Liver tests and outcomes in heart failure with reduced ejection fraction: findings from DAPA-HF

Abstract

Aims: Reflecting both increased venous pressure and reduced cardiac output, abnormal liver tests are common in patients with severe heart failure and are associated with adverse clinical outcomes. We aimed to investigate the prognostic significance of abnormal liver tests in ambulatory patients with heart failure with reduced ejection fraction (HFrEF), explore any treatment interaction between bilirubin and sodium-glucose cotransporter 2 (SGLT2) inhibitors and examine change in liver tests with SGLT2 inhibitor treatment.

Methods and results: We explored these objectives in the Dapagliflozin And Prevention of Adverse outcomes in Heart Failure (DAPA-HF) trial, with focus on bilirubin. We calculated the incidence of cardiovascular death or worsening heart failure by bilirubin tertile. Secondary cardiovascular outcomes were examined, along with the change in liver tests at the end-of-study visit. Baseline bilirubin was available in 4720 patients (99.5%). Participants in the highest bilirubin tertile (T3) have more severe HFrEF (lower left ventricular ejection fraction, higher N-terminal pro-B-type natriuretic peptide [NT-proBNP] and worse New York Heart Association class), had a greater burden of atrial fibrillation but less diabetes. Higher bilirubin (T3 vs. T1) was associated with worse outcomes even after adjustment for other predictive variables, including NT-proBNP and troponin T (adjusted hazard ratio for the primary outcome 1.73 [95% confidence interval 1.37-2.17], p < 0.001; and 1.52 [1.12-2.07], p = 0.01 for cardiovascular death). Baseline bilirubin did not modify the benefits of dapagliflozin. During follow-up, dapagliflozin had no effect on liver tests.

Conclusion: Bilirubin concentration was an independent predictor of worse outcomes but did not modify the benefits of dapagliflozin in HFrEF. Dapagliflozin was not associated with change in liver tests.

Clinical trial registration: ClinicalTrials.gov NCT03036124.

Keywords: Alkaline phosphatase; Bilirubin; Dapagliflozin; Heart failure; Hepatic function; SGLT2 inhibitor.

Figure 1

Unadjusted estimates for the cumulative incidence of the main study endpoints in tertiles of baseline bilirubin. Kaplan–Meier curves for each tertile of baseline bilirubin for the primary composite endpoint (A), hospitalization or urgent visit for heart failure (B), death from cardiovascular causes (C), or death from any cause (D).

Figure 2

Association between total bilirubin as a continuous variable and the risk of the main study endpoints. Restricted cubic splines for the risk of the primary composite endpoint (A), hospitalization or urgent visit for heart failure (B), death from cardiovascular causes (C), or death from any cause (D) with the median bilirubin value (10 μmol/L) as reference.