biomedicines

Review
Exploring the Landscape of Anti-Inflammatory Trials:
A Comprehensive Review of Strategies for Targeting
Inflammation in Acute Myocardial Infraction
Andreas Mitsis 1 , Michaela Kyriakou 1 , Stefanos Sokratous 1 , Georgia Karmioti 1 , Michail Drakomathioulakis 1 ,
Michael Myrianthefs 1 , Antonios Ziakas 2 , Stergios Tzikas 3 and George Kassimis 4, *

1 Cardiology Department, Nicosia General Hospital, Nicosia 2029, Cyprus; andymits7@gmail.com (A.M.);
michaelakyriakou95@yahoo.com (M.K.); stefanossokratous94@gmail.com (S.S.);
georgiakarm@outlook.com (G.K.); bageragr@gmail.com (M.D.); myr.michael@shso.org.cy (M.M.)
2 First Department of Cardiology, AHEPA University Hospital, Aristotle University of Thessaloniki,
54636 Thessaloniki, Greece; aziakas@auth.gr
3 Third Department of Cardiology, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
4 Second Department of Cardiology, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
* Correspondence: gksup@yahoo.gr; Tel.: +30-2310892349

Abstract: The role of inflammation in the pathophysiology of acute myocardial infarction (AMI)
is well established. In recognizing inflammation’s pivotal role in AMI, this manuscript systemati-
cally traces the historical studies spanning from early attempts to the present landscape. Several
anti-inflammatory trials targeting inflammation in post-AMI have been performed, and this review in-
cludes the key trials, as well as examines their designs, patient demographics, and primary outcomes.
Efficacies and challenges are analyzed, thereby shedding light on the translational implications of
trial outcomes. This article also discusses emerging trends, ongoing research, and potential future
directions in the field. Practical applications and implications for clinical practice are considered by
Citation: Mitsis, A.; Kyriakou, M.; providing a holistic view of the evolving landscape of anti-inflammatory interventions in the context
Sokratous, S.; Karmioti, G.;
of AMI.
Drakomathioulakis, M.; Myrianthefs,
M.; Ziakas, A.; Tzikas, S.; Kassimis, G.
Keywords: acute myocardial infarction; anti-inflammatory interventions; canakinumab; colchicine;
Exploring the Landscape of
coronary artery disease; IL-6; inflammation
Anti-Inflammatory Trials: A
Comprehensive Review of Strategies
for Targeting Inflammation in Acute
Myocardial Infraction. Biomedicines
2024, 12, 701. https://doi.org/ 1. Introduction
10.3390/biomedicines12030701 Acute myocardial infarction (AMI) stands as a primary contributor to mortality and
morbidity in cardiovascular disease (CVD) [1]. AMI is characterized by a complex interplay
Academic Editor: Dong
Wang
of physiological responses, including inflammation. The significance of inflammation in
AMI is underlined by its role in aggravating tissue damage, influencing plaque stability, and
Received: 25 February 2024 contributing to adverse cardiac remodeling [2,3]. Recognizing inflammation as a key player
Revised: 18 March 2024 in the outcome of AMI has prompted a growing interest in anti-inflammatory interventions
Accepted: 20 March 2024 as potential therapeutic strategies [4].
Published: 21 March 2024
Early attempts to address inflammation in the context of AMI were marked by a
gradual understanding of the complex relationship between inflammation and cardiac
events [5,6]. Initial interventions primarily focused on broad-spectrum, anti-inflammatory
Copyright: © 2024 by the authors.
agents, and the aim was to mitigate the inflammatory response associated with AMI [7,8].
Licensee MDPI, Basel, Switzerland. Over time, as our understanding of the inflammatory pathways has developed, interven-
This article is an open access article tions have evolved to target specific components of the inflammatory cascade [9], and there
distributed under the terms and has been a shift toward more dedicated strategies, including the exploration of cytokine
conditions of the Creative Commons modulation, antiplatelet agents [10,11], and immune-modulating therapies [12]. The evo-
Attribution (CC BY) license (https:// lution of these interventions reflects a growing awareness of the multifaceted nature of
creativecommons.org/licenses/by/ inflammation in AMI, thereby leading to more refined and targeted approaches to address
4.0/). this crucial aspect of cardiovascular (CV) pathology [13].

Biomedicines 2024, 12, 701. https://doi.org/10.3390/biomedicines12030701 https://www.mdpi.com/journal/biomedicines

Biomedicines 2024, 12, 701 2 of 18

This comprehensive review aims to explore various strategies targeting inflammation

post-AMI by providing insights into their mechanisms and clinical outcomes, thereby em-
phasizing their importance in enhancing CV health. The scope encompasses an exploration
of various agents, mechanisms, and clinical outcomes, thus shedding light on the evolving
landscape of therapeutic interventions that are aimed at mitigating inflammation in the
context of AMI.

2. Classification of Anti-Inflammatory Trials in AMI

Organizing and classifying anti-inflammatory trials in CVD can be approached system-
atically. Anti-inflammatory trials can be classified according to the targeted inflammatory
pathway, according to the class of anti-inflammatory drugs under investigation, and ac-
cording to the patient population, as well as according to the outcome measures or even
the trial phase (Table 1). This methodical approach enhances a thorough comprehension
of the landscape and provides systematic organization for researchers, clinicians, and
policymakers engaged in AMI-related inflammation research.

Table 1. Approaches to organize and classify anti-inflammatory trials.

Targeted Class of
Inflammatory Anti-Inflammatory Patient Population Outcome Measures Trial Phase Trial Result
Pathway Drug
Trials assessing the
Early-phase trials
Studies with impact on infarct
Studies targeting the (trials assessing the
specific-target anti- ACS patients size through Positive result
IL-6 pathway safety and
inflammatory agents anti-inflammatory
initial efficacy)
interventions.
Late-phase trials
Trials measuring
Studies with broad (larger trials
Trials outside the IL-6 clinical endpoints
anti- Stable CAD patients evaluating Negative result
pathway like
inflammatory agents effectiveness in a
MACE reduction.
broader population)
ACS: acute coronary syndrome; CAD: coronary artery disease; IL-6: interleukine-6; and MACE: major adverse
cardiovascular event.

