Abstract
Background
The LoDoCo2 (Low‐Dose Colchicine 2) trial showed that colchicine reduced the risk for cardiovascular events in patients with chronic coronary syndrome. Current guidelines recommend colchicine use in selected high‐risk patients. The aim of this secondary analysis was to explore the relative and absolute benefits of colchicine according to baseline risk.
Methods
The LoDoCo2 trial randomized 5522 patients to colchicine 0.5 mg or placebo. The primary end point was a composite of cardiovascular death, spontaneous myocardial infarction, ischemic stroke, or ischemia‐driven coronary revascularization. First, a LoDoCo2 risk score was developed by Cox regression to identify high‐risk features for the primary end point. Second, the Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention was applied to explore robustness of findings.
Results
In the LoDoCo2 risk score, high‐risk features were age ≥75, diabetes, and current smoker. In high‐risk (≥1 high‐risk feature), compared with low‐risk (0 high‐risk features) patients, colchicine was associated with consistent relative (high risk: hazard ratio [HR], 0.72 [95% CI, 0.56–0.94] versus low risk: HR, 0.67 [95% CI, 0.52–0.88]; P for interaction=0.73) and absolute benefits (high risk: HR, −1.33 [95% CI, −2.38 to −0.27] versus low risk: HR, −0.93 [95% CI −1.57 to −0.30] events per 100 person‐years). Using the Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention, consistent relative and absolute benefits were found in high‐, intermediate‐, and low‐risk patients.
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.
Registration
URL: https://www.anzctr.org.au; Unique identifier: 12614000093684.
Keywords: chronic coronary syndrome, colchicine, risk stratification, secondary prevention
Subject Categories: Cardiovascular Disease, Risk Factors
Nonstandard Abbreviations and Acronyms
- CANTOS
Canakinumab Antiinflammatory Thrombosis Outcomes Study
- CCS
chronic coronary syndrome
- CLEAR SYNERGY
A 2×2 Factorial Randomized Controlled Trial of Colchicine and Spironolactone in Patients With ST Elevation Myocardial Infarction/SYNERGY Stent Registry–Organization to Assess Strategies for Ischemic Syndromes 9
- COLCOT
Colchicine Cardiovascular Outcomes Trial
- JUPITER
Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin
- LoDoCo2
Low‐Dose Colchicine 2
- TRS 2°P
Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention
Clinical Perspective.
What Is New?
Current European Society of Cardiology and American College of Cardiology/American Heart Association guidelines for secondary prevention recommend colchicine for selected high‐risk patients.
The LoDoCo2 (Low‐Dose Colchicine 2) trial was a low‐risk chronic coronary syndrome population that provided the opportunity to assess benefit in low‐risk patients.
What Are the Clinical Implications?
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.
Inflammation contributes substantially to the atherosclerotic process. 1 Anti‐inflammatory therapy in the prevention of cardiovascular disease has been investigated in the CANTOS (Canakinumab Antiinflammatory Thrombosis Outcomes Study) trial. 2 Canakinumab, a human monoclonal antibody targeted at interleukin‐1β, showed significant reduction for major adverse cardiovascular events in a high‐risk population, with a history of myocardial infarction, selected for inflammation (defined as high‐sensitivity C‐reactive protein ≥2 mg/L). Additional trials have investigated the use of the anti‐inflammatory drug colchicine for secondary prevention including the COLCOT (Colchicine Cardiovascular Outcomes Trial) and theLoDoCo2 (Low‐Dose Colchicine 2) trial. 3 , 4 COLCOT studied patients with an acute coronary syndrome, whereas LoDoCo2 studied patients with chronic coronary syndrome (CCS). Both trials showed that colchicine reduced the risk of subsequent ischemic cardiovascular events.
In 2023, the US Food and Drug Administration approved colchicine 0.5 mg once daily for the secondary prevention of cardiovascular disease. The 2021 European Society of Cardiology and the 2023 American College of Cardiology/American Heart Association guidelines recommend use of colchicine in selected high‐risk patients with recurrent cardiovascular events despite optimal medical treatment. 5 , 6 For recurrent events, a secondary analysis of the LoDoCo2 (Low‐Dose Colchicine 2) trial has already shown that the relative risk reduction established by colchicine was independent of baseline history of an acute coronary syndrome. 7 This suggests that no history of acute coronary syndrome (ie, the first event and not a recurrent event) should not be a reason to withhold colchicine. The objective of this secondary analysis of the LoDoCo2 trial was to investigate the relative and absolute benefits of colchicine according to baseline risk.
METHODS
Trial Design and Population
The data that support the findings of this study will be made accessible for analyses approved by the LoDoCo2 steering committee, to be contacted via a.mosterd@meandermc.nl. The LoDoCo2 (ACRTN: 12614000093684) randomized 5522 patients with CCS in a 1‐to‐1 ratio to colchicine 0.5 mg once daily or placebo. The primary end point consisted of a composite of cardiovascular death, spontaneous myocardial infarction, ischemic stroke, or ischemia‐driven coronary revascularization, and the secondary end point was a composite of cardiovascular death, spontaneous myocardial infarction, or ischemic stroke. Colchicine reduced the primary composite end point by 31%. The secondary end point was the composite of cardiovascular death, spontaneous myocardial infarction, or ischemic stroke (28% risk reduction). For the current analyses, the end points death from any cause and noncardiovascular death were also explored. Medical ethics approval for the LoDoCo2 trial was obtained in both participating countries (Sir Charles Gairdner Group HREC, Perth, Australia; and MEC‐U, Nieuwegein, the Netherlands), and all patients provided written informed consent for participation in the trial. Further details can be found elsewhere. 4 , 8
Risk Stratification
The purpose of our analyses was to stratify patients into different risk categories at baseline and not to create a new risk score or validate existing risk scores. Two risk scores were used to stratify baseline risk. The first score was based on the LoDoCo2 database (LoDoCo2 Risk Score). All baseline characteristics known to be associated with cardiovascular events in the literature were selected for analysis from the LoDoCo2 database. 7 , 9 , 10 The following baseline predictors were added to the model in the total cohort: treatment allocation, age ≥75, 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.
The Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention (TRS 2°P) was used as a second risk score to explore robustness of the findings, because this risk score contained the most risk features that were available in the LodoCo2 data set. 11 The risk score includes the following 9 risk features: congestive heart failure, hypertension, age ≥75, 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. In the LoDoCo2 database, 6 of these features were available, because “prior stroke,” “congestive heart failure,” and “peripheral artery disease” were not collected.
Statistical Analysis
Baseline characteristics were compared in the high (median or higher) and low risk (less than median) group using 1‐way analysis of variance or χ2, as appropriate. For the LoDoCo2 Risk Score, univariate associations between risk predictors and the end points were identified using time to first event data by Cox regression analysis with corresponding hazard ratios (HRs) and 95% CIs. All risk predictors were added in a Cox regression model, and backward elimination with the Akaike information criterion was used to identify the strongest combination of variables for the primary outcome, which were subsequently combined in the multivariable analysis. 12 , 13 These variables were considered high‐risk features. The cumulative number of high‐risk features was calculated for each patient. The median was used as a cutoff between high and low risk. The Schoenfeld residuals were visually inspected and tested to assess whether the proportional hazards assumption of the Cox models was violated. No violations were found. Event rates for all end points were calculated per 100 person‐years and presented according to number of high‐risk features and baseline risk. Treatment interaction with baseline risk was assessed by adding a risk‐by‐treatment variable into the model. Absolute risk difference with corresponding 95% CI and absolute risk reduction with corresponding number needed to treat (NNT) were calculated over the duration of the trial. Kaplan–Meier estimates were plotted for the high‐ and low‐risk group and treatment group. The same analyses were performed by stratifying patients into high, intermediate, and low baseline risk using the TRS 2°P. P values were 2‐tailed with an α of 0.05. Statistical analysis was performed using RStudio version 2022.02.1 (Posit PBC, Boston, MA).
RESULTS
The LoDoCo2 trial included 5522 patients randomized to colchicine 0.5 mg or placebo once daily. The primary event occurred in 451 patients (8.2%) of the trial population. The presence of the risk factors that were used to classify risk are shown in Table S1, according to whether patients experienced a primary outcome event.
Risk Stratification Using the LoDoCo2 Risk Score
After performing backward elimination on the Cox regression analysis, age ≥75, current smoker, diabetes, and colchicine treatment were identified as the strongest predictors of the primary end point. The HRs in multivariable analysis for age ≥75, current smoker, diabetes, and colchicine treatment were 1.45 (95% CI, 1.16–1.82; P<0.01), 1.28 (95% CI, 0.96–1.72; P=0.09), 1.75 (95% CI, 1.42–2.15; P<0.001) and 0.70 (95% CI, 0.58–0.85; P<0.001), respectively (Table 1). Similar analyses conducted separately in the colchicine and placebo cohort identified the same high‐risk features as in the complete cohort (Tables S2 and S3). The median number of high‐risk features was 1. Therefore, high‐risk patients were identified as those with at least 1 high‐risk feature, and low‐risk patients were identified as those without any high‐risk feature.
Table 1.
Univariate and Multivariable Cox Regression Analysis for Baseline Predictors of the Primary Outcome in the Complete Cohort
| Variables | Univariate | Multivariable* | ||
|---|---|---|---|---|
| Hazard ratio (95% CI) | P value | Hazard ratio (95% CI) | P value | |
| Age≥75 y | 1.45 (1.16–1.82) | <0.01 | 1.45 (1.16–1.82) | <0.01 |
| Male sex | 1.21 (0.92–1.61) | 0.17 | ||
| Current smoker | 1.24 (0.92–1.65) | 0.15 | 1.28 (0.96–1.72) | 0.09 |
| Hypertension | 1.04 (0.86–1.25) | 0.70 | ||
| Diabetes | 1.77 (1.44–2.18) | <0.001 | 1.75 (1.42–2.15) | <0.001 |
| eGFR 45–59 mL/min per 1.73 m2 | 1.24 (0.82–1.88) | 0.31 | ||
| Prior acute coronary syndrome | 0.98 (0.77–1.25) | 0.87 | ||
| Prior coronary revascularization | 1.13 (0.89–1.45) | 0.32 | ||
| History of atrial fibrillation | 1.24 (0.95–1.62) | 0.11 | ||
| History of gout | 1.11 (0.80–1.54) | 0.52 | ||
| Colchicine treatment | 0.69 (0.57–0.83) | <0.001 | 0.70 (0.58–0.85) | <0.001 |
Similar analyses were performed in the colchicine and placebo group without treatment as a covariate, identifying the same predictor variables: age≥75 years, smoker, and diabetes. eGFR indicates estimated glomerular filtration rate.
Backward elimination using the Akaike information criterion was used to identify the strongest combination of predictors for the outcome in the multivariable analysis.
