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

• [article] Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction
• [further reading] Trial presentation by primary author

Metadata

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