Colchicine trial revives cardiovascular quest to target inflammation

Hopes have been revived that the cheap anti-inflammatory drug colchicine may be re-purposed to reduce cardiovascular events in heart attack survivors.

A large randomised controlled trial of low-dose colchicine in patients with a recent MI has shown it led to a significantly lower risk of ischaemic cardiovascular events than placebo. 

In the Canadian COLCOT study, 4,645 patients received either 0.5 mg daily colchicine or placebo and were followed for a median of 22.6 months. Most patients were already on aspirin, another antiplatelet agent, a statin and beta-blocker after PCI for their index MI. 

The primary endpoint was a composite of death from cardiovascular causes, resuscitated cardiac arrest, MI, stroke or urgent hospitalisation for angina leading to coronary revascularisation. 

The study found the primary end point occurred in 5.5% of the colchicine-treated group compared to 7.1% of the control group (HR 0.77; p=0.02).

The difference was due predominantly to a lower incidence of strokes (HR 0.26) and urgent hospitalisations for angina leading to coronary revascularisation (HR 0.50).

“The benefits of colchicine with regard to cardiovascular end points in COLCOT were at least as large as those of canakinumab in CANTOS,” the study authors said. 

Colchicine’s mechanism of action on inflammation is through the inhibition of tubulin polymerisation and microtubule generation and, possibly, effects on cellular adhesion molecules, inflammatory chemokines, and the inflammasome.

In a small sub-group of patients with inflammatory biomarkers available, changes in C-reactive protein at six months from baseline were not significantly different between the treated and control groups.  

The study noted infections were more commonly reported as an adverse event with colchicine compared to placebo (2.2% v 1.6%) particularly pneumonia (0.9% v 0.4%). 

An editorial also published in the NEJM said the CANTOS study had “provided encouragement that targeting inflammation may be an effective treatment in chronic coronary artery disease”. 

However the findings in other studies with other agents and endpoints have been inconsistent. 

For example, as reported in the limbic recently, the smaller LoDoCo-MI study found colchicine compared to placebo was not associated with a significantly increased likelihood of achieving a CRP level <2 mg/L or lower absolute levels of CRP 30 days after an acute MI.

“These observations do not lessen the overall importance of inflammation in atherosclerosis, nor should they halt efforts to find more effective antiinflammatory agents with better side-effect profiles,” the editorial said.

“However, they should encourage us to revisit whether inflammation itself is the best treatment target or whether opportunities exist to identify and better understand pathophysiological processes or mediators that incite inflammation and drive atherosclerosis in order to intervene further upstream.”

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