Baseline Characteristics
Baseline characteristics of patients across the different risk categories using the LoDoCo2 Risk Score are shown in Table 2. Using the LoDoCo2 Risk Score, in addition to the higher prevalence of high‐risk features, high‐risk compared with low‐risk patients more often had hypertension (56.2% versus 47.3%; P<0.001), a history of gout (9.2% versus 7.4%; P=0.02), an estimated glomerular filtration rate between 45 and 59 mL/min per 1.732 (7.3% versus 4.4%; P<0.001), and a history of atrial fibrillation (15.6% versus 9.2%; P<0.001). Single antiplatelet therapy was less common in those at high risk (64.7% versus 68.5%; P<0.01), whereas the use of anticoagulants (16.4% versus 9.4%; P<0.001), β blockers (67.7% versus 58.4%; P<0.001), calcium channel blocker (26.4% versus 20.0%; P<0.001), and renin–angiotensin inhibitor use (74.1% versus 70.2%; P<0.01) were higher. Those at high risk more often used ≥5 cardiovascular medications (28.9% versus 17.1%; P<0.001).
Table 2.
Baseline Characteristics According to Risk Group
| LoDoCo2 risk score | TIMI risk score for secondary prevention | ||||||
|---|---|---|---|---|---|---|---|
| High risk N=2189 | Low risk N=3333 | P value | High risk N=1813 | Intermediate risk N=2149 | Low risk N=1560 | P value | |
| Age, y, mean±SD | 68.8±9.3 | 63.8±7.4 | <0.001 | 69.6±8.3 | 65.1±8.3 | 62.4±7.6 | <0.001 |
| Male sex, n (%) | 1830 (83.6) | 2846 (85.4) | 0.08 | 1515 (83.6) | 1801 (83.8) | 1360 (87.2) | <0.01 |
| Clinical characteristics | |||||||
| Current smoker, n (%) | 648 (29.6) | 0 (0.0) | <0.001 | 397 (21.9) | 251 (11.7) | 0 (0.0) | <0.001 |
| Hypertension, n (%) | 1231 (56.2) | 1577 (47.3) | <0.001 | 1507 (83.1) | 1301 (60.5) | 0 (0.0) | <0.001 |
| Diabetes, n (%) | 1007 (46.0) | 0 (0.0) | <0.001 | 803 (44.3) | 204 (9.5) | 0 (0.0) | <0.001 |
| eGFR 45–59 mL/min per 1.73 m2, n (%) | 160 (7.3) | 146 (4.4) | <0.001 | 246 (13.6) | 60 (2.8) | 0 (0.0) | <0.001 |
| Prior acute coronary syndrome, n (%) | 1850 (84.5) | 2808 (84.2) | 0.82 | 1531 (84.4) | 1779 (82.8) | 1348 (86.4) | 0.01 |
| Prior coronary revascularization, n (%) | 1835 (83.8) | 2786 (83.6) | 0.84 | 1582 (87.3) | 1739 (80.9) | 1300 (83.3) | <0.001 |
| History of atrial fibrillation, n (%) | 341 (15.6) | 308 (9.2) | <0.001 | 303 (16.7) | 223 (10.4) | 123 (7.9) | <0.001 |
| History of gout, n (%) | 201 (9.2) | 245 (7.4) | 0.02 | 201 (11.1) | 167 (7.8) | 78 (5.0) | <0.001 |
| Medication at baseline | |||||||
| Single antiplatelet therapy, n (%) | 1417 (64.7) | 2284 (68.5) | <0.01 | 1182 (65.2) | 1458 (67.8) | 1061 (68.0) | 0.13 |
| Dual antiplatelet therapy, n (%) | 502 (22.9) | 828 (24.8) | 0.11 | 400 (22.1) | 518 (24.1) | 412 (26.4) | 0.01 |
| Anticoagulant, n (%) | 359 (16.4) | 313 (9.4) | <0.001 | 303 (16.7) | 243 (11.3) | 126 (8.1) | <0.001 |
| β blocker, n (%) | 1481 (67.7) | 1946 (58.4) | <0.001 | 1235 (68.1) | 1320 (61.4) | 872 (55.9) | <0.001 |
| Calcium channel blocker, n (%) | 577 (26.4) | 667 (20.0) | <0.001 | 565 (31.2) | 529 (24.6) | 150 (9.6) | <0.001 |
| Renin–angiotensin inhibitor, n (%) | 1621 (74.1) | 2339 (70.2) | <0.01 | 1456 (80.3) | 1602 (74.5) | 902 (57.8) | <0.001 |
| Insulin use, n (%) | 287 (13.1) | 0 (0.0) | <0.001 | 230 (12.7) | 57 (2.7) | 0 (0.0) | <0.001 |
| Ezetimibe, n (%) | 429 (19.6) | 644 (19.3) | 0.83 | 367 (20.2) | 422 (19.6) | 284 (18.2) | 0.31 |
| Any statin, n (%) | 2045 (93.4) | 3143 (94.3) | 0.20 | 1696 (93.5) | 2021 (94.0) | 1471 (94.3) | 0.64 |
| Lipid‐lowering therapy, n (%) | 2101 (96.0) | 3234 (97.0) | 0.04 | 1746 (96.3) | 2077 (96.6) | 1512 (96.9) | 0.61 |
| Total number of cardiovascular medications* | <0.001 | <0.001 | |||||
| 0–2, n (%) | 138 (6.3) | 370 (11.1) | 67 (3.7) | 154 (7.2) | 287 (18.4) | ||
| 3–4, n (%) | 1418 (64.8) | 2392 (71.8) | 1160 (64.0) | 1537 (71.5) | 1113 (71.3) | ||
| ≥5, n (%) | 633 (28.9) | 571 (17.1) | 586 (32.3) | 458 (21.3) | 160 (10.3) | ||
Values are mean±SD or n (%). For the LoDoCo2 Risk Score, high‐risk patients were those with at least 1 of the following variables: age≥75 years, smoking, and diabetes. LoDoCo2, Low‐Dose Colchicine 2; and TIMI, Thrombolysis in Myocardial Infarction.
