Low Dose Colchicine for Secondary Prevention of Cardiovascular Disease - LoDoCo

Description:

Colchicine has known anti-inflammatory effects. The current trial sought to investigate if addition to colchicines to routine medical management would be superior to placebo in patients with established coronary artery disease (CAD).

Hypothesis:

Colchicine would be superior to placebo in reducing cardiovascular events in patients with established CAD already on optimal medical management.

Study Design

  • Parallel
  • Placebo Controlled
  • Randomized
  • Stratified

Patient Populations:

  • Angiographic proof of CAD:
    - Clinically stable for >6 months
    - Patients with CABG included if surgery >10 years or graft failure or stenting
  • Ages from 35-85 years
  • No other major competing comorbidity or contraindication to colchicine
  • Not taking colchicine for any other purpose
  • Considered compliant with their usual therapy

    Number of screened applicants: 901
    Number of enrollees: 532
    Duration of follow-up: 3 years
    Mean patient age: 66.5 years
    Percentage female: 11%

Primary Endpoints:

  • Primary outcome composite (time to first occurrence):
    - ACS event
    - Cardiac arrest with resuscitation
    - Noncardioembolic ischemic stroke

Secondary Endpoints:

  • The time to each component of the primary outcome
  • The time to ACS and each of its components (acute myocardial infarction and unstable angina) unrelated to stent disease

Drug/Procedures Used:

Patients were randomized in a 1:1 fashion to either colchicine 0.5 mg/d or matching placebo.

Concomitant Medications:

High-dose statin (95%), aspirin and/or clopidogrel (94%), beta-blockers (67%), angiotensin-converting enzyme inhibitors (58%)

Principal Findings:

A total of 532 patients were randomized, 282 to colchicine and 250 to placebo. About 30% had diabetes mellitus. Entry criterion was past acute coronary syndrome (ACS) in 24%, coronary artery bypass grafting (CABG) in 19%, and percutaneous coronary intervention (PCI) in the remainder. Intolerance to colchicine occurred in 11% of patients early and late in 11% of the patients. The most common side effect leading to withdrawal was gastrointestinal upset (2.5%). 

The primary outcome of ACS/cardiac arrest/ischemic stroke was significantly lower in the colchicine arm as compared with the placebo arm (5.3% vs. 16%, hazard ratio [HR] 0.33, 95% confidence interval [CI] 0.18-0.59; p < 0.0001). This was driven mainly by a reduction in nonstent-related (i.e., de novo) ACS (3.2% vs. 12%, HR 0.26, 95% CI 0.12-0.55). The reduction in the primary endpoint was robust across multiple subgroups including age and diabetes.

Interpretation:

The results of the LoDoCo trial indicate that low-dose colchicine at a dose of 0.5 mg/day is efficacious as compared with placebo in reducing recurrent cardiovascular events, mostly ACS events, in patients with established CAD. These results are hypothesis generating, and will need further validation. The authors did not present data on inflammatory biomarkers, which would have been helpful in understanding the mechanism of potential benefit. This trial also was not double-blinded and did not have a placebo arm.

Colchicine has recently been shown to be beneficial in a number of inflammatory settings such as pericarditis and atrial fibrillation (primary and secondary). In the past, it had also been tested as an antirestenotic agent in patients undergoing PCI due to its anti-inflammatory and anti-mitotic effects, but did not demonstrate efficacy. This trial suggests that the mechanism of benefit is in de novo lesions, not stented lesions, and will require further study.

References:

Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol 2012;Dec 19:[Epub ahead of print].

Presented by Dr. Stefan Nidorf at American Heart Association Scientific Sessions, Los Angeles, CA, November 5, 2012.

Clinical Topics: Acute Coronary Syndromes, Arrhythmias and Clinical EP, Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, Pericardial Disease, ACS and Cardiac Biomarkers, Implantable Devices, SCD/Ventricular Arrhythmias, Aortic Surgery, Cardiac Surgery and Arrhythmias, Interventions and ACS

Keywords: Stroke, Acute Coronary Syndrome, Follow-Up Studies, Colchicine, Comorbidity, Heart Arrest, Pericarditis, Angioplasty, Balloon, Coronary, Biological Markers, Confidence Intervals, Coronary Artery Bypass, Diabetes Mellitus


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