Estimated pulse wave velocity improves risk stratification for all-cause mortality in patients with COVID-19

Abstract

Accurate risk stratification in COVID-19 patients consists a major clinical need to guide therapeutic strategies. We sought to evaluate the prognostic role of estimated pulse wave velocity (ePWV), a marker of arterial stiffness which reflects overall arterial integrity and aging, in risk stratification of hospitalized patients with COVID-19. This retrospective, longitudinal cohort study, analyzed a total population of 1671 subjects consisting of 737 hospitalized COVID-19 patients consecutively recruited from two tertiary centers (Newcastle cohort: n = 471 and Pisa cohort: n = 266) and a non-COVID control cohort (n = 934). Arterial stiffness was calculated using validated formulae for ePWV. ePWV progressively increased across the control group, COVID-19 survivors and deceased patients (adjusted mean increase per group 1.89 m/s, P < 0.001). Using a machine learning approach, ePWV provided incremental prognostic value and improved reclassification for mortality over the core model including age, sex and comorbidities [AUC (core model + ePWV vs. core model) = 0.864 vs. 0.755]. ePWV provided similar prognostic value when pulse pressure or hs-Troponin were added to the core model or over its components including age and mean blood pressure (p < 0.05 for all). The optimal prognostic ePWV value was 13.0 m/s. ePWV conferred additive discrimination (AUC: 0.817 versus 0.779, P < 0.001) and reclassification value (NRI = 0.381, P < 0.001) over the 4C Mortality score, a validated score for predicting mortality in COVID-19 and the Charlson comorbidity index. We suggest that calculation of ePWV, a readily applicable estimation of arterial stiffness, may serve as an additional clinical tool to refine risk stratification of hospitalized patients with COVID-19 beyond established risk factors and scores.

Figure 1

(A) Histogram and Kernel Density Estimates of the ePWV in patients with COVID-19 and controls after propensity matching for age, sex, smoking, hypertension, CKD, diabetes mellitus, smoking, history of CVD and hyperlipidemia. (B) Difference in ePWV among control subjects without COVID-19, COVID-19 patients who were discharged from hospital and 28-day deceased patients with COVID-19. Estimates of ePWV are adjusted for sex, hypertension, CKD, DM, smoking, history of CVD and hyperlipidemia. Circles represent mean value of ePWV per group and bars the 95% confidence intervals. Asterisks indicate significant (P < 0.001) difference from the reference category (i.e., controls from the Athens Vascular Registry). CKD: chronic kidney disease, DM: diabetes mellitus, CVD: cardiovascular disease, including history of coronary artery disease and/or heart failure, PWV: pulse wave velocity.

Figure 2

Receiver Operating Characteristic (ROC) curves and corresponding areas under the ROC curve for ePWV on top of the baseline model with respect to 28-day death. Areas under the curve were derived from an appropriate test set (20% of the total sample) after 1,000 bootstrap replicates and training of the boost gradient algorithm on the remaining 80% of the population (training set). Baseline model included age, sex, history of hypertension, DM, CKD, CVD, lung disease and active cancer. To enhance visual clarity a limited number of bootstrapped ROC curves are provided in pale colors as opposed to intense blue and red average estimates. AUC: area under the curve, CKD: chronic kidney disease, DM: diabetes mellitus, CVD: cardiovascular disease including history of coronary artery disease and/or heart failure, ePWV: estimated pulse wave velocity.