From the pathophysiology viewpoint, the ideal approach is to categorize inflammatory

trials based on the specific inflammatory pathways or mediators targeted. Based on this,
anti-inflammatory strategies can be classified into two main groups: those targeting the central
interleukin-1 (IL-1), tumor necrosis factor-a (TNF-α), and interleukin-6 (IL-6) inflammatory
signaling pathways; and those that operate independently of it [14]. The central IL-6 pathway
plays a crucial role in the inflammatory signaling involved in the onset and advancement of
CVD [15]. IL-6 coordinates the recruitment of immune cells to the injured myocardium [16].
It promotes the production of acute-phase proteins, such as the C-reactive protein (CRP),
which serve as markers of inflammation [17]. Additionally, IL-6 influences the differentiation
and activation of immune cells, thereby contributing to the inflammatory environment in
the infarcted tissue [18,19]. In the other inflammatory cascade during AMI, key molecules
outside the IL-6 pathway include matrix metalloproteinase-9 (MMP-9) [20], phospholipase-
2 (PLA2) [21], P-selectin, E-selectin, intercellular cell adhesion molecule-1 (ICAM-1) [22],
growth differentiation factor-15 (GDF-15) [23,24], and p38-mitogen-activated protein kinase
(MAPK) [25]. These molecules collectively contribute to the interplay responses observed
in the outcome of AMI, showing the complex nature of the inflammatory cascade in CV
pathology. Therefore, addressing these elements within the central IL-6 signaling pathway or
alternative inflammatory signaling pathways has the potential to delay the advancement of
CV and systemic inflammation, thereby improving CV prognosis [26].
The pathophysiological organization of the anti-inflammatory trials is actual and
reasonable but increasing the complexity might create confusion. For the purposes of this
review, we decided to present the available studies based on the class of anti-inflammatory
drugs under investigation, and the studies were divided in two categories: specific-target
anti-inflammatory agents and broad-spectrum, anti-inflammatory agents (Tables 2 and 3,
Biomedicines 2024, 12, 701 3 of 18

respectively). This review encompasses the late-phase trials meeting the specific following
criteria: (1) those conducted on individuals with established CVD; (2) those comparing
anti-inflammatory therapies to a placebo; and (3) those designed to not only evaluate CV
clinical outcomes and reporting on CV events and/or infarct size, but also on the effect on
specific inflammatory biomarkers.

Table 2. Summary of clinical studies with specific-target, anti-inflammatory agents.

Notable Features
Patient Follow up Population
Trial Name Year Intervention Key Findings and
Population Period (Number)
Considerations
Notable for
CANTOS Reduction in
targeting
(Canakinumab recurrent
Patients with interleukin-1β and
Anti- Canakinumab cardiovascular
prior MI and demonstrating a
inflammatory 2017 (IL-1β 48 months 10,061 events in
elevated link between
Thrombosis inhibitor) patients
hsCRP inflammation
Outcomes receiving
(hsCRP) and
Study) canakinumab.
cardiovascular risk.
VISTA-16
(Vascular No significant Failed to prove the
Inflammation Varespladib ACS patients reduction in benefit of
Suppression to (phospholi- (47% STEMI, major varespladib in
2014 16 weeks 5145
Treat Acute pase A2 38% NSTEMI, cardiovascular patients with recent
Coronary inhibitor) 15% UA) events with ACS who were on
Syndrome for varespladib. atorvastatin.
16 Weeks)
LATITUDE-
TIMI 60 trial No reduction
(Losmapimod for recurrent
Failed to support a
to Inhibit p38 MACEs events
strategy of p38
MAP Kinase as over the
Losmapimod ACS patients MAPK inhibition
a Therapeutic 12-week
2016 (p38 MAPK (25% STEMI, 24 weeks 3503 with losmapimod
Target and treatment
inhibitor) 75% NSTEMI) in patients
Modify period in
hospitalized
Outcomes patients
with MI.
After an Acute hospitalized
Coronary with ACS.
Syndrome)
SOLID-TIMI 52
trial
Darapladib Darapladib did Failed to support
(Stabilization
(lipoprotein- ACS patients not reduce the the use of targeted
of plaques
associated (45.2% STEMI, 2.5 years risk of Lp-PLA2 inhibition
using 2014 13,026
phospholipase 42.7 NSTEMI, median recurrent with darapladib in
Darapladib-
A2 (Lp-PLA2) and 12.2% UA) major coronary patients stabilized
Thrombolysis
inhibitor) events. after an ACS event.
in Myocardial
Infarction)
Conducted at three
Tocilizumab
high-volume PCI
increased the
centers in Norway;
ASSAIL-MI myocardial
the single infusion
(Assessing the salvage index
of 280 mg
effect of Tocilizumab STEMI patients compared to
tocilizumab or
Anti-IL-6 2021 (IL-6 receptor admitted 7 days 199 placebo. No
placebo; and the
treatment in antagonist) within 6 h significant
primary endpoint:
Myocardial difference in
the myocardial
Infarction) the final infarct
salvage index
size (7.2% vs.
measured by MRI
9.1%, p = 0.08).
after 3 to 7 days.
Biomedicines 2024, 12, 701 4 of 18

Table 2. Cont.

Notable Features
Patient Follow up Population
Trial Name Year Intervention Key Findings and
Population Period (Number)
Considerations
Inclacumab at
SELECT ACS 20 mg/kg
(Effects of the demonstrated
P-Selectin a significant
Antagonist reduction in The P-selectin
Inclacumab on troponin I antagonist
24 h for
Myocardial NSTEMI levels at 24 h (p inclacumab
Inclacumab efficacy and
Damage After patients = 0.05) and 16 reduced
2013 (anti-P- 120 days for 544
Percutaneous undergoing h (p = 0.07) myocardial
selectin) safety
Coronary PCI after PCI damage after PCI
evaluations
Intervention compared to in patients with
for Non-ST- placebo. NSTEMI.
Elevation Adverse events
Myocardial did not
Infarction) significantly
differ.
ACS: acute coronary syndrome; hsCRP: high-sensitive C reactive protein; MI: myocardial infarction; NSTEMI:
non-ST elevation MI; PCI: percutaneous coronary intervention; p38 MAPK: p38 mitogen-activated protein kinases;
STEMI: ST elevation MI; and UA: unstable angina.

Table 3. Summary of the clinical studies with broad-spectrum, anti-inflammatory agents.

Notable Features
Trial Patient Follow up Population
Year Intervention Key Findings and
Name Population Period (Number)
Considerations
Diarrhea was
COLCOT Reduction in reported in 9.7% of
(Colchicine cardiovascular the patients in the
Cardiovas- Patients Median 22.6 events in colchicine group
2019 Colchicine 4745
cular post-MI months patients and in 8.9% of
Out- receiving those in the
comes Trial) colchicine. placebo group
(p = 0.35).
LoDoCo2 Reduction in Focused on
(Low-Dose major evaluating the
Colchicine Patients Median 28.6 cardiovascular efficacy of a lower
2020 Colchicine 5522
after My- post-MI months events with colchicine dose in
ocardial low-dose cardiovascular
Infarction) colchicine. event prevention.
The addition of
colchicine to
standard
COPS medical
(Colchicine therapy did
Colchicine was
in Patients not
associated with a
with Acute 2020 Colchicine ACS 12 months 795 significantly
higher rate of
Coronary affect
mortality.
Syn- cardiovascular
dromes) outcomes at 12
months in
patients with
ACS.
Biomedicines 2024, 12, 701 5 of 18

Table 3. Cont.

Notable Features
Trial Patient Follow up Population
Year Intervention Key Findings and
Name Population Period (Number)
Considerations
Methotrexate was
associated with
modest elevations
CIRT Methotrexate in liver enzyme
History of MI
(Cardio- did not affect levels and
or multi-vessel
vascular the reductions in
CAD, and type Median 2.3
Inflamma- 2019 Methotrexate 4786 cardiovascular leukocyte counts
2 DM and/or years
tion outcomes or and hematocrit
metabolic
Reduction plasma levels, as well as a
syndrome
Trial) markers. higher incidence of
non-basal cell skin
cancers than
placebo.
AIM-
HIGH
(Atherothrom-
bosis
Interven-
The trial did Raised questions
tion in
not about the efficacy
Metabolic Patients with a
demonstrate of niacin in
Syndrome Extended- history of
2011 3 years 3414 additional improving
with Low Release Niacin cardiovascular
cardiovascular cardiovascular
HDL/High disease
benefit from outcomes in this
Triglyc-
niacin therapy. patient population.
erides:
Impact on
Global
Health
Outcomes)
ALL-
HEART While allopurinol
study (Al- has benefits in
lopurinol No significant other conditions
Patients with a
versus difference in like gout, its role in
history of
usual care the primary reducing
Allopurinol cardiovascular Mean 4.8 years 5721
in UK outcome cardiovascular
disease and
patients between the events in patients
without gout
with two groups with CAD without
ischemic gout may be
heart limited
disease))
ACS: acute coronary syndrome; CAD: coronary artery disease; DM: diabetes mellitus; and MI: myocardial
infarction.

3. Studies with Specific-Target Anti-Inflammatory Agents

3.1. CANTOS Study (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study)
The canakinumab anti-inflammatory thrombosis outcome study (CANTOS) was a ran-
domized, double-blind, and placebo-controlled trial involving stable patients with previous
myocardial infarction (MI), and it was evaluated whether canakinumab could prevent
recurrent vascular events in men and women who have a persistent proinflammatory
response [27].
Canakinumab, an interleukin-1 beta (IL-1β) inhibitor, was approved for use in several
rare, heritable pediatric conditions associated with IL-1β over-expression [28]. The CAN-
TOS trial examined the efficacy of canakinumab in reducing the CV events among 10,061
patients with a history of MI and elevated high-sensitivity C-reactive proteins (hsCRPs).
The primary endpoint included major adverse CV events (MACE)—a composite of non-
fatal MI, stroke, and CV death. The trial demonstrated a significant reduction in MACE
in the canakinumab group, with a hazard ratio (HR) of 0.85 [95% confidence interval (CI)
0.74–0.98] and a p-value below 0.05. This landmark trial highlighted the link between in-
Biomedicines 2024, 12, 701 6 of 18

flammation, as indicated by hsCRP levels, and CV risk, thereby paving the way for targeted
anti-inflammatory therapies in CVD [29]. The CANTOS trial demonstrated that inflamma-
tion plays a treatable role in atherosclerosis. By pinpointing IL-1β as a viable therapeutic
target, it is poised to stimulate additional clinical investigations and the development of
anti-inflammatory agents for CV prevention [30].

