smoking and never smoked >10, 5.1 10, 0.1 5.0 and 0 g alcohol/day <23, 23 24.9, 25 29.9 and >30 bmi >5.5, 3.6 5.5, 2.3 3.5, 1 2.2 and < 1 hr of exercise/wk 1,2,3,4 and 5 diet “score” (ao. fibers, n-3 fatty acids, folate, PUFA/SFA)

• 14 yrs of follow-up

• 832 nonfatal mi and 296 coronary death (I)

Stampfer MJ. NEJM 2000;343:16

risicofactormodificatie (II)

• BMI < 25 kg/m2 en buikomtrek < 102 (88) cm

• bloeddruk < 140/90 mmhg (<130/85 mmhg)

• totaal cholesterol < 190 mg/dl (5 mmol/ L) LDL cholesterol < 115 mg/dl (3 mmol/L)

• diabetes : HbA1c < 7.5%

De Backer. EHJ.2003;24:1601

medicatie (III)

plaatjesremmers

statines

ace-inhibitoren

beta-blockers

…

Antithrombotic Trialists’ Collaboration. BMJ 2002;324:71

antiplatelet therapy in high risk patients

aspirin for primary prevention of chd

Sanmuganathan PS. Heart 2001;85:265

other antiplatelet agents…

CollagenThrombin

TxA2

ASA

(Fibrinogen(Fibrinogenreceptor)receptor)

Clopidogrel

TxA2

ADPADP

GP IIb/IIIaGP IIb/IIIa ActivationActivation

Schafer AI Am J Med 1996;101:199–209

COXCOX

ADPADP

CAPRIE

• 19.185 pts with “atherosclerosis” : recent ischaemic stroke, recent mi or symptomatic peripheral arterial disease

• 75 mg clopidogrel vs 325 mg asa

• 1-3 yrs follow-up

• ischaemic stroke + mi + cv death

Lancet 1996;348:1329Lancet 1996;348:1329

CAPRIE

clopidogrel (n=9577)

asa (n=9566)

RR p

MAVE (%)

rash (%) any bleeding (%) intracranial bleeding (%) gastrointestinal bleeding (%)

price (Euro/d)

5.32

0.26 1.38 0.31 0.49

2.12

5.83

0.10 1.55 0.43 0.71

0.08 0.13

8.7 0.043

<0.05 NS NS

<0.05

Lancet 1996;348:1329Lancet 1996;348:1329

CURE (NEJM 2001;345:494) (NEJM 2001;345:494)

CREDO (JAMA 2002;288:2411)(JAMA 2002;288:2411)

… …

statines

pts. statine

n

totchol

WOSCOP AF/TexCAPS ASCOT ALL-HAT

hyperchol. low HDL

aht aht

prava 40 lova 20-40 atorva 10 prava 40

6595 6605

10305 10355

272 221 215 224

HPS PROSPER

high cv risk old

simva 40 prava 40

20536 5804

220 221

4S CARE LIPID LIPS

hyperchol. low chol.

ptca

simva 20-40 prave 40 prava 40 fluva 80

4444 4159 9014 1677

263 209 218 200

79.495

HPS

• 20.536 pts 40-80 yrs and “vascular” disease or diabetes mellitus or (treated hypertension and male and > 65 yrs)

• simvastatine 40 mg vs placebo• total mortality and cardiovascular mortality and

non-cardiovascular mortality (I) • MAVE = MACE + strokes + revascularisations

(II)

Lancet 2002;360:7-22

SIMVASTATIN: MAJOR VASCULAR EVENTS

Risk ratio and 95% CISTATIN PLACEBOVascularevent (10269) (10267) STATIN better STATIN worse

Total CHD 914 1234

Total stroke 456 613

Revascularisation 926 1185

ANY OF ABOVE 2042 2606(19.9%) (25.4%)

24% SE 2.6reduction(2P<0.00001)

0.4 0.6 0.8 1.0 1.2 1.4

Lancet 2002;360:7-22

Lancet 2002;360:7-22

SIMVASTATIN: VASCULAR EVENT by AGE & SEX

Risk ratio and 95% CISTATIN PLACEBOBaselinefeature (10269) (10267) STATIN better STATIN worse

