LoDoCo

Published

Nidorf SM, et al. "Low-dose colchicine for secondary prevention of cardiovascular disease". Journal of the American College of Cardiology. 2013. 61(4):404-410.
PubMed • Full text

Clinical Question

In patients with clinically stable coronary disease, does taking colchicine 0.5 mg/day as compared to no colchicine reduce the risk of cardiovascular events?

Bottom Line

The addition of colchicine 0.5 mg/day to standard secondary prevention treatment with aspirin/clopidogrel and high-dose statins decreased the risk of cardiovascular events in patients with stable coronary disease. However, this trial was limited by its poor design.

Major Points

A retrospective study published in 2012 demonstrated a lower incidence of MI in patients with gout on colchicine, although a randomized prospective trial was lacking.

The 2013 Low-Dose Colchicine (LoDoCo) trial randomized 532 patients with stable CAD to colchicine or observation. At a median follow-up of 3 years, the colchicine group had a significant reduction in ACS, non-cardioembolic CVA, or out-of-hospital cardiac arrest when compared to the control group (5.3% vs. 16%), primarily driven by reduction in ACS (4.6% vs. 13.6%). More than 10% of participants in the colchicine arm discontinued the therapy from side effects.

LoDoCo was significantly limited by its lack of blinding, lack of placebo control, and addition of patients to the colchicine group to replace dropouts. It should be considered a hypothesis-generating paper rather than one that influences clinical practice. The larger, placebo-controlled, blinded COLCOT (2019) and LoDoCo2 (2020) trials assessed the role of colchicine post-MI and in stable CAD, respectively.

Guidelines

As of April 2015, no guidelines have been published that reflect the results of this trial.

Design

• Prospective, randomized, comparative, non-placebo controlled trial
• N=532
  • Colchicine (n=282)
  • Control (n=250)
• Timeline: 2008-2012 (stopped early after the second interim safety analysis)
• Median follow-up: 3 years
• Sites: Outpatient cardiology practices in Australia
• Analysis: Intention-to-treat
• Primary outcome: ACS, out-of-hospital cardiac arrest, or noncardioembolic ischemic stroke

Population

Inclusion Criteria

• Age 35-85 years
• Angiographically proven CAD
• Clinically stable for at least 6 months
• No major competing comorbidities or contraindication to colchicine
• Compliant with therapy

Exclusion Criteria

• Patients with previous bypass surgery with evidence of graft failure or who had undergone previous stenting
• Patients who had undergone bypass surgery within past 10 years

Baseline Characteristics

Data is from the colchicine group and does not differ from the control group except where otherwise specified. Comparisons are control vs. colchicine.

• Demographics: Age 66 years (SD 9.6 yrs), female 11%
• Heart disease history: MI/UA 23%, CABG 22%, PTCA 60%
• Other PMH: Diabetes 33%, smoker 4%
• Medications: Aspirin or clopidogrel 93% (both 13%), high-dose statin 96%, ACE-inhibitor 55%, beta blocker 71% vs. 62% (P<0.05), CCB 10% vs. 18% (P<0.01)

Interventions

• Randomization to colchicine starting at 0.5 mg mg PO qday or control (no colchicine)
• For every patient that discontinued colchicine in the first month of therapy, the research assistants randomized one more extra patient to the colchicine group to ensure that 250 patients would be treated with colchicine for at least 1 month to match the size of the control group.

Outcomes

Comparisons are colchicine vs. control.

Primary Outcomes

Acute coronary syndrome, non-cardioembolic CVA, or out-of-hospital cardiac arrest

Intention to treat: 5.3% vs. 16% (HR 0.33; 95% CI 0.18-0.59; P<0.001; NNT=10)

On-Treatment Analysis: 5.3% vs. 16% (HR 0.29; 95% CI 0.15-0.56; P<0.001; NNT=10)

Secondary Outcomes

Acute Coronary Syndrome

4.6% vs. 13.6% (HR 0.33; 95% CI 0.18-0.63; P<0.001; NNT=12)

Stent-related: 1.4% vs. 1.6% (NS)

Non-stent related: 3.2% vs. 12% (HR 0.26; 95% CI 0.12-0.55; P<0.001; NNT=12)

Non-stent AMI: 1.6% vs. 5.6% (HR 0.25; 95% CI 0.08-0.76; P=0.014; NNT=25)

Non-stent UA: 2.4% vs. 12% (HR 0.27; 95% CI 0.10-0.75; P=0.011; NNT=11)

Out-of-hospital cardiac arrest

0.35% vs. 0.8% (HR 0.47; 95% CI 0.04-5.15; P=0.534)

Non-cardioembolic CVA

0.35% vs. 1.6% (HR 0.23; 95% CI 0.03-2.03; P=0.184)

Subgroup Analysis

The primary endpoint was similar for multiple subgroups including age <65 or ≥65 years, DM, MI/UA, CABG, dual antiplatelet therapy, beta blocker, or ACE-inhibitor use.

Adverse Events

Withdrawals from the colchicine group

Early dropouts: 32 (all due to GI side effects)

Late dropouts: 30 (11 due to unrelated illness, 5 due to patient choice, 7 due to GI side effects, 7 due to other minor side effects such as myalgia, myositis, rash, alopecia, itch, and peripheral neuritis)

Criticisms

• Patient compliance, and lack of diversity
• Low quality design because of the lack of blinding and placebo control
• Early discontinuation and additional recruitment may have skewed randomization process
• Specific medications and doses were not mentioned
• Unclear long-term safety of colchicine

Funding

• Heart Research Institute of Western Australia
• Authors with multiple disclosures

Further Reading

3. Nidorf S, Eikelboom J, Thompson P. Targeting Cholesterol Crystal-Induced Inflammation for the Secondary Prevention of Cardiovascular Disease. Journal of Cardiovascular Pharmacology and Therapeutics. 2013;19(1):45-52.

4. Pashun R, Frishman W. Therapeutic Role of Innovative Anti-Inflammatory Medications in the Prevention of Acute Coronary Syndrome. Cardiology in Review. 2015;1.