Let’s COLCOT to the Chase: Colchicine for Secondary Prevention of CV Events

Author(s)
Jessica Wearden, PharmD
Augustus (Rob) Hough, PharmD, BCPS, BCCP

Reviewed By
Anthony Todd, PharmD
Daniel Longyhore, PharmD, BCACP

Citation
Tardif J-C, Kouz S, Waters DD, et al. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N Engl J Med 2019; 381: 2497-2505.

The Problem

 

Millions of Americans will have a myocardial infarction (MI) in their lifetime. In the five years following an MI, 20% will have a recurrent fatal or non-fatal coronary heart disease (CHD) event.¹  Several modifiable risk factors, including elevated blood pressure, cholesterol, and glucose as well as tobacco use, can and should be addressed to reduce the risk of recurrent cardiovascular (CV) events.  Systemic inflammation has also been associated with poor CV outcomes.  Is systemic inflammation a modifiable CV risk factor?  And if so, should an anti-inflammatory agent be added to the recommend post-MI drug cocktail to reduce the risk of morbidity and mortality?

 

What’s Known

 

Inflammation is a key component of the atherosclerotic process that can precipitate MI, ischemic stroke, and peripheral artery disease.² While multiple medications have been shown to reduce the risk of recurrent events in patients following an acute event, the broad impact of atherosclerotic disease makes systemic inflammation an attractive therapeutic target. Unfortunately, the results of previous studies using medications to modify the inflammatory process to reduce major adverse cardiovascular events (MACE) rates have been mixed. 

 

The CANTOS study, which used canakinumab, an interlukin-1β (IL-1β) inhibitor, found a 15% relative reduction in the MACE composite.³  Conversely, the CIRT study, which used methotrexate to reduce systemic inflammation, failed to show a significant improvement in MACE outcomes.⁴ While both agents target inflammation, the differences in their mechanisms of action may explain the dissimilar results.  Specifically, methotrexate does not reduce IL-1β, IL-6, or C-reactive protein.  Thus, how inflammation is reduced may be critical.⁴ Unfortunately, canakinumab was also associated with higher rates of fatal infections and sepsis.  This fact, along with an astronomical price tag, led the FDA to reject canakinumab’s application for approval for use in patients with coronary artery disease (CAD), effectively killing its prospects.

 

The quest to find an effective and less expensive anti-inflammatory agent has led to colchicine – a drug that has been used for nearly 60 years primarily to treat acute gout attacks and pericarditis. Its potential to reduce CV risk was first explored in the LoDoCo study.⁵ In LoDoCo, colchicine was added to standard secondary prevention treatments in patients with stable CAD. While the study was limited by a very small sample size and not placebo-controlled, there was a remarkable reduction in CV events.  A much larger and robustly designed study was needed before colchicine could be considered a standard of care.

 

What’s New

 

COLCOT was a randomized, double-blind, placebo-controlled, time-to-event trial comparing colchicine 0.5 mg once daily to placebo in post-MI patients.⁶ Patients were randomized within 30 days from an acute MI event and after completing any planned percutaneous revascularization procedures. Patients were excluded if they had compromised immune function or higher infection risk. Additionally, those with inflammatory bowel disease, chronic diarrhea, elevated creatinine kinase (non-transiently greater than 3 times upper limit of normal (ULN)) or serum creatinine (greater than 2 times ULN), severe hepatic disease, or hematologic abnormalities (e.g., significant WBC reductions) at baseline were considered poor candidates for therapy and were excluded from COLCOT.⁶ Colchicine was used as an add-on therapy and patients received standard guideline-recommended treatments. The primary composite endpoint was death from CV causes, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina leading to revascularization.

 

A total of 4745 patients were assigned to colchicine (n=2366) or placebo (n=2379) and followed for a median of 22.6 months. Patients were enrolled a mean of 13.5 days following their index MI, with 93% undergoing PCI.  Nearly all patients were taking aspirin (99%) with an additional antiplatelet agent (98%), a statin (99%), and beta-blocker (BB) (89%).  The primary composite endpoint was significantly reduced with colchicine therapy, occurring in 5.5% of the patients receiving colchicine compared to 7.1% of placebo treated patients (HR, 0.77; 95% CI, 0.61-0.96; p=0.02), resulting in a number needed to treat of 63 patients to prevent 1 composite event over 22.6 months. Reductions in the composite endpoint were driven primarily by reductions in urgent hospitalization for angina leading to revascularization and stroke (See Table 1). Colchicine was relatively well-tolerated.  The rate of treatment discontinuation, approximately 18% of patients, was similar in both groups.  Only nausea (1.8% versus 1%, p=0.02) and flatulence (0.6% versus 0.2%, p=0.02) were higher in the colchicine group. Of the reported serious adverse events, only pneumonia was statistically higher in the colchicine group (0.9% versus 0.4%, p=0.03) but no fatal infections were reported.

