© The Author(s) 2023Article reuse guidelines:sagepub.com/journals-permissionsDOI: 10.1177/17151635231191491
Mr. TH is a 48-year-old man who had a myocardial infarction at home. His wife found him unresponsive and called 911, who supported her in the provision of cardiopulmonary resuscitation until emergency medical services arrived, at which point he was resuscitated and transported to hospital. At hospital, he went directly to the cardiac catheterization lab, where diffuse disease was noted and a single stent implanted. Through his hospitalization, he was initiated on a beta-blocker, an angiotensin-converting enzyme (ACE) inhibitor, a statin, acetyl salicylic acid (ASA) and ticagrelor. His blood pressure is 125/80 mmHg, low-density lipoprotein (LDL) is 1.8 mmol/L and he has normal left ventricular function. He was discharged home in stable condition.
Despite advancements in management, atherosclerotic cardiovascular disease (ASCVD) remains prevalent and results in significant morbidity and mortality.1 In 2019, cardiovascular disease (CV) accounted for almost one-third of deaths worldwide, and in Canada, ASCVD was the second leading cause of hospitalization in 2020-2021. Data from the Global Registry of Acute Coronary Events indicate 1 in 14 patients died within 2 years of their acute coronary syndrome (ACS) event, 1 in 22 patients experienced a myocardial (re)infarction and 1 in 16 developed heart failure.2 Given the impact of ASCVD and the subsequent associated morbidity and mortality, opportunities to mitigate risk are important and warranted.
Secondary prevention measures following an ACS event are essential to limit progression of coronary heart disease and to reduce cardiovascular events and mortality. These involve both nonpharmacologic and pharmacologic approaches. Nonpharmacologic interventions include smoking cessation, weight reduction, increased physical activity, stress management, depression counselling, healthy diet and referral to cardiac rehabilitation. Pharmacologic secondary prevention strategies include use of antiplatelet agents, beta-blockers, ACE inhibitors/angiotensin receptor blockers (ARBs), statins and cardioprotective diabetes strategies. The American Heart Association/American College of Cardiology guidelines and the European Society of Cardiology recommend that all patients be prescribed secondary prevention medications prior to discharge from the hospital.3,4
Specific pharmacologic interventions demonstrated in the post-ACS population for secondary prevention include the following5 :
You see Mr. TH in follow-up 3 months after his cardiac event. He tells you he is feeling well, is attending a cardiac rehabilitation program and has returned to work. His medication regimen includes the following:
His blood pressure and cholesterol continue to be well controlled, and his A1C is not elevated. He asks if there is anything he can do to further decrease his cardiac risk.
Despite the use of secondary prevention strategies, patients with ASCVD remain at risk for recurrent cardiovascular events—this is termed residual risk, which is dependent on multiple factors, including the patient’s underlying comorbidity and pathophysiology, age and optimization of therapy. Those at highest risk generally have the highest residual risk. Given substantial residual risk, there is interest in the use of multimodal pharmacologic pathways that target lipid, thrombotic and inflammatory mechanisms in hopes of further diminishing negative outcomes.10
Pathways to minimize residual risk in patients with or at high risk of ASCVD include the following11 :
Inflammation is important in the development and progression of coronary artery disease. Inflammatory cells play a role in cytokine release, with subsequent plaque erosion and rupture. Interventions that target inflammatory pathways provide an opportunity to further improve outcomes in patients with ASCVD.12
Several agents with anti-inflammatory properties have been assessed in cardiovascular trials. Canakinumab, a monoclonal antibody targeting interleukin 1β, was studied in CANTOS (Canakinumab Antiinflammatory Thrombosis Outcome Study). A reduction in high-sensitivity C-reactive protein levels (inflammatory marker) and ASCVD events was demonstrated, but an increase in total deaths occurred in those receiving canakinumab due to an increased risk of fatal infections compared to placebo.10,11 The CIRT (Cardiovascular Inflammation Reduction Trial) trial assessed the effect of low-dose methotrexate in patients with previous myocardial infarction (MI) or multivessel coronary disease, who additionally had either type 2 diabetes or metabolic syndrome. This trial was stopped early due to lack of benefit.13
Low-dose colchicine (0.5-1.0 mg/day) was initially assessed in the Low Dose Colchicine for Secondary Prevention of Cardiovascular Disease (LoDoCo) study, which was a prospective, randomized trial of 532 patients with stable coronary artery disease. Patients were randomized to colchicine (0.5 mg day) or placebo and followed for 3 years. A significant reduction in cardiac events occurred in those randomized to colchicine vs control (5.3% vs 16.0%; hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.18-0.59; p < 0.001). Although the results were impressive, the trial had a number of limitations, and further evidence was felt to be required.14
LoDoCo2, a larger, more rigorous trial, included 5522 patients with chronic coronary disease who were clinically stable for at least 6 months and randomized to 0.5 mg of colchicine daily or placebo.15 Colchicine significantly reduced the primary endpoint of cardiovascular death, MI, ischemic stroke or ischemia-driven coronary revascularization compared to placebo (6.8% vs 9.6%; HR, 0.69; 95% CI, 0.57-0.83; p < 0.001; numbers needed to treat (NNT) = 36). Despite the positive cardiac endpoints, non-CV deaths were more frequent in those who received colchicine (0.7 vs 0.5 per 100 person years; HR, 1.51; 95% CI, 0.99-2.31). Adverse effects were similar in both groups.
