Les grandes avancées en Prévention Cardiovasculaire

Les grandes avancées en

Prévention CardiovasculaireQuelles leçons pour la prévention du déclin des

fonctions cognitives?

Jean Ferrières

Fédération de Cardiologie, Service d’Epidémiologie,

INSERM UMR 1027

CHU de Toulouse

Anthropologie

Scanning ancient history for evidence of modern diseases

Lancet 2013 Apr 6;381(9873):1211-22

Physiopathologie

Dysfonction Endothéliale : Étape Initiale des

Lésions Athéroscléreuses

Glass, Cell

2001, 104:

503-516

Progression et Développement des Lésions

Athéroscléreuses

Glass,

Cell 2001,

104:503-516

Complications des Lésions Athéroscléreuses :

Rupture de Plaque

Glass,

Cell 2001,

104:503-516

Traditional Contemporary

Atherosclerosis

Traditional vs. Contemporary Model

Plaque Morphology: Vulnerable vs. Stable

Thick Fibrous Cap Thin Fibrous Cap

Large lipid core

Rich in cholesterol

Rich in activated macrophages

Thin fibrous cap richin inflammatory cells

Poor in smooth muscle cells

Low grade stenosis

The Vulnerable Human Atherosclerotic Plaque

Atherosclerosis and Inflammation

TNF-

IL1, IL6, IL8

M-CSF, GM-CSF

MCP-1

macrophage

mLDL

AGE

smooth muscle cells

monocyte

activation

& differentiation

activation

& proliferation

Cytokine

production

activation

LDL

endothelium

Foam cells

Activation Adhesion Foam cell formation

Ve

sse

l w

all

lum

en

Novel Inflammatory Markers of Coronary Risk

Vascular and extravascular sources

Primary Pro-Inflammatory Cytokines

(e.g. IL-1, TNF-)

Pro-Inflammatory Risk Factors(oxidized LDL, infectious agents, etc)

Liver

IL-6“Messenger” Cytokine

CRP

SAA

Circulation

Endothelium

& other cells

ICAM-1Selectins, HSPs, etc.

Circulation 1999;100(11):1148-50

Clinique

J Am Coll Cardiol 2015;65(8):846-55

The Myth of the "Vulnerable Plaque": Transitioning From a Focus on

Individual Lesions to Atherosclerotic Disease Burden for Coronary

Artery Disease Risk Assessment

Risk Due to Nonobstructive Versus Obstructive Coronary Artery Disease

Annualized risk (percent) of myocardial infarction (MI) or cardiovascular (CV) death in 3,242 patients followed for a median of

3.6 years after baseline computed tomographic coronary angiography, according to the extent and severity of coronary artery

disease. Risk is low in patients with nonobstructive disease (<50% stenosis) involving 4 or fewer coronary artery segments

(limited disease). Conversely, risk is similarly high in patients with nonobstructive disease if more than 4 segments are

affected (extensive disease) compared with patients with obstructive disease (≥50% stenosis). Modified with permission from

Bittencourt et al.

J Am Coll Cardiol 2015;65(8):846-55

The Myth of the "Vulnerable Plaque": Transitioning From a Focus on

Individual Lesions to Atherosclerotic Disease Burden for Coronary

Artery Disease Risk Assessment

Fate of Ruptured Coronary Atherosclerotic Plaques According to Thrombotic Milieu

In the most common scenario, small thrombus formation associated with plaque rupture is contained and vascular

occlusive thrombus is inhibited.

Interventions - RCT

Eur Heart J 2015;36(8):472-4

How does lipid lowering prevent coronary events? New insights from

human imaging trials

The lumen remains largely unchanged, the lipid core shrinks, the amount of fibrous tissue may increase as

a proportion of the intima, but modestly decrease in absolute terms, while the content of calcified tissue

actually rises with lipid lowering.

An integrated depiction of the effects of aggressive lipid lowering on human coronary

plaques as revealed by ‘virtual histology’ and other cross-sectional imaging studies.

