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International Journal of Stroke 19(4)
an approach could be tested following stroke in an RCT
with a 2 × 2 factorial design, with PCSK-9 inhibitors and
anti-inflammatory therapy compared with best medical
therapy (BMT).
Colchicine in cardiovascular
diseases
Colchicine is an anti-inflammatory which inhibits microtubule
and inflammasome assembly, reduces cytokine/adhesion
molecule expression, and reduces inflammatory cell
mitosis and motility.62 In a substudy of an RCT, colchicine
reduced on-treatment levels of hsCRP by 0.5 mg/L and
reduced several proteins downstream of the NLRP3 inflammasome,
including IL-6 and IL-1β. However, the antiinflammatory
effects of colchicine also extended to the
adaptive immune system,
degranulation.63
hemostasis,
and
neutrophil
In 2013, Colchicine was first evaluated for secondary
prevention in a phase-3 prospective, randomized,
observer-blinded endpoint (PROBE) designed trial
(LoDoCo) in patients with stable CAD. Low-dose colchicine
lowered the risk of 3-year MACE by two-thirds with
a number needed to treat (NNT) of 11 compared with
BMT.64 The findings were confirmed in LoDoCo2, which
reported a 30% reduced risk of MACE in stable coronary
patients treated with colchicine.65 The COLCOT trial,
which recruited patients with recent MI, reported similar
results.66 In a subsequent meta-analysis of four RCTs
(Supplemental Material), colchicine reduced the risk of
MACE by 26%, with supportive direction of effect for
MI and revascularization, but not cardiovascular death.
The risk of stroke with colchicine was halved.3 In the
LoDoCo2 trial, there was a non-statistically significant
increased risk of non-cardiovascular death in the colchicine
arm (excess of 0.2 events per 100 person-years).65 In
the meta-analysis of the four trials, a similar trend toward
an increased risk of non-cardiovascular death was shown,
but the results were largely driven by the findings in
LoDoCo2 and were not explained by an increased risk of
infection, pneumonia, or cancer. Colchicine was well tolerated
and not associated with the increased risk of gastrointestinal
side effects or myalgias.3 The findings of
these trials led to a change of clinical practice recommendation
in the recent guidelines of the European Society of
Cardiology and colchicine was approved for treatment of
cardiovascular disease by the FDA in June 2023.67
Advantages of colchicine include low cost, wide availability
globally including in low- and middle-income
countries, good tolerability, and established safety profile
at low doses. However, colchicine is contraindicated
in patients with severe chronic kidney disease (CKD)
and the known drug interactions should be taken into
consideration.
International Journal of Stroke, 19(4)
Colchicine in secondary stroke
prevention
Colchicine is now under evaluation for the secondary prevention
of vascular events after stroke in the CONVINCE
trial (NCT02898610), with results expected in 2024. In
total, 3154 non-cardioembolic stroke patients were enrolled.
Several other RCTs evaluating the effect of colchicine after
stroke are either underway or are planned. CHANCE-3
(NCT05439356) is a placebo-controlled double-blind RCT
currently recruiting patients with acute non-cardioembolic
minor stroke or TIA with elevated hsCRP ⩾ 2 mg/L in
China. The primary outcome is recurrent stroke at 90 days
and results are anticipated in 2025. The RIISC-THETIS
trial (NCT05476991) has a 2 × 2 factorial design and will
evaluate the efficacy of ticagrelor and colchicine compared
with aspirin in patients with atherosclerotic stroke.
Targeting the IL-1β-IL-6-CRP axis
Canakinumab is a human monoclonal antibody (mAb) to
IL-1β, interrupts the central inflammatory signaling pathway,
and is associated with substantial reductions in circulating
levels of hsCRP-IL-6. The CANTOS trial enrolled
participants with a history of MI and a hsCRP of > 2 mg/L
despite
aggressive
secondary
prevention
therapy
and
showed that canakinumab reduces the risk of MACE.
However, canakinumab was associated with a higher risk
of death due to sepsis/infection (excess of 0.13 deaths per
100 person-years), neutropenia, and thrombocytopenia.4 A
greater magnitude of benefit was observed for MACE in
patients achieving IL-6 suppression on canakinumab, but
no benefit was seen in patients with persistently elevated
IL-6. A marked reduction on cardiovascular and all-cause
mortality was also observed in patients achieving IL-6 suppression.68
A similar pattern was demonstrated in participants
who achieved on-treatment hsCRP
levels
of < 2 mg/L.69 The CANTOS trial demonstrated proof-ofprinciple
that targeting the IL-6-CRP axis can reduce
MACE in patients with established atherosclerosis and benefit
was proportionate to the extent of IL-6-CRP
inhibition.
Ziltivekimab is an mAb IL-6 inhibitor which binds
directly to the IL-6 ligand and administered by monthly
subcutaneous injections. In a phase-2 trial, which recruited
patients with CKD and hsCRP ⩾ 2 mg/L, ziltivekimab lowered
circulating hsCRP levels by up to 92% without any
serious adverse events (AEs) and had a neutral effect on
lipids.70 The ZEUS trial is a phase-3 RCT which is recruiting
patients with CKD, atherosclerotic cardiovascular disease
risk, and with
elevated hsCRP.
Participants
are
randomized to subcutaneous ziltivekimab versus placebo
and the primary outcome is any MACE during follow-up
(NCT05021835).
WSO - April 2024

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