Anti-inflammatory therapy in ischaemic heart disease: from canakinumab to colchicine

Abstract

Four large trials have recently evaluated the effects of anti-inflammatory drugs in the secondary prevention of major cardiovascular events (MACE) in over 25 000 patients followed for 1.9–3.7 years. CANTOS tested subcutaneous canakinumab [an anti-interleukin (IL) 1β antibody] 300 mg every 3 months against placebo in patients with a history of myocardial infarction (MI) and serum C-reactive protein (CRP) >2 mg/L, demonstrating efficacy in preventing MACE but increased rates of fatal infections. COLCOT (in patients with recent MI) and LoDoCo2 (in patients with chronic coronary syndromes) tested oral colchicine (an NLRP3 inflammasome inhibitor) 0.5 mg daily vs. placebo, demonstrating prevention of MACE with a slightly increased risk of pneumonia in COLCOT (0.9 vs. 0.4%) but not in LoDoCo2. CIRT tested oral methotrexate (an anti-rheumatic anti-nuclear factor-kB) 15–20 mg per week against placebo in ischaemic heart disease patients with diabetes or metabolic syndrome, without significant reduction in MACE rates or in circulating IL6 or CRP levels, and with increased risk of skin cancers. In summary, canakinumab and colchicine have shown efficacy in preventing MACE in ischaemic heart disease patients, but only colchicine has acceptable safety (and cost) for use in secondary cardiovascular prevention. Clinical results are expected with the anti-IL6 ziltivekimab.

Full text

Anti-inflammatory therapy in ischaemic heart
disease: from canakinumab to colchicine
Felicita Andreotti
1,2,3
*, Aldo Pietro Maggioni
4,5
, Alice Campeggi
2
,
Adelaide Iervolino
2
, Giovanni Scambia
1,2
, and Massimo Massetti
2,3
1
Direzione Scientifica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy;
2
Universita` Cattolica del Sacro Cuore, Rome, Italy;
3
Dipartimento di Scienze Cardiovascolari, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy;
4
ANMCO Research Center, Fondazione per il Tuo cuore, Florence, Italy;
5
GVM Care & Research, Maria Cecilia Hospital, Cotignola, Italy
KEYWORDS
Inflammation;
Ischaemic heart disease;
Atherothrombosis;
Canakinumab;
Colchicine
Four large trials have recently evaluated the effects of anti-inflammatory drugs in
the secondary prevention of major cardiovascular events (MACE) in over 25 000
patients followed for 1.9–3.7 years. CANTOS tested subcutaneous canakinumab [an
anti-interleukin (IL) 1bantibody] 300 mg every 3 months against placebo in patients
with a history of myocardial infarction (MI) and serum C-reactive protein (CRP)
>2 mg/L, demonstrating efficacy in preventing MACE but increased rates of fatal
infections. COLCOT (in patients with recent MI) and LoDoCo2 (in patients with
chronic coronary syndromes) tested oral colchicine (an NLRP3 inflammasome inhibi-
tor) 0.5 mg daily vs. placebo, demonstrating prevention of MACE with a slightly in-
creased risk of pneumonia in COLCOT (0.9 vs. 0.4%) but not in LoDoCo2. CIRT tested
oral methotrexate (an anti-rheumatic anti-nuclear factor-kB) 15–20 mg per week
against placebo in ischaemic heart disease patients with diabetes or metabolic syn-
drome, without significant reduction in MACE rates or in circulating IL6 or CRP levels,
and with increased risk of skin cancers. In summary, canakinumab and colchicine
have shown efficacy in preventing MACE in ischaemic heart disease patients, but
only colchicine has acceptable safety (and cost) for use in secondary cardiovascular
prevention. Clinical results are expected with the anti-IL6 ziltivekimab.
Introduction
Four large trials conducted in recent years have tested the
hypothesis that anti-inflammatory drugs, such as canakinu-
mab and colchicine, can reduce the incidence of major car-
diovascular events (MACE) in patients with previous
myocardial infarction (MI) or chronic coronary syndromes.
