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