Medications at baseline were single antiplatelet therapy, dual antiplatelet therapy, anticoagulant use, β blocker, calcium channel blocker, renin–angiotensin inhibitor, insulin, ezetimibe, and statin. The P values were calculated using 1‐way ANOVA or χ2.
Event Rates According to Number of High‐Risk Features for the LoDoCo2 Risk Score
Event rates per 100 person‐years for the primary end point are shown in Figure S1. Using the LoDoCo2 Risk Score, event rates increased with the number of high‐risk features. The HRs by increasing number of high‐risk features compared with those without high‐risk features were 1.63 (95% CI, 1.34–1.98; P<0.001) for 1 high‐risk feature, and 2.27 (95% CI, 1.63–3.17; P<0.001) for ≥2 high‐risk features. High‐risk patients compared with low‐risk patients had an HR of 1.72 (95% CI, 1.43–2.07; P<0.001) for the primary end point.
Treatment Effect of Colchicine for Primary and Secondary End Point in the LoDoCo2 Risk Score
Figure 1 and Table 3 show the event rates stratified by treatment and risk category. Colchicine reduced the incidence of the primary end point across the spectrum of baseline risk without a significant treatment interaction when stratified by high or low risk by the LoDoCo2 Risk Score (high risk: HR, 0.72 [95% CI, 0.56–0.94] versus low risk: HR, 0.67 [95% CI, 0.52–0.88]; P for interaction=0.73). For the LoDoCo2 Risk Score, the absolute rate difference established with colchicine in the high‐ compared with low‐risk group was similar (high risk: −1.33 [95% CI, −2.38 to −0.27] events per 100 person‐years versus low risk: −0.93 [95% CI, −1.57 to −0.30] events per 100 person‐years). Absolute risk reduction established with colchicine in the high‐ and low‐risk group were consistent (3.3% with an NNT=31 versus 2.4% with an NNT=43, respectively). Kaplan–Meier estimates were plotted for the primary end point by risk groups in Figure 2. Similar findings were found for the secondary end point, with consistent relative risk reduction across the spectrum of baseline risk, stratified by the LoDoCo2 Risk Score (high risk: HR, 0.83 [95% CI, 0.60–1.14] versus low risk: HR, 0.63 [95% CI, 0.44–0.91]; P for interaction=0.27).
Figure 1. Event rates by risk group stratified by treatment during the trial.
For the LoDoCo2 risk score, high risk was the presence of any high‐risk feature, defined as age ≥75 years, diabetes, or current smoker with a minimum of 1. Low risk was defined as those without any high‐risk features. For TRS 2°P, high risk was defined as ≥2 risk features, intermediate risk as 1 risk feature, and low risk as no risk feature. P value indicates treatment interaction. ARR indicates absolute risk reduction; HR, hazard ratio; LoDoCo2, Low‐Dose Colchicine 2 trial; LoDoCo2 RS, LoDoCo2 Risk Score; NNT, number needed to treat; and TRS 2°P, Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention.
Table 3.
Event Rates for the Primary and Secondary End Point According to Risk Group
| Colchicine | Placebo | Overall | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Events (n/N) | Percentage | Event rate per 100 person‐years (95% CI) | Events (n/N) | Percentage | Event rate per 100 person‐years (95% CI) | P value for interaction | Absolute rate difference (95% CI) | Absolute risk reduction (NNT), n (%) | |
| Primary end point | |||||||||
| LoDoCo2 Risk Score | 0.73 | ||||||||
| High risk | 95/1069 | 8.9 | 3.43 (2.77 to 4.19) | 136/1120 | 12.1 | 4.75 (3.99 to 5.62) | −1.33 (−2.38 to −0.27) | 31 (3.3) | |
| Low risk | 92/1693 | 5.4 | 1.94 (1.56 to 2.37) | 128/1640 | 7.8 | 2.87 (2.39 to 3.41) | −0.93 (−1.57 to −0.30) | 43 (2.4) | |
| TRS 2°P | 0.30 | ||||||||
| High risk | 81/866 | 9.4 | 3.61 (2.87 to 4.49) | 112/947 | 11.8 | 4.57 (3.76 to 5.50) | −0.96 (−2.12 to 0.19) | 41 (2.5) | |
| Intermediate risk | 70/1122 | 6.2 | 2.27 (1.77 to 2.87) | 96/1027 | 9.3 | 3.48 (2.82 to 4.25) | −1.21 (−2.09 to −0.34) | 33 (3.1) | |
| Low risk | 36/774 | 4.7 | 1.64 (1.15 to 2.27) | 56/786 | 7.1 | 2.64 (2.00 to 3.43) | −1.00 (−1.88 to −0.13) | 41 (2.5) | |
| Secondary end point | |||||||||
| LoDoCo2 Risk Score | 0.27 | ||||||||
| High risk | 67/1069 | 6.3 | 2.37 (1.84 to 3.01) | 85/1120 | 7.6 | 2.87 (2.29 to 3.55) | −0.50 (−1.33 to 0.34) | 76 (1.3) | |
| Low risk | 48/1693 | 2.8 | 1.00 (0.74 to 1.32) | 72/1640 | 4.4 | 1.58 (1.24 to 1.99) | −0.58 (−1.04 to −0.12) | 65 (1.6) | |
| TRS 2°P | 0.07 | ||||||||
| High risk | 54/866 | 6.2 | 2.37 (1.78 to 3.09) | 66/947 | 7.0 | 2.60 (2.01 to 3.31) | −0.24 (−1.13 to 0.65) | 137 (0.7) | |
| Intermediate risk | 45/1122 | 4.0 | 1.44 (1.05 to 1.92) | 59/1027 | 5.7 | 2.09 (1.59 to 2.69) | −0.65 (−1.33 to 0.03) | 58 (1.7) | |
| Low risk | 16/774 | 2.1 | 0.72 (0.41 to 1.17) | 32/786 | 4.1 | 1.48 (1.02 to 2.10) | −0.76 (−1.39 to −0.14) | 50 (2.0) | |
The primary end point consisted of a composite of cardiovascular death, spontaneous myocardial infarction, ischemic stroke, or ischemia‐driven coronary revascularization, and the secondary end point was a composite of cardiovascular death, spontaneous myocardial infarction, or ischemic stroke. ARR indicates absolute risk reduction; LoDoCo2, Low‐Dose Colchicine 2 trial; NNT, number needed to treat; and TRS 2°P, Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention.