1
To optimize the understanding of these studies we briefly
illustrate the mechanisms of action of the tested drugs, the
multiple aspects that relate inflammation to ischaemic
heart disease, and some preliminary results with aspirin
and ziltivekimab; the main findings of the large placebo-
controlled trials with canakinumab, colchicine, and metho-
trexate are presented and their clinical implications briefly
discussed.
Anti-inflammatory drugs and ischaemic
heart disease
The anti-inflammatory effects of low-dose aspirin (100–
300 mg/day), although less well known than its antiplatelet
effects, are documented in various clinical settings
2–4
and
may contribute to aspirin’s benefits in the secondary pre-
vention of MACE
2
; the exact molecular mechanisms of such
effects are under investigation.
2–4
Canakinumab is a recom-
binant human monoclonal G1k immunoglobulin against
*Corresponding author. Email: felicita.andreotti@unicatt.it
Published on behalf of the European Society of Cardiology. V
CThe Author(s) 2021.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License
(https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any
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European Heart Journal Supplements (2021) 23 (Supplement E), E13–E18
The Heart of the Matter
doi:10.1093/eurheartj/suab084
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interleukin (IL) 1bthat neutralizes the signals induced by
IL1bon lymphoid, myeloid, endothelial, and other cell
types; canakinumab administration reduces circulating
IL6, fibrinogen, and C-reactive protein (CRP) levels com-
pared to placebo.
1,5
Colchicine is a plant alkaloid that
inhibits tubulin polymerization and the nod-like receptor
pyrin domain containing protein-3 (NLRP3) inflammasome
within monocytes and other cell types
1
;in vitro,colchicine
is reported to reduce platelet aggregation, superoxide pro-
duction, neutrophil recruitment and adhesion, mast cell
degranulation, monocyte chemotaxis, endothelial pyropto-
sis by cholesterol crystals, and endothelial activation by
oxidized LDL cholesterol
1
; in rats, colchicine has been
found to inhibit hepatic secretion of fibrinogen causing fi-
brinogen accumulation within the endoplasmic reticulum
and Golgi apparatus
6
; rabbits subjected to hypercholester-
olaemic diets treated with colchicine show reduced ath-
erosclerotic development and reduced circulating
fibrinogen levels
7
; in rodents, colchicine was found to pro-
tect against acute cerebral ischaemia by inhibiting cell
chemotaxis and exocytosis.
1
Methotrexate—used to treat
rheumatic diseases and cancer—has multiple effects in-
cluding inhibition of the nuclear transcription factor-kB, of
DNA/RNA synthesis and of dihydrofolate reductase
1
;in
patients with previous MI, methotrexate did not reduce cir-
culating IL6 levels.
8
Ziltivekimab is an anti-IL6 human
monoclonal antibody; unlike antibodies directed against
the IL6 receptor, ziltivekimab may act at lower concentra-
tions causing fewer adverse events.
9
The actions of the
aforementioned drugs are schematically illustrated in
Figure 1.
Inflammation and ischaemic heart disease
The close links between inflammation, atherothrombosis,
and coronary syndromes have long been known,
stemming from pathological, mechanistic, and clinical
data (Ta bl e 1). Atherosclerosis itself has been defined as
a chronic vascular inflammatory process.
10
Unstable pla-
ques have specific characteristics, with an increased
share of macrophages and neutrophils compared to sta-
ble plaques.
11
Coronary thrombi contain leucocytes, in
addition to platelets, fibrin, and red cells.
12
Various pro-
thrombotic factors, such as fibrinogen (the precursor of
fibrin and bridging molecule among aggregated plate-
lets), plasminogen activator inhibitor-1 (rapid inhibitor
of endogenous fibrinolysis and profibrotic factor), and
von Willebrand factor (platelet adhesion molecule), are
acute phase proteins.
13,14
As stated, in animal models,
colchicine can slow the development of atherosclerosis
7
and hepatic fibrinogen secretion.
6,7
In humans, inhibition
of IL1bor IL6 reduces circulating levels not only of other
inflammatory cytokines and CRP but also of prothrom-
botic factors such as fibrinogen.
