Serial assessment of high-sensitivity cardiac troponin and the effect of dapagliflozin in patients with heart failure with reduced ejection fraction: an analysis of the DAPA-HF trial

Background: Circulating high-sensitivity cardiac troponin T (hsTnT) predominantly reflects myocardial injury, and higher levels are associated with a higher risk of worsening heart failure (HF) and death in patients with HF with reduced ejection fraction (HFrEF). Less is known about the prognostic significance of changes in hsTnT over time, the effects of dapagliflozin on clinical outcomes in relation to baseline hsTnT levels, and the effect of dapagliflozin on hsTnT levels. Methods: DAPA-HF was a randomized, double-blind, placebo-controlled trial of dapagliflozin (10 mg daily) in patients with NYHA class II-IV symptoms and left ventricular ejection fraction ≤40% (median follow-up = 18.2 months). hsTnT (Roche Diagnostics) was measured at baseline in 3,112 patients and at 1 year in 2,506 patients. The primary endpoint was adjudicated worsening HF or cardiovascular death. Clinical endpoints were analyzed according to baseline hsTnT and change in hsTnT from baseline to 1 year. Comparative treatment effects on clinical endpoints with dapagliflozin vs. placebo were assessed by baseline hsTnT. The effect of dapagliflozin on hsTnT was explored. Results: Median baseline hsTnT concentration was 20.0 (25th-75th percentile, 13.7 to 30.2) ng/L. Over 1 year, 67.9% of patients had a ≥10% relative increase or decrease in hsTnT concentrations, and 43.5% had a ≥20% relative change. A stepwise gradient of higher risk for the primary endpoint was observed across increasing quartiles of baseline hsTnT concentration (adjusted hazard ratio [aHR] Q4 vs. Q1, 5.10; 95% CI, 3.67-7.08). Relative and absolute increases in hsTnT over 1 year were associated with higher subsequent risk of the primary endpoint. The relative reduction in the primary endpoint with dapagliflozin was consistent across quartiles of baseline hsTnT (p-interaction = 0.55), but patients in the top quartile tended to have the greatest absolute risk reduction (absolute risk difference, 7.5%; 95% CI, 1.0% - 14.0%). Dapagliflozin tended to attenuate the increase in hsTnT over time compared to placebo (relative least squares mean reduction, -3% [-6% to 0%]; p=0.076). Conclusions: Higher baseline hsTnT and greater increase in hsTnT over 1 year are associated with worse clinical outcomes. Dapagliflozin consistently reduced the risk of the primary endpoint, irrespective of baseline hsTnT levels. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique Identifier: NCT03036124.