COMMENTARY

Paul Ridker on Inflammation and Residual CV Risk

Seth Bilazarian, MD; Paul M. Ridker, MD, MPH

Disclosures

June 23, 2014

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Editor's Note: Dr. Bilazarian interviews Dr. Paul Ridker on the inflammation hypothesis and 2 ongoing trials in this area: the National Heart, Lung, and Blood Institute (NHLBI)-funded Cardiovascular Inflammation Reduction Trial (CIRT),[1] which is testing whether taking low-dose methotrexate reduces myocardial infarction (MI), stroke, or death in people with type 2 diabetes or metabolic syndrome who have had a heart attack or have stable coronary artery disease; and the Novartis-sponsored Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS),[2] which is assessing whether blocking the proinflammatory cytokine interleukin (IL)-1β with canakinumab, as compared with placebo, can reduce rates of recurrent MI, stroke, and cardiovascular death in patients post-MI with elevated high-sensitivity C-reactive protein (CRP; ≥ 2 mg/L).

Seth Bilazarian, MD: Hi. I am Seth Bilazarian from theheart.org on Medscape here at the American College of Cardiology (ACC) meeting in Washington, DC. I am very excited to be able to sit down with Dr. Paul Ridker, Professor of Medicine at Harvard Medical School and the Brigham and Women's Hospital; he is an international leader on research and clinical trials in inflammation and atherosclerosis and the principle investigator of 2 large trials, which I'm going to ask him to review and in which, for disclosure purposes, I am an investigator.

Dr. Ridker speaks frequently on inflammation and atherosclerosis. I have been the beneficiary of hearing him speak at investigator meetings and here at the national meeting. I want to ask Paul some questions about inflammation, and I'm going to launch right in.

Paul, you have done a lot of work in this area. I want to focus primarily on secondary prevention. There are a lot of questions about primary prevention. You have been a significant contributor with the Reynolds risk score for primary prevention. There isn't much controversy that we should be aggressive in secondary prevention and that lipid therapy with statins is the cornerstone of therapy. After that, there is a lot of so-called "residual risk." How should we manage patients? Before we discuss clinical trials, what should we be doing in the inflammation realm? Is there a role for CRP testing, for instance?

Paul M. Ridker, MD, MPH: Let me begin by saying that you are the number one enroller in both of our clinical trials in the entire United States. I'm very grateful to you and your organization for helping us out so much and understanding why this is so important for our patients.

You are absolutely right. In the spectrum of disease that we divide into primary and secondary prevention, the inflammatory process is present throughout the whole disease, from the earliest initiation of foam cells through plaque development, and ultimately through plaque rupture and plaque rerupture in secondary events.

Right now we attack that with statins -- phenomenally effective drugs, low-density lipoprotein cholesterol (LDL-C)-lowering, very important drugs. This is not an argument between the LDL-C world and the inflammation world. This is about how these 2 things interact. One of the most interesting issues is that the statins turn out to be both LDL-C-lowering drugs and anti-inflammatory drugs. We have learned that over the years.

You ask about secondary prevention for a very good reason. We have stable post-MI patients who have been in the catheterization lab and had stents put in who are at remarkably high residual risk despite statin therapy.

The cardiology world right now is very exciting. We are going in 2 simultaneous directions. One is: "Let's just take the LDL-C lower." That's the PCSK9 [proprotein convertase subtilisin/kexin type 9] direction. It's a great opportunity. I am very excited about it. The second is: "Can we attack residual risk through an anti-inflammatory approach?" This will be a very novel way of getting at it. My bias is that both are probably going to work, and that might be our direction for the future.

Dr. Bilazarian: Before we get into that, is there a role for checking CRP as a strategy to evaluate patients for inflammation right now?

Dr. Ridker: CRP works very well in primary prevention. We all understand that. If a patient has a high CRP level in primary prevention, that patient should probably be on a statin. That was shown in the JUPITER trial[3] that all of us, including you, contributed to. We know that already.

In secondary prevention, a patient with a persistently elevated CRP (let's just say >2 mg/L) despite being on a statin is a very high-risk patient in my mind. That is the wedge that we are using in these clinical trials, saying, "I want people who -- despite having had a first event, starting the drugs, and becoming pacified -- are still at particularly high inflammatory risk." There are only 2 groups of patients who fit that. One is patients with diabetes and metabolic syndrome. We will come back to that. That's the National Institutes of Health (NIH) trial.[1] The other is patients with a persistently high CRP level. That's the Novartis trial.[2] Either way in, you end up with a proinflammatory, persistent inflammatory response that is not being adequately reduced with statins alone. That is a very high-risk group, and that is where we have the opportunity to intervene.