5,9
The main traditional
cardiovascular risk factors (hypertension, diabetes, dysli-
pidaemia, smoking, obesity, sedentary lifestyle) are asso-
ciated with systemic low-grade inflammation: for each
additional factor, an approximate increase of 1 mg/L of
circulating CRP is observed.
15
Subclinical low-grade in-
flammation increases the risk of MACE among healthy
subjects: elevated fibrinogen concentrations
16
and white
blood cell counts,
17
even within the normal range, are
predictors of MACE. Common inflammatory markers pre-
dict the risk of MACE in patients with both acute
18
and
chronic
19
coronary syndromes. In patients with chronic
coronary syndromes, low-dose aspirin reduces the circu-
lating levels of inflammatory biomarkers and the
incidence of inducible ischaemia.
2
Finally, acute MI stim-
ulates an acute-phase and prothrombotic response, with
peak values and duration of response directly
proportional to the extent of MI.
12,13
Based on this ex-
tensive collection of data, phase II studies and recent
large-scale trials have evaluated the effects of anti-
IL6
Metotrexate
Colchicine
Canakinumab
Aspirin
Ziltivekimab
X
?
IL1β
IL6
Fibrinogen
CRP
PAI-1
VWF
NF-kB
NLRP3
?
Figure 1 Anti-inflammatory drugs and ischaemic heart disease. Colchicine, canakinumab, and aspirin (but not low-dose methotrexate) have shown effi-
cacy in preventing major adverse cardiovascular events in phase III trials of patients with ischaemic heart disease (left blue arrow). These three agents
inhibit the inflammatory cascade at various levels, from the NLRP3 inflammasome to interleukin-1band interleukin-6 (right blue arrow). Their adminis-
tration leads to significant reductions in circulating levels of C-reactive protein and of prothrombotic factors such as fibrinogen and—presumably—plas-
minogen activator inhibitor type 1 and von Willebrand factor. A phase III trial is planned with ziltivekimab in patients at high atherothrombotic risk. CRP,
C-reactive protein; IL, interleukin; NF-kB, nuclear transcription factor-kB; NLRP3, nod-like receptor pyrin domain containing protein-3; PAI-1, plasmino-
gen activator inhibitor type 1; VWF, von Willebrand factor.
E14 F. Andreotti et al.
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inflammatory drugs for the secondary prevention of
atherothrombotic events.
Selected phase II studies
RESCUE (Trial to Evaluate Reduction in Inflammation in
Patients With Advanced Chronic Renal Disease Utilizing
Antibody-Mediated IL-6 Inhibition) is a recent, double-
blind, randomized US study that tested increasing doses of
subcutaneous ziltivekimab (7.5, 15, or 30 mg monthly) vs.
placebo in 215 patients with moderate to severe renal im-
pairment and circulating CRP levels >2mg/Lconsideredto
be at high risk for atherothrombotic events.
9
The dose of
30 mg per month for three months vs. placebo reduced cir-
culating CRP by 80%, fibrinogen by 35%, and lipoprotein(a)
by 20%, with persistent results at 6 months and without ex-
cess adverse events. A large-scale trial will evaluate the ef-
ficacy and safety of ziltivekimab in secondary prevention
of MACE.
9
In another phase II study, patients with stable obstruc-
tive coronary artery disease, compared to age-matched
healthy controls, had more than double the plasma concen-
trations of the inflammatory markers macrophage colony
stimulating factor (800 vs. 372 pg/mL), IL6 (3.9 vs. 1.7 pg/
mL), and CRP (1.25 vs. 0.23 mg/L; P<0.01 for all compari-
sons).
2
Patients with inducible ischaemia on ambulatory
electrocardiogram, randomized in a double blind crossover
fashion to aspirin 300 mg daily or placebo for 3 weeks,
showed significantly reduced MCSF, IL6, and CRP plasma
levels after aspirin vs. placebo (P<0.05).
2
MCSF was asso-
ciated with ischaemic burden (P<0.01) and low ischaemic
threshold (P<0.01) and, together with IL1b,withnumber
of diseased epicardial arteries (P<0.05).