3.2. VISTA-16 Trial (Vascular Inflammation Suppression to Treat Acute Coronary Syndrome
for 16 Weeks)
The plasma level of secretory PLA2 is a known risk factor for CAD and is associ-
ated with adverse outcomes in patients with stable CAD and acute coronary syndromes
(ACS) [31–33]. The VISTA-16 trial, initiated in 2006, set out to investigate the efficacy of
varespladib, which is a potent anti-inflammatory agent, by interfering with arachidonic acid
metabolism (inhibitor of secretory PLA2) in terms of suppressing the vascular inflammation
among patients with ACS. This randomized, double-blind trial enrolled 5145 participants
and aimed to evaluate the impact of varespladib on MACE [34].
The trial was prematurely terminated in 2012 due to futility, as varespladib failed to
demonstrate a statistically significant reduction in CV events compared to the placebo group
(6.1% vs. 5.1%; HR, 1.25; 95% CI, 0.97–1.61; and p-value = 0.08). Of note, the composite
secondary outcome of CV mortality, MI, and stroke was higher in the varespladib arm
(4.6% vs. 3.8%, HR, 1.36; 95% CI, 1.02–1.82; p-value = 0.04). This was due primarily to a
greater incidence of MI in the varespladib arm (3.4% vs. 2.2%; p = 0.005) [35]. The absence
of a meaningful clinical benefit, coupled with the trial’s termination, underscored the
limitations and challenges associated with targeting the secretory PLA2 as a therapeutic
approach in ACS [36]. The findings prompted a critical reevaluation of the potential role of
this pathway in ACS treatment strategies.

3.3. LATITUDE-TIMI 60 Trial (Losmapimod to Inhibit p38 MAP Kinase as a Therapeutic Target
and Modify Outcomes after an Acute Coronary Syndrome)
Losmapimod is a selective, reversible, and competitive inhibitor of p38 MAPK [37].
MAPK-mediated inflammatory augmentation has been implicated in atherogenesis, plaque
destabilization, and the detrimental processes in infarction and recovery [38], and it is
considered an alternative inflammatory signaling pathway that acts outside the IL-6 path-
way [39,40]. Preliminary data have shown that the use of losmapimod in non ST elevation
MI (NSTEMI) patients attenuates inflammation and may improve outcomes [41].
The LATITUDE-TIMI 60 trial, a pivotal multinational investigation that delved into
the efficacy and safety of losmapimod, was administered at a dosage of 7.5 mg twice daily
in a cohort of 3503 patients that were presenting with ACS [42]. Contrary to expectations,
the trial did not reveal a significant reduction in MACEs, including CV death, MI, and
stroke (8.1% vs. 7.0%, HR, 1.16; 95% CI, 0.91–1.47; p-value = 0.24) [42]. Losmapimod
did not demonstrate a risk reduction for recurrent MACE events over the 12-week treat-
ment period in patients hospitalized with ACS. Additionally, there was no indication that
losmapimod influenced the occurrence of secondary outcomes, including all-cause mor-
tality. Consequently, this study does not endorse the adoption of a strategy involving p38
MAPK inhibition with losmapimod for patients admitted with MI [43].

3.4. SOLID-TIMI 52 Trial (Stabilization of Plaques Using Darapladib-Thrombolysis in Myocardial

Infarction 52)
Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been proposed as a potential
causal factor in atherosclerosis development, and it has also been suggested to contribute
to plaque instability via the pathways associated with inflammation [32,44]. Darapladib
is an oral selective Lp-PLA2 inhibitor that reduces Lp-PLA2 activity in plasma5 and in
atherosclerotic plaques [45]. The use of darapladib in stable coronary artery patients did
not show a significant reduction in the primary composite endpoint [46].
The SOLID-TIMI 52 trial, which was initiated in 2010, was a randomized, double-blind,
placebo-controlled, multicenter, and event-driven trial. The focus was on investigating
Biomedicines 2024, 12, 701 7 of 18

the role of darapladib in stabilizing atherosclerotic plaques and reducing CV events [47].
Enrolling over 13,000 patients, the trial aimed to evaluate darapladib’s impact on MACEs,
such as CV death, MI, and stroke. However, the trial did not meet its primary endpoint
as darapladib did not significantly reduce the risk of MACE compared to placebo [48].
The findings of SOLID-TIMI 52 raised questions about the role of Lp-PLA2 inhibition as a
therapeutic target and prompted a further exploration of alternative approaches to address
CV risk in patients with chronic CAD.

3.5. ASSAIL-MI-Trial (Assessing the Effect of Anti-IL-6 Treatment in Myocardial Infarction)

IL-6 is the crucial pro-inflammatory cytokine that is upregulated during MI, and it
affects both plaque destabilization and myocardial remodeling [49,50]. Tocilizumab, an IL-6
receptor antagonist, can attenuate the inflammatory response and primarily the PCI-related
TnT release in NSTEMI patients [12]. The ASSAIL-MI trial, a randomized, double-blind,
and placebo-controlled study, was conducted at three high-volume PCI centers in Norway,
where it was designed to evaluate the effect of tocilizumab on myocardial salvage in
patients with acute ST-elevation MI (STEMI) [51,52]. Eligible participants included patients
admitted with STEMI within 6 h of symptom onset. In a 1:1 randomization, consenting
patients received a single infusion of either 280 mg tocilizumab or placebo promptly.
The primary endpoint, evaluated using magnetic resonance imaging after 3 to 7 days, was
the myocardial salvage index [52].
Out of the total, 101 patients were randomized to receive tocilizumab, and 98 patients
received the placebo. The tocilizumab group exhibited a larger myocardial salvage index
compared to the placebo group, with an adjusted between-group difference of 5.6 (95%
CI: 0.2 to 11.3) percentage points (p-value = 0.04). While microvascular obstruction was
less extensive in the tocilizumab arm, there was no significant difference in the final
infarct size between the tocilizumab and placebo arms (7.2% vs. 9.1% of myocardial
volume, p-value = 0.08). Adverse events were evenly distributed across the treatment
groups. In conclusion, tocilizumab demonstrated an increase in myocardial salvage among
patients with acute STEMI in the ASSAIL-MI trial [52].