 

Table 1: Major Clinical End Points (Intention-to-Treat Population)

End Point	Colchicine (N = 2366)	Placebo (N = 2379)	Hazard Ratio (95% CI)
Primary composite end point	5.5%	7.1%	0.77 (0.61-0.96)
Death from cardiovascular causes	0.8%	1.0%	0.84 (0.46-1.52)
Resuscitated cardiac arrest	0.2%	0.3%	0.83 (0.25-2.73)
Myocardial infarction	3.8%	4.1%	0.91 (0.68-1.21)
Stroke	0.2%	0.8%	0.26 (0.10-0.70)
Urgent hospitalization for angina leading to revascularization	1.1%	2.1%	0.50 (0.31-0.81)

Our Critical Appraisal

 

COLCOT provides the best evidence to date to support the use of a focused anti-inflammatory agent for the prevention of CV events.⁶ COLCOT corroborates the findings in LoDoCo, albeit in a higher risk cohort.⁵ These results were observed in a cohort of patients who were receiving appropriate background therapy in an intention-to-treat population.  Thus, the findings are likely transferable to real world application.

 

Several points regarding COLCOT are worth noting when considering colchicine use in post MI patients.  First, is the potentially high treatment discontinuation rate of roughly 18% at 2 years.  However, discontinuation rates were similar in both treatment arms mitigating these concerns. Unlike CANTOS, the reductions in CV risk in COLCOT were not offset by an increased risk of fatal infections. ³ Next, while colchicine carries a much smaller price tag than canakinumab, cost is still a major concern as the current National Average Drug Acquisition Cost (NADAC) is $142.20 per 30-day supply of colchicine 0.6mg daily (as of Dec 2019).⁷ The cost associated with therapy may vary significantly between medical systems and among payors. Cost may be a significant factor for patients and may play a major role when considering therapy. Finally, the 0.5mg dose of colchicine used in COLCOT is not available in the United States (US); thus, clinicians would need to prescribe the 0.6mg tablets. It is unclear if this 20% dose increase would impact the ultimate efficacy or safety profile.

 

The positive results seen with colchicine therapy in COLCOT may lead to guideline changes and colchicine might become a recommended treatment along with antiplatelet agents, statins, and BBs following an MI.^8,9  Guideline committees will have to reflect on colchicine’s primary benefit – a reduction in urgent hospitalizations for angina leading to revascularization.⁶ Though this benefit may be considered softer when compared to a reduction in CV mortality or recurrent MI, it seems reasonable to support a class IIa recommendation for colchicine in the post-MI setting in the absence of any contraindications. While mortality risk reduction is often a goal, it is not requirement when defining a compelling indication. For example, dual antiplatelet therapy is given a class Ia recommendation in patients post-MI even though it does not reduce mortality (versus aspirin alone).  This recommendation is based on a reduction in the rate of non-fatal MI in the CURE study.¹⁰ 

 

Not all patients are good candidates for colchicine therapy, however. Patients with compromised immune function and those at a higher infection risk should not receive colchicine therapy.⁶  Conversely, it would be reasonable, based on the reduction in hospitalization for angina requiring revascularization, to target post-MI patients with ongoing chest pain from stable angina or multivessel disease.  Additionally, patients at higher risk of stroke might benefit from colchicine therapy.

 

Bottom Line

 

In the absence of specific guideline recommendations regarding colchicine’s place in post-MI therapy, we encourage practitioners to engage in a shared decision-making discussion with patients about the potential benefits and risks with colchicine therapy.  Colchicine should at least be considered when creating the post-MI cocktail for patients.

 

Key Points

1. Systemic inflammation appears to be a contributor to atherosclerotic vascular events and some medications that target inflammation have been shown to reduce recurrent event rates
2. Low-dose colchicine reduced non-fatal ischemic cardiovascular events when initiated within 30 days following a MI
3. While not cheap, colchicine should be considered as a potential ingredient in the post-MI treatment cocktail

FINAL NOTE:  This program will be available for recertification credit through the American Pharmacists Association (APhA) Ambulatory Care Review and Recertification Program.  To learn more, visit https://www.pharmacist.com/ambulatory-care-review-and-recertification-activities.