Les nouveaux facteurs de risque CV ?

Pr Atul PATHAK

Clinique Pasteur

INSERM 1048

Biomedical Engineering Department de l’Ecole Polytechnique

apathak@clinique-pasteur.com

Quoi de neuf autour des FDR CV traditionnels?

CANHEART-HDL : HDL-C and Cause-Specific

Mortality in Individuals Without Prior CV Conditions

Ko, D.T. et al. J Am Coll Cardiol. 2016;68(19):2073–83.

CANHEART-HDL : HDL-C and Cause-Specific

Mortality in Individuals Without Prior CV Conditions

SCORE Still up to date !

Potential reclassification • Family history of premature CVD

• *Socio-economic status, social isolation or lack support social *Psychosocial stress *Major psychiatric disorders

• *Sedentarity *BMI – central obesity

• *CKD *Autoimmunes and other inflammatory disorders (rheumatoid arthritis : IIa –B)

*HIV and treatment for HIV infection *AF *LVH *Obstructive sleep apnoea syndrome

• *CT coronary calcium score (IIb - B) *Athero-sclerotic plaques (IIb - B) *ABI (IIb - B) *IMT and biomarkers(III – A)

Patient management

Stress finally recognized and confirmed !

Nouveaux FDR

Epidemiological studies: Pollution and Cardiovascular Mortality

. Cardiovascular Mortality / PM :

Comparative HRs (95% CIs) associated with a 10-μg/m3 change in

long-term exposure to PM2.5 in several cohort studies conducted in

the United States. Ostro et al. Environ Health Perspect 118:363–369

Cardiovascular complications of Chemotherapy

Anthracyclines

Molecular Targeted Agent

But also PAH, valvular disease,

PVD….

What does Early Detection of cardiotoxicity mean? • Before occurrence of any symptoms?

• Before decrease of LVEF?

• Before decline of myocardial deformation?

Cardinale D, Curr Cardio Reports 2016 D.MOHTY JESFC 2071

Cardiotoxicity - Detection

EF <53% (50%)

Re-assess every 5 years

CV Long-term Surveillance Programs for Cancer Survivors exposed to chest radiation

Food Therapy

Intake of olive oil & oleic acid and CVD

Schwingshackl L, Hoffmann G. Lipids Health Dis 2014;13:154.

Meta-analysis. Intake of fish but not n-3 FA

Chowdhury R, et al. BMJ 2012;345:e6698.

RED MEAT AND TYPE 2 DIABETES

META-ANALYSIS

10 studies

442 101 subjects

Red meat« unprocessed » and « processed »

AJCN 2011, 94, 1-9

MEAT AND CEREBROVASCULAR EVENT

META-ANALYIS

5 STUDIES

- Total

- « Red »

- « Processed »

EJCN 2013, 67, 91-95

A MITIGATE SOLUTION

FLEXI OR SEMI VEGETARIANISM

- LESS MEAT 3 - 4 TIMES / WEEK

MAINLY LESS RED MEAT 1 - 2 TIMES / WEEK

- MORE FISH 2 TIMES / WEEK

- EGGS 2 - 3 TIMES / WEEK

- MORE LEGUMES, SEEDS, VEGETABLES, FRUITS, NUTS

- VEGETARIAN MENU 5 - 7 TIMES / WEEK

= THE MEDITERRANEAN DIET !

Meta-analysis of fruit and vegetable consumption and risk of mortality: the effect on all-cause mortality is mainly driven by the

effect on CV mortality

Wang, BMJ 2014;349:g4490

Dose-response relation between fruit and vegetable consumption and risk of all cause mortality

Wang, BMJ 2014;349:g4490

CV mortality is decreased by

extra fruit or vegetables servings

A higher consumption of fruit and vegetables was associated with a reduced risk of all cause mortality, with an average reduction in risk of 5% for each additional serving a day (6% for fruit and 5% for vegetables)

There was a threshold around five servings a day, after which the risk of death did not reduce further

1. Olive oil use as main culinary fat 8. Wine ≥7 glasses/wk 2. Olive oil ≥4 tbs/d 9. Legumes ≥3/wk 3. Vegetables ≥2/d 10. Fish & seafood ≥3/wk 4. Fruit ≥3/d 11. Cakes, sweets <3/wk 5. Red meat, meat products <1/d 12. Nuts ≥1/wk 6. Butter, cream, margarine <1/d 13. Poultry > red meats 7. Soda drinks <1/d 14. Sofrito sauce ≥2/wk

PREDIMED - 14-point MeDiet score

Positive effects beyond CV disease : •A Fib •Diabetes •Breast Cancer

Management of Dyslipidemia

LE HDL ?

ACCELERATE

ACCELERATE : results (CV death, MI, stroke, coronary revascularization or hosp. for

unstable angina)

CETP inhibition ?

• Torcetrapib…Etude ILLUMINATE negative

• Evacetrapib…Etude ACCELERATE negative

• Dalcetrapib … etude DALCOR gene en cours

• Anacetrapib..

• RCV à Barcelone pour ESC

LE LDL ?

Candesartan 16+ HCTZ 12.5 PLacebo

Rosuvastatine 10 mg 3.7 %

PLacebo 4.8% RR=

The first coprimary outcome was the composite of death

from cardiovascular causes, nonfatal myocardial infarction,

or nonfatal stroke, and the second coprimary outcome

additionally included resuscitated cardiac arrest, heart

failure, and revascularization.