Dr. Bilazarian: When I'm talking with patients or physician colleagues about the trials that you are conducting and advocating that this is a worthwhile strategy to at least investigate, sometimes they push back. A colleague will say: "If anti-inflammatory strategies are effective, why is there a concern about nonsteroidal anti-inflammatory drugs (NSAIDs) with cardiovascular disease? How does aspirin play into it?" You mentioned how we believe that statins have both a lipid and an anti-inflammatory effect. In 1997, you published in the New England Journal of Medicine[4] that aspirin has antiplatelet effects, and potentially some of its benefit occurs through an anti-inflammatory effect. How would you respond to that?

Dr. Ridker: The aspirin data are very important. You have a great memory. This was a study we did with Charlie Hennekens, my scientific mentor. It was Dr. Hennekens who put aspirin on the map in primary prevention.[5] We made the observation that CRP levels predicted risk, but the magnitude of benefit for aspirin was greatest when the CRP was highest. In other words, this antiplatelet drug seemed to have some anti-inflammatory properties. That's actually the beginning of this 20-year development process that brings us to today. People do get confused about NSAIDs. The way that NSAIDs affect inflammation after we play tennis, or when we go out running, is a very different pathway than what we are talking about here.

The 2 trials that we are running are about lowering IL-6 and the IL-1 to IL-6 pathway, something that many of us aren't quite comfortable with yet. That's a different anti-inflammatory pathway, but we think that's where the biology sits, in there.

Dr. Bilazarian: Help us contextualize some of the clinical data around some anti-inflammatory therapies. You teach that there are large data sets (not randomized trials) -- registries of patients on low-dose methotrexate. We have a trial called the LoDoCo (low-dose colchicine) trial.[6] Help us understand. What does that all mean? How should clinicians who are practicing and reading journals begin to contextualize anti-inflammatory strategies?

Dr. Ridker: Maybe the best way to do this is to go through the 2 trials separately because they have some things in common but others that are distinct. The first trial -- with NHLBI support -- is the low-dose methotrexate trial. That's called CIRT -- the Cardiovascular Inflammation Reduction Trial.[1]

That trial is based on 2 fundamental observations beyond the fact that inflammation is crucial to this process. The first is the remarkable observation from our rheumatology colleagues that if you give methotrexate to patients with rheumatoid arthritis, they seem to have fewer heart attacks and fewer strokes.[7,8,9,10,11,12] Those are observational data, not randomized trial data, but very interesting clinical data saying that if we can slow down the plaque volume and plaque development by giving you an anti-inflammatory drug, we might have access.

The second observation is the vascular biology piece. There are elegant data[13] showing that if you pretreat certain animal models of atherosclerosis -- with all of their caveats -- with methotrexate, you get less atherosclerosis and fewer signs and signals of increasing inflammation.

Under that rubric, the NHLBI has given us the opportunity to take the secondary prevention patients (MI in the last 5 years or multivessel coronary disease who are already on statins, aspirin, and beta-blockers) and randomize them to low-dose methotrexate. This is very important. This is 2-magnitude log-orders lower than what you might remember from residency years in an oncology setting. This is the dose of methotrexate routinely used by hundreds of thousands of people with rheumatoid arthritis and psoriasis. The drug has been around for 45 years. It's inexpensive -- a few pennies a week. It's generic. But we know how to use it safely. In that trial, the randomization is to 15 mg or 20 mg of methotrexate weekly vs placebo on top of standard care. We have randomized about 500 patients across the United States now, and we are just in the ramp-up part of the study. So far it looks very safe, and we are very excited about that.

The second clinical trial, which is funded by Novartis, is called CANTOS, the Canakinumab Anti-inflammatory Thrombosis Outcomes Study.[2] That study uses a more targeted focal anti-inflammatory drug called canakinumab. Canakinumab is a human monoclonal antibody against IL-1 beta. This is sometimes where the cardiologists I work with glaze over a little bit.

IL-1 is named that way for a reason. It's at the top of the inflammatory cascade. IL-1 will lead to the production of IL-6, which goes down to the liver and among other things induces CRP, and we think this is where the inflammatory cascade is most important. By giving this drug, we actually inhibit this pathway in a more focal, narrow way than with methotrexate.

I look at these 2 trials as 2 swings at the bat for the inflammation inhibition hypothesis. They both look at this in a similar way, one using patients who have a high CRP after MI; the other looking at patients with diabetes and metabolic syndrome after MI. Neither is aimed at lowering the biomarkers. We have already shown that. Yes, if I give either drug, CRP and IL-6 come down. The question is: Can I lower event rates? This is the residual risk issue you asked about. On top of a statin, this is getting at what drives residual risk. If either of these drugs work, it will be a home run for us -- the idea that we can actually attack the inflammation, not just the lipids.

