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

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.

Methods and findings: We conducted a retrospective cohort study based on the National Institute for Health Research Health Informatics Collaborative data of 257,948 patients with suspected ACS who had a troponin measured at 5 cardiac centres in the United Kingdom between 2010 and 2017. Patients were divided into 4 hsCRP groups (<2, 2 to 4.9, 5 to 9.9, and 10 to 15 mg/L). The main outcome measure was mortality within 3 years of index presentation. The association between hsCRP levels and all-cause mortality was assessed using multivariable Cox regression analysis adjusted for age, sex, haemoglobin, white cell count (WCC), platelet count, creatinine, and troponin. Following the exclusion criteria, there were 102,337 patients included in the analysis (hsCRP <2 mg/L (n = 38,390), 2 to 4.9 mg/L (n = 27,397), 5 to 9.9 mg/L (n = 26,957), and 10 to 15 mg/L (n = 9,593)). On multivariable Cox regression analysis, there was a positive and graded relationship between hsCRP level and mortality at baseline, which remained at 3 years (hazard ratio (HR) (95% CI) of 1.32 (1.18 to 1.48) for those with hsCRP 2.0 to 4.9 mg/L and 1.40 (1.26 to 1.57) and 2.00 (1.75 to 2.28) for those with hsCRP 5 to 9.9 mg/L and 10 to 15 mg/L, respectively. This relationship was independent of troponin in all suspected ACS patients and was further verified in those who were confirmed to have an ACS diagnosis by clinical coding. The main limitation of our study is that we did not have data on underlying cause of death; however, the exclusion of those with abnormal WCC or hsCRP levels >15 mg/L makes it unlikely that sepsis was a major contributor.

Conclusions: These multicentre, real-world data from a large cohort of patients with suspected ACS suggest that mildly elevated hsCRP (up to 15 mg/L) may be a clinically meaningful prognostic marker beyond troponin and point to its potential utility in selecting patients for novel treatments targeting inflammation.

Trial registration: ClinicalTrials.gov - NCT03507309.

Conflict of interest statement

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.

Figures

Fig 1. Flow of patients through the study.

*Suspected ACS characterised by the request of a troponin. ACS, acute coronary syndrome; hsCRP, high-sensitivity C-reactive protein; ICD, International Classification of Diseases; WCC, white cell count.

Fig 2

Unadjusted Kaplan–Meier mortality curves by (A) hsCRP level, (B) hsCRP level and troponin positivity, and (C) hsCRP level in a subgroup of patients with ACS. ACS, acute coronary syndrome; hsCRP, high-sensitivity C-reactive protein; Tn +, troponin positive, Tn −, troponin negative.

Fig 3. Multivariable Cox regression analysis with time-varying coefficients.

HRs are adjusted for age, sex, haemoglobin, WCC, platelet count, creatinine, and troponin level. The adjusted HRs were calculated during the following time periods:

Fig 4

Relationship between negative predictive value of hsCRP and troponin testing with (A) 30-day and (B) 3-year mortality. hsCRP, high-sensitivity C-reactive protein; hsCRP −, negative high-sensitivity C-reactive protein; Tn −, negative troponin.