2
Significantly re-
duced inflammatory cytokine levels after aspirin (100 and
300 mg daily) have also been documented in healthy sub-
jects
3
and in patients with metabolic syndrome.
4
Among
chronic coronary syndrome patients, MCSF and CRP values
are predictive of long-term adverse events.
19
Large randomized placebo-controlled trials
CANTOS: Canakinumab ANti-inflammatory
Trombosis Outcomes Study
CANTOS
20
is a double blind, randomized study of over
10 000 patients followed for an average of 3.7 years. It
compared three doses of canakinumab, a drug already ap-
proved for the treatment of rheumatic diseases (50, 150,
or 300 mg subcutaneously every 3 months), against pla-
cebo. Patients had a history of MI, serum CRP levels
>2 mg/L, and good control of other cardiovascular risk fac-
tors. At higher doses (300 mg every 3 months), canakinu-
mab vs. placebo significantly reduced plasma levels of IL6
and CRP and the combined endpoint of cardiovascular
death, nonfatal MI and nonfatal stroke: 3.9 vs. 4.5 events
per 100 person-years [hazard ratio 0.86; 95% confidence in-
terval (CI) 0.75–0.99; P¼0.031]. The other two tested
doses did not yield favourable results. Regarding safety,
canakinumab was associated with a higher rate of fatal
infections than placebo, with no significant difference in
the rates of death from any cause. Canakinumab did not
enter the cardiovascular therapeutic arena, mainly due to
the high cost and potential risk of fatal sepsis. However,
the study was very relevant in defining the role of the IL1/
IL6/CRP cascade in the development of atherothrombotic
events. The ongoing search for sustainable, safe and viable
large-scale treatments has led to two other drug
approaches in specific trials: low-dose methotrexate
(CIRT)and low-dose colchicine (COLCOT and LoDoCo2).
CIRT: Cardiovascular Inflammation Reduction
Trial
CIRT
8
is a double blind, randomized study sponsored by the
National Institutes of Health. It compared low-dose metho-
trexate (target 15–30 mg once weekly) vs. placebo in 4786
patients with previous MI or multivessel epicardial artery
disease plus diabetes or metabolic syndrome followed for a
median of 2.3years. The primary endpoint was the classi-
cal triple composite of MACE, i.e. non-fatal MI, non-fatal
stroke or cardiovascular death; subsequently, for a lower
than expected event rate, hospitalization for revascular-
ization from unstable angina was added. The results were
Table 1 Multiple interrelations between inflammation and
ischaemic heart disease
Histopathology
•Atherosclerosis is a chronic vascular inflammatory process
•Unstable plaques contain a higher percentage of macro-
phages and neutrophils than stable plaques
•Arterial thrombi contain platelets, fibrin, erythrocytes,
and leucocytes
Molecular and experimental data
•Prothrombotic factors (fibrinogen, PAI-1, and VWF) are
acute phase proteins
•Inhibition of IL1bor IL6 reduces circulating fibrinogen lev-
els in humans
•Colchicine slows the development of atherosclerosis and
hepatic secretion of fibrinogen in experimental models
Pathophysiology and prognostic data
•Traditional CV risk factors induce low grade systemic
inflammation
•Low grade inflammation increases the risk of major CV
events
•Inflammatory biomarkers predict the risk of CV events in
patients with acute or chronic coronary syndromes
•Aspirin reduces the levels of inflammatory biomarkers and
the risk of major CV events
•Acute MI stimulates an acute phase response in proportion
to the extent of necrosis
Large randomized trials
•Canakinumab prevents CV events in patients with previous
MI and elevated CRP but increases the risk of fatal
infections
•Colchicine prevents CV events in patients with acute or
chronic coronary syndromes without excess of adverse
events
CRP, C-reactive protein; CV, cardiovascular; IL, interleukin; MI,
myocardial infarction; PAI-1, plasminogen activator inhibitor type 1;
VWF, von Willebrand factor.
