Should Colchicine Join the Anti-Inflammatory Toolbox?

Patrice Wendling

November 07, 2017

NEW SOUTH WALES, AUSTRALIA — Adding colchicine to optimal medical therapy (OMT) with high-intensity statins appears to stabilize potentially vulnerable plaque better than OMT alone in patients recently diagnosed with acute coronary syndrome (ACS), results of a small observational study suggest[1].

Regular low-dose colchicine significantly reduced the primary outcome of low-attenuation plaque volume (LAPV) — a marker of plaque instability on coronary CT angiography and a powerful predictor of major adverse coronary events — by a mean of 15.9 mm3 vs 6.6 mm3 with OMT alone.

There was a moderate positive correlation between change in LDL cholesterol and change in LAPV, suggesting that LDL lowering may have contributed to plaque stabilization.

LDL reduction was comparable in both groups, however, indicating that the anti-inflammatory properties of colchicine may also be driving the changes in plaque morphology, Dr Kaivan Vaidya (Royal Prince Alfred Hospital, Sydney, New South Wales, Australia) and colleagues reported recently in JACC Imaging.

Lending further support, the mean reduction in high-sensitivity C-reactive protein (hs-CRP) levels was substantially larger with colchicine plus OMT than with OMT-alone (1.10 mg/L vs 0.38 mg/L).

In all, 40 patients were assigned to OMT including high-intensity statins (targeting an LDL cholesterol <70 mg/dL) and 40 to OMT plus colchicine 0.5 mg/day.

Earlier this year, the cardiology community was rocked when the CANTOS trial validated the inflammatory hypothesis of atherothrombosis by reporting a 15% relative risk reduction in hard cardiovascular events in patients with prior MI and elevated hs-CRP levels treated with canakinumab, a monoclonal antibody targeting the inflammatory cytokine interleukin (IL)-1β.

Notably, the Australian researchers previously showed that short-term use of colchicine reduces transcoronary levels of IL-1β as well as IL-18 and IL-6 by 40% to 88% in ACS patients[2].

In an editorial accompanying the current trial[3], CANTOS lead investigator Dr Paul Ridker (Brigham and Women's Hospital, Boston, MA) and Dr Jagat Narula (Icahn School of Medicine at Mount Sinai, New York, NY) write that the results are "provocative" and that "colchicine represents another potentially useful agent for investigating the inflammatory of hypothesis of atherogenesis."

Still, "Although imaging-verified change in the plaque composition (including LAP or inflammation) should be intuitively more informative than the interval change in percent atheroma volume in response to therapeutic intervention, it is likely that no imaging modality would succeed as a validated surrogate for hard clinical events," they add.

"This is an as-yet unproven surrogate end point, and we've learned with so many surrogate end points over so many years to be very, very cautious," Ridker told | Medscape Cardiology.

Senior study author Prof Sanjay Patel (Royal Prince Alfred Hospital) said in an interview, "I certainly agree that the results should be interpreted with caution as Dr Ridker stated. This is a nonrandomized study, and so there are issues with that."

He added, "Low-attenuation plaque has been shown to be associated with recurrent events in CT studies, but there have been no studies that have shown that a reduction in low-attenuation plaque leads to a reduction in clinical events. It's hypothesis-generating in that we've shown plaque stabilization, but whether that actually leads to a reduction in clinical end points is for another, larger study to answer."

The anti-inflammatory effects of colchicine have been documented by its efficacy against gout and pericarditis and in the pilot open-label LoDoCo trial, in which low doses of the drug resulted in a 67% relative risk reduction in major cardiovascular events in patients with stable coronary artery disease.

On that basis, two double-blind randomized cardiovascular outcomes trials of colchicine are currently underway, LoDoCo2 in 3000 patients with stable coronary disease and COLCOT in 4500 patients with a recent MI.

Low-dose methotrexate is also being tested by Ridker and colleagues in the CIRT trial in 7000 patients with type 2 diabetes or metabolic syndrome who have had an MI or multiple coronary blockages.

"It's a very exciting time post-CANTOS, but we have to be very careful and very rigorous in how we move forward with other potential anti-inflammatory agents. So I'm glad that the COLCOT trial is being done, and obviously we are running our methotrexate trial, and the outcomes of those will help us understand this field," Ridker said.

If validated, "I think the clinical implications are enormous," Patel said. "Colchicine has been around for a long time, it's very safe, and it's well established. There have been thousands of patients treated over the past 20 to 30 years."

The study was supported by grants from Perpetual IMPACT Philanthropy. The authors report no relevant financial relationships. Ridker reports being a coinventor on patents held by Brigham and Women's Hospital related to the use of inflammatory markers in cardiovascular disease and diabetes that have been licensed to AstraZeneca and Siemens; and research grants from Novartis, AstraZeneca, and the National Heart Lung Blood Institute.

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