Impact of Statins on Serial Coronary Calcification During Atheroma

Progression and Regression

JACC 2015;65(13):1273-82

Natural plaque progression likely involves lipid-pool expansion coupled

with microcalcifications within lipid pools. Following long-term high-

intensity statin therapy, plaque regression manifests as delipidation and

probable vascular smooth muscle cell calcification, promoting plaque

stability.

Plaque Calcification in the Setting of No-Statin Therapy or High-Intensity Statin Therapy

Epidémiologie et

Santé Publique

La continuité de la prévention des maladies chroniques

Amélioration de la prise en charge

des facteurs de risque connus et

utilisation de nouveaux facteurs de

risque (génétique, modes de vie)

Mise au point de nouveaux outils

de dépistage non invasifs et

meilleure prise en charge des

phases précoces de

l’athérosclérose

Meilleur repérage des sujets à risque

de complications et amélioration de

la prise en charge (médicale et

communautaire) des formes

terminales de l’athérosclérose

Prévention

PRIMAIRE

Prévention

SECONDAIRE

Prévention

TERTIAIRE

Diminution de

l’INCIDENCE

Diminution de la

PREVALENCE/SÉVÉRITÉ

Diminution des

SÉQUELLES/HANDICAPS

Sujets malades

asymptomatiques ou

symptomatiques

Sujets dans une

phase avancée

de la maladie

Sujets

à risque

Ferrières J. Sciences Humaines et Sociales. Abrégés PCEM1. MASSON. Paris 2006

Trends in age-specific coronary heart disease mortality in the

European Union over three decades: 1980–2009

European Heart Journal 2013;34:3017-27

Age-standardized mortality rates, total percentage change, average annual percentage

changes, and Joinpoint analysis by country and sex, all ages combined

Values are unadjusted averages of rates for each 5-year period, or for as many years as datawere available within the period. Exceptions, where data

were not available for all years, are: Belgium (to 2006); Denmark (to 2006); France (to 2008); Italy (no data 2005); Lithuania (no data 1980, 1983,

1984); Portugal (no data 2004 to 2006); and Slovenia (no data before 1985).a25-year total crude change calculated from difference between 1980–84 average rate and 2005–09 average rate.bData for Germany prior to 1990 calculated from raw data for the Former East and West Germany. 1980–84 data for Czech Republic and Slovakia are

combined data from Czechoslovakia, therefore, not directly comparable.

Males

* 25-year crude total % changea

0

20

40

60

80

100

120

140

160

180

200

Italy

Poland

Greece

Portugal

Spain

France

1980-84 1990-94 2000-04 2005-09

-50

-7

-49

-36

-16

-46

Evolution des taux spécifiques de mortalité en France de 1980 à 2008

Taux standardisés sur l’âge (population de référence, France 1990)

InVS. Bulletin Epidémiologique Hebdomadaire,2007;35-36.

InVS. Bulletin Epidémiologique Hebdomadaire,2011;249-55.

2008

194

218

Maladies cardiovasculaires

- 56 % sur 28 ans

Pathologies tumorales

- 15% sur 28 ans

Evolution des causes médicales de décès en France

Evolution du taux proportionnel de mortalité

par maladies cardiovasculaires

en France de 1980 à 2008

1980 2004 2008

%

37.4 %

28.9 %

- 26 % sur 28 ans

Source : CépiDc

27.5 %

2000

30.5 %


Evolution du taux proportionnel de mortalité par maladies

cardiovasculaires et pathologies tumorales

en France de 1980 à 2008

1980 2004 2008

%

37.4 %

28.9 %

Maladies cardiovasculaires - 26 % sur 28 ans

Source : CépiDc

27.5 %

2000

30.5 %

21.6 %

29.6 %

Pathologies tumorales

+ 37 % sur 28 ans


Baisse de la

mortalité

cardiovasculaire

Baisse de la létalité des

accidents

cardiovasculaires

Baisse de l’incidence des

maladies

cardiovasculaires

Coronary event ratewith 95% confidence interval, age standardized, age 35-64

WHO MONICA Project

Lancet 1999 ; 353 : 1547-1557

Définition d’un registre

Structure ayant pour but d’enregistrer de façon continue et exhaustive des renseignements sur une

pathologie donnée, dans le cadre d’un territoire géographique déterminé.