Anti-inflammatory therapy in ischaemic heart disease E15
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disappointing: low-dose methotrexate did not reduce cir-
culating levels of IL1b, IL6, or CRP, nor cardiovascular
events vs. placebo (201 vs. 207; hazard ratio 0.96, CI 0.79–
1.16). With methotrexate vs. placebo, there was an in-
creased incidence of oral lesions, leucopenia, unwanted
weight loss, transaminase elevation, and cancer (mostly
non-basal cell skin cancers; 52 vs. 30, P¼0.02). For these
reasons, the trial was terminated prematurely.
COLCOT: COLchicine Cardiovascular Outcome
Trial
COLCOT
21
is an independent, multinational study funded
by the Canadian government. It randomized double-blindly
4745 patients with recent MI (within 30 days), regardless of
CRP values, to colchicine (0.5 mg daily) or placebo.
Patients were treated with optimal medical therapy and
followed for a median of 2.3 years. The primary endpoint
was the combination of cardiovascular death, resuscitated
cardiac arrest, non-fatal MI, non-fatal stroke, and revascu-
larization for unstable angina. The primary endpoint was
documented in 5.5% of patients treated with colchicine
and in 7.1% treated with placebo, a significant relative re-
duction of 23% (hazard ratio 0.77, CI 0.61–0.96; P¼0.02).
Treatment with colchicine had favourable effects on each
individual component of the composite primary endpoint.
All-cause mortality was not different in the two arms (43
deaths with colchicine vs. 44 with placebo). A higher rate
of pneumonia was observed with colchicine vs. placebo, al-
beit with a low incidence (0.9% vs. 0.5%, P¼0.03), while
the frequency of diarrhoea (9.7% vs. 8.9%) did not differ
significantly in the two arms. Study limitations include the
relatively short follow-up and the relatively small sample
size, providing reliable answers for the entire population
but not for specific subgroups.
COLCOT has confirmed the crucial role of inflammation
in the progression of ischaemic heart disease by providing
an effective, low cost, reasonably safe preventive treat-
ment with a drug already known to the medical community
for the treatment of gout, familial Mediterranean fever
and pericarditis. The COLCOT results, however, cannot be
generalized to all ischaemic heart disease patients, being
limited to patients with recent MI, in whom the intensity of
inflammation may be more relevant than in stable patients
with either an old MI or no previous history of acute coro-
nary syndromes.
LoDoCo2: Low-Dose Colchicine 2 trial
LoDoCo2
22
is a double blind, randomized study that tested
low-dose colchicine (0.5 mg daily) vs. placebo in 5500
patients with documented obstructive epicardial artery
disease, stable for at least 6 months, followed for a median
of 2.4 years. It was conducted in Australia and the
Netherlands, and funded by public and private foundations
and a consortium of pharmaceutical companies. The pri-
mary endpoint was a composite of cardiovascular death,
spontaneous (non-procedural) MI, ischaemic stroke, and
ischaemia-driven coronary revascularization. The main
secondary endpoint was the classical triple composite of
cardiovascular death, MI, or stroke. The results were, once
again, favourable. The primary endpoint occurred in 6.8%
of patients treated with colchicine and in 9.6% of patients
treated with placebo, representing a highly significant rel-
ative reduction of 31% (hazard ratio 0.69, CI 0.57–0.83;
P<0.001). The primary secondary endpoint showed a
Secondary prevenon strategies for paents
with chronic coronary syndromes
Life style changes (smoking cessaon, body weight control, heart-
healthy diet, exercise), SBP <130 mmHg and HbA1c in diabecs <6.5%
Thrombosis
All paents
ASA
High ischaemic risk and
low bleeding risk
ASA+ADPi/P2Yi
or
ASA+low-dose
rivaroxaban
Neurohormonal system
All paents
ACE-I (ARBs if not tolerated)
Betablockers
Paents with LVD and HF
ACE-I (ARBs if not tolerated)
ARNI (if low EF)
Betablockers
MRAs
Lipid metabolism
All paents
High intensity stans
If LDL target not
achievable or if stan
intolerance
Ezemibe
PCSK9-i
Inflammaon
All paents
Low-dose colchicine
Therapeuc targets
Diabec paents
As for non diabecs
plus
GLP1 RA
or
SGLT2-i
Figure 2 Secondary prevention strategies in patients with chronic coronary syndromes. Future clinical guidelines on the management of chronic coro-
nary syndromes will likely include anti-inflammatory strategies. ACE, angiotensin converting enzyme; ADP, adenosine diphosphate; ARB, angiotensin II re-
ceptor blocker; ASA, aspirin; EF, ejection fraction; GLP1 RA, glucagon-like peptide 1 receptor agonist; Hb, haemoglobin; HF, heart failure; i, inhibitor;
LDL, low-density lipoprotein; LVD, left ventricular dysfunction; MRAs, mineralocorticoid receptor antagonists; PCSK9, proprotein convertase subtilisin/
kexin type 9; SBP, systolic blood pressure; SGLT2, sodium glucose cotransporter type 2.
