COMMENTARY

Homing in on the Inflammatory Pathway of CVD

Interviewer: John M. Mandrola, MD; Interviewee: Paul M. Ridker, MD, MPH

Disclosures

January 03, 2019

John M. Mandrola, MD: Hi, everyone. This is John Mandrola from theheart.org | Medscape Cardiology, at the American Heart Association (AHA) meeting in Chicago. I'm delighted to be here with Dr Paul Ridker, who is the Eugene Braunwald Professor of Medicine at Harvard Medical School. Dr Ridker presented the CIRT trial,[1] which is going to teach us a lot about inflammation. Tell us what we have learned about inflammation here at AHA.

Paul M. Ridker, MD, MPH: It's always great to be here and do these updates because it's been a really fascinating period for inflammation biology. [For the view from] 30,000, we now know that inflammation is a major driver of atherosclerotic risk. We have had a novel simple blood test for inflammation, the high-sensitivity C-reactive protein (hs-CRP) test, for some 20 years. We actually have guidelines[2] now that say, "Go ahead and measure the hs-CRP if you want to understand risk." We showed years ago that statins are twofers: lipid-lowering anti-inflammatory drugs. CANTOS[3] was the first of these inflammation-reduction trials that we designed and ran in parallel.

CANTOS took a very narrow-spectrum, incredibly targeted drug that blocks interleukin-1-beta (IL-1-beta), which in turn lowers interleukin-6 (IL-6), which in turn ultimately lowers our biomarker, the CRP. We found that that pathway, when inhibited, reduced major adverse cardiovascular events by 17%.[3] What is so cool is that this is the same risk reduction we see in FOURIER[4], in SPIRE,[5] and in ODYSSEY.[6] These are great things to do to lower the low-density lipoprotein cholesterol (LDL-C). Of course, in CANTOS, this IL-1-beta inhibitor did it without changing LDL-C levels at all. CANTOS was proof of principle that inhibiting inflammation can lower vascular events, but it is an expensive way to get there.

CIRT Study

Mandrola: Methotrexate (MTX) is more of a nonspecific anti-inflammatory drug. How did that turn out?

The future is terrific, because we now know exactly where to go for inflammation inhibition.

Ridker: When we began this process, we wanted two swings of the bat. CANTOS was swing A, and it was a home run. With funding from the National Heart, Lung and Blood Institute, swing B was a very different approach. We used low-dose MTX,15-20 mg given once a week, which is the dose routinely used to treat rheumatoid arthritis (RA). Interestingly enough, MTX is a terrific drug for RA but canakinumab isn't, and we'll come back to why that is important. We randomized just shy of 5000 patients in the United States and Canada only. Actually, one of the most interesting things is (and very much with the guidelines) that the average LDL-C in this trial was 68 mg/dL. Our site physicians did a terrific job on the lipid side.

At the end of the trial we saw, somewhat to our surprise, no reduction in IL-1-beta, IL-6, and CRP, and perhaps, as a consequence, no change in event rates at all. You might say that that is disappointing. But on the other hand, we have learned phenomenal biology. We now have a positive study saying that this pathway worked and an informative neutral study saying that if you don't do those things, you can't expect it to work. The future is terrific, because we now know exactly where to go for inflammation inhibition.

Unraveling and Understanding Inflammation

Mandrola: Do you think that the reason MTX didn't reduce outcomes is because it didn't reduce inflammatory markers that had previously been shown to be important?

Ridker: We are learning about pathways. Inflammation is a catchall term for everything from, "I have a sprained ankle" to "I have lupus," and there are different pieces of this inflammatory process. I said earlier that canakinumab, which clearly worked for atherosclerosis, is not a very useful drug for RA, whereas MTX is quite good. Some anti-inflammatories work with some diseases and don't work with others. We both know that nonsteroidals are pretty good for our headaches and achy pains but are not very good for heart disease. There are certain types of inflammation—we are talking here about a specific innate immune function that works from this IL-1-beta, IL-6 pathway.

What is exciting is that there are many other ways of inhibiting that. Drugs are already available, some drugs are already in clinical trials. One of them is colchicine, an anti-inflammatory drug that other people are doing clinical trials of, and we will see where those go. If you're a pharmaceutical company, you look at this data and say, "Wow—here's a big piece of the atherosclerosis puzzle that we have not attacked." It's getting a little technical, but you can go one step upstream from IL-1 to something called the NLRP3 inflammasome. The inflammasome is where you generate IL-1, and there are ways to inhibit that. There are oral drugs and they could be inexpensive. You can go one step downstream and attack IL-6 itself, and there are lots of drugs we already have for other diseases that do that. We are going to find something, and it's going to work.