Fournir des statistiques sanitaires :

Incidence

Taux de létalité, taux spécifique et proportionnel de mortalité

Evolution dans le temps : effet du dépistage et de la prévention

Disparités géographiques : hypothèses étiologiques

Roger VL, et al. Circulation 2010;121(7):863-9

L’incidence des STEMI a diminué et celle des NSTEMI a augmenté

La mortalité à court terme (≤ 30 jours) a diminué de plus de 50 %

• Objectif de l’étude : Analyser l’impact de l’ajout du

dosage de la troponine pour le diagnostic de l’infarctus

du myocarde

• Méthodologie de l’étude : Étude sur 2 816 patients

hospitalisés pour un infarctus du myocarde(IDM)

Recrutement des patients entre 1987 et 2006

• Critères d’évaluation : Incidence des infarctus du

myocarde, sévérité et survie sur une période

de 6 ans

Tau

x d

’in

cid

en

ce a

justé

su

r

l’âg

e e

t le

sexe

(po

ur

100 0

00)

Avec dosage de la Troponine T

Sans dosage de la Troponine T

On observe une augmentation des NSTEMI

Incidence des hospitalisations pour un IDM, entre 1987 et 2006, dans le

Comté d’Olmsted, Minnesota, selon le statut de l’élévation du segment ST

Comment a évolué l’épidémiologie de l’infarctus du myocarde

depuis 20 ans ?

Incident MI and stroke in France

Average annuel rates per 100 000

Data from the MONICA (MI) and Dijon (stroke) population-based registries

* <45 years for stroke rates.

Data collected in 1997-2000 (MI) and 1995-1997 (stroke)

0

400

800

1200

1600

2000

35-44* 45-54 55-64 65-74 75-84 85 and

over

Myocardial infarction in men

Stroke in men

Myocardial infarction in women

Stroke in women

years

/ 100 000 persons/year

Wolfe CDA, et al. Stroke 2000;31:2074-9.

Montaye M, et al. BEH 2006;62-4.

Age standardized coronary heart disease mortality and event rate in

selected European regions (men, aged 35-64 years)

Population Official CHD CHD mortality Coronary events

mortality rate per 100 000† per 100 000‡

per 100 000*

Glascow (United Kingdom) 332 365 777

Belfast (United Kingdom) 280 279 695

Lille (Northern France) 89 172 298

Strasbourg (North-Eastern France) 80 141 292

Toulouse (South-Western France) 53 91 233

Barcelone (North-Eastern Spain) 63 76 210

Ferrières J. Heart 2004 ; 90: 107

* Based on death-certificate enumeration

† Fatal events included definite, possible and unclassifiable (mainly sudden deaths

with no available diagnostic information) coronary deaths

‡ Coronary events included non-fatal events (definite myocardial infarction) and fatal

events

Les formules de risque

cardiovasculaire

Diagramme SCORE : risque à 10 ans de décès cardiovasculaire dans les pays

à bas risque cardiovasculaire basé sur les facteurs de risque suivants : âge,

sexe, tabagisme, pression artérielle systolique et cholestérol total

Les pays à bas risque sont

l’Andorre, l’Autriche, la

Belgique, Chypre, le

Danemark, la Finlande, la

France, l’Allemagne, la

Grèce, l’Islande, l’Irlande,

Israël, l’Italie, le

Luxembourg, Malte,

Monaco, les Pays Bas, la

Norvège, le Portugal, la

république de Saint Marin, la

Slovénie, l’Espagne, la

Suède, la Suisse, le

Royaume-Uni.

