Systemic inflammation, long recognized to be associated with an increased risk for cardiovascular (CV) events, has now been labelled “actionable” by the American College of Cardiology (ACC). This means it should be assessed, monitored, and modified for the goal of preventing CV disease (CVD) events and deaths.
“In aggregate, the evidence linking inflammation with atherosclerotic CVD is no longer exploratory,” according to a recent ACC Scientific Statement led by George A. Mensah, MD, director of the Center for Translation Research and Implementation Science at the National Heart, Lung, and Blood Institute in Bethesda, Maryland.
The link between inflammation and CVD was highlighted over 20 years ago in a joint paper from the CDC and the American Heart Association — though they didn’t claim a role for routine screening. At that point, inflammation was not known to be causal or modifiable.
Growing Body of Research
Much has changed. Based on subsequent research, including randomized clinical trials, the ACC has labeled screening for inflammation with high sensitivity C-reactive protein (hsCRP) a “major clinical opportunity” for guiding and improving primary and secondary CVD prevention.
This push for screening is an immediate and important change, according to the statement writing committee that included Paul M. Ridker, MD, MPH, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital in Boston.
“The ACC Statement says explicitly that we now know that inflammation is a modifiable risk factor and we need to operationalize it,” said Ridker, a principal investigator of several key trials, including JUPITER and CANTOS, that led ultimately to what is a fundamental change in CVD risk management.
Essentially, the statement identifies inflammation as an independent risk factor comparable to risk factors such as pathogenically elevated levels of serum cholesterol or blood pressure. Like these, the ACC recommends inflammation should be measured at baseline, serially monitored, and treated if above target levels.
There are multiple possible approaches for monitoring inflammation, but hsCRP has been singled out as a simple biomarker obtained at low cost.
“Cardiovascular risk increases linearly across the hsCRP range,” Mensah told Medscape Medical News. Typical of other modifiable risk factors, he said “a higher hsCRP conveys higher risk after adjustment for traditional modifiable risk factors.”
The ACC statement includes evidence-based hsCRP cut points for decision-making. These are < 1 mg/L, 1-3 mg/L, and > 3 mg/mL, which, according to the data, correspond to low, moderate, and high levels of inflammation as it pertains to CVD risk.
Clinical Intervention
Comparable to the guideline-recommended targets for low-density lipoprotein (LDL) or systolic blood pressure, “persistent elevation of hsCRP above these thresholds, rather than any specific percent change, should inform intensification” of therapies targeted at inflammation, Mensah said.
According to Mensah and his coauthors, clinicians “will not treat what they do not measure.” Consequently, the new admonition to uniformly measure hsCRP along with the directive to reach the hsCRP targets is an advance in clinical cardiology. It is based on the evidence, as outlined in the ACC statement, that doing so will substantially reduce CVD risk on top of any other form of risk management.
In all adults at risk for CVD or who already have CVD, “hsCRP should be viewed as a continuous risk marker with the recommended action threshold as outlined in the statement,” Mensah said.
As described by several seminal review articles in the early 2000s, including those in Circulation and The New England Journal of Medicine, there was then an enormous amount of data to link inflammation to both aging and CVD risk. Over time the link has only strengthened.
Yet even though inflammation can stand alone as a risk factor, it is also important to understand its role as a common denominator to many other key risk factors, including hypercholesterolemia and smoking, Ridker said. Many standard risk factors, referred to by the acronym SMuRFs in the ACC statement, are proinflammatory and, at least in part, mediate CVD risk through this activity, Ridker said.
Contemporary summaries of the role of inflammation make this point. One published in 2022 by a collaborating group of European clinicians and researchers, concluded that inflammation is a cause of CV events not just an association. In this summary, led by Michael Y. Henein, MD, PhD, a professor of cardiology at the Imperial College London, London, England, the inflammatory response was traced to the earliest steps of vascular disease.