S T A T IN w o rs e

Age group (years)

Het2

3 = 4.4

< 65 838 1093

65 - 69 516 677

70-74 550 62875 138 208

Sex

Het2

1 = 0.4Male 1676 2148

Female 366 458

ALL PATIENTS 2042 2606(19.9%) (25.4%)

24%SE 2.6reduction(2P<0.00001)

0.4 0.6 0.8 1.0 1.2 1.4

SIMVASTATIN: VASCULAR EVENT by PRIOR LIPID LEVELS

Risk ratio and 95% CISTATIN PLACEBOBaselinefeature (10269) (10267) STATIN better STATIN worse

LDL (mmol/l)

Het2

2 = 3.0

< 3.0 (116 mg/dl) 602 761 3.0 < 3.5 483 655 3.5 (135 mg/dl) 957 1190

Total cholesterol (mmol/l)

Het2

2 = 0.5

<5.0 (193 mg/dl) 361 476 5.0 < 6.0 746 965 6.0 (232 mg/dl) 935 1165

ALL PATIENTS 2042 2606(19.9%) (25.4%)

24%SE 2.6reduction(2P<0.00001)

0.4 0.6 0.8 1.0 1.2 1.4

Lancet 2002;360:7-22

statin = aspirin0.74 1.68 Euro/d 0.08 0.13

Euro/d

ace-inhibitoren post-mi

long-term post-mi:SAVE (n=2231,captopril )

AIRE (n=2006, ramipril)

TRACE (n=1749, trandolapril)

(ischemic) heart failure:CONSENSUS (n=253,enalapril)

VHeFT II (n=804,enalapril)

SOLVD (n=2569+4228,enalapril)

Heart Outcome Protection Study

• 9.297 pts > 55 yrs without heart failure but with increased cardiovascular risk (atherosclerosis or diabetes + 1 risk factor).

• 10 mg ramipril vs placebo

• 4.5 yrs of follow-up

• 1477 MAVE (nonfatal mi + nonfatal stroke + cv death)

NEJM 2000;342:145

myocardial infarction + stroke + cardiovascular mortality

651 pts

826 pts

NEJM 2000;342:145

beta-blockers post-mi

long-term post-mi:B-HAT (n=,3837propranolol)

BBPP (n=13.679)

(ischemic) heart failure:CIBIS (n=350,bisoprolol)

carvedilol (n=521)

CIBIS II (n=1316,bisoprolol)

MERIT-HF (n=2606,metoprolol)

COPERNICUS (n=1533,carvedilol)

Beta-blockers and reduction of cardiac events innoncardiac surgery.

Auerbach JAMA 2002;287:1435

medicatie (III)

plaatjesremmers

statines

ace-inhibitoren

beta-blockers

…

foliumzuur

3-vetzuren

prices

prijs per dag (Euro)

prijs patiënt per dag (Euro)

asaflow 160 mg od zocor 40 mg od tritace 10 mg od seloken 100 mg od totaal per dag totaal per jaar

0.13 1.26 1.28 0.17 2.84

1037.00

0.13 0.15 0.32 0.05 0.65

237.00

www.socmut.be

expanding statin use … is causing financial heartburn

UK : 8% of adults are HPS-like patients and only 23% are currently treated with statins (Bandolier)

Ireland : statin budget is doubling every 15 to 18 months and now accounts for over 6% of all drug expenditures (Barry)

the Netherlands : 800 million Euro/yr or 50 Euro/person is spended on statins (Simoons)

Mitka JAMA 2003;290:2243

the “polypill”

A strategy to reduce cardiovascular disease by more than 80%.NJ Wald, MR Law. BMJ 2003;326:1419-23.

A cure for cardiovascular disease : combination teratment has enormous potential. A. Rodgers. BMJ 2003;326:1408-9.

besluit

cardiovasculair risico :

laag

hoog

preventiemaatregelen :

gezonde levenswijze

risicofactoren

asa,statines,ace-i,…