Prof Paul M Ridker (Brigham and Women’s Hospital, Boston, US) discusses The Cardiovascular Inflammation Reduction Trial (CIRT) - Low Dose Methotrexate for the Prevention of Atherosclerotic Events.
Filmed on site at AHA 2018 by Radcliffe Cardiology.
I'm Paul Ridker. I'm a professor in medicine at the Harvard Medical School in Boston and a cardiologist. And I'm here at the American Heart Association meeting in Chicago and it's really a pleasure to talk about where we are today in terms of the inflammation hypothesis of atherothrombosis.
It's been an extraordinarily interesting two years, as we've just made enormous advances in this field. Let me start at 30,000 feet. We've known for 20 years now that half of all heart attacks and strokes occur among people who do not have high lipid levels. And yes we want to lower LDL cholesterol as far as we can - that works. But many of our patients are at risk for a heart attack or a stroke or cardiovascular death because they have a different process that we call residual inflammatory risk rather than residual cholesterol risk. These are people who have a high level of high sensitivity c-reactive protein. We showed 22 years ago that those patients were at very high risk. We learned that those patients respond to statin therapy even better. Statins are "two-fers" - they both lower cholesterol and they lower inflammation.
Our JUPITER Trial published now 10 years ago, made it very clear that in primary prevention, patients with high levels of CRP, really need to be on a statin, regardless of what their LDL cholesterol is. Most clinicians and cardiologists have absorbed that information. But we had not yet proven that lowering inflammation in the absence of lowering cholesterol or the absence of changing blood pressure, might lower risk.
So a year ago, we presented data from the first of our inflammation reduction trials, that was the CANTOS trial, that was a trial that used a very narrow spectrum drug, an interleukin-1β inhibitor, that hits a very critical pathway of innate immunity. Interleukin 1 to interleukin 6 and ultimately to CRP which is the biomarker of the process.
Well, what CANTOS showed, which was very exciting, is that without changing cholesterol at all, without changing blood pressure at all, without changing coagulation at all, we can get a 17% reduction in major adverse cardiovascular events by simply inhibiting the immune system, by knocking out IL 1 beta.
Now, CANTOS was proof of principle that inflammation inhibition mattered, and in a follow up analysis of that study, we showed that the magnitude of the reduction in that inflammation, was the driver of the magnitude of the reduction of risk. In other words - the bigger the interleukin 6 reduction, the bigger the CRP reduction, the greater the benefit for the patient. So, the question becomes, how can we find other agents, preferably oral drugs that are less expensive, that might do this?
So, backwards in time, 10 years ago, when we were thinking about starting what became CANTOS, my group also designed with help from the National Heart, Lung and Blood Institute a second clinical trial called CIRT, Cardiovascular Inflammation Reduction Trial or CIRT.
Now CIRT took the same beginning place - prior myocardial infarction, evidence of systemic atherosclerosis, multi-vessel coronary disease and patients who either had metabolic syndrome or diabetes and instead of giving them a narrow spectrum IL 1 inhibitor, we gave an inexpensive broad spectrum anti inflammatory - low dose methotrexate. That's the same drug routinely used to treat rheumatoid arthritis around the world.
Fast forward, we randomised nearly 5,000 patients and we learned a beautiful piece of biology albeit a little disappointing clinically. What we found was that low dose methotrexate did not reduce either interleukin 1, interleukin 6 or CRP and perhaps as a consequence of that, had no effect at all on cardiovascular events. Well as a vascular biologist who has been fascinated by this field for now 30 years, this is enormously important information.
It’s an informative neutral study, because it's telling us between the two different trials, we now know exactly what the pathway is likely to be for reducing atherosclerotic events with inflammation. In other words, CANTOS tells us IL 1 to IL 6 is crucial and CIRT is telling us, if you don't do that don't expect a benefit.
So, “where's this going to go?” is the big question. As of right now we don't have an easy clinical drug to give. So, first things first. Diet, exercise, smoking cessation, all these things lower CRP, they all lower vascular risk. I use high sensitivity CRP screening on all of my patients to emphasize the importance of this process and to get everyone to behave better from a lifestyle perspective and I also use it to increase the statin dose and get to a higher intensity statin therapy.
OK. What about the future? Every major pharmaceutical company in the world has drugs that already target this IL 1 to IL 6 pathway and so we're going to see an enormous explosion of data. I'm certain, looking at “can alternative drugs do this that are less expensive?”
Both our CIRT trial and the CANTOS trial showed pretty low levels of toxicity. Infection rates were nowhere near what was anticipated. That's good news. So we also know that taking this pathway down can be done safely. So the big challenge is, how do we get inexpensive oral drugs to serve us the same way we have statin drugs for LDLP's?
So big picture. Inflammation works. The high sensitivity CRP test, I think should be used very broadly as a motivational tool, as a tool to get the patient to understand the biology. What I say to my clinical colleagues is, we can't treat things we don't measure. We measure LDL cholesterol to lower it. We measure blood pressure to change it. If you don't measure the CRP, I don't know how you know what you're treating and I can tell you in a standard atherosclerosis clinic, there's far more patients with residual inflammatory risk, than there are with residual cholesterol risk, and the only way to know who they are is to actually test.
But the big picture is - it's an exciting time, there's a lot of work to be done, but we can now see the future for this field.