3.6. SELECT-ACS (Effects of the P-Selectin Antagonist Inclacumab on Myocardial Damage after
Percutaneous Coronary Intervention for Non-ST-Elevation Myocardial Infarction)
The SELECT ACS trial aimed to assess the efficacy of inclacumab in reducing myocar-
dial damage during percutaneous coronary intervention (PCI) in patients with NSTEMI [53].
P-selectin, an adhesion molecule involved in cellular interactions (particularly among
endothelial cells, platelets, and leukocytes), served as the target [54]. Inclacumab, a re-
combinant monoclonal antibody against P-selectin, was evaluated for its potential anti-
inflammatory, antithrombotic, and antiatherogenic properties [55].
In this randomized trial involving 544 NSTEMI patients scheduled for coronary an-
giography and possible ad hoc PCI, the participants received one pre-procedural infusion
of inclacumab at either 5 or 20 mg/kg or a placebo. The primary endpoint, assessed in
patients who underwent PCI and received the study medication with available efficacy
data (n = 322), was the change in troponin I from the baseline at 16 and 24 h after PCI.
The results indicated that inclacumab at 20 mg/kg demonstrated a significant reduc-
tion in troponin I levels, with a placebo-adjusted geometric mean percent change of −24.4%
at 24 h (p-value = 0.05) and −22.4% at 16 h (p-value = 0.07). Similar trends were observed
in the peak troponin I levels and the area under the curve over 24 h. The creatine kinase–
myocardial band also showed reductions with inclacumab at 20 mg/kg [53]. Notably,
adverse events did not significantly differ between the groups. In conclusion, inclacumab
appeared to effectively diminish the myocardial damage following PCI in patients with
NSTEMI [56].
Biomedicines 2024, 12, 701 8 of 18

4. Studies with Broad-Spectrum Anti-Inflammatory Agents

4.1. COLCOT Trial (Colchicine Cardiovascular Outcomes Trial)
Published in 2019, the COLCOT trial investigated the use of colchicine in 4745 post-MI
patients [57]. Colchicine has a broad cellular effect that includes the inhibition of tubulin
polymerization and the alteration of leukocyte responsiveness [58]. The primary endpoint,
a composite of CV death, MI, stroke, resuscitated cardiac arrest, and urgent hospitalization
for angina leading to coronary revascularization, exhibited an HR of 0.77 (95% CI 0.61–0.96),
with a statistically significant p-value of 0.02. In individuals who recently experienced
an MI, the use of low-dose colchicine demonstrated efficacy in preventing MACEs when
compared to a placebo. The primary benefit stemmed from a notable reduction in the
occurrence of stroke and the need for urgent hospitalization due to unstable angina leading
to revascularization. Notably, colchicine exhibited positive effects, particularly among
patients with diabetes. The study drug was well tolerated and exhibited a similar incidence
of infection and diarrhea compared to the placebo (9.7% vs. 8.9%, p-value = 0.35). Addi-
tionally, colchicine was deemed cost-effective. The observed advantages of colchicine were
attributed to the anti-inflammatory properties inherent in the drug. This trial underscored
the potential of colchicine in preventing major CV events in this high-risk population,
thereby shedding light on a novel anti-inflammatory approach in post-MI care [59].

4.2. LoDoCo2 Trial (Low-Dose Colchicine after Myocardial Infarction)

The LoDoCo trial was designed to determine whether colchicine—a broad-spectrum,
anti-inflammatory agent—when administered at 0.5 mg/day could minimize the risk of CV
events in patients with clinically stable coronary disease [60]. The study was not placebo-
controlled, and the primary outcome was the composite incidence of ACS, out-of-hospital
cardiac arrest, or non-cardioembolic ischemic stroke. A total of 532 patients were included in
the study. The primary outcome occurred in 15 of 282 patients (5.3%) who received colchicine
and 40 of 250 patients (16.0%) who were assigned no colchicine (hazard ratio: 0.33; 95%
confidence interval [CI] 0.18 to 0.59; p < 0.001; and number needed to treat: 11) [60].
The larger LoDoCo2 trial aimed to confirm the result of the LoDoCo trial. It was
conducted in 2020 and enrolled 5522 post-myocardial infarction participants, and it focused
on assessing the impact of low-dose colchicine on MACEs [61]. The primary endpoint, a
composite of CV death, MI, ischemic stroke, or urgent hospitalization for angina requiring
revascularization, exhibited a hazard ratio of 0.69 (95% CI 0.50–0.96), with a statistically
significant p-value of 0.02 [62]. These trials not only confirmed the efficacy of colchicine in
reducing CV risk, but also highlighted the potential benefits of using a lower colchicine
dose in post-MI patients [63].

4.3. COPS Trial (Colchicine in Patients with Acute Coronary Syndrome)

COPS was multicenter, randomized, double-blind, and placebo-controlled trial in-
volving 17 hospitals in Australia that provide acute cardiac care service [64]. The study
enrolled 795 participants with ACS and investigated the potential utility of colchicine.
The patients were randomized to receive colchicine or placebo in addition to standard
secondary prevention pharmacotherapy, and they were followed up with for a minimum
of 12 months. The primary outcome—a composite of all-cause mortality, ACS, unplanned
urgent revascularization, and noncardioembolic ischemic stroke—did not significantly
differ between the colchicine and placebo groups at 12 months (24 vs. 38 events and
p-value = 0.09). Of note, the colchicine group showed a higher rate of total death, par-
ticularly non-CV death (p-value= 0.024). Adverse effects were similar between groups.
In conclusion, colchicine did not significantly impact CV outcomes and was associated
with a higher mortality rate in ACS patients.

