1. The COLCOT trial found that in patients who recently suffered a myocardial infarction, low-dose colchicine was effective at preventing major adverse cardiovascular events compared to placebo. 2. The LoDoCo 2 trial found that in patients with chronic coronary disease, low-dose colchicine resulted in a 31% lower risk of cardiovascular death, heart attack, stroke, or revascularization than placebo. 3. Colchicine has anti-inflammatory properties through its inhibition of the NLRP3 inflammasome complex and has a well-established safety profile, making it a promising secondary prevention treatment for cardiovascular disease.

1. cholchicine
Dr Safwat Nahrawi

2. Agenda Style
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Atherosclerosis (The enemy).
Old lessons (Trials)
COLCOT Trial.
LoDoCo 2 Trial.
Home Message

3. Introduction:
Atherosclerosis is the most common cause of myocardial infarction, stroke
and peripheral arterial disease.
Inflammation has a key role in the initiation, progression and manifestations of
atherosclerosis, through accumulation of lipid-laden cells (primarily macropha
ges) beneath the endothelium.
Further accumulation of cells, connective-tissue elements, lipids and debris
through immunological and inflammatory activation.
Neutrophils and other inflammatory cells have been shown to invade culprit
atherosclerotic lesions in acute coronary syndromes.

4. Anti inflammatory Drugs In Trials.
the Canakinumab Anti inflammatory Thrombosis
Outcomes Study
Inhibition of interleukin-1β by the injectable monoclonal
antibody canakinumab led to a 15% lower risk of
cardiovascular events than was observed with Placebo, also
led to a slightly higher incidence of fatal infections.
the Cardiovascular Inflammation Reduction Trial
Methotrexate did not affect cardiovascular outcomes or
plasma markers of inflammation
the Low-Dose Colchicine
Stable coronary disease treated with colchicine at a dose of
0.5 mg once daily had fewer cardiovascular events than
those not receiving colchicine, but the study enrolled
onlyv532 patients and was not placebo-controlled.

5. The COLCOT TRIAL
COLCHICINE CARDIOVASCULAR OUTCOMES TRIAL

6. COLCOT Trial.
Evaluate the effects of colchicine on cardiovascular outcomes as well as its long
-term safety profile in patients who had recently had a myocardial infarction.
Objective :
A randomized, double-blind, placebo-controlled.
Patients assigned to receive either colchicine (at a dose of 0.5 mg once daily) or
placebo.
Study Design:
Adult patients who had a myocardial infarction within 30 days before enrollment,
had completed any planned percutaneous revascularization procedures, and
were treated according to national guidelines.
Approximately 4500 patients undergoing randomization
Target Population:
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7. COLCOT Trial.
• Severe Heart Failure, LVEF>35%
• Stroke Within The Previous 3 Months
• Type 2 Index Myocardial Infarction, Coronary-bypass Surgery Either Within The Previous
3 Years Or Planned.
• History Of Non Cutaneous Cancer Within The Previous 3 Years,
History Of inflammatory bowel disease or chronic diarrhea,
neuromuscular disease or a non transient creatine kinase level that was greater than
three times the upper limit of the normal range,
significant hepatic, renal diseases or non transient hematologic abnormalities,
drug or alcohol abuse,
glucocorticoid therapy, or sensitivity to colchicine.
Exclusion Criteria:04
Clinical evaluations occurred at 1 month and 3 months after
randomization and every 3 months thereafter.
Evaluation:05

8. COLCOT Trial.

9. COLCOT Trial.

10. COLCOT Trial.
In the small subgroup of patients, a large (>65%) reduction in the C-reactive
protein level occurred over the first 6 months after myocardial infarction in both
trial groups (not significant- small subgroup).
CRP Level :
Postinfarction pericarditis typically occurs within the first few days after the
injury, benefits of colchicine in the treatment of pericarditis were not at play in
COLCOT
Pericarditis:
 The duration of follow-up was relatively short at 23 months.
 Results apply only to patients who have recently had a myocardial infarction.
 Primary outcome had a fragility index that was less that the number of
patients whose vital status was unknown
Limitations:
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11. Conclusion:
1. Patients suffered a recent myocardial infarction, low-dose
colchicine was effective at preventing major adverse
cardiovascular events compared with placebo.
2. Benefit was primarily due to a reduction in the incidence
of stroke and urgent hospitalization for unstable angina
leading to revascularization.
3. The study drug was well tolerated and associated with
similar incidence of infection and diarrhea compared with
placebo.
4. Colchicine was also cost-effective.
5. The benefit of colchicine was purported to be due to
anti-inflammatory properties of the drug.

12. The LoDoCo 2 TRIAL
Low Dose Colchicine 2 Trial

13. LoDoCo 2 Trial.
Evaluate the effects of colchicine on cardiovascular outcomes as well as its long
-term safety profile in patients who had recently had a myocardial infarction.
Objective :
A randomized, double-blind, placebo-controlled.
Patients assigned to receive either colchicine (at a dose of 0.5 mg once daily) or
placebo.
Study Design:
Patients 35 to 82 years of age with any evidence of coronary disease on:
• invasive coronary angiography.
• computed tomography angiography.
• a coronary-artery calcium score of at least 400 Agatston units on
a coronary-artery calcium scan.
Patients should be in Stable condition for at least 6 months before enrollment.
Approximately a total of 5522 patients underwent randomization.
Target Population:
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14. LoDoCo 2 Trial.
• Moderate-to-severe renal impairment
• Severe heart failure
• Severe valvular heart disease
• Known side effects from colchicine
Exclusion Criteria:04
Patients entered an open-label run-in phase for 1 month.
Then patients with stable condition, no unacceptable side effects,
had adhered to the open-label colchicine regimen,
and remained willing to continue participation
were randomly assigned in a 1:1 ratio.
Clinical evaluations were scheduled before the run-in phase,
at the time of randomization, and at 6-month intervals until
the completion of the trial.
Evaluation:05

15. LoDoCo 2 Trial.

16. LoDoCo 2 Trial.

17. LoDoCo 2 Trial.
 The percentage of women in the trial was lower than would be
expected given the percentage of women with chronic coronary
disease in the general population.
 blood-pressure or lipid levels was not measured at baseline or during
the trial, and so outcomes cannot be reported according to risk actor
control.
 C-reactive protein levels or other laboratory indicators of
inflammation was not measured at the baseline, and so the effects of
treatment cannot explored according to inflammatory state at
baseline.
However, the effects of treatments were consistent across the
majority of clinical subgroups examined.
Limitations:06

18. Conclusion:
1. Patients with chronic coronary disease, most of whom
were already receiving proven secondary prevention
therapies, 0.5 mg of colchicine once daily resulted in a
31% lower relative risk of cardiovascular death,
spontaneous myocardial infarction, ischemic stroke, or
ischemia-driven coronary revascularization (the primary
end point) than placebo.
2. No evidence for a clinically important interaction between
low dose colchicine and high-dose statins, which were
used by 3413 patients (61.8%) in the trial.

19. THE ROLE OF COLCHICINE:
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 Anti-inflammatory medication with a well-established adverse effect
profile and is widely available and inexpensive.
 Inhibits the activation of the NLRP3 inflammasome protein
complex.
This occurs through direct monocyte caspase-1 inhibition
,inhibition of the MEFV gene preventing inflammasome assembly
,inhibition of colocalization of inflammasome cytoplasmic proteins
,inhibition of P2×7-mediated pore formation, which is a key step in
NLRP3 inflammasome response to adenosine triphosphate
 effect on mitosis by binding to tubulin and promoting microtubule
depolymerization.
Anti inflammatory action: