LoDoCo2

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Nidorf SM, et al. "Colchicine in patients with chronic coronary disease". The New England Journal of Medicine. 2020. 383(19):1838-1847.
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Clinical Question

In patients with chronic coronary disease, does colchicine improve cardiovascular outcomes?

Bottom Line

In patients with chronic coronary disease, colchicine reduced the composite outcome of cardiovascular death, spontaneous myocardial infarction (MI), ischemic stroke, or ischemia-driven coronary revascularization over a median follow-up of 28.6 months.

Major Points

The anti-inflammatory medication Colchicine was postulated to have cardioprotective effects after a retrospective analysis found that patients with gout treated with colchicine had a lower rate of myocardial infarction.[1] Prior studies had demonstrated that inflammation increased patient's risk of cardiovascular events, and the 2019 CANTOS study found improved cardiovascular outcomes with the immunosuppressant canakinumab. The 2013 Low-Dose Colchicine (LoDoCo) trial randomized patients with stable CAD to colchicine or usual care with improved cardiovascular outcomes, particularly ACS. The trial was open label and criticized for its lack of placebo control and blinding to treatment group. Additionally, patients were added to the treatment group to replace patients that dropped out of the trial. More recently, interest in colchicine's cardioprotective effects have garnered renewed interest after the 2019 Colchicine Cardiovascular Outcomes Trial (COLCOT) in patients with recent myocardial infarction randomized patients to colchicine vs placebo and found a reduced risk of cardiovascular outcomes.

The Low-dose Colchicine 2 (LoDoCo 2) Trial was a randomized, double-blind, placebo controlled trial of colchicine vs placebo in adults with chronic coronary syndrome. The patient population characteristics were notable for predominance of prior ACS 84%, with 27% of patients having had an ACS event in the preceding 24 months and 23% on dual antiplatelet therapy. After median follow-up of 28.6 months, the colchicine group was found to have fewer CV mortality, MI, ischemic stroke, or coronary revascularization driven by ischemia events (6.8% vs. 9.6%; HR 0.69; 95% CI 0.57-0.83; NNT=36). Notably there was a strong trend towards increased non-CV mortality in the colchicine group (1.9% vs 1.3%; HR 1.51, 95% CI 0.99-2.31), but not for all-cause mortality (2.6% vs 2.2%; HR 1.21, 95% CI 0.86-1.71). The authors also performed a competing risk analysis using the Fine-Gray approach, to account for non-CV death, and the primary outcome as essentially unchanged (Table S6).[2]

Unlike CANTOS, this trial did not include adverse inflammation as an eligibility criteria so it is unclear if there is differential benefit or harm from colchicine by baseline inflammation. Overall, the results of this trial support the cardioprotective effects of colchicine for secondary prevention, tempered by concern for a trend towards increased non-cardiovascular mortality. In combination with the results of the COLCOT trial in patients post-MI, colchicine is a possible therapy for patients with CAD.

Guidelines

As of February 2021, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, double-blind, randomized, controlled trial
  • N=5,522
    • Colchicine (n=2,762)
    • Placebo (n=2,760)
  • Setting: 33 centers in Australia and the Netherlands
  • Enrollment: August 4, 2014 to December 3, 2018.
  • Mean follow-up: 28.6 months
  • Analysis: Intention-to-treat
  • Primary outcome: CV mortality, MI, ischemic stroke, or coronary revascularization driven by ischemia

Population

Inclusion Criteria

  • Age 35-82 years of age
  • Coronary artery disease diagnosed by ≥1 of the following:
    • Coronary angiography
    • Coronary CT angiography
    • Coronary artery calcium scan with CAC score ≥400 Agatston units
  • Clinically stable for ≥6 months

Exclusion Criteria

  • Pregnant/likely to be pregnant or breastfeeding
  • eGFR <50 mL/min/1.73 m2
  • NYHA symptoms ≥3
  • Mod or severe heart valve disease likely to require an intervention
  • Frailty
  • Life expectancy <5 years
  • Peripheral neuritis, myositis, severe statin intolerance
  • Need for long-term colchicine therapy
  • Enrollment in another trial

Baseline Characteristics

From Colchicine arm.

  • Demographics: Age 66 years, female sex 16 years
    • Geographic region: Australia 34%, Netherlands 66%
  • Comorbidities: Smoker 11%, hypertension 51%, DM on insulin 5%, DM not on insulin 18%, CKD stage 1 or 2 95%, CKD stage 3a 5%, gout 8%
  • CVD history: Prior ACS 84%, time since last ACS ≤27%, time since last ACS >24 mo 57%, prior coronary revascularization 83% (CABG 11%, PCI 76%), prior AF 12%
  • Medications: Single antiplatelet 67%, DAPT 23%, anticoagulation 12%, no antiplatelet or anticoagulant <1%, statin 94%, ezetimibe 20%, renin-angiotensin inhibitor 72%, beta-blocker 61%, CCB 23%

Interventions

  • For 1 month, all participants received open label colchicine 0.5 mg po qday. If they tolerated the colchicine without deleterious side effects, they were randomized to an arm:
    • Colchicine - at 0.5 mg daily
    • Placebo

Outcomes

Comparisons are colchicine vs. placebo.

Primary Outcome

CV mortality, MI, ischemic stroke, or coronary revascularization driven by ischemia
CV mortality was any death thought to relate to CVD, including MI, HF, complication from revascularization, CV hemorrhage, or death from other CV causes.
6.8% vs. 9.6% (HR 0.69; 95% CI 0.57-0.83; P<0.001; NNT=36)

Secondary Outcomes

CV mortality, MI, or ischemic stroke
4.2% vs 5.7% (HR 0.72: 95% CI 0.57-0.92; P=0.007; NNT=67)
Mortality
All-cause mortality: 2.6% vs 2.2% (HR 1.21, 95% CI 0.86-1.71)
CV mortality: 0.7% vs 0.9% (HR 0.80, 95% 0.44-1.44)
Non-CV mortality: 1.9% vs 1.3% (HR 1.51, 95% CI 0.99-2.31)
Non-CV causes of death
Cancer: 26 vs. 22
Infection: 4 vs. 4
Multi-organ failure3 vs. 2
Dementia: 4 vs. 1
Accidental: 2 vs. 2
Renal failure: 1 vs. 0
Suicide: 1 vs. 0
Cerebral vasculitis: 1 vs. 0
Intestinal ischemia: 1 vs. 0
Unknown: 1 vs. 0
Ischemic stroke
0.6% vs 0.9% (HR 0.66, 95% CI 0.35-1.25; P=0.20)
Myocardial Infarction
3.0% vs 4.2% (HR 0.70, 95% CI 0.53-0.93; P=0.01)
Ischemia-driven coronary revascularization
4.9% vs 6.4% (HR 0.75, 95% CI 0.60-0.94; P=0.01)

Additional Outcomes

Percent not randomized
All: 15.4%
Intolerance: 9.4%
GI upset: 6.7%
Myalgia: 1.4%
Fatigue or "loss of condition": <1%
Headache: <1%
Skin problems: <1%
Patient preference: 4.8%
Clinical or investigational reason for exclusion: 1%
No rationale: <1%

Subgroup Analysis

There were similar findings for the primary endpoint by demographics and comorbidities. There was less benefit among the population in the Netherlands (HR 0.92; 95% CI 0.71-1.20) than the group in Australia (HR 0.51; 95% CI 0.39-0.67). See Figure S2 for details on the subgroup analysis and Table S4 for characteristics of the study population by country.[2]

Adverse Events

Non-CV mortality
1.9% vs 1.3% (HR 1.51, 95% CI 0.99-2.31)
Cancer
4.3% vs. 4.4%
Hospitalization
For infection: 5.0% vs. 5.2%
For pneumonia: 1.7% vs. 2.0%
For GI reason: 1.9% vs. 1.8%
Gout
1.4% vs. 3.4% (IRR 0.40; 95% CI 0.28-0.58)
Neutropenia
<1% vs. <1%
Myotoxic effects
<1% vs. <1%
Myalgia
In Netherlands subgroup only, which was about 2/3rds of the study population. Differences between the Australian and Netherlands populations appears in table S4 of the supplementary appendix.[2]
21.2% vs. 18.5% (IRR 1.15; 95% CI 1.01-1.31)
Tingling or numbness
In Netherlands subgroup only.
7.9% vs. 8.3% (IRR 0.95; 95% CI 0.76-1.18)

Criticisms

  • The use of a run-in period for colchicine likely selected those patients less likely to experience adverse effects, under-estimating the risk of adverse events in the study.
  • Few women
  • No collection of CV-related biomarkers to assess for differential harm or benefit (e.g., lipids, HS-CRP, HS-troponin, NT-proBNP/BNP). The lack of systematic assessment of inflammatory biomarkers is particularly problematic as colchicine is an anti-inflammatory, and confirming a differential benefit by level of inflammation would confirm a biological basis of this, and potentially identify a subgroup less likely to benefit from use of colchicine.

Funding

Public and private funding from groups in Australia and the Netherlands. Authors with multiple financial disclosures.

Further Reading

  1. Crittenden DB et al. Colchicine use is associated with decreased prevalence of myocardial infarction in patients with gout. J Rheumatol 2012. 39:1458-64.
  2. 2.0 2.1 2.2 Supplementary appendix