Figure 2. Unadjusted Kaplan–Meier estimates for the primary end point, according to the LoDoCo2 Risk Score (left panel) and the Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention (right panel) and treatment (solid lines=Placebo, dotted lines=colchicine).
Red=high risk, yellow=intermediate risk, blue=low risk.
Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention
For risk stratification using the TRS 2°P, patients were divided into high (≥2 risk features), intermediate (1 risk feature), and low (0 risk features) baseline risk. Table 2 shows the baseline characteristics stratified by risk category using TRS 2°P. Those at high risk more often used ≥5 cardiovascular medications (32.3% versus 21.3% versus 10.3%; P<0.001).
Risk stratification using TRS 2°P showed an increase of event rates with incremental number of risk features. Those with 1, 2, and ≥3 TRS 2°P risk features compared with no risk features had HRs of 1.33 (95% CI, 1.03–1.72; P = 0.03), 1.66 (95% CI, 1.27–2.18; P<0.001), and 2.74 (95% CI, 2.00–3.75; P<0.001), respectively (Figure S1). High‐ and intermediate‐risk patients compared with low‐risk patients had HRs of 1.93 (95% CI, 1.51–2.47; P<0.001) and 1.33 (95% CI, 1.03–1.72; P = 0.03) for the primary end point, respectively.
Relative and absolute risk reductions were assessed across the different risk categories using TRS 2°P. Consistent relative (high risk: HR, 0.79 [95% CI, 0.59–1.05] versus intermediate risk: HR, 0.65 [95% CI, 0.48–0.89] versus low risk: HR, 0.62 [95% CI, 0.41–0.94]; P for interaction=0.30; Figures 1 and 2) and absolute risk reduction (high risk: −0.96 [95% CI, –2.12 to 0.19] versus intermediate risk: −1.12 [95% CI, −2.09 to −0.34] versus low risk: −1.00 [95% CI, −1.88 to −0.13] events per 100 person‐years) was found in those at high, intermediate, or low risk. The NNT were 41, 33, and 41, respectively. For the secondary end point, consistent relative (high risk: HR, 0.91 [95% CI, 0.64–1.30] versus intermediate risk: HR, 0.69 [95% CI, 0.47–1.01] versus low risk: HR, 0.48 [95% CI, 0.27–0.88]; P for interaction=0.07) and absolute benefits were found (Figures 1 and 2; Table 3).
Individual End Points
The beneficial effects of colchicine on the primary composite end point were mostly driven by a reduction of ischemia‐driven revascularization and myocardial infarction across risk groups (Table S4). For the LoDoCo2 Risk Score and the TRS 2°P, the incidence of death from any cause and noncardiovascular death across the spectrum of baseline risk stratified by treatment are shown in Table S5. The incidence for both end points was numerically higher in high‐risk patients. For both end points, no consistent higher incidence was found between colchicine and placebo‐treated patients in the low‐risk groups.
DISCUSSION
In this secondary analysis of the LoDoCo2, 2 different risk scores were used to assess the effect of colchicine across the spectrum of baseline risk: the LoDoCo2 Risk Score and the TRS 2°P. The current analysis demonstrated that colchicine therapy consistently reduces the risk in patients across the spectrum of baseline risk, with similar absolute benefits. The 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. These findings indicate that low‐risk patients with CCS also substantially benefitted from low‐dose colchicine therapy.
