A new comprehensive parameter combining residual C-reactive protein and neutrophil risk predicting adverse events in Chinese patients after percutaneous coronary intervention: A multi-center prospective cohort study

To the Editor: Coronary heart disease (CHD) continues to be a predominant cause of mortality in China even after recommended optimal management.^[1] Residual inflammatory risk (RIR) portends increased risk of recurrent cardiovascular events. As an indicator of pro-inflammatory nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)–interleukin (IL)-1β–IL-6 pathway activation, high-sensitivity C-reactive protein (hsCRP) has demonstrated significant value as a predictor of major adverse cardiovascular and cerebrovascular events (MACCEs).^[2] Due to the ethnic differences, East Asian populations exhibited lower hsCRP levels.^[3] It was confirmed by our previous single-center study, in which the median of hsCRP was 1 mg/L at 1-month follow-up, and the 1-month hsCRP >1 mg/L showed a better prediction of the risk of MACCE.^[4] Aside from the NLRP3–IL-1β–IL-6 pathway, neutrophil-mediated inflammation also contributes to the RIR and the representative biomarker neutrophil-lymphocyte ratio (NLR) has shown its value in prediction of MACCEs.^[5]

In this study, to validate the joint prediction of hsCRP and NLR, they were combined as RIR markers to explore the associations between different RIR categories and MACCE among patients undergoing percutaneous coronary intervention (PCI).

This is a prospective multi-center cohort study (ClinicalTrial.gov, identifier NCT05614050). Participants after planned PCI were recruited from 15 hospitals in China from January 2023 to December 2023. The full list of inclusion and exclusion criteria and participating centers was included in the Supplementary Tables 1 and 2, http://links.lww.com/CM9/C676. The study flowchart is shown in Supplementary Figure 1, http://links.lww.com/CM9/C676. This study was approved by the Ethics Committee of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (No. [2022]0523). All participants provided written informed consent.

The primary endpoint was the composite of all-cause death, nonfatal myocardial infarction, nonfatal stroke, and revascularization due to ischemia. Other endpoints included components of MACCE, cardiovascular death, and non-cardiovascular death. All participants were followed up for 12 months. The detailed methods were presented in the Supplementary Methods, http://links.lww.com/CM9/C676.

A total of 2376 patients were included in the analysis, and MACCE was observed in 120 (5.1%) patients. The demographic and clinical features were compared according to MACCE in Supplementary Table 3, http://links.lww.com/CM9/C676. Baseline hsCRP level was higher in patients with MACCE, while there was no significant difference for baseline NLR levels. Whereas, 1-month hsCRP (median [Q₁–Q₃], 1.3 [0.6–3.1] vs. 0.9 [0.4–2.1], P = 0.001) and NLR levels (median [Q₁–Q₃], 2.6 [2.1–3.2] vs. 2.4 [1.8–3.1], P = 0.011) were significantly higher in patients with MACCE.

The results of the univariate Cox model showed that 1-month hsCRP (hazard ratio [HR] = 1.05, 95% confidence intervals [CI]: 1.03–1.07, P <0.001) and 1-month NLR (HR = 1.13, 95% CI: 1.01–1.27, P = 0.037) predicted MACCE. Yet baseline hsCRP (HR = 1.01, 95% CI: 1.00–1.02, P = 0.225) or NLR (HR = 1.07, 95% CI: 1.00–1.16, P = 0.062) did not show a statistically significant prediction of MACCE as shown in Supplementary Figure 2, http://links.lww.com/CM9/C676. Additionally, 1-month hsCRP ≥1 mg/L (HR = 1.61, 95% CI: 1.12–2.33, P = 0.011) and 1-month hsCRP ≥2 mg/L (HR = 1.49, 95% CI: 1.02–2.18, P = 0.040) were significantly associated with MACCE, respectively. After adjustment for covariates, 1-month hsCRP ≥1 mg/L (HR = 1.60, 95% CI: 1.10–2.32, P = 0.013) rather than 1-month hsCRP ≥2 mg/L, served as an independent predictor of MACCEs in this cohort [Supplementary Table 4, http://links.lww.com/CM9/C676]. Subgroup analysis evaluated the association between 1-month hsCRP ≥1 mg/L and MACCEs in different groups [Supplementary Table 5, http://links.lww.com/CM9/C676].

To validate it, the cutoff value with the smallest P-value in the log-rank test was calculated. The result showed that the optimal value in predicting MACCE was 0.77 mg/L (range: 0.52–1.27 mg/L) [Supplemental Table 6, http://links.lww.com/CM9/C676]. For clinical application, we chose 1 mg/L for further investigation.