4.4. CIRT Trial (Cardiovascular Inflammation Reduction Trial)

The Cardiovascular Inflammation Reduction Trial (CIRT), initiated in 2019, inves-
tigated the impact of low-dose methotrexate on CV events among individuals with a
Biomedicines 2024, 12, 701 9 of 18

history of MI or multi-vessel CAD, and either type 2 diabetes or metabolic syndrome [65].
Enrolling a sizable population of 4786 patients, the trial aimed to discern the potential
benefits of methotrexate in reducing MACE for a median follow up period of 2.3 years.
The primary end point at the onset of the trial was a composite of nonfatal MI, nonfa-
tal stroke, or CV death, as well as hospitalization due to unstable angina. Methotrexate
did not result in lower IL-1β, IL-6, or CRP levels than placebo. The final primary end
point occurred in 201 patients in the methotrexate group and in 207 in the placebo group
(4.13 vs. 4.31 per 100 person-years; HR, 0.96; 95% CI, and 0.79 to 1.16). The original primary
end point occurred in 170 patients in the methotrexate group and in 167 in the placebo
group (3.46 vs. 3.43 per 100 person-years; hazard ratio, 1.01; 95% CI, and 0.82 to 1.25) [66].

4.5. AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High

Triglycerides: Impact on Global Health Outcomes)
Conducted in 2011, the AIM-HIGH trial assessed extended-release niacin in 3414 pa-
tients with a history of CVD and dyslipidemia. The trial did not demonstrate additional CV
benefit from niacin therapy compared to placebo. The hazard ratio for the primary compos-
ite endpoint of cardiovascular events was 1.02 (95% CI 0.87–1.21), with a non-significant
p-value of 0.79 [67]. AIM-HIGH raised questions about the efficacy of niacin in improv-
ing cardiovascular outcomes in this specific patient population, influencing subsequent
considerations regarding niacin therapy in CV care [68].

4.6. ALL-Heart Study (Allopurinol versus Usual Care in UK Patients with Ischemic
Heart Disease)
Elevated levels of serum uric acid have been linked to unfavorable CV outcomes [69].
While certain observational studies propose that therapy aimed at lowering uric acid may
decrease CV risk [70], conflicting evidence exists as other studies have not observed similar
benefits [71]. Allopurinol, a xanthine oxidase inhibitor, was approved for gout prophylaxis,
symptomatic hyperuricemia treatment, and hyperuricemia prevention related to cancer
chemotherapy. Allopurinol’s potential benefits for patients with ischemic heart disease
may extend beyond its ability to lower serum uric acid levels. This includes its impact on
decreasing the vascular oxidative stress mediated by xanthine oxidase, which could be a
separate mechanism from its uric acid-lowering effects [72,73].
The ALL-HEART trial, a multicenter, prospective, and randomized study, aimed
to investigate the impact of allopurinol therapy in patients aged 60 years or older with
ischemic heart disease and no history of gout. The primary outcome, a composite of non-
fatal myocardial infarction, non-fatal stroke, or CV death, showed no significant difference
between the allopurinol and usual care groups. Over a mean follow-up of 4.8 years, the
rates of the primary endpoint and overall mortality were similar between the groups, thus
suggesting that allopurinol therapy does not confer additional CV benefits in this specific
population [74].

5. Discussion
The studies reviewed above demonstrate that only CANTOS with canakinumab—as
well as COLCOT, and LoDoCo2 with colchicine—achieved favorable clinical outcomes.
The smaller trials like ASSAIL-MI with tocilizumab and SELECT-ACS with inclacumab,
which assessed myocardial damage using CMR or troponin levels, showed promising
results but need larger controlled studies to fully examine their impact on clinical outcomes.
Conversely, the remaining randomized trials did not show evidence that anti-inflammatory
therapies can alter the prognosis in patients with CVD. This emphasizes that not all anti-
inflammatory treatments are equivalent, and the method by which inflammation is reduced
probably determines whether a particular anti-inflammatory drug will lower CV events. There-
fore, a thorough examination and analysis of each study’s design can yield valuable insights.
When comparing CANTOS and CIRT, significant differences may contribute to their
divergent outcomes [29,66]. While both trials primarily enrolled patients already on statin
therapy, the patients in CIRT study achieved better LDL-C control and fell below the current
Biomedicines 2024, 12, 701 10 of 18

guideline target (<70 mg/dL). Moreover, CANTOS required participants to have hsCRP
levels of ≥2 mg/L, while CIRT did not mandate elevated hsCRP levels. Consequently,
baseline hsCRP values were higher in CANTOS, thereby indicating a population with
greater residual inflammatory risk. The most notable contrast lies in how these trials
addressed inflammation: while CANTOS directly targeted the IL-1β pathway, thereby
reducing the downstream mediators IL-6 and hsCRP, CIRT lowered inflammation (lower
WBC) without altering IL-1β, IL-6, or hsCRP. Hence, the efficacy of anti-inflammatory
therapies may vary, with the mechanism of inflammation reduction likely determining
their impact on CV events.
The extent of hsCRP decrease after a single dose of canakinumab could offer a straight-
forward clinical approach to pinpoint individuals who may gain the greatest advantage
from ongoing treatment [75]. Extracting this discovery in the design of all the other trials
could explain that the inability to show effectiveness could also be linked to the mechanism,
thereby highlighting the importance of selecting the appropriate inflammatory target or
drug when inhibiting inflammation in CVD.
The remarkable outcome from the CANTOS trial demonstrated the successful reduc-
tion in CV risk with canakinumab therapy, thus highlighting the crucial inflammatory
targets likely concentrated within the IL-1β to IL-6 to the CRP pathway [76]. Theoreti-
cally, colchicine, the other effective broad anti-inflammatory medication, has the potential
to irreversibly inhibit the NLRP3 inflammasome, which leads to neutrophil dysfunction.
This mechanism results in decreased circulating levels of IL-1β, IL-6, and CRP [77]. How-
ever, the mechanism of the CV that benefits from colchicine needs further evaluation.
Based on the LoDoCo2 and CLCOT trials, low-dose colchicine has been considered
the ideal anti-inflammatory treatment in patients with stable CAD [78]. Of note, a re-
cent meta-analysis included more than 11,550 patients from the studies COLCOT, COPS,
LoDoCo, and LoDoCo2, which showed that, in the secondary prevention of CV events,
augmented standard medical therapy with low-dose colchicine decreases the occurrence
of major CV events, except for CV mortality, in comparison to standard medical therapy
alone [79]. The decrease in inflammation could be a critical factor in the effectiveness of
low-dose colchicine in reducing the risk of recurrent cardiovascular events post-MI. Regular
monitoring of hs-CRP levels before and after colchicine treatment could be significant [80].
It is important to highlight that many other cardiovascular medications have been
shown to have anti-inflammatory effects. These drugs, through their various mecha-
nisms, contribute to the management of inflammation in the cardiovascular system and
may provide additional benefits beyond their primary indications. Statins, such as ator-
vastatin and rosuvastatin, exert pleiotropic effects beyond cholesterol reduction, includ-
ing anti-inflammatory properties [81]. Ticagrelor, an antiplatelet agent, also shows anti-
inflammatory effects beyond its primary role, and it is potentially achieved via improve-
ment of vascular function and myocardial perfusion [82]. Interestingly, the research com-
paring ticagrelor to clopidogrel has assessed the impact of ticagrelor on CRP levels, which
is a marker of inflammation and hints at potential anti-inflammatory actions beyond its
antithrombotic effects [83]. Similarly, angiotensin-converting enzyme (ACE) inhibitors
like lisinopril and angiotensin II receptor blockers (ARBs), such as losartan exhibit anti-
inflammatory properties, reduce inflammation in the cardiovascular system [84,85]. Met-
formin, commonly used in diabetes management, has been found to have anti-inflammatory
effects, which improves endothelial function [86]. Finally, thiazolidinediones like piogli-
tazone, act on peroxisome proliferator-activated receptors (PPAR-gamma agonists), and
this also demonstrates anti-inflammatory actions [87]. Additional research is required
to investigate the potential prognostic significance of these medications based on their
anti-inflammatory effects.