The Foundation of CVD
“Atherosclerosis is best understood as a chronic inflammatory disease,” Henein said. He traced its involvement in endothelial dysfunction, a state that renders the vascular wall susceptible to atherosclerotic plaque formation through steps that involve recruitment of macrophages. Once present at the vascular wall, they further stoke the inflammatory response with the release of such inflammatory cytokines as interleukin-1beta (IL-1beta) and IL-6.
Once activated, many proinflammatory factors participate in fibro-atheroma formation and growth of stenotic plaques. They also participate in steps leading to plaque rupture — a pivotal event in a myocardial infarction (MI), Henein said.
Henein and his coinvestigators in their 2022 paper expressed caution about the benefit-to-risk of anti-inflammatory drugs. As the inflammatory response also defends against pathogens and malignancy, he speculated that therapies selective for inflammation localized to the CV system might prove critical to safety.
The story of inflammation and CVD events advanced substantially with publication of the JUPITER trial in 2008 and the CANTOS trial in 2017.
In JUPITER, researchers enrolled patients with elevated hsCRP but LDL levels below those warranting guideline-directed therapy at the time the study protocol was written. The trial drug, rosuvastatin, was known to have potent lipid-lowering and an anti-inflammatory effect.
The trial showed that events were reduced on rosuvastatin relative to placebo regardless of baseline LDL, supporting the theory that inflammation was a targetable risk factor independent of LDL. In addition, the study showed a remarkable risk reduction in the more than 8000 patients who had no standard modifiable risk factors as conventionally defined at the time of the trial.
Statins Show Efficacy
In this group of patients, without risk factors other than an elevated hsCRP, “we saw a 45% reduction in major events on rosuvastatin vs placebo,” Ridker said. In other words, a major benefit was achieved in a patient population “completely missed” by conventional methods of determining and treating CVD risk, he said.
Although important, the trial did not prove the inflammation hypothesis, Ridker noted.
The problem was that inflammation could not be declared a causal risk factor when it was modified by a drug with effects on additional risk factors. As a result, it could not be stated conclusively that an anti-inflammatory effect of rosuvastatin was a specific source of benefit.
That “proof of principle” did not come for another 10 years, Ridker said. The experimental therapy in CANTOS was the IL-1beta blocker canakinumab, which targets a major inflammatory cytokine but has no effect on LDL.
In CANTOS, the most effective study dose of canakinumab reduced hsCRP by 26%. Despite the lack of any effect on hsCRP in the placebo arm or any effect on LDL in either arm, there was a 15% reduction (P = .021) in the composite primary endpoint of nonfatal MI, nonfatal stroke, or CV death relative to placebo.
Almost all patients (> 90%) in CANTOS regardless of assigned therapy received a statin.
“We have known since then that, yes, inflammation is causal for atherosclerosis and that altering the inflammatory process, at least with canakinumab, reduces risk of events,” he explained.
Since the CANTOS publication, there have been numerous other studies further supporting the principle that inflammation as measured with hsCRP is an independent and highly modifiable risk factor.
Reducing Risk in the Risk-Less
“We have been telling the SMuRF-less population for years that their risk is very low, but this is just wrong if inflammation is not considered,” Ridker said.
According to the ACC statement, lifestyle interventions, including diets low in proinflammatory foods and exercise, represent the first-line defense against inflammation. These lifestyle changes should be considered in all patients at risk for CVD who have an hsCRP value persistently > 3 mg/mL in the absence of another cause, such as an acute illness.
For primary prevention beyond lifestyle in the event of a persistent elevation of hsCRP, statin therapy is the next step, and it is taken independent of LDL levels. The directive is specific to statins. PCSK9 inhibitors and inclisiran, for example, despite their greater LDL-lowering potency, offer no significant anti-inflammatory effect even if they continue to have an important role in LDL-lowering, Ridker said.
