Background and Overview

Article Title/Citation Colchicine in Patients

with Chronic Coronary Disease (LoDoCo2)
Study objectives/purpose The study aimed to determine if 0.5 mg of
colchicine daily, compared to placebo, would
prevent CVE in patients with chronic coronary
disease.
Brief background Patients with chronic coronary disease are at
extremely high risk for acute cardiovascular
events. One of the pathological pathways of
coronary disease is inflammation. It has been
theorized that anti-inflammatory therapies may
be helpful in preventing serious complications of
the disease. CANTOS, a study looking at the
effects of canakinumab, an interleukin-1
inhibitor, on patients with a history of MI,
showed a reduction in recurrent CVE. However,
another trial with methotrexate by Ridker
showed no benefit.
Colchicine has broad anti-inflammatory effects:
inhibition of tubulin polymerization and
alterations of leukocyte response.
COLCOT looked at past MI patients and the use of
colchicine. 0.5 mg daily reduced the composite of
CV death, cardiac arrest, MI, stroke, or urgent
hospitalization leading to revascularization versus
placebo.
LoDoCo looked at low-dose colchicine (0.5 mg) in
coronary disease patients. It found a lower risk of
CVE with colchicine vs placebo. This was open-
label, and required confirmation. LoDoCo2 is this
study.
Funding sources Drug was supplied by Aspen Pharmacare
Methods
Study design and methodology Randomized, controlled, double-blind trial
Eligible patients first went through an open-label
run-in phase of one month. During this they
received 0.5 mg of colchicine daily to test for
unacceptable side effects, adherence, and
willingness.
The remaining patients were then randomized in
a double-blind manner with a algorithm, in a 1:1
ratio to receive either 0.5 mg of colchicine daily
or matching placebo.
Patients were evaluated before the run-in phase,
at randomization, and at 6-month intervals in in-
person sessions if possible or telephone.

Patient selection and enrollment
Outcome measures/endpoints
Statistical analyses
Results
Baseline info
Summary of study results, focusing on primary
Designed to have a minimum follow-up of one
year.
Inclusion: 35-82 yoa with evidence of coronary
disease on invasive coronary angiography,
computed tomography angiography, coronary-
artery calcium score of at least 400 Agatson units.
Clinically stable for at least 6 months prior.
Exclusion: moderate to severe renal impairment
(KDIGO score), severe HF, severe valvular heart
disease, or known colchicine side effects.
Primary: composite of CV death, spontaneous MI,
ischemic stroke, and ischemia-driven coronary
revascularization
Secondary: composite of CV death, spontaneous
MI, or ischemic stroke; composite of spontaneous
MI or ischemic stroke; composite of spontaneous
MI or ischemia-driven coronary revascularization;
composite of CV death or spontaneous MI; each
individual component; death from any cause
Required to have at least 331 primary end-point
events
Minimum follow-up of 1 year
Target of 6053 patients in open-label phase
Target of 5447 undergoing randomization
Estimated to have 90% power, 2-sided alpha of
0.05 to detect a 30% lower rate of the primary
endpoint
Intention-to-treat model
Cox proportional-hazards models for confidence
intervals
P values used log-rank test with hierarchical
testing
6528 in open-label run-in period
5522 underwent randomization
15.4% who did not undergo randomization most
commonly complained of GI upset (almost 50%)
5478 received at least one dose of colchicine or
placebo
Characteristics were well balanced
Mean age of 66 +/- 8.6 years
15.3% were female
11.7% current smokers
18.2% had DM
84.4% had a history of ACS, 68.2% had it occur
within 24 months of trial
Median duration of follow-up: 28.6 months
and secondary outcomes
Discussion
Brief summary of authors’ main discussion
points
Study strengths and weaknesses
10.5% permanently stopped colchicine or
placebo early
Primary end-point: 6.8% colchicine vs 9.6%
placebo, HR of 0.69, CI of 0.57-0.83, P<0.001
Composite of CV death, MI, ischemic stroke: 4.2%
vs 5.7%, HR 0.72, CI 0.57-0.92, P = 0.007
All secondary end-points were significantly lower
except incidence of death from any cause.
AE: NonCV deaths were more frequent in
colchicine group, HR 1.51, CI 0.99-2.31, not
significant.
The composite of the primary endpoint showed
reduction in risk of cardiovascular disease
complications, as well as in each component of
the primary endpoint and all secondary
endpoints.
The incidence of noncardiovascular death was
not significant, but the HR of 1.51 is of potential
concern. They do not offer a clear interpretation
of this finding due to data. In the COLCOT trial, it
was 23 vs 20.
There is no evidence in the study that there is a
clinically significant interaction with colchicine
and statins which were use concomitantly in
61.8% of the patients.
Results are consistent with the CANTOS, LoDoCo,
and COLCOT trials, providing further support for
anti-inflammatory therapy in coronary disease. It
also shows similar magnitude of benefit as that
shown in trials of other prevention strategies like
lipid-lowering, blood pressure lowering, and
antithrombotic therapies.
Benefit of the therapy emerged early within the
trial and continued to accrue.
Strengths:
Clear outcomes and clinically important
outcomes were measured.
Met there required participation and length of
follow up, and exceeded it, providing a strong
power.
Reevaluated previously tested studies in previous
topics.
Weaknesses:
Lower percentage of women in the study than
the incidence of disease in women.
No assessment of inflammation levels, the
primary reason for the study: Sed rate or C-
reactive protein. Without this assessment of pre
and post-levels, we cannot assess for a
pathological base for the therapy.
No assessment of other factors of coronary
disease: Lipids, blood pressure, remodeling, BNP
Run-in periods eliminated those who would
experience side effects eliminating true
assessment of adverse effects of therapy.