Relative and Absolute Benefits
The finding that low‐risk patients achieve a similar absolute benefit compared with those in the high‐risk group seems counterintuitive considering the higher baseline risk of high‐risk patients. One possible explanation is that high‐risk patients had a greater burden of comorbidities and used more medications, which could have reduced the potential for additional risk reduction by colchicine, as shown in Table 2. However, it is essential to stress that high‐risk patients also substantially benefit from colchicine therapy on top of multiple cardiovascular medications, which supports the addition of colchicine to usual care for secondary prevention in high‐risk patients. There was no evidence of an interaction between colchicine and other baseline cardiovascular medications for outcomes. Previous trials in high‐risk populations as the CANTOS trial, and trials investigating bempedoic acid or proprotein convertase subtilisin/kexin type 9 inhibitors found a relative risk reduction of ≈15% for cardiovascular events, compared with 20% to 30% in the current analysis. 2 , 14 , 15 , 16
The incidence of noncardiovascular death seemed more prominent in those at higher baseline risk compared with lower risk, which is most likely due to competing risk considering the higher number of comorbidities and medications. Previous analysis exploring the specific causes of death in LoDoCo2 did not reveal an adverse effect on any specific causes of death. 17 Moreover, an updated meta‐analysis of the randomized trials as well as the recently published CLEAR SYNERGY (A 2×2 Factorial Randomized Controlled Trial of Colchicine and Spironolactone in Patients With ST Elevation Myocardial Infarction/SYNERGY Stent Registry–Organization to Assess Strategies for Ischemic Syndromes 9) trial did not demonstrate an increase in noncardiovascular death with colchicine. 3 , 18 , 19
Residual Risk
Patients with established CCS remain at high risk for cardiovascular events. 20 In a large cohort study with >1 500 000 individuals, modifiable risk factors (body mass index), high blood pressure, elevated levels of cholesterol, smoking, and diabetes contributed to just over half of the cardiovascular events. 21 This leftover risk is referred to as residual risk, which can be partly attenuated by anti‐inflammatory therapy. 22 This concept was studied in the JUPITER (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin) trial, where patients without elevated cholesterol levels but with increased inflammation showed significant risk reduction and reduced inflammatory levels by treatment with statins. 23 The CANTOS trial demonstrated that targeting residual risk with a potent anti‐inflammatory drug produced substantial benefits. 2 Subgroup analyses did not identify any baseline characteristic that benefited less or more from anti‐inflammatory therapy with canakinumab. 24 Following this landmark trial, COLCOT showed that colchicine reduced the risk for cardiovascular events in patients with a myocardial infarction, the primary composite end point of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization. More than 99% of patients were on statin therapy at baseline in these trials, highlighting the potential for additional risk reduction by addressing inflammation in addition to cholesterol risk. Both the COLCOT and LoDoCo2 trials demonstrated the consistent effects of colchicine in reducing cardiovascular events among patients with and without diabetes. 25 , 26 This suggests that the benefits of colchicine extend across different patient subgroups.
Limitations
This secondary analysis has several limitations. First, body mass index and lipid levels were not available, which limited the analysis to the risk factors available in the LoDoCo2 trial. If available, these features may have been identified as high‐risk features. The event rates using both an internal and external risk score increased with number of risk predictors, which substantiates robustness of the analyses. Second, we modified the TRS 2°P, which may have led to suboptimal risk stratification. However, the sole purpose of the analysis was to stratify baseline risk and not to validate or create a risk score. Third, overall event rates were relatively low, although they are in line with other CCS populations. 14 , 15 Furthermore, event rates in those assigned placebo in the high‐risk group were comparable to that of other high‐risk trial populations. 2 , 14 , 15 , 16 Finally, because this secondary LoDoCo2 analysis was not prespecified, our findings should be interpreted as hypothesis generating.
Implication of the Findings
Current European Society of Cardiology and American College of Cardiology/American Heart Association guidelines for secondary prevention guidelines recommend colchicine for patients with recurrent cardiovascular events or those at high risk. 5 , 6 The LoDoCo2 trial was a low risk CCS population and did not select patients according to baseline inflammatory status, which provided the opportunity to assess benefit in low‐risk patients. The current findings indicate that intermediate‐ and low‐risk patients also derive substantial absolute benefits from colchicine and suggest that more patients could benefit from colchicine than current guidelines recommend. Colchicine is safe and easily accessible worldwide and has been shown to be highly cost effective, further supporting its use across the spectrum of baseline risk. 27 , 28 , 29
CONCLUSIONS
In patients with CCS, 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.
Sources of Funding
The LoDoCo2 trial was supported by the National Health Medical Research Council of Australia; a grant from the Sir Charles Gairdner Research Advisory Committee; the Withering Foundation the Netherlands; the Netherlands Heart Foundation; the Netherlands Organization for Health Research and Development; and a consortium of Teva, Disphar, and Tiofarma in the Netherlands.
Disclosures
W.B. reports membership of advisory boards and/or honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Daiichi‐Sankyo, Novo Nordisk, and Sanofi‐Aventis. A.M. reports membership of advisory boards of and/or consultancy for Tiofarma, TEVA, the Netherlands, and Novartis. A.M. will not accept personal fees; these fees will be donated to research. P.T. reports grants, travel support, and honoraria from Amarin, Amgen, AstraZeneca, Bristol‐Myers Squibb, Merck, and Pfizer. J.E. reports consulting/honoraria support from AstraZeneca, Bayer, Boehringer‐Ingelheim, Bristol‐Myers Squibb, Daiichi‐Sankyo, Eli Lilly, GlaxoSmithKline, Pfizer, Janssen, Sanofi‐Aventis, and Servier, and grants and/or in‐kind support from AstraZeneca, Bayer, Boehringer‐Ingelheim, Bristol‐Myers Squibb, GlaxoSmithKline, Pfizer, Janssen, and Sanofi‐Aventis. J.C. reports membership in advisory boards with Amgen and AstraZeneca. All other authors had nothing to disclose.