E16 F. Andreotti et al.
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relative reduction of 28% (absolute rate 4.2% with colchi-
cine vs. 5.7% with placebo; hazard ratio 0.72, CI 0.57–0.92;
P¼0.007), i.e. a significant reduction not only from a sta-
tistical but also from a clinical standpoint. Regarding
safety, there were no significant differences in the rates of
expected adverse events, such as pneumonia or gastroin-
testinal disturbances, between treatment arms. The inci-
dence of non-cardiovascular death was numerically (but
not statistically) higher with colchicine vs. placebo (0.7 vs.
0.5 events per 100 person-years; hazard ratio 1.51, CI 0.99–
2.31). Subgroup analyses showed homogeneous effects in
all analysed subgroups. An important study limitation was
the lack of information on circulating levels of inflamma-
tory indices before and after treatment.
Thus, LoDoCo2 and COLCOT appear to close the circle,
confirming that inflammation is a determinant of ischae-
mic heart disease progression and atherothrombosis, and
that anti-inflammatory drugs can prevent MACEs in
patients with recent MI (COLCOT) or chronic coronary syn-
drome (LoDoCo2).
Conclusions and perspectives
Recent large-scale placebo-controlled trials have con-
firmed the role of inflammation in the pathogenesis of
atherothrombotic events by demonstrating that specific
anti-inflammatory drugs are able to prevent MACE in
patients with ischaemic heart disease. As a result, the ther-
apeutic options for secondary prevention of cardiovascular
events are expanding. CANTOS demonstrated a significant
involvement of IL1bin atherothrombosis, and the colchi-
cine trials have confirmed the benefits of anti-
inflammatory therapy in patients with recent MI or chronic
coronary syndromes using a well-known, reasonably safe
and economical treatment. Inflammation can therefore be
added to the three traditional therapeutic targets of
atherothrombotic diseases (thrombosis, dyslipidaemia,
neuroendocrine activation) (Figure 2).
1
Forthcoming inter-
national guidelines will very likely provide indications on
the use of colchicine for the secondary prevention of
MACE. The addition of a new drug to existing ones will trig-
ger discussion on the problem of medical adherence, for
both prescribers and patients, and may stimulate de-
prescribing strategies.
1
Education on evidence-based med-
icine and, even more so, implementation strategies may be
useful, including sharing health protocols within, among
and out of hospitals.
1
Research with colchicine is extending
to other vascular fields—such as prevention of MACE in
patients with previous stroke or transient ischaemic attack
and prevention of nephropathy progression in patients with
diabetes and microalbuminuria—as well as areas not
strictly cardiovascular, such as coronavirus-2019 disease.
1
The large-scale evaluation of the specific IL6 inhibitor, zilti-
vekimab, will provide further interesting data.
9
Conflict of interest: F.A. reports receiving personal fees from
Amgen, Bayer, BMS-Pfizer, Daiichi Sankyo, Medscape and Radcliffe
Cardiology outside the present work. A.P.M. reports fees from
AstraZeneca, Bayer, Fresenius, Novartis for participation in study
committees outside the present work. The other authors report
that they are unaware of any economical or personal conflict af-
fecting the content of this work.
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