COLCOT was a post-ACS trial that included 4745 patients with planned revascularization. The primary endpoint occurred in 5.5% of those randomized to colchicine vs 7.1% of those receiving placebo (HR, 0.77; 95% CI, 0.61-0.96; p = 0.02; NNT = 63). Stroke and urgent hospitalizations were more dramatically reduced in the colchicine-treated subgroups (HR, 0.26; 95% CI, 0.10-0.70 and HR, 0.50; 95% CI, 0.31-0.81) as compared to death from CV cause (HR, 0.84; 95% CI, 0.46-1.52), resuscitated cardiac arrest (HR, 0.83; 95% CI, 0.25-2.72) and MI (HR, 0.91; 95% CI, 0.68-1.21). There was no significant difference in the secondary composite endpoint, death, venous thromboembolism or atrial fibrillation. Pneumonia was reported as a serious adverse 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).16
A systematic review and meta-analysis consolidated the 4 available randomized controlled trials of colchicine. It included data from 2 studies in patients with stable coronary artery disease and 2 studies in patients after ACS. This analysis demonstrated a 32% reduction in events with colchicine (CV mortality, MI, ischemic stroke and urgent coronary revascularization; HR, 0.68; 95% CI, 0.54-0.81). Results were driven by reductions in MIs, ischemic stroke and urgent coronary revascularizations. Safety outcomes did not differ between interventions, including rates of infections, pneumonia, hospitalizations for gastrointestinal events and cancer.17 These results are consistent with other analyses. For example, in another systematic review and meta-analysis of 13 randomized trials, colchicine reduced the risk of MI and stroke but increased the risk of gastrointestinal side effects.18
Given the benefit seen with colchicine, a practice tool was designed to aid pharmacists and their patients in making informed decisions about colchicine in high-risk cardiovascular patients (Figure 1).
Key steps include the following:
Colchicine extended release (ER) 0.5 mg daily is indicated for the reduction of atherothrombotic events in adult patients with coronary artery disease and should be considered in patients with recent ACSs or established stable ASCVD to improve cardiovascular outcomes.
High-risk CVD patients should be initiated on well-established secondary prevention medications (antiplatelet therapy, statin, ACE/ARB) prior to initiating colchicine.
To prevent colchicine toxicity, it should not be used with strong P-glycoprotein inhibitors such as clarithromycin and ranolazine. Concomitant use of strong and moderate CYP3A4 inhibitors such as clarithromycin and ketoconazole should also be avoided. Concomitant use of colchicine with high-intensity statin therapy was well tolerated in the COLCOT trial, in which 98% of patients received statins. Colchicine should not be used in patients with an estimated glomerular filtration rate less than 30 mL/min.
Within the clinical trials, adverse events were similar to placebo, and within individual trials, adverse events did include gastrointestinal events, rare blood dyscrasias and pneumonia.
Colchicine is an inexpensive agent, with an acquisition cost of approximately $0.50 per day or approximately $180 per year. Many private drugs plans provide coverage of this agent now.
You discuss the evidence pertaining to colchicine in patients who have had an ACS event with Mr. TH, the adverse effect profile, medication cost and potential coverage options. He indicates his interest in initiating this therapy and requests that you share the discussion with his physician. After discussing this with his physician, Mr. TH is started on colchicine 0.5 mg daily. Follow-up is arranged in 3 months for further assessment to ensure he is tolerating this medication.
Low-dose colchicine has been demonstrated to decrease cardiovascular events in patients with acute and chronic coronary syndromes and to be well tolerated in clinical trials. Within a shared decision-making framework, this agent offers benefit to patients at high risk of future ASCVD events.
From the Provincial Pharmacy Programs (Semchuk), Saskatchewan Health Authority, Regina, Saskatchewan, and the Department of Pharmacy (Bucci), Sunnybrook Health Sciences Centre, Toronto, Ontario. Contact Bill.Semchuk@saskhealthauthority.ca.
Author Contributions: All authors approved the final version of the article.
Funding: The authors received no financial support for the research, authorship and/or publication of this article.
Declaration of Conflicting Interests: The authors have previously received funding from Pendopharm as advisory board members and for development of a practice tool.
ORCID iD: William Semchuk https://orcid.org/0000-0002-8182-7741