Supporting information
Tables S1–S5
Figure S1
Acknowledgments
Figure 1 was created in BioRender. Mohammadnia, N. (2025); https://BioRender.com/k35x469. Peter L. Thompson is deceased.
Jan H. Cornel and Saloua El Messaoudi share senior authorship.
This manuscript was sent to Krishnaraj S. Rathod, MBBS, BMedSci, MRCP, Associate Editor, for review by expert referees, editorial decision, and final disposition.
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/JAHA.124.038687
For Sources of Funding and Disclosures, see page 9.
Contributor Information
Jan H. Cornel, Email: saloua.elmessaoudi@radboudumc.nl.
Saloua El Messaoudi, Email: saloua.elmessaoudi@radboudumc.nl.
References
- 1. Ridker PM, Bhatt DL, Pradhan AD, Glynn RJ, MacFadyen JG, Nissen SE. Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomised trials. Lancet. 2023;401:1293–1301. doi: 10.1016/S0140-6736(23)00215-5 [DOI] [PubMed] [Google Scholar]
- 2. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377:1119–1131. doi: 10.1056/NEJMoa1707914 [DOI] [PubMed] [Google Scholar]
- 3. Tardif J‐C, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, Pinto FJ, Ibrahim R, Gamra H, Kiwan GS, et al. Efficacy and safety of low‐dose colchicine after myocardial infarction. N Engl J Med. 2019;381:2497–2505. doi: 10.1056/NEJMoa1912388 [DOI] [PubMed] [Google Scholar]
- 4. Nidorf SM, Fiolet ATL, Mosterd A, Eikelboom JW, Schut A, Opstal TSJ, The SHK, Xu X‐F, Ireland MA, Lenderink T, et al. Colchicine in patients with chronic coronary disease. N Engl J Med. 2020;383:1838–1847. doi: 10.1056/NEJMoa2021372 [DOI] [PubMed] [Google Scholar]
- 5. Visseren FLJ, Mach F, Smulders YM, Carballo D, Koskinas KC, Bäck M, Benetos A, Biffi A, Boavida J‐M, Capodanno D, 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;42:3227–3337. doi: 10.1093/eurheartj/ehab484 [DOI] [PubMed] [Google Scholar]
- 6. Virani SS, Newby LK, Arnold SV, Bittner V, Brewer LC, Demeter SH, Dixon DL, Fearon WF, Hess B, Johnson HM, 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. doi: 10.1161/CIR.0000000000001168 [DOI] [PubMed] [Google Scholar]
- 7. Opstal TSJ, Fiolet ATL, Broekhoven A, Mosterd A, Eikelboom JW, Nidorf SM, Thompson PL, Duyvendak M, Eck JWM, Beek EA, et al. Colchicine in patients with chronic coronary disease in relation to prior acute coronary syndrome. J Am Coll Cardiol. 2021;78:859–866. doi: 10.1016/j.jacc.2021.06.037 [DOI] [PubMed] [Google Scholar]
- 8. Nidorf SM, Fiolet ATL, Eikelboom JW, Schut A, Opstal TSJ, Bax WA, Budgeon CA, Tijssen JGP, Mosterd A, Cornel JH, et al. The effect of low‐dose colchicine in patients with stable coronary artery disease: the LoDoCo2 trial rationale, design, and baseline characteristics. Am Heart J. 2019;218:46–56. doi: 10.1016/j.ahj.2019.09.011 [DOI] [PubMed] [Google Scholar]
- 9. Anand SS, Eikelboom JW, Dyal L, Bosch J, Neumann C, Widimsky P, Avezum AA, Probstfield J, Cook Bruns N, Fox KAA, et al. Rivaroxaban plus aspirin versus aspirin in relation to vascular risk in the COMPASS trial. J Am Coll Cardiol. 2019;73:3271–3280. doi: 10.1016/j.jacc.2019.02.079 [DOI] [PubMed] [Google Scholar]
- 10. Ferguson LD, Molenberghs G, Verbeke G, Rahimi K, Rao S, McInnes IB, McMurray JJV, Sattar N, Conrad N. Gout and incidence of 12 cardiovascular diseases: a case–control study including 152 663 individuals with gout and 709 981 matched controls. Lancet Rheumatol. 2024;6:e156–e167. doi: 10.1016/S2665-9913(23)00338-7 [DOI] [PubMed] [Google Scholar]
- 11. Bohula EA, Bonaca MP, Braunwald E, Aylward PE, Corbalan R, De Ferrari GM, He P, Lewis BS, Merlini PA, Murphy SA, et al. Atherothrombotic risk stratification and the efficacy and safety of vorapaxar in patients with stable ischemic heart disease and previous myocardial infarction. Circulation. 2016;134:304–313. doi: 10.1161/circulationaha.115.019861 [DOI] [PubMed] [Google Scholar]
- 12. Bozdogan H. Model selection and Akaike's information criterion (AIC): the general theory and its analytical extensions. Psychometrika. 1987;52:345–370. doi: 10.1007/BF02294361 [DOI] [Google Scholar]
- 13. Chowdhury MZI, Turin TC. Variable selection strategies and its importance in Clinical prediction modelling. Fam Med Community Health. 2020;8:e000262. doi: 10.1136/fmch-2019-000262 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, Edelberg JM, Goodman SG, Hanotin C, Harrington RA, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379:2097–2107. doi: 10.1056/NEJMoa1801174 [DOI] [PubMed] [Google Scholar]
