COLCOT

Efficacy and Safety of Low-Dose Colchicine
after Myocardial Infarction

Tardif. NEJM 2019 published on-line Nov 16, 2019. DOI: 10.1056/NEJMoa1912388

Clinical Question

  • In patients post myocardial infarction, does low dose colchicine compared with placebo, reduce ischaemic cardiovascular events?

Background

  • Evidence supports the role of inflammation in atherosclerosis and its complications
  • The CANTOS study reported that the monoclonal antibody canakinumab, that inhibits interleukin-1b, decreased cardiovascular events but also increased fatal infections
  • Colchicine is an anti-inflammatory that is used to treat gout & pericarditis. It is hypothesised that this may reduce the risk of atherosclerotic events in patients with coronary artery disease

Design

  • Randomised controlled trial
    • 1:1 ratio
  • Double blinded, placebo-controlled
  • Blinded assessment of outcomes
  • Registered on clinicaltrials.gov
  • Sample size calculation: 4500 patients would give 80% power with a false positive rate of 5% assuming a 27% lower relative risk of the primary outcome with colchicine, based on an assumed event rate in the placebo group of 7%

Setting

  • 167 centres in 12 countries (predominately Canada, South America & Europe)
  • Trial enrolment December 2015 – August 2018

Population

  • Inclusion criteria:
    • Adult patients who had had a myocardial infarction within the last 30 days
    • Had completed any planned percutaneous revascularisation procedures
    • Were treated according to national guidelines that included the intensive use of statins
  • Exclusion criteria:
    • Severe heart failure, ejection fraction <35%
    • Stroke within previous 3 months
    • Type 2 MI
    • CABG within previous 3 years or planned
    • History of non-cutaneous cancer within the previous 3 years
    • Inflammatory bowel disease or chronic diarrhoea
    • Neuromuscular disease, severe renal or hepatic disease, drug or alcohol abuse, long term steroid use
  • 4745 patients randomised
    • For 23 patients (0.5%) vital status not available
    • 89 (1.9%) patients lost to follow up
    • 30 patients (0.6%) withdrew consent
  • Comparing baseline characteristics of intervention vs. control group
    • Age: 60.6 vs. 60.5 years
    • Female sex: 19.9% vs. 18.4%
    • White race: 73% vs. 72%
    • Time from index MI to randomisation: 13.4 vs. 13.5 days
    • PCI for index MI: 92.7% vs. 93.3%
    • Medication use
      • Aspirin: 98.6% vs. 98.9%
      • Other anti-platelet agent: 97.6% vs. 98.2%
      • Statin: 98.9% vs. 99.1%
      • Beta-blocker: 89.4% vs. 88.3%

Intervention

  • Low dose colchicine
    • 0.5mg once daily
    • Median duration of trial drug: 19.6 months
    • At the end of the trial, the trial regimen had been discontinued in 18.4% of patients with a median duration of 7.1 months

Control

  • Placebo
    • Median duration of trial drug was 19.5 months
    • At the end of the trial, the trial regimen had been discontinued in 18.7% of patients with a median duration of 6.1 months

Management common to both groups

  • Treated according to national guidelines that included the intensive use of statins

Outcome

  • Primary outcome: Composite of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke or urgent hospitalisation for angina leading to coronary revascularisation – significantly reduced in colchicine group
    • 5.5% vs. 7.1% (Hazard ratio 0.77; 95% C.I. 0.61-0.96, p=0.02)
    • NNT 63
    • Fragility index 5 patients
  • Secondary outcomes: – comparing intervention vs. control group
    • No significant difference in:
      • Death from cardiovascular causes – no significant difference
        • 0.8% vs. 1%
        • HR 0.84; 95% C.I. 0.25-2.73
      • Resuscitated cardiac arrest
        • 0.2% vs. 0.3%
        • HR 0.83; 95% C.I. 0.25-2.73
      • Myocardial infarction
        • 3.8% vs. 4.1%
        • HR 0.91; 95% C.I. 0.68-1.21
      • Death
        • 1.8% vs. 1.8%
        • HR 0.98; 95% C.I. 0.64-1.49
    • Significantly reduced in colchicine group
      • Stroke
        • 0.2% vs. 0.8%
        • HR 0.26, 95% C.I. 0.1-0.7
        • NNT 171
        • Fragility index 3
      • Urgent hospitalisation for angina leading to coronary revascularisation
        • 1.1% vs. 2.1%
        • HR 0.5, 95% C.I. 0.31-0.81
        • NNT 96
        • Fragility index 7
    • Side effects
      • Any related adverse event – no significant difference
        • 16% vs. 15.8%, p=0.89
      • Diarrhoea – no significant difference
        • 9.7% vs. 8.9%, p=0.35
      • Pneumonia – significantly increased in colchicine group
        • 0.9% vs. 0.4%, p=0.03

Authors’ Conclusions

  • In patients with a recent myocardial infarction, low dose colchicine significantly reduced ischaemic cardiovascular complications

Strengths

  • Randomised controlled trial
  • Blinding of outcome assessors
  • Multi-centre, multi-national
  • Followed standardised guideline

Weaknesses

  • Composite outcome
  • Primary outcome had a fragility index that was less that the number of patients whose vital status was unknown
  • Duration of follow-up was relatively short at ~23 months

The Bottom Line

  • In patients following myocardial infarction, the use of colchicine compared with placebo, started at a median of 13 days post-infarct, significantly reduced the composite outcome of ischaemic cardiovascular events
  • This was primarily due to a reduction in the number of patients who had a stroke and the number of patients that had an urgent hospitalisation for angina leading to coronary revascularisation. There was no change in mortality
  • Due to the low fragility index there should be some caution with the interpretation of these results

External Links

Metadata

Summary author: David Slessor
Summary date: 21st November 2019
Peer-review editor: Duncan Chambler

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