Dr. Bilazarian: In the past, you have taught that there is a certain taxonomy (not your word, but mine) in terms of how these trials are organized. Broadly, there is the lipid approach. We talked about PCSK9. We put cholesteryl ester transfer protein (CETP) inhibition on that side. On the inflammation side, you mentioned these 2 strategies of IL-6 signaling reduction pathways. You also mentioned that there are some other strategies that are non-IL-6 signaling. Can you comment on those?

Dr. Ridker: That's a great issue to discuss. When you think about what is going on in the inflammation biology world, we like to separate trials into those that focus on reducing the IL-1 to IL-6 pathway. I have talked about methotrexate. I have talked about canakinumab. You mentioned the LoDoCo trial. Colchicine also inhibits that pathway through something called the NLRP3 inflammasome. It's another way of getting at why drugs that treat gout might also treat atherosclerosis.

The second set of studies I classify as anti-inflammatory but not affecting the central IL-6 signaling pathway. This would include such drugs as darapladib, varespladib, and others that have anti-inflammatory effects but not in that central pathway. The reason it's important to separate these out is that all of them have the potential to work, but if a drug in one class doesn't work, I would not use that as evidence for or against another. We are in a period of time when we are going to get back large-outcome data saying if I inhibit IL-6, this is what happens. If I look at other inflammatory pathways and I don't inhibit IL-6, this is what happens.

I have to give the NIH and pharmaceutical companies a great deal of credit for recognizing that we have targets that are more than simply apolipoprotein-B and LDL. Along with these fantastic new PCSK9 targets, it's a great time in cardiology.

Dr. Bilazarian: Can you tell us when clinicians practicing in the community (like me) might be able to expect to see some data from these trials? Can you give us any updates?

Dr. Ridker: I know the data on my trials. The NIH trial is just now in the early enrollment phase. We have enrolled about 500 patients. We anticipate enrolling over the next 1.5-2 years.

The Novartis-funded CANTOS trial is fully enrolled. All 10,000 patients are randomized, and we are about 1.5-2 years in. My guess is that about 2-2.5 years from now we ought to have a readout one way or the other about whether that particular type of inflammation inhibition will lower vascular event rates.

Dr. Bilazarian: You mentioned earlier that this is a new field for many practicing clinicians. Some clinicians take the tack that they don't need to know about anything until it has US Food and Drug Administration approval. Other clinicians -- there's a good number, probably those who are still watching -- would like to know more going forward. Can you give us some final thoughts on what we need to know as clinicians going forward? What should we pay attention to in journal articles about inflammation as the years unfold, looking ahead to CANTOS production?

Ultimately, I would ask sort of a tongue-in-cheek question. In medical school, we learned the Krebs cycle. In residency, we learned the coagulation cascade. Will we have to learn more about immunology and inflammation going forward?

Dr. Ridker: The answer is yes to all of the above. We will have to learn a lot more as vascular biology hits the clinical community. We will have to learn more about innate immunity.

Right now, we already know something fundamental. I'll give you these data. Within the CANTOS trial, in which we are screening post-MI individuals who have a persistently elevated CRP, we are finding that the average CRP is 4-4.5 mg/L. Their event rates are exceptionally high, much higher than in any other ongoing secondary prevention trial. That should be a signal right now to the cardiology community.

When we pull out people who have a persistent proinflammatory response, even if they are already taking aspirin and a statin, and they have a stent, and we think that they are doing well, that group's event rate is exceptionally high. That is the window of opportunity here. It's also the proof that inflammation matters.

The question you are asking -- the billion-dollar question -- is if we lower the inflammation, will we have fewer event rates? For that answer, we have to wait. Right now, I would want to know about the exceptionally high-risk patient. If I had a patient with a high CRP level post-MI or in primary prevention, I would be very aggressive with statin therapy and with lifestyle because that also lowers inflammation. Fat cells (adipocytes) are the factory for all of these proinflammatory cytokines. It's a good way to remind ourselves that diet, exercise, and smoking cessation still matter. In these people, these things are excruciatingly important.

Dr. Bilazarian: What a fantastic review. In a short time, you have given us a primer on inflammation, immunology, and atherosclerosis. I hope that our audience has enjoyed this review with Dr. Paul Ridker on inflammation, atherosclerosis, and an update on the clinical trials. Thanks from the ACC in Washington.

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