- 15. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, et al. Evolocumab and Clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713–1722. doi: 10.1056/NEJMoa1615664 [DOI] [PubMed] [Google Scholar]
- 16. Nissen SE, Lincoff AM, Brennan D, Ray KK, Mason D, Kastelein JJP, Thompson PD, Libby P, Cho L, Plutzky J, et al. Bempedoic acid and cardiovascular outcomes in statin‐intolerant patients. N Engl J Med. 2023;388:1353–1364. doi: 10.1056/NEJMoa2215024 [DOI] [PubMed] [Google Scholar]
- 17. Opstal TSJ, Nidorf SM, Fiolet ATL, Eikelboom JW, Mosterd A, Bax WA, Budgeon CA, Ronner E, Prins FJ, Tijssen JGP, et al. Drivers of mortality in patients with chronic coronary disease in the low‐dose colchicine 2 trial. Int J Cardiol. 2023;372:1–5. doi: 10.1016/j.ijcard.2022.12.026 [DOI] [PubMed] [Google Scholar]
- 18. Jolly SS, d'Entremont M‐A, Lee SF, Mian R, Tyrwhitt J, Kedev S, Montalescot G, Cornel JH, Stanković G, Moreno R, et al. Colchicine in acute myocardial infarction. N Engl J Med. 2025;392:633–642. doi: 10.1056/NEJMoa2405922 [DOI] [PubMed] [Google Scholar]
- 19. Fiolet ATL, Poorthuis MHF, Opstal TSJ, Amarenco P, Boczar KE, Buysschaert I, Budgeon C, Chan NC, Cornel JH, Jolly SS, et al. Colchicine for secondary prevention of ischaemic stroke and atherosclerotic events: a meta‐analysis of randomised trials. eClinicalMedicine. 2024;76:102835. doi: 10.1016/j.eclinm.2024.102835 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Kaasenbrood L, Boekholdt SM, Graaf Y, Ray KK, Peters RJG, Kastelein JJP, Amarenco P, LaRosa JC, Cramer MJM, Westerink J, et al. Distribution of estimated 10‐year risk of recurrent vascular events and residual risk in a secondary prevention population. Circulation. 2016;134:1419–1429. doi: 10.1161/CIRCULATIONAHA.116.021314 [DOI] [PubMed] [Google Scholar]
- 21. Magnussen C, Ojeda FM, Leong DP, Alegre‐Diaz J, Amouyel P, Aviles‐Santa L, De Bacquer D, Ballantyne CM, Bernabé‐Ortiz A, Bobak M, et al. Global effect of modifiable risk factors on cardiovascular disease and mortality. N Engl J Med. 2023;389:1273–1285. doi: 10.1056/NEJMoa2206916 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Ridker PM. How common is residual inflammatory risk? Circ Res. 2017;120:617–619. doi: 10.1161/CIRCRESAHA.116.310527 [DOI] [PubMed] [Google Scholar]
- 23. Ridker PM, Danielson E, Fonseca FAH, Genest J, Gotto AM, Kastelein JJP, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, et al. Rosuvastatin to prevent vascular events in men and women with elevated C‐reactive protein. N Engl J Med. 2008;359:2195–2207. doi: 10.1056/NEJMoa0807646 [DOI] [PubMed] [Google Scholar]
- 24. Ridker PM, MacFadyen JG, Everett BM, Libby P, Thuren T, Glynn RJ. Relationship of C‐reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. Lancet. 2018;391:319–328. doi: 10.1016/s0140-6736(17)32814-3 [DOI] [PubMed] [Google Scholar]
- 25. Roubille F, Bouabdallaoui N, Kouz S, Waters DD, Diaz R, Maggioni AP, Pinto FJ, Grégoire JC, Gamra H, Kiwan GS, et al. Low‐dose colchicine in patients with type 2 diabetes and recent myocardial infarction in the colchicine cardiovascular outcomes trial (COLCOT). Diabetes Care. 2024;47:467–470. doi: 10.2337/dc23-1825 [DOI] [PubMed] [Google Scholar]
- 26. Mohammadnia N, Los J, Opstal TSJ, Fiolet ATL, Eikelboom JW, Mosterd A, Nidorf SM, Budgeon CA, Tijssen JGP, Thompson PL, et al. Colchicine and diabetes in patients with chronic coronary artery disease: insights from the LoDoCo2 randomized controlled trial. Front Cardiovasc Med. 2023;10:1244529. doi: 10.3389/fcvm.2023.1244529 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Nidorf SM, Ben‐Chetrit E, Ridker PM. Low‐dose colchicine for atherosclerosis: long‐term safety. Eur Heart J. 2024;45:ehae208. doi: 10.1093/eurheartj/ehae208 [DOI] [PubMed] [Google Scholar]
- 28. Fiolet ATL, Keusters W, Blokzijl J, Nidorf SM, Eikelboom JE, Budgeon CA, Tijssen JGP, Römer T, Westendorp I, Cornel JH, 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. doi: 10.1093/ehjqcco/qcae021 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Samuel M, Tardif JC, Khairy P, Roubille F, Waters DD, Grégoire JC, Pinto FJ, Maggioni AP, Diaz R, Berry C, et al. Cost‐effectiveness of low‐dose colchicine after myocardial infarction in the colchicine cardiovascular outcomes trial (COLCOT). Eur Heart J Qual Care Clin Outcomes. 2021;7:486–495. doi: 10.1093/ehjqcco/qcaa045 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Tables S1–S5
Figure S1