Insights into the Role of Inflammation in the Management of Atherosclerosis

Figures & data

Table 1 Summary of Clinical Trials of Anti-Inflammatory Drugs for the Prevention of Atherosclerotic Cardiovascular Events

Acute Coronary Syndrome Population
Trial	Population	N	Intervention	Follow-Up	Primary End Point	Secondary End Point	Adverse Events	Drug Targeting
COLCOT^Citation8	MI within 30 days before enrollment	4745	0.5 mg of colchicine vs placebo	Median: 22.6 months	Death from cardiovascular causes, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina leading to coronary revascularization: 5.5% of the patients in the colchicine group, as compared with 7.1% of those in the placebo group (HR, 0.77; 95% confidence interval [CI], 0.61 to 0.96; P=0.02)	Death from cardiovascular causes, resuscitated cardiac arrest, MI, or stroke; and total mortality occurred in 4.7% of the patients in the colchicine group and in 5.5% of those in the placebo group (HR, 0.85; 95% CI, 0.66 to 1.10)	Nausea was more common in the colchicine group than in the placebo group (1.8% vs 1.0%, P=0.02). Pneumonia event in 0.9% of the patients in the colchicine group, as compared with 0.4% of those in the placebo group (P=0.03)	Various anti-inflammatory properties:^Citation107 inhibits components of NLRP3 inflammasome; binds tubulin and subsequent disruption of cell mitosis, transport activities; inhibits neutrophil migration and adhesion
COPS^Citation52	18–85 years who presented with ACS (included STEMI, non-STEMI, and unstable angina) and had evidence of coronary artery disease on coronary angiography	795	Colchicine (0.5 mg twice daily for the first month, then 0.5 mg daily for 11 months) or placebo	12 months treatment	Composite of death from any cause, ACS (STEMI/non-STEMI/unstable angina), ischemia driven urgent revascularization, and noncardioembolic ischemic stroke: colchicine group compared with the placebo group: 24 [6.1%] versus 38 [9.5%]; HR 0.65 (0.38–1.09), p=0.10	Components of the primary end point as well as hospitalization for chest pain (colchicine vs placebo): Deaths from any cause: HR 8.20 (1.03–65.61), p=0.047 Cardiovascular death: HR 3.09 (0.32–29.71), p=0.33 ACS: HR 0.56 (0.27–1.18), p= 0.13 Stroke: HR 0.41 (0.008–2.10), p=0.28 Urgent revascularization: HR 0.26 (0.007–0.092), p= 0.037 Hospitalization for chest pain: HR 0.34 (0.04–3.31), p= 0.36	Any adverse effect: colchicine 91 (23%) vs placebo 99 (24.8%) Gastrointestinal symptoms: colchicine 91 (23%) vs placebo 83 (20.8%)	See above
Chronic coronary disease population
Trial	Population	N	Intervention	Follow-up	Primary end point	Secondary end point	Adverse events	Drug targeting
LoDoCo^Citation51	Angiographically proven coronary disease; age 35 to 85 years; clinically stable for at least 6 months	532	Colchicine 0.5 mg/day or no colchicine	Median: 36 months	Composite of ACS, fatal or nonfatal out-of-hospital cardiac arrest, or noncardioembolic ischemic stroke: 5.3% (colchicines) vs 16% (no colchicines); HR: 0.33; 95% CI 0.18 to 0.59; p= 0.001; number needed to treat: 11	Individual components of the primary outcome and the components of ACS unrelated to stent disease: ACS: 13.6 vs 4.6; HR: 0.33 (0.18–0.63), p<0.001 Cardiac arrest: 0.8 vs 0.35; HR: 0.47 (0.04–5.15), p=0.534 Noncardioembolic stroke: 1.6 vs 0.35; HR: 0.23 (0.03–2.03), p= 0.184	Reported causes of withdrawals from therapy: 7 (2.5%) intestinal upset; 2 (0.9%) myalgia	See above
