Association of hyponatremia and elevated copeptin with death and need for transplantation in ambulatory patients with chronic heart failure

Baseline values, serial measurements, or both of multiple biomarkers (copeptin, a peptide co-secreted with arginine vasopressin; hyponatremia; B-type natriuretic peptide [BNP]; and cardiac troponin T [cTnT]) may improve risk stratification in outpatients with chronic heart failure. A cohort of 157 patients with class III or IV heart failure was prospectively evaluated every 3 months over 2 years with regard to biomarker levels and risk for death or cardiac transplantation. Copeptin ≥40 pmol/L (cohort fourth quartile value), hyponatremia (≤135 mEq/L), BNP >3 times the upper range limitation of normal adjusted for age and gender, and cTnT ≥0.01 ng/ml were pre hoc determined cut points. After multivariate time-dependent regression analysis, copeptin (hazard ratio [HR] 2.26, 95% confidence interval [CI] 1.2 to 4.3, p = 0.014) and BNP (HR 1.89, 95% CI 1.0 to 3.5, p = 0.047), but not hyponatremia, were associated with the primary end point of death or cardiac transplantation. In contrast to univariate prediction of mortality and transplantation, hyponatremia (HR 1.74, 95% CI 0.9 to 3.4, p = 0.099) and cTnT ≥0.01 ng/ml (HR 1.89, 95% CI 1.0 to 3.7, p = 0.064) were not predictive in multivariate models. Interaction models of copeptin with hyponatremia, adjusted for BNP and cTnT, improved the predictive capacity of serial measurements (HR 4.20, 95% CI 1.6 to 8.9, p = 0.004). In conclusion, marked elevations of copeptin, particularly in serial measurements, are independent predictors of poor outcomes. The combination of elevated copeptin with hyponatremia, when adjusted for BNP and cTnT, is an even stronger predictor. These markers appear to reflect activation of the arginine vasopressin system present even in the absence of overt clinical changes. A strategy of serial monitoring of copeptin in combination with hyponatremia may be valuable in identifying higher risk patients with heart failure.