The Time to Initiate Anti-Inflammatory Therapy for Patients With Chronic Coronary Atherosclerosis Has Arrived
In contemporary care, all patients with atherosclerosis should receive lipid-lowering drugs to reduce the risk of recurrent cardiovascular events. Yet despite multiple effective therapies for cholesterol reduction, residual inflammatory risk remains a major and largely untreated concern.
In a recent analysis of 31 245 patients with atherosclerosis receiving guideline-directed medical care including high-intensity statins, residual inflammatory risk (as detected by on-treatment hsCRP [high sensitivity C-reactive protein]) was more strongly associated with recurrent cardiovascular events, cardiovascular death, and all-cause mortality than was residual cholesterol risk (detected by on-treatment LDLC [low-density lipoprotein cholesterol]).1
These contemporary data have implications for the selection of adjunctive therapies to lower cardiovascular risk, an issue reflected by the US Food and Drug Administration’s recent approval of low-dose colchicine (0.5 mg daily) as the first anti-inflammatory therapy to be used on top of statins to reduce the risk of myocardial infarction, stroke, coronary revascularization, and cardiovascular death. Moreover, guidelines in Europe and the United States now include long-term use of low-dose colchicine for the secondary prevention of atherosclerotic events.
For preventive cardiologists moving beyond statin therapy alone, it is worth considering the formal evidence base comparing the adjunctive use of second LDLC-lowering agents compared with the adjunctive use of anti-inflammatory therapies. To date, 7 major randomized trials with similar baseline risk have formally addressed this issue, 1 using adjunctive ezetimibe, 3 using adjunctive PCSK9 inhibitors, and 3 using adjunctive anti-inflammatory therapy. As shown in the Figure, although all these treatments yielded statistically significant results, the magnitudes of benefit when added to statin therapy were greater for the anti-inflammatory interventions. An eighth major randomized trial of icosapent ethyl for triglyceride-lowering that included both primary and secondary prevention patients taking statins reported a 25% relative risk reduction for major adverse cardiovascular events, but interpretation of that trial has been controversial given use of a nonneutral comparator.

On the basis of the LoDoCo2 (Low Dose Colchicine - 2) and COLCOT (Colchicine Cardiovascular Outcomes Trial) trials, low-dose colchicine is currently the anti-inflammatory treatment of choice for patients with stable atherosclerosis.2 In these trials of patients with coronary artery disease, long term low-dose colchicine lowered major adverse cardiovascular events by 31% among those with stable atherosclerosis (hazard ratio [HR], 0.69 [95% CI, 0.57–0.83], P<0.001) and by 23% after recent myocardial infarction (HR, 0.77 [95% CI, 0.61–0.96], P=0.02). No adverse interactions with statin therapy were observed, and the benefits of chronic treatment accrued even when therapy was initiated several years after an initial diagnosis of systemic atherosclerosis was made.3 Although hsCRP levels were not formal entry criteria for LoDoCo2 or COLCOT, median values among those who nonetheless had hsCRP measured range between 3.5 and 4.5 mg/L.
In combined analysis of all low-dose colchicine trials to date, a highly significant 33% reduction in myocardial infarction, stroke, coronary revascularization, or cardiovascular death is reported (HR, 0.67 [95% CI, 0.55–0.82]).4 Benefits of low-dose colchicine on ischemic stroke are even larger (HR, 0.54 [95% CI, 0.34–0.86]). All-cause mortality associated with low-dose colchicine is neutral (HR, 1.08 [95% CI, 0.71–1.62]), reflecting a nonsignificant reduction in cardiovascular deaths (HR, 0.82 [95% CI, 0.55–1.23]) and a nonsignificant increase in noncardiovascular deaths (HR, 1.38 [95% CI, 0.99–1.92]). In detailed analyses of noncardiovascular deaths within LoDoCo2, no specific cause was found.5 Colchicine is associated with neither the development of any specific adverse disorder nor any specific cause of death among individuals with familial Mediterranean fever where lifetime use of high-dose colchicine is routine. Within COLCOT, pneumonia was reported among 0.9% of those allocated to colchicine and 0.4% of those allocated to placebo (P=0.03). Within LoDoCo2, rates of hospitalization for pneumonia or infection were evenly distributed between treatment groups.
Colchicine is contraindicated in patients with severe renal or liver dysfunction and should be temporarily discontinued when taking concomitant agents such as clarithromycin, ketoconazole, and cyclosporine that inhibit the CYP3A4 and P-glycoprotein metabolism pathways.2 The use of colchicine during acute coronary ischemia is currently unproven and requires testing in large outcome trials.
Our biologic understanding of atherosclerosis is radically different today compared with a decade ago. Most important from a therapeutic perspective, lipid-lowering and inflammation inhibition are not in conflict but are fully synergistic interventions that can be given simultaneously. Today, clinicians can elect to add low-dose colchicine to statin therapy, ezetimibe, bempedoic acid, or PCSK9 inhibition for their high-risk patients with residual inflammatory risk. In the future, the combined use of aggressive LDL-lowering and inflammation-inhibiting therapies, perhaps in a widely available polypill form, could become standard of care for a broader group of patients with atherosclerosis.