6. Future Directions and Emerging Trends

Looking into the future of inflammation-targeted strategies in CV health, the trajectory
is being guided by several key elements. Ongoing research and upcoming trials are com-
Biomedicines 2024, 12, 701 11 of 18

posed to unravel deeper insights into the complexities of inflammatory pathways, thereby
providing a novel understanding of their role in CV dynamics [88,89]. As the scientific
community strives to expand its knowledge base, innovative approaches are anticipated
to take center stage. These may encompass precision medicine [90], advanced imaging
techniques [91], and evolving pharmacotherapies designed to modulate inflammation with
greater specificity [92]. Table 4 includes summaries of all the ongoing clinical studies of
treatments targeting inflammation in the context of atherosclerosis and AMI.

Table 4. Summary of the ongoing clinical studies of treatments targeting inflammation in the context
of atherosclerosis and acute myocardial infarction.

Patient Population Primary Clinical Trials

Trial Name Study Design Intervention Target
Population (Number) Outcome Identifier
Phase III,
Patients with
multicenter,
IL-6 blocking CKD stage 3 to Time to first
double-blind,
ZEUS Ziltivekimab monoclonal 4, known CAD, 6200 occurrence of NCT05021835
randomized,
antibody and a hs-CRP MACE
and placebo-
of >2 mg/L
controlled
Time to first
occurrence of
Phase III,
Antisense Patients with expanded
multicenter,
oligonu- established MACE in
Lp(a) double-blind,
Pelacarsen cleotide CVD and a 7680 patients with a NCT04023552
HORIZON randomized,
targeting Lp(a) of ≥70 Lp(a) of ≥ 70
and placebo-
Apo(a) mg/dL mg/dL or a
controlled
Lp(a) of ≥ 90
mg/dL
Phase IIB, Patients aged
Change in
multicenter, LOX-1 receptor ≥ 21 years
non-calcified
double-blind, blocking with a history
GOLDILOX MEDI6570 400 plaque volume NCT04610892
randomized, monoclonal of MI and a
measured by
and placebo- antibody hs-CRP of >1
CTA
controlled mg/L
Phase II
LVEF at 6
multicenter,
B-cell months with
double-blind, Patients with
anaRITA MI2 Rituximab depletion with 558 cardiac NCT05211401
randomized, STEMI
CD20 magnetic
and placebo-
resonance
controlled
Ischemia- Infarct size
Randomized,
A methylpred- reperfusion measured by
multicenter,
nisolone 250 injury late-
double-blind, Patients with
PULSE-MI mg IV in a prevention and 400 gadolinium NCT05462730
and placebo- STEMI
prehospital wide anti- enhancement
controlled
setting inflammatory on CMR at 90
clinical trial
effect days
Change in
Phase II,
vascular
randomized, Patients with
Induces inflammation
double-blind, ACS or UA
expansion of measured by
IVORY placebo- Low dose IL-2 who have a 60 NCT04241601
regulatory T mean TBRmax
controlled, and hsCRP of >2
cells in the index of
a parallel mg/L
18F-FDG
group
PET/CT
ACS: acute coronary syndrome; CAD: coronary artery disease; CKD: chronic kidney disease; CMR: cardiac
magnetic resonance; CTA: computed tomography angiography; FDG PET/CT: fluorodeoxyglucose-positron
emission tomography; hsCRP: high sensitive C reactive protein; IL-2: interleukin-2; IL-6: interleukin 6; IV: intra-
venous; Lp(a): lipoprotein (a); LVEF: left ventricular ejection fraction; MACE: major adverse cardiovascular event;
MI: myocardial infarction; STEMI: ST elevation MI; TBR: target-to-blood pool ratio; UA: unstable angina.

