More insights from the LoDoCo2 (Low-Dose Colchicine 2) trial

July 2025

This latest analysis supports the use of colchicine in patients with chronic coronary syndrome across the spectrum of baseline risk.  

Mohammadnia N, Wesselink BE, Bax WA, et al. Cardiovascular benefit of colchicine in relation to baseline risk: a secondary analysis of the LoDoCo2 Trial. J Am Heart Assoc 2025;14:e038687. DOI: 10.1161/JAHA.124.038687. 

STUDY SUMMARY

Objective

To investigate the relative and absolute benefits of colchicine according to baseline risk, based on data from the LoDoCo2 trial. 

Study design

The LoDoCo2 trial, was a randomized, placebo-controlled, double-blind study in patients with chronic coronary syndrome, who were randomized 1: 1 to treatment with colchicine 0.5 mg once daily or placebo.

Study population 

5522 patients with chronic coronary syndrome. 

Main study variable

In the trial, the primary end point was a composite of cardiovascular death, spontaneous myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization, and the secondary endpoint was a composite of cardiovascular death, spontaneous myocardial infarction, or ischemic stroke.

This analysis also included the endpoints of death from any cause and non-cardiovascular death.

Methods

Two risk scores were used to stratify baseline risk. The first score was based on the LoDoCo2 database (LoDoCo2 Risk Score) and included all baseline characteristics known to be associated with cardiovascular events in the literature.  Treatment allocation, age ≥75 years, sex, current smoker, hypertension, diabetes, history of gout, estimated glomerular filtration rate <60 mL/min per 1.73 m2, prior acute coronary syndrome, prior coronary revascularization, and history of atrial fibrillation were included in this model. The Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention (TRS 2°P) was the second risk score and was used to investigate the robustness of the results. This score incorporates 9 risk features: congestive heart failure, hypertension, age ≥75 years, diabetes, prior stroke, prior coronary artery bypass grafting, peripheral artery disease, estimated glomerular filtration rate <60 mL/min per 1.73 m2 and current smoker: however, data on prior stroke, congestive heart failure, and peripheral artery disease were not collected in the LoDoCo2 database. 

Key results

In the LoDoCo2 risk score, high-risk features were age ≥75 years, diabetes, and current smoker. Patients with at least one of these features were categorized as high-risk, whereas those without any of these features were categorized as low-risk. In the TRS 2°P score, high-risk was defined as ≥2 risk features, intermediate-risk as 1 risk feature, and low-risk as no risk feature. Analysis using either score showed that the relative and absolute benefit of colchicine treatment was consistent across the spectrum of risk (Table 1). The number needed to treat (NNT) was 31 for high-risk patients and 43 for low-risk patients using the LoDoCo2 Risk Score and 41 for high- and low-risk patients using TRS 2°P.

Table 1. Effect of colchicine treatment on the primary endpoint categorized by baseline risk 

Hazard ratio 

(95% CI)

Absolute risk reduction, NNT

LoDoCo2 score

High-risk

0.72 

(0.56–0.94)

3.3%, NNT=31

Low-risk

0.67 

(0.52–0.88)

2.4%, NNT=43

P for interaction 

0.73

TRS 2°P score

High-risk

0.79 (0.59–1.05)

2.5%, NNT=41

Intermediate-risk

0.65 (0.48–0.89)

3.1%, NNT=33

Low-risk

0.62 (0.41–0.94)

2.5%, NNT=41

P for interaction

0.30

Author conclusions

In patients with chronic coronary syndrome, the relative and absolute benefits of colchicine were consistent in those at high-, intermediate-, and low-risk for cardiovascular events. These findings support the use of colchicine across the spectrum of baseline risk. 

Comment

Residual inflammatory risk is a major burden for atherosclerotic cardiovascular disease in secondary prevention patients even if low-density lipoprotein cholesterol (LDL-C) is well-controlled. Indeed, in an analysis of three major trials (PROMINENT, REDUCE-IT and STRENGTH), residual inflammatory risk, as indicated by levels of high-sensitivity C-reactive protein (hsCRP) was a more powerful determinant of recurrent cardiovascular events, cardiovascular death, and all-cause mortality than was on-treatment LDL-C (1).

Colchicine is an established anti-inflammatory therapy, with low dose treatment shown to benefit patients with stable coronary artery disease (2), as well as the stable phase following acute myocardial infarction (3). In the LoDoCo2 trial in patients with chronic coronary syndrome, low-dose colchicine reduced the risk of cardiovascular death, myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization by 31% compared with placebo (p<0.001), with a NNT of 35, consistent with the benefits of aspirin, statins, and antihypertensive therapy in secondary prevention (2,4,5). Supported by these findings, European and US guidelines recommend the use of colchicine in selected high-risk patients with recurrent cardiovascular events despite optimal medical treatment (6,7)

A key question is whether colchicine benefits all patients with stable coronary artery disease irrespective of their baseline cardiovascular risk. This latest analysis from the LoDoCo2 trial shows that the relative and absolute benefits of colchicine in patients with stable coronary artery disease were consistent in high- , intermediate- and low-risk groups. Given that colchicine has been shown to be safe, readily accessible and cost-effective (8,9), implies that it has utility in reducing residual inflammatory risk across the spectrum of cardiovascular risk in stable atherosclerosis. 

References

  1. Ridker P, Bhatt D, Pradhan A, et al. Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomized trials. Lancet 2023;401:1293-301.
  2. Nidorf S, Fiolet A, Mosterd A, et al. Colchicine in patients with chronic coronary disease. N Engl J Med 2020;383:1838-47.
  3. Tardif JC, Kouz S, Waters D, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med 2019;381:2497-505.
  4. Bittl JA, Maron DJ. Using absolute event rates to see what works in cardiovascular medicine. J Am Coll Cardiol 2017;70:1376-8.
  5. Marquis-Gravel G, Goodman S, Anderson T. et al. Colchicine for prevention of atherothrombotic events in patients with coronary artery disease: review and practical approach for clinicians. Can J Cardiol 2021;37:1837-45.
  6. Visseren FLJ, Mach F, Smulders YM, et al. 2021 ESC guidelines on cardiovascular disease prevention in Clinical practice: developed by the task force for cardiovascular disease prevention in Clinical practice with representatives of the European Society of Cardiology and 12 medical societies with the special contribution of the European Association of Preventive Cardiology (EAPC). Eur Heart J 2021;42:3227–337.
  7. Virani SS, Newby LK, Arnold SV, et al. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA guideline for the Management of Patients with Chronic Coronary Disease: a report of the American Heart Association/American College of Cardiology Joint Committee on Clinical practice guidelines. Circulation 2023;148:e9–e119. 
  8. Nidorf SM, Ben-Chetrit E, Ridker PM. Low-dose colchicine for atherosclerosis: long-term safety. Eur Heart J 2024;45:ehae208.
  9. Fiolet ATL, Keusters W, Blokzijl J, et al. Cost-effectiveness of low-dose colchicine in patients with chronic coronary disease in The Netherlands. Eur Heart J Qual Care Clin Outcomes 2024;11:89–96.

Key words: Colchicine; LoDoCo 2 trial; baseline cardiovascular risk; relative and absolute clinical benefit