Inflammation a Strong Predictor of Adverse CVD Events in Patients on Statin Therapy
In this video, Paul M. Ridker, MD, MPH, discusses his team's recent study, which found that vascular inflammation levels in patients on statin therapy are better predictors of future cardiovascular (CV) events and death than residual cholesterol levels.
Ridker PM, Bhatt DL, Pradhan AD, et al. Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomised trials. Lancet. 2023;401(10384):1293-1301. doi:10.1016/S0140-6736(23)00215-5.
Paul M. Ridker, MD, MPH, is the director of the Center for Cardiovascular Disease Prevention and the Eugene Braunwald Professor of Medicine at Brigham and Women’s Hospital (Boston, Massachusetts)
CONSULTANT360: What was the impetus for this research? Why now?
Paul M. Ridker, MD, MPH: As a cardiologist, my colleagues and I have been aware for some 30 years that lipid lowering, dropping cholesterol, is probably our most important pharmacologic intervention we can do to lower the risk of heart attack and stroke, other than good primary care. Other than diet, exercise and smoking cessation. In my clinic, everybody gets a high intensity statin. That's how we basically do things. The tension in the field has been that, for that same 30 year period, and actually, it was our group that first demonstrated this, biomarkers of inflammation, this process of how your body addresses foreign toxins, is also fundamentally important for cardiovascular risk. We demonstrated, again, nearly 30 years ago that the inflammatory biomarker, high-sensitivity CRP is as good a predictor of future cardiovascular risk as is LDL cholesterol. But that was 30 years ago. The question today is, in a era when almost everybody with atherosclerotic disease is on a statin, what do those relationships look like? And is that information informative to how we as physicians might want to best take care of our patients?
C360: Can you summarize your paper’s results?
Dr Ridker: To summarize a lot of work, what we did is decided to address three different, large-scale contemporary clinical trials. Those trials are the PROMINENT, REDUCE-IT, and STRENGTH trials. The point is, all of them is about 10,000 patients each. So it's around 30,000 patients total. We simply ask the question, "If you're already on a statin and you already have atherosclerotic disease, what are the relationships we see today between what we call residual inflammatory risk, that is the high-sensitivity CRP, and what we call residual cholesterol risk, that is the LDL?" Now, most physicians measure LDL cholesterol. Many measure CRP, many don't. That's what this paper's really going to address. I think it's a wake up call to your listeners.
Anyway, the bottom line is that across all three of these very large trials, with everybody getting guideline directed medical care and everybody receiving statin therapy, the strongest predictor of the likelihood of you're having another heart attack, another stroke, and in particular, dying of cardiovascular disease or having all-cause mortality, it was not the LDL cholesterol, it was actually the high-sensitivity CRP.
C360: How do these study results fill a gap in our knowledge?
Dr Ridker: If you're not measuring CRP, or high-sensitivity CRP, you really don't even know what the underlying biologic problem your patient has sitting in front of you. I know that many of my colleagues do measure residual inflammatory risk. Many folks in practice don't. That's because our guidelines have really lagged behind the biology for a long time. That's number one, is that if you really want to know, "Which one of my patients in clinic are at risk?" You've got to measure both. I mean, imagine trying to manage lipid therapy without ever measuring LDL. Or imagine trying to manage blood pressure without measuring the blood pressure itself. This is not even knowing what their inflammatory profile looks like. So that's number one.
Number two was equally concerning in all three of these major contemporary clinical trials. The risk was lowest, as you might imagine, among those with a low CRP, that is less than two milligrams per liter, and a low level of LDL cholesterol, say less than 70 milligrams per deciliter. So far so good. The highest risk was also seen among those who had the highest values for both. Okay. So if you have both hyperlipidemia and high inflammation, you're at high risk. But the in between groups were really striking. As it turns out, if your LDL was high, but your CRP was low, we weren't worried about it. There's almost no events. That's very interesting. It challenges this whole idea about, "What do I do after I have a patient on a statin? Do I provide another lipid lowering drug?" Many of your listeners are under a lot of pressure from pharmaceutical companies and others to do that. Or, "Do I add an anti-inflammatory drug?"
The observation was, when the LDL was above 70, but the CRP was low, there wasn't much risk. But when the LDL was low and the CRP was high, there was a lot of risk. One of the implications here is, "Well, in practice, in daily practice, what do I really want to focus on?" Part of the argument we're making is, "Yes, of course we want to lower cholesterol, but you've already done that with a high intensity statin. Do you really want to put the patient on another lipid lowering drug?" You could. They've been proven to work. They're expensive, and the relative risk reductions we get, the absolute risk reductions we get are getting smaller and smaller, but certainly, it works. Or do you consider an anti-inflammatory drug?
Now, 5 years ago, we couldn't have had that conversation, but today we have three major clinical trials that show that targeting inflammation directly does reduce cardiovascular event rates as much, if not more than lowering LDL cholesterol. The first of those trials was our own CANTOS trial using an interleukin-1 beta inhibitor. That drug's not available for clinical use because it's being used actually in an oncology setting.
But we have two trials of an inexpensive drug, low-dose colchicine. That's the COLCOT trial and the LoDoCo2 trial. Randomized, double-blind, placebo controlled trials of patients with atherosclerotic disease. They both show that putting patients on colchicine, which has been around for 70 years, it's a anti-inflammatory drug, gives relative risk reduction between 25 and 30%. 25 to 30%, that's more than you get from a PCSK9 inhibitor. That's more than you get from ezetimibe. It's more than you get from other lipid lowering drugs. That's a real eye-opener, because of course, colchicine is inexpensive. It's available widely. Unfortunately, there'll be no pharmaceutical company promoting it because it's not going to be out there. So doctors should probably look at that data and say, "Huh, maybe I need to use some drugs that actually are effective, but that I'm not getting promoted for."
C360: How are these results impactful from a clinical perspective?
Dr Ridker: I am a cardiologist. I do lower lipids aggressively. The future of this field, I think is going to be combination therapies that aggressively lower both LDL cholesterol and high-sensitivity CRP. These are not in competition with each other. Again, if you're not measuring hs-CRP, you really don't know if your patient has residual inflammatory risk. So I'd say measure it. If the value is greater than two milligrams per liter, you may want to consider targeting the inflammation instead of necessarily targeting the LDL cholesterol. Because again, remember, I'm making the assumption you already have the patient on a statin. Presumably a high-intensity statin.
So the paper is a real wake-up call. It's been very well received. It's really been interesting both from a drug development perspective. It's been interesting from a clinical perspective. And it's telling us something quite profound, which is that in 2023, we need to address more than just cholesterol lowering, and we can do that with some very simple therapies.