Multiple novel anti-inflammatory therapies are undergoing current investigation. Building on the CANTOS interleukin-1β inhibition trial (Canakinumab Anti-inflammatory Thrombosis Outcomes Study), which first demonstrated the utility of targeting inflammation in chronic atherosclerosis, ongoing trials of ziltivekimab and clazakizumab are addressing whether inhibition of the downstream cytokine interleukin-6 can safely lower cardiovascular events in the settings of chronic kidney disease, heart failure with preserved ejection fraction, acute coronary ischemia, and among patients undergoing dialysis. Of these trials, ZEUS (Ziltivekimab Cardiovascular Outcomes Study; Registration: URL: http://www.clinicaltrials.gov; Unique identifier: NCT05021835) is likely to complete first and will be crucial for patients with significant chronic kidney disease where low-dose colchicine is contraindicated.
The new Food and Drug Administration label states that low-dose colchicine is indicated to reduce the risk of myocardial infarction, stroke, coronary revascularization, and cardiovascular death in adult patients with established atherosclerotic disease or with multiple risk factors for cardiovascular disease. I, however, will initially be considering low-dose colchicine for my high-risk “frequent flyer” secondary prevention patients who have recurrent coronary events and persistent symptoms despite aggressive guideline directed therapy. For now, I am also likely to take a conservative stance and limit low-dose colchicine to those with hsCRP levels >2 mg/L for whom I am concerned that inflammation is a silent driver of disease progression.
Although results from CANTOS, LoDoCo2, and COLCOT are persuasive, much remains uncertain. Will anti-inflammatory therapy be useful for patients with large-vessel peripheral arterial disease where few medical therapies are effective? Might early anti-inflammatory therapy provide a novel intervention to reduce vascular risk among patients with metabolic syndrome and insulin resistance? Might anti-inflammatory therapy provide benefit for those who present with chronic carotid rather than chronic coronary disease? Will the proven role of anti-inflammatory therapy in stable coronary disease extend to individuals with acute coronary ischemia or acute stroke where issues of rapid reperfusion are typically more important than issues of underlying disease progression?
All these questions will be addressed by the clinical research community. However, as of today, barring contraindications, the time to consider initiating anti-inflammatory therapy for patients with chronic coronary atherosclerosis and residual inflammatory risk has already arrived.
REFERENCES
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Ridker PM, Bhatt DL, Pradhan AD, Glynn RJ, MacFadyen JG, Nissen SE; PROMINENT, REDUCE-IT, and STRENGTH Investigators. Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomized trials. Lancet. 2023;401:1293–1301. doi: 10.1016/S0140-6736(23)00215-5
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Nelson K, Fuster V, Ridker PM. Low-dose colchicine for secondary prevention of coronary artery disease. JACC review topic of the week. J Am Coll Cardiol. 2023;82:648–660. doi: 10.1016/j.jacc.2023.05.055
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Opstal T, Fiolet A, van Broekhoven A, Mosterd A, Eikelboom JW, Nidorf SM, Thompson PL, Duyvendak M, van Eck JWM, van 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
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Fiolet A, Opstal T, Mosterd A, Eikelboom JW, Jolly SS, Keech AC, Kelly P, Tong DC, Layland J, Nidorf SM, et al. Efficacy and safety of low-dose colchicine in patients with coronary disease: a systematic review and meta-analysis of randomized trials. Eur Heart J. 2021;42:2765–2775. doi: 10.1093/eurheartj/ehab115
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Opstal T, Nidorf S, Fiolet A, 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
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© 2023 American Heart Association, Inc.
History
Published online: 2 October 2023
Published in print: 3 October 2023
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Disclosures Dr Ridker has received institutional research grant support from the National Heart, Lung, and Blood Institute, Novartis, and Novo Nordisk (to evaluate the role of anti-inflammatory agents including methotrexate, interleukin-1 inhibitors, and interleukin-6 inhibitors) as well as Kowa, Amarin, Pfizer, and Esperion; has served as a consultant to Novartis, Novo Nordisk, Janssen, Flame, Agepha, Ardelyx, Zomagen, Horizon Therapeutics, CSL Behring, and Cardio Therapeutics (entities developing anti-inflammatory therapies including as examples colchicine, interleukin-1 inhibitors, interleukin-6 inhibitors, and agents that potentially target or interact with the NLRP3 inflammasome); has served as a consultant to AstraZeneca, Civi Biopharm, Glaxo Smith Kline, SOCAR, Health Outlook, Montai Health, Eli Lilly, New Amsterdam, Boehringer-Ingelheim, RTI, and Cytokinetics; has minority shareholder equity positions in Uppton, Bitteroot Bio, and Angiowave; and receives compensation for service on the Peter Munk Advisory Board (University of Toronto), the Leducq Foundation, Paris FR, and the Baim Institute (Boston, MA).
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