To further evaluate whether hsCRP ≥1 mg/L could serve as an appropriate standard for the definition of RIR in Chinese CHD patients, we categorized participants as persistent low RIR, attenuated RIR (first high-, then low-hsCRP), increased RIR (first low-, then high-hsCRP), and persistent high RIR groups according to the baseline and 1-month hsCRP. The results of Cox regression showed an increasing risk for the four groups of patients and a significantly higher risk of MACCE for patients with persistent high RIR (HR = 1.80, 95% CI: 1.11–2.92, P = 0.016) [Supplementary Table 7, http://links.lww.com/CM9/C676]. Since the median level of NLR at 1-month was 2.4 and the 1-month NLR ≥2.4 predicted MACCE (HR = 1.55, 95% CI: 1.06–2.26, P = 0.023) [Supplementary Figure 2, http://links.lww.com/CM9/C676], we used 1-month hsCRP and NLR to categorize the participants into four groups: No residual C-reactive protein (CRP) and neutrophil risk, hsCRP <1 mg/L and NLR <2.4 (no RCNR group); residual neutrophil risk, hsCRP <1 mg/L and NLR ≥2.4 (RNR group); residual CRP risk, hsCRP ≥1 mg/L and NLR <2.4 (RCR group); and residual CRP and neutrophil risk, hsCRP ≥1 mg/L and NLR ≥2.4 (RCNR group). The demographic and clinical features were compared among the four groups in Supplementary Table 8, http://links.lww.com/CM9/C676. The primary endpoint, MACCE, was observed in 2.5% (17/691) of patients in the no RCNR, 5.5% (30/541) in the RNR, 5.4% (28/522) in the RCR, and 7.2% (45/622) in the RCNR groups, P = 0.001 [Supplementary Table 9, http://links.lww.com/CM9/C676]. During the 12-month follow-up, HR for MACCE was significantly higher in RCNR groups [Supplementary Figure 3, http://links.lww.com/CM9/C676]. The unadjusted and adjusted HRs across four distinct RIR groups are shown in Supplementary Table 10, http://links.lww.com/CM9/C676.

We performed a subgroup analysis according to diabetes, dyslipidemia, heart failure, chronic kidney disease, low-density lipoprotein cholesterol (LDL-c) level, and presentation with acute coronary syndromes or chronic coronary syndromes (CCS) in Supplemental Table 11, http://links.lww.com/CM9/C676.

This study clarified the distinct attributes of RIR in patients receiving PCI and presents the following principal points: (1) The 1-month post-PCI hsCRP levels possessed prognostic relevance; (2) a hsCRP threshold of ≥1 mg/L, as opposed to ≥2 mg/L, predicted MACCEs in Chinese patients undergoing PCI; and (3) a new evaluation parameter (RCNR) that includes both hsCRP and NLR adds to traditional predictors of adverse events by assessing inflammatory risk.

This study has limitations. First, the sample size was relatively small, which resulted in a lack of significant differences in some of the secondary endpoints. This multi-center prospective study is planned to conduct a longer follow-up.

Our findings suggested that 1-month inflammatory biomarkers after PCI predict MACCE better than baseline measurements. The RCNR, a more complete RIR assessment combining hsCRP and NLR, reflects more completely the inflammatory status of patients after PCI, and also suggests the necessity of anti-inflammatory treatment targeting both NLRP3 inflammatory pathway and neutrophil pathway. Notably, treatment like Colchicine diversely acts on both NLRP3 inflammatory pathway and neutrophil pathway might be a satisfying choice for clinical practice.

Funding

This work was supported by grants from the Noncommunicable Chronic Diseases—National Science and Technology Major Project (No. 2025ZD0548400), the National Key Research and Development Program (No. 2022YFC2503501), Chinese Society of Cardiology’s Foundation (No. CSCF2023A04), Hubei Technology Innovation Project (No. 2024BCB046), and Key Research and Development Program of Wuhan (No. 2024020702030092) to Xiang Cheng. The National Heart, Lung, and Blood Institute (Nos. 1R01HL134892 and 1R01HL163099-01), the RRM Charitable Fund, and the Simard Fund to Peter Libby.

Acknowledgements

The authors thank all the participants and all the researchers in this work.

Conflicts of interest

Dr. Libby is an unpaid consultant to or involved in clinical trials for Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, Medimmune, Merck, Moderna, Novo Nordisk, Novartis, Pfizer, and Sanofi-Regeneron. Dr. Libby is a member of the scientific advisory board for Amgen, Caristo Diagnostics, Cartesian Therapeutics, CSL Behring, DalCor Pharmaceuticals, Dewpoint Therapeutics, Eulicid Bioimaging, Kancera, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Novartis, PlaqueTec, TenSixteen Bio, Soley Therapeutics, and XBiotech, Inc. Dr. Libby’s laboratory has received research funding in the last 2 years from Novartis, Novo Nordisk, and Genentech. Dr. Libby is on the Board of Directors of XBiotech, Inc. Dr. Libby has a financial interest in Xbiotech, a company developing therapeutic human antibodies, in TenSixteen Bio, a company targeting somatic mosaicism and clonal hematopoiesis of indeterminate potential (CHIP) to discover and develop novel therapeutics to treat age-related diseases, and in Soley Therapeutics, a biotechnology company that is combining artificial intelligence with molecular and cellular response detection for discovering and developing new drugs, currently focusing on cancer therapeutics.

Supplementary Material

cm9-139-139-s001.docx ^{(567.2KB, docx)}