A noter que le risque

d’événements

cardiovasculaires totaux

(fatals + non-fatals) va

être approximativement

3 fois supérieur aux

chiffres donnés

Ten-year risk of all-cause mortality: assessment of a risk prediction

algorithm in a French general population

Independent predictors of 10-year all-cause mortality and corresponding score of

the risk prediction algorithm

Hazard Ratio 95% p ScoreConfidence Interval

Toulouse centre (South-Western France) 1.00 0Strasbourg centre (North-Eastern France) 1.04 [0.67 - 1.61] 0.857 0Lille centre (Northern France) 1.76 [1.21 - 2.58] 0.003 335-44 years old 1.00 045-54 years old 1.64 [1.02 - 2.64] 0.040 355-64 years old 3.89 [2.49 - 6.09] < 0.001 7Women 1.00 0Men 2.11 [1.48 - 3.01] < 0.001 4Educational level ≥ high school completion 1.00 0Educational level < high school completion 1.57 [1.05 - 2.33] 0.026 2Non-smoking 1.00 0Smoking < 15 pack-years 2.61 [1.45 - 4.70] 0.001 5Smoking ≥ 15 pack-years 2.90 [2.01 - 4.17] < 0.001 6Non diabetes 1.00 0Diabetes 1.62 [1.10 - 2.37] 0.014 3Systolic blood pressure < 160 mmHg 1.00 0Systolic blood pressure ≥ 160 mmHg 1.57 [1.03 - 2.39] 0.036 2LDL-cholesterol < 5.2 mmol/l (200 mg/dl) 1.00 0LDL-cholesterol ≥ 5.2 mmol/l (200 mg/dl) 1.62 [1.01 - 2.61] 0.047 3

Bérard et al. Eur J Epidemiol 2011:26(5):359-68

(1) Reference is 35-44 years old; (2) Reference is never smokers; (3) Reference is Southwestern France.

* Educational level < high school completion

** Risk estimate corresponds to 1-unit change in Smoking (in pack-years)

*** LDL-cholesterol ≥ 5.2 mmol/L or ≥ 200 mg/dL [7.8% (168/2162)]

**** Diabetes was assessed for subjects with fasting blood glucose ≥ 7 mmol/l (126 mg/dl) or under hypoglycaemic drug treatment

Predictors of 16-year risk of all-cause mortality

Multivariate survival analysis

Preventive Medicine 2015;81:195-201

HR 95% CI p

45-54 years old (1) 1.33 0.87-2.03 0.181

55-64 years old (1) 3.43 2.32-5.07 <0.001

Men 1.56 1.09-2.22 0.014

Low educational level* 1.75 1.21-2.53 0.003

Former smokers (2) 0.93 0.57-1.50 0.756

Current smokers (2) 2.63 1.71-4.02 <0.001

Smoking (pack-years)** 1.01 1.00-1.01 <0.001

Centre: Northeastern France (3) 0.95 0.56-1.61 0.850

Centre: Northern France (3) 1.77 1.30-2.42 <0.001

Blood pressure ≥ 160/95 mmHg 1.67 1.22-2.30 <0.002

LDL-cholesterol ≥ 5.2 mmol/L*** 1.72 1.09-2.72 0.019

Diabetes**** 2.03 1.36-3.01 <0.001

Conflits d’intérêt:

Amgen, MSD, Sanofi

Blanco et al. 2016

Le risque attribuable en

population générale

0

10

20

30

40

50

60

70

80

90

100

Pression artérielle, LDL-C, HDL-C, triglycérides, tabagisme et

diabète

IMC ≥ 27 (+3%)

76%

%

21% inexpliqué

79%

Risque attribuable au niveau de la population pour la

maladie coronaire

Congress of the European Society of Cardiology. September 1-5, 2007, Vienna (Austria)Eur Heart J 2007;(suppl):147

PAR 16% pour LDL>1,6g/L

Comparison of coronary heart disease and stroke risks attributable to

vascular risk factors: Results from the PRIME Study

Full adjusted population-attributable risks for CHD and stroke events

Bongard et al. Annual Congress of the European Society of Cardiology. August 31-September 4, 2013, Amsterdam (Netherlands).