Mechanism of Action of Methotrexate

Mandrola: Why does MTX work for these other inflammatory conditions and not work for atherosclerosis?

Ridker: One of the most interesting things is that the mechanism by which MTX helps our patients with RA is actually unknown. But MTX clearly does help: Symptoms are better, bones are better, joints are better. The leading hypothesis has to do with adenosine signaling and how that might impact on this process, but it is not through this other pathway that really matters. At the end of the day, inflammation is many different things and many different pathways. From an evolutionary biology perspective, that is really important, because different diseases affect different people. We all have intact immune systems, but some people get lupus, some people get juvenile rheumatoid arthritis, some get arthritis, some get atherosclerosis. We think we now know which pathway is the right one for heart disease.

Mandrola: CIRT and CANTOS were started at the same time. With the CIRT trial, it seemed like there was not that high a level of inflammation as you would like. If there were higher levels of inflammation in the patients enrolled in CIRT, do you think that it would have been more like CANTOS? Can you say that MTX does not work, or could you say that maybe it just was not a selected enough patient population?

Ridker: It's a great and important question. We have developed a concept over these 10 years called "residual inflammatory risk." For example, a patient who was on a statin now has LDL-C down to 70 mg/dL, but the CRP went from 4.5 mg/L to 3 mg/L. To me, that is too high, and we call that residual inflammatory risk. That is who we put into CANTOS. In CIRT we were not so certain what to do, and so we substituted having diabetes and metabolic syndrome for the actual CRP itself. Maybe, in retrospect, that was the wrong decision, but it's hard to second-guess at this point. That being said, even in CIRT where the CRP levels were really normal, some people had higher levels, and even in that group we didn't see any effect on IL-1, IL-6. or CRP. I think it's just a different pathway.

Importance of 'Just Doing Trials'

Mandrola: You have been doing this a long time and you are a pro. One thing that I want you to comment on is the business about having to have a positive trial for it to be seen as successful, versus having a neutral trial that is informative. Can you comment on the importance of just doing trials versus doing positive trials?

We think we now know which pathway is the right one for heart disease.

Ridker: Sure. Let me even expand that a little further. One of the reasons we pursued MTX was because there was observational epidemiology. There were reports in the literature suggesting that patients with RA, psoriasis, or psoriatic arthritis who got MTX had lower cardiovascular event rates. We have all learned in observational epidemiology that you get what you pay for, and sometimes it's right and sometimes it's not. If we don't continue to do randomized trials where we can control the confounding, randomly allocate the exposure, and figure out what the truth is, I don't think we are going to learn very much at all. I know there is a lot of interest in simple, large studies and registry trials and real-world studies (whatever that means). But I'm not in that camp. I think we'd better do science correctly. I think the only way to do it is to have randomized, double-blind trials. This is a good example of how we really need to know what we are doing. The flipside is, when you do it right and you get a big hit, like proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition, like IL-1 inhibition, you learn a lot quickly and the field moves forward.

Future of Targeting Inflammation as Treatment of Atherosclerosis

Mandrola: Excellent. What do you think are in the near and distant future of inflammation as treatment of atherosclerosis?

Ridker: We have proof of principle, so we have come a long way in this period of time. One of the things I tell my clinical colleagues is, if you don't measure it, you can't treat it and you don't even know what is wrong with your patient. We all measure LDL-C because if we find out you have hyperlipidemia, we put you on LDL-lowering drugs and we measure the on-treatment LDL. Our new guidelines are back to where they used to be. We measure blood pressure and we put you on a blood pressure-lowering drug; we measure the response to know where we are. I've been measuring CRP in my patients for a long time. If you're not, how do you even know the biological reason for your patients having recurrent events? It might well be a proinflammatory response, and you are chasing the wrong biology.

The first thing to do is measure and figure out what is wrong, so you can think about it. What would you do if the CRP is high? I use diet, exercise, and smoking cessation as a motivating factor. All three things lower inflammation and CRP, and these give the patient a sense that their physician is correct, because these mom-and-pop things work—which is great. We learned from JUPITER and other trials that with statin therapy, the dose should be increased if the CRP is still high, or you should go to a more potent statin. Again, [staying] within guidelines is a good idea. Down the road, maybe we will figure out an inexpensive way to recapitulate CANTOS.

Mandrola: Excellent. Thank you so much for being with us.

Ridker: It's a pleasure.

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