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The evolving recognition of inflammation as a driver of cardiovaacular risk and has led some to speculate around a potential role for colchicine 0.5 mg, which has a PDUFA date in June 2023, for reducing risk in patients with ASCVD.
A persistent theme across cardiology, and all of medicine, are the swift shifts in therapeutic interests and exploration pursuant to revelations of pathophysiology or elucidations of risk drivers in disease management.
At present, key opinion leaders point to recent findings in regard to the role of inflammation in driving cardiovascular risk as one of the great revolutions in understanding of disease management. Considering the prevalence of atherosclerotic cardiovascular disease in the US and across the globe, the prospect of an agent with a mechanism to mitigate inflammation could play a major role in addressing this unmet need.
At the American College of Cardiology 2023 annual meeting, Paul Ridker, MD, provided new insight into the risk posed by residual inflammation among patients receiving statin therapy. An analysis of data from the REDUCE-IT, STRENGTH, and PROMINENT trials, investigators examined risk of cardiovascular events associated with inflammation, which was assessed using hsCRP.
In the study, results indicated increased levels of inflammation were associated with a 30% increase in relative risk of cardiovascular events and a more than doubling in risk of cardiovascular and all-cause mortality in fully adjusted analyses accounting for LDL-C and residual cholesterol risk.1
“To all of our surprise, all 3 trials showed exactly the same thing that we had seen in PROMINENT, with LDL as a mild predictor and hsCRP a very powerful predictor,” said Ridker in an interview with HCPLive. “It's very powerful, because we all agree that lowering LDL cholesterol is fundamental to preventing this disease, but, I would argue, we're not even measuring hsCRP in most of our patients.”
Some in the cardiology community, including Ridker, believe the therapy to play this role may not be a novel, investigational agent, but a familiar face: colchicine.
With a 0.6 mg formulation of colchicine receiving approval by the US Food and Drug Administration in 19612, use of the agent has become common for the prophylaxis and treatment of gout flares. However, as it stands, there are no forms of colchicine approved by the FDA for reducing cardiovascular risk associated with atherosclerosis. Among major studies examining he effects of colchicine on cardiovascular risk, LoDoCo2 and COLCOT have offered the greatest insight, according to Ridker.
Published in the New England Journal of Medicine in 2019, the COLCOT trial was a randomized, double-blind trial where patients were randomly assigned to placebo or 0.5 mg colchicine once-daily, with randomization occurring within 30 days of a myocardial infarction. A 4745-person trial, results of the study indicate use of colchicine was associated with relative risk reductions of 16% for cardiovascular death, 17% for resuscitated cardiac arrest, 9% for myocardial infarction, 74% for stroke, and 50% for angina leading to coronary revascularization.3
Published in the New England Journal of Medicine in 2020, the LoDoCo2 trial was designed to compare the effects of 0.5 mg once-daily colchicine relative to placebo therapy for a composite endpoint of cardiovascular death, spontaneous myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization among a cohort of patients with chronic coronary disease. The randomized, double-blind enrolled 5522 patients and concluded use of colchicine was associated with a 31% relative risk reduction for the primary composite endpoint, with further analysis indicating use was associated with a 28% relative reduction in risk of a secondary composite endpoint of cardiovascular death, spontaneous myocardial infarction, or ischemic stroke.4
AGEPHA Pharma is hopeful their New Drug Application (NDA) for a 0.5 mg, once-daily formulation of colchicine may soon become the first agent with such an indication. According to AGEPHA Pharma, the agent has a PDUFA date in June 2023 for its NDA, which is seeking an indication for risk reduction of major cardiac events in adults with stable atherosclerotic disease or with multiple risk factors for cardiovascular disease.
Although he cautioned against use in certain patient populations, such as those with chronic kidney disease, Ridker expressed his belief this agent or other anti-inflammatory agents could play a role in secondary prevention populations.
“Diet, exercise, and smoking cessation is the first thing we should talk about, but adding these anti-inflammatory drugs is going to be the future,” Ridker said. “So, I would predict 5-10 years from now, I think all atherosclerosis patients are going to be aggressively treated with lipid-lowering drugs and anti-inflammatory therapies. All we have to do, as investigators and as scientists, is we have to get there and then we will have made a major dent in this disease.”
An advantage of the familiarity some clinicians may have with colchicine is the potential for increased confidence to prescribe the agent among both cardiologists and general practitioners. However, Ridker acknowledged there would be “considerable” hurdles for optimal uptake of this agent. In his interview, Ridker noted inherent flaws within the US healthcare system will hinder uptake, but the main priority would be a need for increased education surrounding the role of inflammation in driving risk.
“We're not very good at using inexpensive drugs that really work. Particularly when there's no major backing for them. So, I think that this is going to be a process of physician education and patient education,” Ridker said.