CHD versus Stroke versus

no event (n=410) no event (n=118)

High blood pressure (BP ≥ 140/90 mmHg) 21.1 [12.1-30.1] 32.8 [17.0-48.6]

Diabetes mellitus 1.9 [0.3-4.1] 6.4 [1.0-11.9]

Current smoking 14.8 [8.5-21.0] 15.9 [4.2-27.6]

Hypercholesterolemia (LDL-c ≥ 4.1 mmol/L) 11.1 [4.3-18.0] -

Low HDL-c (< 1 mmol/L) 9.8 [2.6-17.0] -

Hypertriglyceridemia (≥ 1.7 mmol/L) - -

Obesity (BMI ≥ 30 kg/m²) 5.4 [0.7-10.1] -

Teetotallers 8.5 [2.9-14.1] -

Excessive alcohol consumption - -

Overall † 71.2 [57.4-85.0] 43.7 [24.4-62.9]

BMI: body mass index

† To compute overall PAR for CHD, exposure was defined as high blood pressure or diabetes or current smoking or

hypercholesterolemia or low HDL-c or obesity or no alcohol consumption. To compute overall PAR for stroke, exposure was

defined as high blood pressure or diabetes mellitus or current smoking.

Overall PARs were adjusted for age, centre, antihypertensive drug treatment, and lipid-lowering drug treatment. All other

estimates are adjusted for age, centre, antihypertensive drug treatment, lipid-lowering drug treatment in addition to other

variables significant in the column.

Risk factor distribution

Population strategy High risk strategy

“Threshold of normality”

Risk factor

AFTER BEFORE

AFTER

Preventive Medicine: “High risk” strategy or

population strategy

Benefits, challenges and registerability of the

polypill

– Recognition that the individual titration of each component

does not work on grounds of cost and practibility.

– Costs are lower with generics.

– Easier patient compliance.

– Ensures that all the evidence-based medicines are given.

– More widespread use.

– Potentially very large public health benefits at affordable

costs.

Sleight. Eur Heart J 2006;27:1651

The cost of cardiovascular disease:

rising, declining or staying still?

– Although major cardiovascular disease risk factors such as smoking,

hypercholesterolemia and hypertension are better prevented, detected and

treated, risk factors trends in obesity and associated diabetes are likely to

decelerate the observed cardiovascular disease morbidity and mortality

decreasing trends.

– Even if age-standardised morbidity and mortality might continue to decrease,

demographic factors, both in relation to ageing of the general population and

the relatively faster ageing of ethnic subgroups, may inflate healthcare

expenditure.

– As demand for services and interventions is a major determinant of healthcare

costs, the advent of new and more expensive healthcare technology may

negate the potential for any savings.

– Therefore, epidemiological, demographic and health technology factors

combined are likely to inflate future healthcare cardiovascular disease costs.

Lyratzopoulos. Heart 2006;92:1361

Future trends in epidemiology, demography and new health technology

Primary prevention and risk factor reduction in coronary heart disease mortality among working aged men and women in eastern Finland over 40

years: population based observational study

BMJ 2016;352:i721

Age standardised mortality from coronary heart disease in 1969-2012 (logarithmic scale), for

working aged men and women (age 35-64 years) in eastern Finland



BMJ 2016;352:i721

Predicted and observed reduction (%) in coronary heart disease mortality

in men aged 35-64 years, 1972-2012



BMJ 2016;352:i721

Predicted and observed reduction (%) in coronary heart disease mortality

in women aged 35-64 years, 1972-2012

Documents

Les grandes avancées en Prévention Cardiovasculaire