Low-Dose Colchicine Post-MI: Reducing Inflammation?

Recent evidence shows that inflammation contributes to atherosclerotic heart disease. Researchers have now tested 3 medications used for inflammatory diseases— canakinumab, methotrexate (MTX), and colchicine—to see if they may prevent atherosclerotic disease.

Canakinumab, a fully human monoclonal antibody, targets interleukin-1β, has anti-inflammatory effects, and is FDA-approved for rheumatologic disorders. Interleukein-1β is a cytokine that drives the interleukin(IL)-6 signaling pathway in inflammatory response. A previous phase 2 trial involving patients with diabetes showed that canakinumab’s IL-1β inhibition markedly reduced plasma levels of IL-6 and high-sensitivity C-reactive protein without lowering low-density lipoprotein (LDL) cholesterol.

The New England Journal of Medicine (NEJM) published a randomized, double-blind trial published in 2017 that associated canakinumab with a 15% lower risk of cardiovascular events than placebo. But it also led to a slightly higher incidence of fatal infections. These results suggest that inhibiting inflammation can prevent atherosclerotic events.¹

Methotrexate was tested for its potential to prevent atherosclerotic events. Inexpensive, effective, and widely prescribed for inflammatory conditions, MTX was linked to fewer cardiovascular events than other therapies or placebo in observational studies. In February 2019, NEJM published a randomized, double-blind trial that showed MTX did not affect cardiovascular outcomes or plasma markers of inflammation.²

Another specific target within the inflammatory cascade, neutrophil infiltration, has been studied. Lipid-rich plaques within the atherosclerotic wall are susceptible to injury, which make the plaques vulnerable to neutrophil infiltration. Neutrophils may become activated when exposed to plaque contents and set off an aggressive inflammatory response. That may accelerate plaque instability, increasing the risk of plaque enlargement and rupture. Plaque enlargement and rupture increases risk of clinical atherosclerotic events.³

Colchicine is approved for gout flares and Familial Mediterranean fever; it has anti-inflammatory properties including an antitubulin effect that inhibits neutrophil function. Previous research showed that treating patients with stable coronary disease with low-dose colchicine led to fewer cardiovascular events than those not receiving colchicine. This trial, which enrolled 532 patients, was not placebo controlled.³

A study published in NEJM’s December issue associated low-dose colchicine with a significantly lower risk of ischemic cardiovascular events than placebo. The trial enrolled 4745 patients who had a myocardial infarction within 30 days. The researchers randomized patients to either low-dose colchicine (0.5 mg once daily) or placebo. They followed patients for a median of 22.6 months.

The researchers found that colchicine-treated patients had a lower risk of ischemic cardiovascular events: ischemic cardiovascular events occurred in 5.5% of patients in the colchicine group and in 7.1% in the placebo group, reaching statistical significance. The group also found that the most common adverse effects in the trial were gastrointestinal. Diarrhea was reported in 9.7% of patients in the colchicine group and in 8.9% of those in the placebo group. Nausea occurred in 1.8% and 1% respectively. Infection as a serious adverse event occurred more frequently in the colchicine group with 2.2% of patients in the colchicine group and 1.6% in the placebo group.

The research team concluded in patients who had recent myocardial infarctions, low-dose colchicine led to a significantly lower percentage of patients with ischemic cardiovascular events than placebo.⁴

Krystal Scinto is a 2020 PharmD candidate at the University of Connecticut in Storrs.

REFERENCES

• Ridker PM, Everett EM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Eng J Med. 2017;377:1119-11131.
• Ridker PM, Everett EM, Pradham A, et al. Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med. 2019;80:752-762.
• Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol. 2013;61:404-410.
• Tardif JC, Kouz S, Waters D, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med. 2019;381:2497-2505.