HRI’s Atherosclerosis and Vascular Remodelling Group, led by Dr Ashish Misra, has published two papers in the prestigious Nature Cardiovascular Research journal, including an analysis of low-dose colchicine use in cardiovascular patients.
The first paper, authored by a team of Australian researchers led by Dr Misra, and including HRI Honours student Amandeep Mondal, addresses the recent controversy surrounding the neutral trial of colchicine (CLEAR SYNERGY).
Based on evidence from several large trials with up to five years of follow-up, low-dose colchicine is the only FDA-approved anti-inflammatory drug currently used for cardiovascular benefits in thousands of patients with coronary artery disease and those recovering from heart attacks. Current guidelines suggest it is reasonable to consider adding colchicine 0.5 mg daily to lipid-lowering therapy for secondary prevention in such patients.
“However, the recently published CLEAR SYNERGY trial reported no significant benefits for patients with heart disease,” Dr Misra explained. “This has created uncertainty among clinicians and patients about whether to continue or discontinue colchicine therapy. It has also generated considerable media attention.”
“To address this, we conducted a critical analysis of the CLEAR SYNERGY trial, comparing its findings with those of previously published large trials to explore why the results of this trial were neutral in contrast to earlier studies.”
The paper, titled 'Implications and limitations of the CLEAR-SYNERGY trial for the use of low-dose colchicine in cardiovascular disease', revealed that the low number of heart attack-related hospitalizations during the COVID-19 pandemic likely played a big role in the results of the CLEAR SYNERGY trial.
“Colchicine should continue to be used as it has been, providing valuable benefits for these patients.” — Dr Ashish Misra
Potential anti-inflammatory effects of colchicine on human atherosclerotic plaque phenotype and composition.
“The pandemic, which was ongoing during the study, also impacted the outcomes of other heart-related trials,” Dr Misra said. “While missed or misclassified events can always influence trial results, this issue was especially common in heart studies conducted during COVID-19 and was probably a significant factor in CLEAR’s findings.”
According to Dr Misra, despite the challenges with the CLEAR trial, there is no compelling reason to change current guidelines for using low-dose colchicine.
“It has consistently been shown to be safe and effective in reducing the long-term risk of heart attacks, strokes, and repeat procedures in patients with chronic heart disease when prescribed after the initial recovery phase,” he concluded. “Colchicine should continue to be used as it has been, providing valuable benefits for these patients.”
“We believe our article will pave the way for a new direction in drug development.”
The second paper, ‘Chronic inflammation and vascular cell plasticity in atherosclerosis’, is a comprehensive review paper with PhD student Alexander Lin as the first author.
Atherosclerosis, the main underlying cause of cardiovascular disease (CVD), is the process in which plaques that are made up of fat, cholesterol, calcium and other substances build up in the walls of arteries. It is most serious when it occurs in arteries to the heart or to the brain, as this can lead to heart attack or stroke.
Explaining the findings of both papers, Dr Misra said that atherosclerosis was historically considered to be a lipid storage disease. However, the last couple decades have unravelled the importance of inflammation in disease progression.
“We have now had multiple anti-inflammatory clinical trials that have led to the FDA (Food and Drug Administration in the US) approving colchicine for cardiovascular disease – a milestone in anti-inflammatory therapy,” he said. “But not all anti-inflammatory therapies show cardiovascular benefit, and we are unsure why some work better than others. A potential explanation is that these drugs have different effects on the individual cells within the atherosclerotic plaque.”
PhD student Alexander Lin
The review paper examined how exactly inflammation accelerates the disease progression and the implications for treatment.
“Currently, available therapies focus on reducing systemic inflammation or lowering lipid levels but do not specifically target the cells within arterial plaques,” said Dr Misra.
“We believe our article will pave the way for a new direction in drug development, aiming to design treatments that directly target plaque cells (such as smooth muscle and endothelial cells), while minimising effects on other organs and cells in the body.”