For secondary prevention, elevated hsCRP is now understood to be “at least as powerful a predictor of recurrent vascular events as that of LDL cholesterol,” according to the ACC statement. For those whose standard modifiable risk factors are tightly controlled, the statement identifies treatment of inflammation as a critical step toward reducing residual risk.
Colchicine is the only evidence-based drug therapy available for targeting inflammation other than statins. It has had an FDA indication for this purpose since 2023, but Ridker reported that uptake of this therapy so far has been disappointing.
“There is not just one but two major trials published in The New England Journal showing CVD risk reductions with colchicine,” said Ridker, pointing out that the FDA issued the indication based on these data but in the absence of any industry support.
Support for Colchicine Therapy
In a placebo-controlled multicenter double-blind trial, published in 2019, patients were randomized within 30 days of an MI. Colchicine in a once-daily dose of 5 mg was associated with a significant 23% reduction relative to placebo in the primary composite endpoint of death from CV causes, cardiac arrest, MI, stroke, and urgent coronary revascularization after a median of 22.6 months of follow-up.
In the second trial, published in 2020, patients with chronic coronary disease were randomized. After a median of 28.6 months of follow-up, there were significant 31% and 28% reductions, respectively, in the primary and secondary composite major adverse cardiovascular event endpoints for colchicine relative to placebo.
The limited use of colchicine in clinical practice persists even though it has been more than 5 years since these studies were published and almost 3 years since an indication was granted. Ridker hopes the directive to measure hsCRP routinely will jump start attention to inflammation and treatment options.
It is likely that statins and colchicine will be joined by other treatment options. Although canakinumab was not further developed for prevention or treatment of CVD despite positive results from CANTOS, trials with other drugs targeted at specific mediators of inflammation are planned or ongoing.
Of these, a double-blind trial called ZEUS with the anti-IL-6 monoclonal antibody ziltivekimab is expected to be completed by the end of 2026, said Ridker, who is primary investigator of this multinational study. Described in the published protocol, the trial is enrolling more than 6000 patients with atherosclerotic CVD, chronic kidney disease, and elevated systemic inflammation (hsCRP ≥ 2 mg/L). Patients will be randomized to 15 mg of ziltivekimab or placebo administered monthly.
The primary endpoint is a composite of CVD events. The secondary endpoint includes milestones of CKD progression.
CKD is one of many diseases associated with high levels of systemic inflammation and high risk for CVD. It is not an exception. Autoimmune disorders, driven generally by an upregulated inflammatory response, have long been associated with an increased risk for CV events. Examples include rheumatologic disorders and psoriasis.
As a routinely measured marker for CVD risk, hsCRP is expected to bring these populations to the attention of cardiologists, Ridker said.
Change in Practice?
“When patients with an elevated hsCRP and a history of autoimmune disease present in the clinic, a light bulb should go on, prompting clinicians to recognize that this is a patient at higher risk of cardiovascular events than would have been presumed without this history and without measuring the hsCRP,” he said.
Whether or not the ZEUS trial or other studies of potent anti-inflammatory agents identify new options for managing inflammation as a CVD risk factor, the ACC statement calls for an immediate change in practice monitoring hsCRP and introducing therapies when cut points are reached, Mensah and Ridker said.
While the ACC statement also provides insight about the relationship of inflammation to several specific CV conditions, such as pericarditis, heart failure, and acute coronary ischemia, the main point is a “call to action,” according to Mensah and his coauthors.
“The time has come for clinical practice guidelines to implement broad screening of primary and secondary prevention patients for hsCRP,” wrote, adding that physician awareness is critical to establish documentation of inflammation and evidence-based, guideline-directed, anti-inflammatory therapy a standard in CVD risk management.
Mensah reported having no potential conflicts of interest. Ridker reported financial relationships with Agepha, AstraZeneca, Cardiol, Caristo, Lilly, Merck, NW Amsterdam, Nodthera, Novartis, Novo Nordisk, Pfizer, and Tourmaline. Henein reported having no potential conflicts of interest.
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