The landscape is also marked by emerging trends that signify a paradigm shift in
addressing inflammation-related CV risks. From harnessing the potential of artificial
intelligence in data analysis to exploring the role of microbiota in CV health, these trends
Biomedicines 2024, 12, 701 12 of 18

underscore the multidimensional nature of ongoing investigations [93,94]. In this direction,

attention has been drawn toward inflamm-aging. Inflamm-aging, which is characterized
by chronic low-grade inflammation during aging, has been linked to various age-related
diseases [95]. This phenomenon involves the presence of systemic inflammatory mediators
in elderly individuals, which can exacerbate immune system disturbances and contribute to
the development of several persistent diseases. Understanding the molecular mechanisms
underlying inflamm-aging is crucial for developing targeted therapeutic strategies to
mitigate its impact on health in aging individuals [96]. Similarly, attention was called into
early arterial aging. Early arterial aging was considered when arterial age was higher
than the biological age. Many studies have correlated high-sensitivity C-reactive protein
with early arterial aging [97,98]. Therefore, systemic inflammation via elevated serum CRP
levels may be related to a higher baseline disability from cardiovascular events [99].
Additionally, the assessment of diet factors seems to be important as another inflam-
matory component. For this purpose, the use of the dietary inflammatory index (DII),
which is a tool developed to assess the inflammatory potential of diets by quantifying the
cumulative effect of various dietary components on inflammation, has been widely used to
evaluate the relationship between dietary patterns and the prevalence of various health
conditions, including hypertension, cancer, endometriosis, hyperuricemia, sarcopenia, and
diabetes [100]. Recent research has shown that the DII is positively correlated with the
all-cause mortality of CAD patients. The intake of a pro-inflammatory diet may increase
mortality in CAD patients [101].
Similarly, the use of the Systemic Immune-Inflammation Index (SII), a novel biomarker
that integrates various components of the immune system to provide insights into systemic
inflammation and its implications in different clinical scenarios, could be important in the
evaluation of the degree of inflammation in CAD individuals. SII has been shown that it
can also be used as a prognostic indicator in different cardiovascular scenarios [102–104].
Its ability to integrate immune parameters and provide valuable prognostic insights under-
scores its potential as a valuable tool in clinical practice for risk stratification and treatment
decision making.
These potential advancements not only hold implications for scientific understanding,
but also bear a profound impact on future clinical practice. A shift toward personalized,
targeted interventions may redefine treatment strategies, thereby offering more effective
and tailored approaches to patients [105]. As these trends unfold, they are set to shape the
landscape of CV care, thus paving the way for a new era in the prevention and management
of CVD.

7. Implications for Clinical Practice

In considering the implications for clinical practice, the integration of anti-inflammatory
strategies into the management of AMI emerges as a transformative avenue. The practi-
cal applications of these strategies, which is explored in this section, shed light on their
potential to redefine how we approach AMI treatment. As we navigate the intricacies
of AMI management, understanding the significance of incorporating anti-inflammatory
interventions into existing protocols becomes paramount [106]. This involves not only
recognizing the specific clinical scenarios where such strategies prove most effective, but
also ensuring a seamless integration that aligns with the broader treatment landscape [107].
In this direction, the new 2021 guidelines on CVD prevention that was issued by the
European Society of Cardiology have suggested the consideration of low-dose colchicine
(0.5 mg once daily) for the secondary prevention of CVD, especially in cases where recurrent
events persist despite optimal therapy [108].
Moreover, the discussion extends beyond general applications to delve into the realm
of personalized medicine. Tailoring anti-inflammatory interventions to the unique charac-
teristics of individual patients represents a paradigm shift in clinical practice. By acknowl-
edging patient-specific considerations, such as comorbidities, genetic predispositions, and
lifestyle factors, clinicians can optimize the efficacy of anti-inflammatory strategies while
Biomedicines 2024, 12, 701 13 of 18

minimizing potential risks. As we advance, these considerations forge a path toward a

more patient-centered approach in the realm of AMI management, thus promising not only
improved outcomes, but also a more tailored and compassionate form of CV care.
The ideal AMI target might be a patient with a large inflammatory burden. Extensive
MIs, which are characterized by significant ischemic damage, release higher levels of in-
flammatory mediators, thereby leading to a more pronounced acute inflammatory response.
These patients with extensive MIs, and consequently elevated inflammatory burden, might
experience greater advantages from early anti-inflammatory treatments. Thus, the selection
of patients with STEMI rather than NSTEMI, or the selection of patients with elevated
levels of cardiac troponins, might be a useful approach in terms of promptly identifying
individuals with substantial AMI and identifying the most suitable surrogate markers for
anti-inflammatory therapy [109]. Additionally, the use of available biomarkers of inflam-
mation (e.g., CRP and IL-6) could further improve the identification of individuals with a
large inflammatory burden post-AMI, who would benefit from anti-inflammatory strate-
gies. Finally, the ideal patient would benefit by the administration of anti-inflammatory
therapy at early stages after the acute event. Inflammatory response may be protective
in the early stage of the myocardial infarction through stimulation of myocyte autophagy.
Anti-inflammatory treatment that is administered early after coronary occlusion may have
an adverse effect [110]. A treatment plan aimed at addressing the initial stages of excessive
and harmful post-AMI inflammation could potentially restrict further myocardial damage.

8. Conclusions
In conclusion, through the meticulous examination of pivotal trials, we uncovered
diverse approaches, which range from therapies targeting the central IL-6 pathway to broad-
spectrum, anti-inflammatory interventions. Despite the undoubted complexities in trial
designs, patient populations, and primary outcomes, an understanding emerges, thereby
highlighting both successes and challenges in the pursuit of effective anti-inflammatory
interventions post-AMI. As we navigate this evolving field, our review not only synthe-
sizes existing knowledge, but also underscores the need for continued exploration and
innovation. This comprehensive overview sets the stage for future research and clinical
endeavors, thereby providing a foundation for refining anti-inflammatory strategies and
improving CV outcomes in AMI patients.

Author Contributions: A.M., S.T. and G.K. (George Kassimis) were involved in the conceptualization,
writing, and editing. M.K., S.S., G.K. (Georgia Karmioti), M.D., M.M. and A.Z. were involved in the
editing and reviewing. Supervision was conducted by S.T. and G.K (George Kassimis). All authors
have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflicts of interest.

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