CIRT^Citation54	Stable condition with history of myocardial infarction or multivessel coronary disease and either type 2 diabetes or the metabolic syndrome	4786	Low-dose methotrexate (at a target dose of 15 to 20 mg weekly) vs placebo	Median: 2.3 years	Nonfatal MI, nonfatal stroke, or cardiovascular death: incidence rate, 4.13 (methotrexate) vs 4.31 (placebo) per 100 person-years; hazard ratio, 0.96; 95% confidence interval [CI], 0.79 to 1.16	Methotrexate vs placebo: Death from any cause: 1.80 vs 1.55; HR: 1.16 (0.87–1.56); Composite of major adverse cardiovascular events plus any coronary revascularization: 5.86 vs 6.15; HR: 0.95 (0.81–1.12) Hospitalization for congestive heart failure: 0.95 vs 1.0; HR: 0.89 (0.60–1.31) Composite of major adverse cardiovascular events plus coronary revascularization, hospitalization for congestive heart failure, or death from any cause: 7.30 vs 7.42; HR: 0.98 (0.84–1.14)	Methotrexate was associated with elevations in liver-enzyme levels, reductions in leukocyte counts and hematocrit levels, and a higher incidence of non–basal-cell skin cancers than placebo.	Modulates inflammation via inhibition of aminoimidazole-4-carboxamide ribonucleotide, which leads to elevated adenosine levels^Citation53
CANTOS^Citation6	History of MI (at least 30 days before randomization) and had a blood level of high-sensitivity CRP of 2 mg or more per liter	10.061	Three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) vs placebo	Median: 3.7 years	Nonfatal MI, any nonfatal stroke, or cardiovascular death: Placebo: 4.50 events per 100 persons-years 50 mg: 4.11 events per 100 persons-years (HR, 0.93; P=0.30) 150 mg: 3.86 events per 100 persons-years (HR vs placebo, 0.85; P=0.02075) 300 mg: 3.90 events per 100 persons-years (HR vs placebo, 0.86; P=0.0314)	Secondary end point included the components of the primary end point as well as hospitalization for unstable angina that led to urgent revascularization. 150 mg: HR versus placebo 0.83 (P = 0.00525, with a threshold P value of 0.00529). OBS: formal significance testing for the prespecified secondary end point was not performed for the 50 mg group and the 300 mg group	Neutropenia, thrombocytopenia and more deaths attributed to infection or sepsis in canakinumab than placebo	Fully human monoclonal antibody targeting interleukin-1β^Citation45
LoDoCo2^Citation7	Patients 35 to 82 years with chronic coronary disease on invasive coronary angiography or computed tomography angiography or a coronary-artery calcium score of at least 400 Agatston units	5522	0.5 mg of colchicine vs placebo	Median: 28.6 months	Cardiovascular death, spontaneous MI, ischemic stroke, or ischemia-driven coronary revascularization occurred in 187 patients (6.8%) in the colchicine group and in 264 patients (9.6%) in the placebo group, with incidence rates of 2.5 and 3.6 events, respectively, per 100 person-years (HR, 0.69; 95% confidence interval [CI], 0.57 to 0.83; P<0.001)	Cardiovascular death, spontaneous MI, or ischemic stroke occurred in 115 patients (4.2%) in the colchicine group and in 157 patients (5.7%) in the placebo group, with incidence rates of 1.5 and 2.1 events, respectively, per 100 person-years (HR, 0.72; 95% CI, 0.57 to 0.92; P=0.007)	Non cardiovascular deaths occurred more frequently among the patients who received colchicine than among those who received placebo, with incidence rates of 0.7 and 0.5 events, respectively, per 100 person-years (HR, 1.51; 95% CI, 0.99 to 2.31)	See above

Abbreviations: MI, Myocardial infarction; ACS, Acute coronary syndrome; HR, Hazard ratio; STEMI, ST elevation myocardial infarction; CRP, C-reactive protein.

Figure 1 Therapies targeting inflammation and atherosclerotic cardiovascular disease (ASCVD) prevention. This figure summarizes some of the main inflammatory targets for CVD prevention and their directed therapies: NLRP3 and microtubule polymerisation inhibitors, IL-1 and IL-6 blockade and TNF targeting.

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