Colchicine: A Novel Treatment Of Coronary Artery Disease
Written by Joseph Kummer, MD
The role of inflammation in development of atherosclerotic coronary artery disease (CAD) has long been a source of debate. Pro-inflammatory markers are often elevated in patients with CAD, and inflammation appears to be pro-atherogenic. Despite this, numerous studies of anti-inflammatory medications have failed to demonstrate a reduction in cardiac events. In fact, several agents actually demonstrate a tendency toward increased adverse cardiac outcomes. Renewed interest in this area was sparked by the CANTOS Trial in 2017 which suggested beneficial cardiac outcomes from the monoclonal antibody canakinumab. Although the results of this trial are compelling, this medication was not approved in the United States for cardiovascular protection.1
The LoDoCo Trial in 2013 also fueled interest in anti-inflammatory therapies for CAD. This study demonstrated a strong cardiovascular benefit of anti-inflammatory therapy with colchicine in patients with stable CAD.2 The LoDoCo Trial was relatively small, enrolling 532 patients and had some minor methodologic shortcomings.
Primary Outcome of LoDoCo
The primary outcome was the composite incidence of acute coronary syndromes, out-of-hospital cardiac arrests, and noncardioembolic ischemic strokes. This outcome was decreased by 67% in the colchicine group. The trial was encouraging as the needed number to treat (NNT) was only 11 and side effects were uncommon.
The salutary findings from LoDoCo prompted the COLCOT Trial.3 This investigation studied the potential benefit of low-dose colchicine in patients following an acute myocardial infarction. 4,745 patients were randomized to 0.5 mg of colchicine once daily vs. placebo. Patients were enrolled on average about two weeks after their ischemic event, and average follow-up was just under two years. 93% received a coronary stent for their myocardial infarction (MI), and almost all were on dual antiplatelet therapy and a statin. The primary endpoint was a composite of death from cardiovascular disease, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization.
Primary Outcome of COLCOT
The primary outcome occurred in 5.5% of the colchicine group and 7.1% of the placebo arm (hazard ratio, 0.77; 95% confidence interval [CI], 0.61 to 0.96; P=0.02). Of note, individual hazard ratios were not significant for reduction in death, cardiac arrest or MI but were significant for reduction in rates of stroke and urgent revascularization. This stands in contrast to the findings from LoDoCo, where the primary benefit was driven entirely by a major reduction in the rates of acute coronary syndromes.
Although nausea was more common in the colchicine group, surprisingly the rates of diarrhea and cumulative adverse GI side effects in COLCOT were not significantly different amongst the two groups. Discontinuation of the study medication was nearly identical between the two groups, but it should be noted that this was fairly high in both placebo (18.7%) and therapeutic groups (18.4%). As far as other side effects, pneumonia occurred about twice as often in those treated with colchicine.
Post-Hoc COLCOT Findings
A post-hoc study of the COLCOT data looked at outcomes based upon time-to-treat analysis. Patients were categorized into one of three categories based upon when colchicine was initiated after their MI:
- 3 days or less
- 4 to 7 days
- 8 days or more
The composite primary outcome as well as revascularization rates were about half as common in those whose colchicine was initiated within the first three days of the infarct. However, there was no significant difference in the two groups whose colchicine was initiated after the fourth post-infarct day. This makes one wonder if colchicine works best due to immediate immunomodulation from the acute stress of the infarct rather than a long-term protective effect. Perhaps there is a beneficial role from colchicine in modulation of the early healing of a ruptured coronary plaque.
LoDoCo 2 Trial
In contrast to that theory, however, the LoDoCo investigators just published a much larger trial (LoDoCo2) involving 5,522 patients randomized to 0.5 mg of colchicine vs. placebo.5 In contrast to LoDoCo and COLCOT, the LoDoCo2 Trial investigated patients with chronic ischemic coronary disease rather than those with a recent infarct. The primary end point was a composite of:
- Cardiovascular death
- Myocardial infarction
- Ischemic stroke OR
- Ischemia-driven coronary revascularization
The hazard ratio in those treated with colchicine was significantly lower at 0.69 [CI = 0.57 -0.83, p < 0.001)]. Of note, although myocardial infarction and coronary revascularization were independently lowered, cardiac death and all cause mortality were not improved. In fact, there was actually a strong trend toward an increase in non-cardiac death despite the overall reduction in events.
My Take on Trials Surrounding Colchicine
Even though these three trials had some differences in design and specific outcomes, all three did demonstrate a beneficial role of colchicine for patients with CAD. Although it’s a widely held belief that there is a role of inflammation in the development of CAD, exactly what that role is and how to modulate it for clinical benefit remains elusive. Even though colchicine clearly seems to be beneficial for reducing non-fatal cardiac events, we have seen strong anti-inflammatory medications such as COX-2 Inhibitors receive Black Box Warnings about increased risk of cardiac events. The immunomodulator canakinumab has suggested benefit, whereas methotrexate has not.
The discrepancy may well be related to the precise mechanism of inflammatory suppression. Note that the above agents work via different pathways. Differential effects may be mediated by other means, such as modulation of lipid levels, blood pressure, thrombogenicity, etc. Such factors were not specifically evaluated in the above trials. Even though the general role of inflammation remains unclear, I think the above trials (and subsequent meta-analyses) have shown that colchicine specifically needs to be considered in the short and possibly long-term treatment regimen for patients with coronary disease.
Hopefully future investigations will shed some light on the precise mechanism of cardiovascular benefit from colchicine and perhaps better define the group of patients who will benefit the most from this exciting new treatment.
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- Ridker PM, Everett BM, et al. Anti inflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119-1131.
- Nidorf, SM, Eikelboom, JW, et al. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol 2013;61:404-410.
- Tardif JC, Kouz S, et al. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N Engl J Med 2019; 381:2497-2505.
- Time-to-treatment initiation of colchicine and cardiovascular outcomes after myocardial infarction in the Colchicine Cardiovascular Outcomes Trial (COLCOT). Bouabdallaoui N, Tardif JC, et al. Eur Heart J. 2020;41(42):4092.
- Colchicine in Patients with Chronic Coronary Disease. Nidorf SM, Fiolet ATL, et al. N Engl J Med. 2020;383(19):1838. Epub 2020 Aug 31.