Brian Mandell, MD, PhD

I find this study interesting in many regards; it clearly was a positive study and generally well done in terms of the conduct of the trial. There was a good number of people who discontinued therapy, but they still had follow-up on a significant proportion of patients.

We know the outcome, and it was a positive study in terms of decreasing several key events, but the major events that drove the whole positivity were representation with acute coronary syndrome or angina and decrease in stroke, which are clinically significant. I think that’s important, and it shows that there’s promise in this therapy.

The couple of things that were really striking to me, however, were:

1. The population of people that were studied. All these people had an MI, and almost all of them were stented and were stable, and then followed. But this is a clearly diseased population who had stents placed in vulnerable lesions. That’s important because prior studies of colchicine that were smaller, but also had positive outcomes, showed that the stented population seemed to be less responsive to colchicine than the nonstented population. So, the positive outcome of this may be the tip of the iceberg in terms of the efficacy of colchicine. We really need to see a large study of patients treated with colchicine who were not stented, maybe with stable coronary disease, because that, to me, may be where the real benefit of this drug comes into play.

2. This is taken as proof of concept that atherosclerosis is an inflammatory disease and inflammation drives the outcomes. I don’t think I’d argue with that, but all inflammation is not the same. For instance, methotrexate didn’t have a benefit on coronary outcomes from a large trial — maybe the dose was too low, but it didn’t show. Directly blocking IL-6 with canakinumab (Ilaris, Novartis) did have some benefit — albeit not huge — and colchicine may share that blocking of IL-1-driven inflammation. It contributes to our understanding in a way that certain types of inflammation may be reasonable targets to add to patients with coronary disease.

How does this come to play in routine rheumatology practice? Patients with gout and often with pseudo gout are placed on colchicine. With gout, we tend to limit the chronic use of colchicine because once you get rid of all the deposits, we don’t need it to treat the gouty arthritis. But this says, maybe we should leave them on longer because we do know that the population of patients with gout also have more coronary disease. So that’s a population in which I think it’s not unreasonable to change our practice patterns and say, those patients who have tolerated colchicine when it was given as prophylaxis against gout attacks, if they have multiple risk factors for coronary disease, why not continue therapy at a low dose? I think that’s the practice implication that’s reasonable to consider. I don’t think I would put everyone on colchicine right now.

Surprises from this study were how well this was tolerated. In those who maintained it, there were not a lot of GI issues complicating long-term therapy. And that’s a bit of a surprise because we know that it does that. But there was a significant proportion of folks who had the colchicine discontinued very early on, and that was probably the GI-intolerant group. So maybe it wasn’t so surprising, but a large proportion of people who were able to get past the first couple weeks of therapy seemed to do well on it, which is good. Once you exclude the people who are intolerant of colchicine, it’s no surprise in terms of how well it was tolerated once you get past the first couple of weeks.

Cardiologists prescribing colchicine need to be wary of patients who have some degree of renal insufficiency, which could be based just on age alone. And the one thing cardiologists need to be aware of is neuromuscular toxicity of the drug, particularly in patients who have renal insufficiency. Numbness, tingling and weakness have to be taken exceedingly seriously. There are some drug interactions that they need to be aware of pharmacokinetically, including statins, but in this study virtually all of these patients were on statin therapy. That’s the other thing about this study — patients were treated very aggressively, as they should be, for their coronary disease and yet still there was a small benefit of colchicine but there weren’t issues of any significance with neuromuscular toxicity. I don’t think this in any way requires that somebody see a rheumatologist before they get treated with colchicine; cardiologists are treating people with pericarditis with this now.

Lastly, this is not the first study that’s shown benefit of colchicine as secondary prevention. There was a very nice study — the LoDoCo study — from Nidorf et al, that showed benefit of colchicine primarily in patients who had not had stents placed. In an observational study done even earlier, Pillinger et al, published data suggesting that colchicine was a benefit at reducing coronary events. This is not new, but it’s the largest study to date. But we definitely need to see the studies of patients with coronary disease who have not had stents placed because I think, with maybe some sense of optimism, that it will look even better than what this study showed because this was a modest benefit, but clearly positive.

Paul M. Ridker, MD, MPH, FACC, FAHA

This is an external and independent confirmation that the inflammation hypothesis is real. That is really crucial. When we presented our CANTOS data 2 years ago, it was the first study. Like any field, we need replication, and this clearly provides it. It is going to dictate what is going to happen in atherosclerosis. Down the road, I would like to see cardiologists treating all atherosclerosis patients with some combination of powerful lipid-lowering drugs and powerful anti-inflammatory drugs. It is clear now that we need to do both. One can imagine using colchicine in high-risk patients in whom we are already doing the recommended things. Right now, that is probably the group I would consider using this in because the evidence is positive, and I don’t have an alternative anti-inflammatory drug that is proven. Additionally, there will be at least three more large colchicine trials coming out in the next year or 2. If they are all consistent, this could well become a new therapy for atherosclerosis, so it is very exciting.