Cardiologist Michelle O'Donoghue asks Paul Ridker about the dos and don'ts for the anti-inflammatory drug colchicine in patients with atherosclerotic cardiovascular disease.

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Michelle L. O'Donoghue, MD, MPH: Hi. This is Dr Michelle O'Donoghue, reporting for Medscape. Joining me today is Dr Paul Ridker. He's the Eugene Braunwald Professor of Medicine at Harvard Medical School. He's also the director of the cardiovascular prevention program at Brigham and Women's Hospital.

He's going to be joining me today to discuss a very important and emerging topic, which is the use of low-dose colchicine. I think there's much interest in the use of this drug, which now has a US Food and Drug Administration (FDA) indication, which we'll talk about further, and it's also been written into both European and American guidelines that have been recently released.

Many people are talking about where this fits into our current armamentarium, and I think there probably is no better person to discuss this than Paul Ridker, who's been at the forefront of research into anti-inflammatory therapeutics. Thank you for joining me, Paul.

Paul M. Ridker, MD, MPH: Michelle, it's a pleasure to be with you on Medscape today.

Lifestyle Lipid-Lowering Paramount
O'Donoghue: As we think about the concept behind the use of colchicine, we've obviously done a large amount of research into lipid-lowering drugs, but where does colchicine now fit in?

Ridker: Let's make sure we get the basics down. Anti-inflammatory therapy is going to be added on top of quality other care. This is not a replacement for lipids; it's not a change in diet, exercise, and smoking cessation. The new data are really telling us that a patient who's aggressively treated to guideline-recommended levels can still do much better in terms of preventing heart attack, stroke, cardiovascular death, and revascularization by adding low-dose colchicine as the first proven anti-inflammatory therapy for atherosclerotic disease.

I have to say, Michelle, for me, it's been a wonderful end of a journey in many ways. This story starts almost 30 years ago for quite a few of us, thinking about inflammation and atherosclerosis. The whole C-reactive protein (CRP) story is still an ongoing one. We recently showed, for example, that residual inflammatory risk in some 30,000 patients, all taking a statin, was a far better predictor of the likelihood of more cardiovascular events, in particular cardiovascular death, than was residual cholesterol risk.

Think about that. We're all aggressively giving second lipid-lowering drugs in our very sick patients, but that means inflammation is really the untapped piece of this.

The two clinical trials we have in front of us, the COLCOT trial and the LoDoCo2 trial — both New England Journal of Medicine papers, both with roughly 5000 patients — provide very clear evidence that following a relatively recent myocardial infarction (that's COLCOT) in chronic stable atherosclerosis (that's LoDoCo2), we're getting 25%-30% relative risk reductions in major adverse cardiovascular events (MACEs) on top of aggressive statin therapy. That's a big deal. It's safe, it works, and it's fully consistent with all the information we have about inflammation being part and parcel of atherosclerosis. It's a pretty exciting time.

Inflammatory Pathway
O'Donoghue: It beautifully proves the inflammatory hypothesis in many ways. You led CANTOS, and that was a much more specific target. Here, in terms of the effects of colchicine, what do we know about how it may work on the inflammatory cascade?

Ridker: Our CANTOS trial was proof of principle that you could directly target, with a very specific monoclonal antibody, a specific piece of this innate immune cascade and lower cardiovascular event rates.

Colchicine is a more broad-spectrum drug. It does have a number of antineutrophil effects — that's important, by the way. Neutrophils are really becoming very important in atherosclerotic disease progression. It's an indirect inhibitor of the so-called NLRP3 inflammasome, which is where both interleukin (IL)-1 (that's the target for canakinumab) and IL-6 are upregulated. As you know, it's been used to treat gout and pericarditis in high doses in short, little bursts.

The change here is this use of low-dose colchicine, that's 0.5 mg once a day for years to treat chronic, stable atherosclerosis. It is very much like using a statin. The idea here is to prevent the progression of the disease by slowing down and maybe stabilizing the plaque so we have fewer heart attacks and strokes down the road.

It's entering the armamentarium — at least my armamentarium — as chronic, stable secondary prevention. That's where the new ACC/AHA guidelines also put it. It's really in as a treatment for chronic, stable atherosclerosis. I think that's where it belongs.

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