Mortality risk prediction of high-sensitivity C-reactive protein in suspected acute coronary syndrome: A cohort study

Amit Kaura, Adam Hartley, Vasileios Panoulas, Ben Glampson, Anoop S. V. Shah, Jim Davies, Abdulrahim Mulla, Kerrie Woods, Joe Omigie, Anoop D. Shah, Mark R. Thursz, Paul Elliott, Harry Hemmingway, Ramzi Khamis

Abstract
Background

There is limited evidence on the use of high-sensitivity C-reactive protein (hsCRP) as a biomarker for selecting patients for advanced cardiovascular (CV) therapies in the modern era. The prognostic value of mildly elevated hsCRP beyond troponin in a large real-world cohort of unselected patients presenting with suspected acute coronary syndrome (ACS) is unknown. We evaluated whether a mildly elevated hsCRP (up to 15 mg/L) was associated with mortality risk, beyond troponin level, in patients with suspected ACS.

Introduction
Inflammation has been extensively studied and postulated as mechanistic in atherothrombosis [1]. Much debate has been on whether the immune system plays a protective or pathogenic role in atherogenesis and subsequent cardiovascular (CV) events. In addition to exploiting elements of the immune system as targets for novel therapies, some have been investigated for their role as potential biomarkers, aiming to permit better cardiovascular disease (CVD) risk stratification [2,3]. C-reactive protein (CRP) is the most widely evaluated of these biomarkers, given its relatively long circulating half-life and commonplace use in clinical practice.

Methods
We conducted a retrospective cohort study based on the National Institute for Health Research Health Informatics Collaborative data [20–22] of 257,948 patients with suspected ACS who had a troponin measured at 5 cardiac centres in the UK between 2010 and 2017 (Imperial College Healthcare, University College Hospital, Oxford University Hospital, Kings College Hospital and Guys and St Thomas’‘ Hospital). Ethical approval for the dataset was obtained. The data acquisition and statistical analysis plan are available as S1 Data Aquisition and S1 Analysis Plan, respectively.

Results
Baseline Population Characteristics

A total of 257,948 patients presented with suspected ACS to 5 acute cardiac centres and were included in the NIHR Health Informatics Collaborative dataset. Moreover, 71,262 patients did not undergo hsCRP testing during their hospital care episode and were therefore excluded from further analysis. A further 67,206 patients were excluded based on hsCRP level >15 mg/L. The remaining 129,480 patients were divided into 4 groups by hsCRP levels, reflecting low grade inflammation. After further exclusion of patients with abnormal WCCs (<4 or >11 × 109/L) or those who did not have a WCC blood test, 102,337 patients were included in the final analysis.

Discussion
In this large retrospective cohort study, we demonstrate a positive and graded relationship between mildly elevated hsCRP levels (up to 15 mg/L) and all-cause mortality over 3 years. The mortality risk associated with increased hsCRP was independent of age, sex, haemoglobin, WCC, platelet count, creatinine, and troponin positivity, suggesting its value as a clinically useful biomarker in the context of suspected ACS.

Conclusion
The data from this large real-world population in a modern healthcare system emphasise the importance of hsCRP in this setting and warrant attention and consideration from clinical guideline committees to include hsCRP in risk stratification of patients presenting with suspected ACS.

Citation: Kaura A, Hartley A, Panoulas V, Glampson B, Shah ASV, Davies J, et al. (2022) Mortality risk prediction of high-sensitivity C-reactive protein in suspected acute coronary syndrome: A cohort study. PLoS Med 19(2): e1003911. https://doi.org/10.1371/journal.pmed.1003911

Academic Editor: Sanjay Basu, Harvard Medical School, UNITED STATES

Received: September 15, 2021; Accepted: January 11, 2022; Published: February 22, 2022

Copyright: © 2022 Kaura et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: We are unable to extract or publish patient level data due to data protection and governance restrictions under the NIHR Health Informatics Collaborative data sharing agreement. Any request to access data can be made via imperial.cvhic@nhs.net referring to the title of this paper.

Funding: AK is funded by a British Heart Foundation clinical research training fellowship (FS/20/18/34972). AH is funded by a Wellcome Trust clinical research fellowship (WIII_P67144). ASVS is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/19/17/34172). ADS is funded by a THIS Institute postdoctoral fellowship. JACS is funded by National Institute for Health Research Senior Investigator award (NF-SI-0611-10168). AMS is funded by a British Heart Foundation Professorship (CH/1999001/11735). RSP is funded by a British Heart Foundation intermediate fellowship (FS/14/76/30933). JM is supported by the British Heart Foundation Imperial Centre for Research Excellence (RE/18/4/34215). RK is funded by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/17/16/32560). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: WK is a member of the Executive Steering Committee of CANTOS and has received modest amounts for consulting from Novartis). All remaining authors declare no competing interests.

Abbreviations: ACS, acute coronary syndrome; AUROC, area under the receiver operating characteristic curve; CAMI-1, CRP apheresis in Acute Myocardial Infarction; CANTOS, Canakinumab Anti-inflammatory Thrombosis Outcome Study; CIRT, Cardiovascular Inflammation Reduction Trial; COLCOT, Colchicine Cardiovascular Outcomes Trial; CRP, C-reactive protein; CV, cardiovascular; CVD, cardiovascular disease; HR, hazard ratio; hsCRP, high-sensitivity C-reactive protein; ICD, International Classification of Diseases; IDI, integrated discrimination improvement; IL, interleukin; IQR, interquartile range; LoDoCo2, Low Dose Colchicine; MACE, major adverse cardiovascular event; NHS, National Health Service; NRI, net reclassification index; NSTEMI, non-ST segment elevation myocardial infarction; PCI, percutaneous coronary intervention; SREC, Research Ethics Committee; STEMI, ST segment elevation myocardial infarction; STROBE, Strengthening the Reporting of Observational Studies in Epidemiology; ULN, upper limit of normal; WCC, white cell count.

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