Peter Libby, MD

It is no longer controversial that inflammation drives atherosclerosis and atherosclerotic events. A large and coherent body of experimental work and biomarker studies in humans support the participation of inflammation in atherosclerosis. The challenge has remained to translate this large body of experimental research and observational work into clinically practicable approaches to taming inflammation in humans at risk for CV events.

The CANTOS study first showed that a selective anti-inflammatory intervention could reduce CV events in stable patients post-MI. (Ridker PM, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1707914). In part because of a striking effect of this intervention on incident cancer and death from lung cancer (Ridker PM et al. Lancet. 2017;doi:10.1016/S0140-6736(17)32247-X), the agent used in CANTOS, the interleukin-1 beta inhibitor canakinumab, is being developed for oncologic indications rather than use in the CV arena. The LoDoCo study was a non-blinded pilot trial that suggested treatment with colchicine, a natural product with anti-inflammatory properties, could reduce recurrent CV events (Nidorf SM, et al. J Am Coll Cardiol. 2013;doi:10.1016/j.jacc.2012.10.027). COLCOT, the first large-scale double-blind randomized controlled CV outcomes trial with colchicine, demonstrated a striking 23% reduction in clinical events in the primary endpoint (Tardif JC, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1912388).  

To deploy this strategy in humans most effectively, selection of the patients most likely to benefit would be desirable. In a secondary analysis of COLCOT, the investigators determined the benefits of the colchicine therapy started at different stages post-onset of MI. COLCOT enrolled individuals within the first month of a MI. The investigators studied individuals who enrolled from day 0 to 3, the acute hospital phase of the ACS. Another group arbitrarily defined from day 4 to 7 corresponded to the usual early period following discharge from hospital care. A third group analyzed had initiation from day 8 to 30. The investigators found a hierarchy of benefit that led to the conclusion “earlier is better.” Initiating the therapy within the first 3 days provided the greatest and most statistically significant benefit in the subgroup analysis. As in the primary analysis, urgent hospitalization for angina requiring coronary revascularization was a major contributor to the composite primary endpoint.

These results have clinical import, suggesting that those who receive colchicine early stand to benefit the most. This observation lends a sense of urgency for consideration of starting this regimen, should it receive regulatory approval and be sanctioned by guidelines. Those who present late with “missed” MIs may derive less benefit from colchicine treatment. Although colchicine in the dose and population studied appears overall safe, COLCOT showed a statistically significant increase in pneumonia. Moreover, colchicine interacts with some drugs commonly used in cardiology such as verapamil and requires care when used in patients with reduced renal function. Thus, we may wish to reserve colchicine therapy for those who present early within the first 4 days, without advanced renal disease, and strive to initiate therapy early. The mortality signal seen in the LoDoCo2 (Nidorf SM, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa2021372) and COPS trials (Tong DC, et al. Circulation. 2020;doi:10.1161/CIRCULATIONAHA.120.050771) requires further exploration and vigilance.

The COLCOT substudy does have some limitations. The time windows chosen were arbitrary, although they correspond to clinically plausible phases in the patient’s journey following onset of an ACS. There were also differences in the baseline characteristics of the individuals in the different treatment groups. Those who had treatment initiated in the first 3 days were younger and many more of them were smokers, raising the question of whether smokers might tend to benefit more from early treatment with colchicine.

We are in exciting times in secondary prevention. COLCOT provided a rigorous confirmation of LoDoCo. The recent reporting of LoDoCo2, which studied patients in the chronic phase of CAD, provided further reinforcement for the benefit of colchicine in patients with acute and chronic coronary disease. This cluster of colchicine studies deserves careful consideration by regulatory agencies and groups that emit guidelines.

We have close at hand a venerable anti-inflammatory therapy that is generally surprisingly well tolerated at the low doses used and provides benefit over and above all standard of care therapies including effective statin treatment. The practical clinical application of the theory of inflammation in atherosclerosis is now within our grasp. We can look forward to many further explorations of anti-inflammatory therapies and further work to allocate them to those who stand to benefit the most. This time-to-treatment analysis from COLCOT provides an example of how we will begin to learn to allocate anti-inflammatory therapies in an evidence-based and rational manner.