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Les nouveaux facteurs de risque CV ?
Pr Atul PATHAK
Clinique Pasteur
INSERM 1048
Biomedical Engineering Department de l’Ecole Polytechnique
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
