Upload
lykiet
View
224
Download
0
Embed Size (px)
Citation preview
Discussant review: - CANTOS -
The Canakinumab Anti-Inflammatory ThrombosisOutcomes Study
Malte Kelm, MDProfessor and Chairman
Department of Cardiology, Pulmology and Vascular MedicineUniversity Hospital Düsseldorf
• Chronic inflammation in atherosclerosis
• Patient (and target) population
• Effect size, tailoring therapy
• Non-cardiovascular effects and safety
CANTOS: Canakinumab Anti-Inflammatory Thrombosis Outcomes Study
N Engl J Med 1997;336:973-979
effect size
stability
hsCRP reflects inflammation in humans
N Engl J Med 1997;336:973-979
IL6 upstream signalling
independent risk indicationeffect size
stability
Lancet. 2010;375:132-140 Eur Heart J. 2014;35:578-89
hsCRP reflects inflammation in humans
Activation of inflammasome - “clinical utility”
Circ Res. 2016;118:145-156
& Ischemia NLRP3inflammasome
IL-1β
TNF
IL-6
hsCRP
target
converter
distributor
biomarker
Canakinumab
Cholesterol crystals induce local and systemic inflammationexperimental studies
monocytes & macrophages volume expansion intima perforation
Cholesterol crystals induce local and systemic inflammationexperimental studies
monocytes & macrophages volume expansion intima perforation human studies
Carotid artery coronary artery systemic effects Eur Heart J. 2016;37:1959-67,Science. 2015;349:237-8, Circ. Res. 2017;120:1947-57
Additional LDL Reduction
IMPROVE-IT : Ezetimibe 6% RRR FOURIER/SPIRE: PCSK9 Inhibition q2 weeks 15% RRR
Known Cardiovascular Disease LDL 150 mg/dLhsCRP 4.5mg/L
Additional Inflammation Reduction
CANTOS: Proof of Concept
High Intensity Statin
LDL 80 mg/dLhsCRP 3.8 mg/L
LDL 110 mg/dLhsCRP 1.8 mg/L
“Residual Cholesterol Risk” “Residual Inflammatory Risk”
Residual risk in HR-patients with CAD: >50%
Eur Heart J 2016;37:1720-22
CANTOS - baseline clinical characteristics
Ridker ESC 2017N Engl J Med 2011;364:226-35
PROSPECT - event rate post pPCI / AMI
Ridker ESC 2017
Tailored therapy in CAD
Additional LDL Reduction
Known Cardiovascular Disease LDL 150 mg/dLhsCRP 4.5mg/L
Additional Inflammation Reduction
High Intensity Statin
LDL lowhsCRP high
LDL highhsCRP low
“Residual Cholesterol Risk” “Residual Inflammatory Risk” “Residual Thrombotic Risk”
HTPR
Additional antiplatelet & anticoagulant therapy?
IL-1β in sterile inflammation and non-CVD
Nat Rev Drug Discov; 2012,11: 633-652
Canakinumab
CRP & (non) cardiovascular mortality
Lancet 2010; 375: 132-40
Ridker ESC 2017
• supports the concept of causal anti-inflammatory therapy in atherosclerosis
• offers the perspective of tailored indication, treatment & monitoring of anti-inflammatory therapy in secondary prevention in high risk patients
• need to proof the transition of this concept to patients with AMI• safety has to be further evaluated in post-trial registries in cardiology and oncology, as with other anti-inflammatory agents tested in ongoing trials
CANTOS: Canakinumab Anti-Inflammatory Thrombosis Outcomes Study