Inflammatory risk better predicts events vs. cholesterol risk in statin-treated patients
Click Here to Manage Email Alerts
Key takeaways:
- In patients at high cardiovascular risk already taking statin therapy, level of inflammation better predicted future cardiovascular events or death than level of LDL.
- The findings indicate that this population may need anti-inflammatory therapy just as much as cholesterol-lowering therapy to prevent cardiovascular events and death.
NEW ORLEANS — In high-risk patients on statin therapy, residual inflammatory risk as assessed by high-sensitivity C-reactive protein better predicted CV events and death than residual cholesterol risk as assessed by LDL, data show.
“We are now in an era where everyone with atherosclerosis ... should be on a high-intensity statin,” Paul M. Ridker, MD, MPH, director of the Center for Cardiovascular Disease Prevention and the Eugene Braunwald Professor of Medicine at Brigham and Women’s Hospital and Harvard Medical School, told Healio. “I asked the question, what has happened in 25 or 30 years? Have we made progress [in prevention of CV events]?”
Ridker and colleagues analyzed 31,245 contemporary statin-treated patients with or at high risk for atherosclerotic CVD from the PROMINENT, REDUCE-IT and STRENGTH trials to determine the contributions of inflammation and cholesterol to risk for CV events and death. The findings were presented at the American College of Cardiology Scientific Session and simultaneously published in The Lancet.
“I looked at [the PROMINENT] database and asked a simple question: What is the predicted value of contemporary, aggressive guideline-mediated-and-directed care, including high-intensity statins, today compared with 25 years ago, when no one was taking these drugs? All I expected was to have a similar predictive value for LDL and CRP that I had shown 25 years ago,” Ridker told Healio. “When I did the analysis with increasing quartiles of LDL and increasing quartiles of CRP, to my surprise, the CRP was a very powerful predictor of [major adverse CV events], a very powerful predictor of cardiovascular death and all-cause mortality, but the LDL was quite marginal. That surprised me a little bit. I called up Steven E. Nissen, MD, MACC, and [asked for] access to the STRENGTH data, and I called up Deepak L. Bhatt, MD, MPH, and [asked for] access to the REDUCE-IT data. Why those three trials? None of them were directed at CRP lowering and none of them were directed at LDL lowering, so there wasn’t any confounding by the agents.”
In the three cohorts, mean age ranged from 63 to 64 years, the percentage of women ranged from 29% to 35%, the percentage on a high-intensity statin ranged from 31% to 72%, mean triglyceride levels ranged from 216 mg/dL to 240 mg/dL, mean LDL ranged from 75 mg/dL to 78 mg/dL and mean hsCRP ranged from 2 mg/L to 2.3 mg/L. Mean follow-up ranged from 3 to 5 years.
Ridker and colleagues found that residual inflammatory risk was associated with incident major adverse CV events (adjusted HR for highest hsCRP quartile vs. lowest = 1.31; 95% CI, 1.2-1.43; P < .0001), CV mortality (aHR for highest hsCRP quartile vs. lowest = 2.68; 95% CI, 2.22-3.23; P < .0001) and all-cause mortality (aHR for highest hsCRP quartile vs. lowest = 2.42; 95% CI, 2.12-2.77; P < .0001). However, residual cholesterol risk was not associated with incident major adverse CV events (aHR for highest LDL quartile vs. lowest = 1.07; 95% CI, 0.98-1.17; P = .11) and was associated with CV mortality (aHR for highest LDL quartile vs. lowest = 1.27; 95% CI, 1.07-1.5; P = .0086) and all-cause mortality (aHR for highest LDL quartile vs. lowest = 1.16; 95% CI, 1.03-1.32; P = .025) to a lesser degree than residual inflammatory risk.
“We have 31,245 contemporary aggressively treated patients on high-intensity statins, and the punchline is ... we are doing a very poor job at addressing this inflammatory response,” Ridker told Healio.
The findings have many implications for treatment of high-risk patients already on statins, Ridker told Healio.
“Implication No. 1 is, if you don’t measure [CRP], you have no idea what you are doing,” he said. “This is a big deal because we still have guidelines that barely recommend CRP screening. That’s embarrassing. No physician would ever treat LDL without knowing the LDL before and after. No physician would ever treat blood pressure without knowing the blood pressure before and after. It’s absurd to say this other phenomenally important process is being ignored. You don’t know who in your clinic has residual inflammatory risk because you are not even looking. That’s just terrible medical care and it’s got to be fixed.
