Head-to-head comparison of the incremental value of the three established risk markers hs-troponin I, hs-C-reactive protein and NT-proBNP in secondary prevention of coronary artery disease
Authors: Nikorowitsch J , Ojeda F , Lackner K.J , Schnabel R.B , Blankenberg S , Zeller T , Karakas M 
Published: November 2020

Abstract

Background
Risk stratification among patients with coronary artery disease (CAD) and acute coronary syndrome (ACS) is of considerable interest due to the potential to guide secondary preventive therapies. Cardiac troponins as well as the inflammatory biomarker C-reactive protein (CRP) and natriuretic peptides have now emerged as useful blood-based biomarkers for risk stratification concerning incident cardiac events. Nevertheless, it has not been tested, whether one of these biomarkers yields predictive value beyond the others. Thus, we evaluated the head-to-head potential of high-sensitivity troponin I (hsTnI), high-sensitivity (hs) CRP and NT-proBNP as prognostic biomarkers for adverse outcome in patients with manifest CAD.

Methods
Plasma levels of hsTnI, hsCRP and NT-proBNP were measured in a cohort of 2,193 patients with documented CAD –including 837 patients with ACS and 1,356 patients with stable angina pectoris (SAP). Cardiovascular death and/or non-fatal acute myocardial infarction (MI) were defined as the main outcome measures. The association of circulating biomarker levels, used after log-transformation, with cardiovascular mortality and non-fatal MI during follow-up was assessed by Cox proportional hazards analyses adjusted according to three different models including cardiovascular risk factors and either the biomarkers hsCRP, NT-proBNP or hsTnI. Additionally, the net reclassification index (NRI) was calculated using the category five-year event probabilities for two models.

Results
During a median follow-up of 3.8 years, a total of 231 events were registered (10.5%). All three biomarkers reliably predicted cardiovascular death and/or MI, as evidenced by survival curves stratified for tertiles of circulating levels.
In Cox regression analyses with adjustments for sex, age, and conventional cardiovascular risk factors, the hazard ratio (HR) per standard deviation (SD) for the prediction of cardiovascular (CV) death and/or non-fatal MI during follow-up was 1.39 [95% CI: 1.24–1.57, p&lt;0.001] for hsTnI, 1.41 [95% CI: 1.24–1.60, p&lt;0.001] for hsCRP, and 1.64 [95% CI: 1.39–1.92, p&lt;0.001] for NT-proBNP. Nevertheless, upon further adjustment for the other two biomarkers, the significance of the association for hsTnI got lost, association for hsCRP attenuated, and only NT-proBNP kept its predictive value and was still strongly associated with the combined endpoint (1.47 [95% CI: 1.19–1.82, p&lt;0.001]), but also with CV death alone (2.42 [95% CI: 1.86–3.15, p&lt;0.001]). Moreover, only NT-proBNP significantly improved C-statistics and net reclassification index (NRI) for the prediction of cardiovascular death.

Conclusions
NT-proBNP reliably predicted cardiovascular death and myocardial infarction in patients with manifest CAD and provides incremental value beyond hsCRP and hsTnI.

Funding Acknowledgement
Type of funding source: Public grant(s) – National budget only. Main funding source(s): “Stiftung Rheinland-Pfalz für Innovation”, Ministry for Science and Education