Yusuf S et al. N Engl J Med. 2016

Essai FOURIER: CV Death, MI, Stroke, Hospitalization for UA, or Coronary

Revascularization

HR 0.85 (95% CI 0.79 to 0.92); P < 0.001

CV = Cardiovascular; MI = Myocardial infarction; UA = Unstable angina; HR = Hazard ratio Sabatine MS, et al . NEJM. [published online ahead of print March 17, 2017]. doi:

10.1056/NEJMoa1615664

6.0

10.7

14.6

5.3

9.1

12.6

No. at Risk Placebo 13,780 13,278 12,825 1 1,871 7,610 3,690 686 Evolocumab 13,784 13,351 12,939 12,070 7,771 3,746 689

Cu

mu

lati

ve I

ncid

en

ce (

%) Placebo

Evolocumab

0

2

4

6

8

10

12

14

16

0 6 18 12 24 36 30 Months

Unanticipated

• attenuation of LDL-C lowering over time

• higher level of immunogenicity and

• higher rate of injection-site reactions

with the novel drug compared with other drugs

in the same class

SPIRE 1 (17 000 pts) and SPIRE 2 (11 000 pts)

Nov 1st 2016

www.medscape.com

Ridker Am Heart J, 2016

(Bococizumab) Humanized MAB vs Human MAB ?

Inclisiran clinical trial: ORION 1

K Ray AHA, 2016

Primary endpoint

% change LDL D1 – D180

Secondary endpoint

LDL level at D90

LDL and PCSK-9 over time

Safety Tolerance

LDL level

HM Colhoun Eur Heart J, 2016

PCSK-9 inhibition doesn’t increase incidence of diabetes

Pooled analysis from 10 ODYSSEY phase 3 studies (alirocumab)

D. ANGOULEVANT

H Milionis Eur J Internal Med, 2016

No reduction of ischemic stroke risk

Meta analysis of long terme RCT with alirocumab and evolocumab

Ischemic stroke event alone Ischemic stroke event + TIA (in OSLER)

• Very low stroke rate in both studies

• No hemorrhagic stroke were reported in either study

• Longer exposure and larger cohort needed (efficacy and safety)

ODYSSEY OSLER

Ischemic Stroke Ischemic Stroke Transient Ischemic Attack

Active 9 3 1

Control 2 2 5

Bezin J, et al. Impact of a public media event on the use of statins in the French population. Arch Cardiovasc Dis. In press.

Relative risk of statin discontinuation and all-cause mortality (1/2)

+40%

+17!%

Negative statin-related news stories decrease statin persistence and increase myocardial

infarction and cardiovascular mortality

Nielsen & Nordestgaard EHJ 2016

Diabete

Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial P.VALENSI

LEADER : Primary Outcome

15

10

20

5

0

0 6 12 18 24 30 36 42 48 54

Placebo

Liraglutide

Pati

ents

wit

h a

n e

ven

t (%

)

Months since randomisation

Hazard ratio, 0.87 (95% CI, 0.78–0.97)

P<0.001 for noninferiority

P=0.01 for superiority

First occurrence of CV death, nonfatal myocardial infarction, or nonfatal stroke in the time-to-event analysis

Adapted from: Marso SP et al., NEJM 2016

n = 9340 ; median follow-up: 3,8 years

Hazard ratio (95% CI)

P value

Primary composite endpoint* 0.87 (0.78-0.97) 0.01

Expanded composite endpoint† 0.88 (0.81-0.96) 0.005

Death from any cause 0.85 (0.74-0.97) 0.02

CV death 0.78 (0.66-0.93) 0.007

Fatal or nonfatal MI 0.86 (0.73-1.00) 0.046

Nephropathy 0.78 (0.67-0.92) 0.003

n = 9340 ; median follow-up: 3,8 years

*CV death, nonfatal MI (including silent MI), or nonfatal stroke; †CV death, nonfatal MI (including silent MI), nonfatal stroke, coronary revascularization, and hospitalization for unstable angina or HF.

CI, confidence interval; CV, cardiovascular; MI, myocardial infarction.

Marso SP, et al. N Engl J Med. 2016 Jun 13. [Epub ahead of print]

0,00 0,50 1,00 1,50

Favors liraglutide

LEADER : main results

Liraglutide : only a glycemic effect?

CAUTION: Randomized Trial of Liraglutide for High-Risk Heart Failure Patients

with Reduced Ejection Fraction

FIGHT study: Functional Impact of GLP-1 for Heart Failure Treatment

300 adults with Heart Failure (majority NYHA III-IV) and LVEF ≤40% (mean 25%)

recently (<14 days) hospitalized for acute HF. 60% with T2D (rather well controlled: HbA1c <7.9%)

Liraglutide 1.8 mg/day vs. placebo. 180 day follow-up

Margulies et al. JAMA 2016;316:500-508

GLP1-RA SUSTAIN-6

Marso et al. NEJM 2016 Will be available as LA tablets

SGLT2 inhibitor : Empagliflozine EMPAREG CV Outcomes: early effect to volemia reduction

Zinman et al. NEJM 2015;373:2117-28

EMPAREG: sustained BP lowering

SBP

DBP

HR

Zinman et al. NEJM 2015;373:2117-28

- 4 mmHg

- 2 mmHg

No change

P.VALENSI

Liraglutide Empaglifozine

First demonstration of a CV benefit (MI and stroke) in type 2 diabetes

For Cardiologists : is it time to move

to first line therapy for diabetes

in secondary prevention?

Conclusions

• Traditional CV risk factors : not always as expected

(HDL)

• Risk assesment taking into account reclassification

factors and psychosocial approach

• Rise of cardio – oncology

• Keep it up with statin (Benefit / Ris Ratio positive)

• Ready for PCSK 9 inhibitor

• Take over diabetes