“No. 2, I have used CRP for years to emphasize the critical importance of diet, exercise and smoking cessation. All three of these things lower CRP and CV risk.
“No. 3, we are now in an era where we have targeted anti-inflammatory drugs that have been proven to work ... but no one is using [them]. We have to ask some questions about why.”
Inexpensive anti-inflammatory treatments such as colchicine need to be adopted more widely, Ridker said in an interview.
“I strongly believe that 5 to 10 years from now, all atherosclerosis patients will be treated with aggressive lipid-lowering and aggressive anti-inflammatory therapy,” Ridker told Healio. “That is the way to beat this disease. We just have to get there. That is the real signal of the data we presented.”
Reference:
Perspective
Back to Top
When viewed correctly, this is another good academic and clinical indication that physicians should be paying attention to the degree of “residual” inflammation, and that it is something that, currently, doctors don't always measure or assess by drawing a blood test like hsCRP. There is one drug that is clinically available to treat for residual inflammation, namely colchicine, which is inexpensive. We have a fair amount of experience in dealing with this drug and there are several well-run trials that have documented its efficacy. But yet, the number of individuals who look for inflammation or those who then try to treat it are small. I think that this paper will help convince people that this is something that should not be ignored.
The medical community should understand that inflammation is caused by a lot of things. Your patient who walks into the room with a prominent abdomen: The fat that's sitting around their intestines, around their liver, around their muscles, even around their heart, can contribute to inflammation. Diabetes contributes to it. Women who are postmenopausal have greater inflammation, as do people who smoke. There are variety of things that can increase what we call inflammatory stress. A lot of times, there are so many different players involved. One of the unifying features of what we do in risk management and risk factor modification is by correcting BP, glucose, smoking and lipids, we are ultimately reducing inflammation. What this paper is telling us is that there are degrees of residual inflammation that are left even after we do what we do.
This is the reason why the authors selected the papers that they did to include in the meta-analysis. These were all papers in which LDL was not the target for intervention, but rather triglycerides. And they were able to look at what happens after the individual is treated. They got a chance to look at residual inflammation vs. LDL. They were able to identify that those individuals with higher degrees of LDL at the end of the trial vs. individuals whose LDLs were lower — in the 60s and 70s vs. over 100 mg/dL.
But the reality in my mind is that many patients who fit into the category of the trial participants, if they had an LDL cholesterol over 100 mg/dL, many doctors, certainly those of us at the prevention group at NYU Langone, would be intensifying lipid lowering, which may have had an impact on their inflammatory risk. At the same time, we will be focusing on several things at one time. So if someone's LDL is a little bit high, and their glucose is high, they're very overweight and they smoke, we are going to try to impact all of these other inflammation-inducing factors. But I think the point that is being made in the paper is that Dr. Ridker and his colleagues are looking to convince physicians about the role of residual inflammation and try to drive home that sometimes the efforts of the doctor may not be as good as it should be in lowering CRP, and that maybe there should be recognition of this and efforts should be taken to try to make it better.
What the results indicate is that if your idea of prevention is just LDL reduction, you have to reacquaint yourself. I think you need to have your head on a swivel looking at everything that confronts you when the patient comes into your office. There are some things that are easy to pick up on. You certainly don't need a lab to pick up the fact that someone's very overweight, or that the smell of tobacco odor lets you know that they're still smoking. Historical information about the food choices that they eat is useful, because we know certain diets, independent of weight loss, can influence inflammation and the typical American diet is more likely to cause it. There are so many things that need to be addressed. Doctors have thought of weight loss, and they've thought about blood sugar, but maybe they should be thinking about what is at the ground level with all of these risk factors, and that is inflammatory stress.
In the introduction to the Lancet article, the authors discuss the frustration with the fact that we do have a drug that is generic and inexpensive, and with which there is a lot of clinical experience, including cardiac benefits. This hasn't been picked up by most physicians. I think a lot of it may come down to so-called pill fatigue. If you add one extra pill for some patients, they question why you want them to take another pill, which can sometimes lead to a little stress between the physician and patient. As a result, the caregiver tries to keep the pill count down. But that doesn't mean you can't tell the patient to watch their diet, try to exercise and stop smoking. Because all of those have anti-inflammatory capabilities. By knowing this and actively measuring inflammation and focusing on it, I think we can produce better outcomes.
Collapse
Ridker PM, et al. Featured Clinical Research III. Presented at: American College of Cardiology Scientific Session; March 4-6, 2023; New Orleans (hybrid meeting).
Read more about
Click Here to Manage Email Alerts