ESC Congress in Review - Main Edition 2019 - 30

New Treatment Updates
The Inflammatory Hypothesis:
Learning from the CANTOS and
CIRT Trials
Written by Rachel Giles

Over the last decades we learnt to appreciate atherosclerosis as an inflammatory disease based on solid evidence
deriving from experimental studies and epidemiological
association between inflammatory markers and cardiovascular events, Donato Santovito, MD, PhD, Institute
for Cardiovascular Prevention (IPEK), Ludwig Maximilian
University, Munich, Germany, began his presentation.
"We were missing an important piece of science though,
that treating inflammation would indeed improve cardiovascular outcomes," Dr Santovito added. In the last
2 years, with 2 large clinical trials specifically designed
to test the inflammation hypothesis of atherothrombosis
have been presented, however, with somewhat contradictory results.
First, the 10,061 patient Cardiovascular Risk Reduction
Study: Canakinumab Anti-inflammatory Thrombosis
Outcomes Study [CANTOS; NCT01327846] demonstrated
that specific targeting of interleukin (IL)-1β can significantly reduce cardiovascular risk independent of lipid or
blood pressure lowering. In CANTOS, canakinumab given
at doses of either 150 or 300 mg subcutaneously once
every 3 months lowered the inflammatory biomarkers
IL-6 and C-reactive protein (hsCRP) by 35% to 40% when

compared with placebo; effects that led to a 17% reduction
in rates of the composite outcome of recurrent myocardial
infarction (MI), stroke, hospitalisation for unstable angina
leading to urgent need for revascularisation, or cardiovascular death (P < .001) [Ridker PM et al. N Engl J Med 2017].
As such, CANTOS has provided proof-of-principle regarding
the inflammation hypothesis of atherothrombosis.
Canakinumab was well tolerated. However, while rates
of total infection were similar in the canakinumab and placebo groups, fatal infections were increased with active
therapy at a rate of approximately 1 per 1,000 treated
patients (P = .02 comparing all doses of canakinumab to
placebo). Moreover, the elevated costs make canakinumab not cost-effective for prevention of recurrent cardiovascular events [Sehested TSG et al. JAMA Cardiol.
2019]. Altogether, these aspects prompted research into
additional therapeutic agents and targets.
The Cardiovascular Inflammation Reduction Trial
[CIRT; NCT01594333] was designed in parallel with
CANTOS to evaluate the hypothesis that an alternative
approach to inflammation inhibition using low-dose methotrexate might also lower vascular events rates. Thus,
whereas CANTOS used a narrow-spectrum approach to
inflammation inhibition through use of a targeted antiIL-1β monoclonal antibody, CIRT elected to use a broader
spectrum anti-inflammatory approach known to have
clinical efficacy in multiple systemic disorders, but with
a low-dose of an agent where far less is known about its
mechanisms of effect (Figure 14). In CIRT, investigators

Figure 14. Illustration of the Molecular Rationale Behind Inhibition of IL-1β (in CANTOS trial) or IL-6 (in CIRT trial)

Vessel wall
Cardiovascular
events
Atherosclerotic
lesion

Activated macrophage
Endothelial cells
Vascular smooth muscle cells
Inflammasome

Monocyte/
Macrophage

TNF-1α

IL-1ß

IL-6

Canakinumab
(CANTOS)

?
Liver
hsCRP

Low Dose
Methotrexate
(CIRT)

CRP

CRP, C-reactive protein; hsCRP, high-sensitivity CRP; IL, interleukin; TNF, tumour necrosis factor.
Reprinted from Yamashita T et al. Anti-inflammatory and immune-modulatory therapies for preventing atherosclerotic cardiovascular disease. J Cardiol. 2015;66:1-8.
Copyright 2019. With permission from Elsevier.

October 2019

medicom-publishers.com/mcr

http://www.medicom-publishers.com/mcr

ESC Congress in Review - Main Edition 2019

Table of Contents for the Digital Edition of ESC Congress in Review - Main Edition 2019