Liver tests, cardiovascular outcomes and effects of empagliflozin in patients with heart failure and preserved ejection fraction: The EMPEROR-Preserved trial.

AIM: The prognostic implication of elevated liver tests in heart failure with preserved ejection fraction (HFpEF) is uncertain. This analysis investigates the association of liver markers with hospitalization for heart failure (HHF) and cardiovascular death (CVD), and the treatment effect of empagliflozin across the range of liver marker levels. METHODS AND RESULTS: The double-blind, placebo-controlled EMPEROR-Preserved (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure with Preserved Ejection Fraction) enrolled 5988 patients with HFpEF (ejection fraction >40%). Patients in New York Heart Association class II-IV and elevated N-terminal pro-B-type natriuretic peptide were randomized to receive empagliflozin 10 mg daily or placebo in addition to usual therapy. Patients with significant liver disease were excluded. The primary endpoint was time to first adjudicated HHF or CVD. We explored the association of liver function abnormalities with heart failure outcomes in patients on placebo, the effects of empagliflozin on liver tests and the treatment effects of empagliflozin on heart failure outcomes across categories of liver laboratory values. High alkaline phosphatase (p trend < 0.0001), low albumin (p trend < 0.0001) and high bilirubin (p = 0.02) were associated with poorer outcomes for HHF or CVD, while high aspartate aminotransferase was not, and high alanine aminotransferase was associated with better outcomes. Empagliflozin had no significant effects on liver tests compared to placebo except for albumin which was significantly increased. The treatment effect of empagliflozin on outcomes was not modified by liver tests. CONCLUSION: Abnormalities of liver function tests are associated differently with heart failure outcomes. Salutary effects of empagliflozin on liver tests were not observed although albumin increased. The treatment benefits of empagliflozin were not affected by baseline values of liver parameters.

Heart failure outcomes according to heart rate and effects of empagliflozin in patients of the EMPEROR-Preserved trial.

AIMS: Empagliflozin reduces cardiovascular death (CVD) or heart failure hospitalization (HHF) in patients with heart failure and preserved ejection fraction (HFpEF). Treatment effects and safety in relation to resting heart rate (RHR) have not been studied. METHODS AND RESULTS: The interplay of RHR and empagliflozin effects in EMPEROR-Preserved was evaluated. We grouped patients (n = 5988) according to their baseline RHR (<70 bpm [n = 2650], 70-75 bpm [n = 967], >75 bpm [n = 1736]) and explored the influence of RHR on CVD or HHF (primary outcome) and its components in sinus rhythm or atrial fibrillation/flutter (AF) and adverse events. We studied the efficacy of empagliflozin across the RHR spectrum. Compared to placebo, empagliflozin did not change heart rate over time. The primary outcome (p for trend = 0.0004) and its components CVD (p trend = 0.0002), first HHF (p for trend = 0.0099) and all-cause death (p <  0.0001) increased with RHR only in sinus rhythm but not AF. The risk increase with RHR was similar in patients with heart failure and mildly reduced ejection fraction (left ventricular ejection fraction [LVEF] 40-49%) and HFpEF (LVEF ≥50%). Baseline RHR had no influence on the effect of empagliflozin on the primary outcomes (p for trend = 0.20), first HHF (p for trend = 0.49). There were no clinically relevant differences in adverse events between empagliflozin and placebo across the RHR groups. CONCLUSION: Resting heart rate associates with outcomes only in sinus rhythm but not in AF. Empagliflozin reduced outcomes over the entire RHR spectrum without increase of adverse events.

Empagliflozin and serum potassium in heart failure: an analysis from EMPEROR-Pooled.

AIMS: Hyperkalaemia frequently leads to interruption and discontinuation of neurohormonal antagonists, which may worsen heart failure prognosis. Some studies suggested that sodium-glucose cotransporter 2 inhibitors reduce hyperkalaemia, an effect that may have important clinical implications. This analysis evaluates the effect of empagliflozin on the occurrence of hyper- and hypokalaemia in HF. METHODS AND RESULTS: EMPEROR-Pooled (i.e. EMPEROR-Reduced and EMPEROR-Preserved combined) included 9583 patients with available serum potassium levels at baseline (98.6% of the total EMPEROR-Pooled population, n = 9718). Hyperkalaemia was identified by investigators' reports of adverse events, and by a laboratory serum potassium value above 5.5 mmol/L and 6.0 mmol/L. The main outcome was a composite of investigator-reported hyperkalaemia or initiation of potassium binders. Patients with high potassium at baseline were more frequently diagnosed with diabetes and ischaemic HF aetiology and had lower left ventricular ejection fraction and estimated glomerular filtration rate but were more frequently treated with sacubitril/valsartan or mineralocorticoid receptor antagonists. Empagliflozin (compared with placebo) reduced the composite of investigator-reported hyperkalaemia or initiation of potassium binders [6.5% vs. 7.7%, hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.71-0.95, P = 0.01]. Empagliflozin reduced hyperkalaemia rates regardless of the definition used (serum potassium >5.5 mmol/l: 8.6% vs. 9.9%, HR 0.85, 95% CI 0.74-0.97, P = 0.017; serum potassium >6.0 mmol/l: 1.9% vs. 2.9%, HR 0.62, 95% CI 0.48-0.81, P < 0.001). The incidence of hypokalaemia (investigator-reported or serum potassium <3.0 mmol/l) was not significantly increased with empagliflozin. CONCLUSIONS: Empagliflozin reduced the incidence of hyperkalaemia without significant increase in hypokalaemia.

Effects of empagliflozin on markers of liver steatosis and fibrosis and their relationship to cardiorenal outcomes.

AIMS: Empagliflozin treatment reduced liver fat in small type 2 diabetes cohorts. This post-hoc study evaluated effects of empagliflozin on risk for non-alcoholic fatty liver disease-related steatosis and fibrosis, as well as the relationship between risk categories and cardiorenal outcomes in the randomized, placebo-controlled EMPA-REG OUTCOME trial. MATERIALS AND METHODS: EMPA-REG OUTCOME treated 7020 people with type 2 diabetes and cardiovascular disease with 10/25 mg/day empagliflozin or placebo. For this analysis, the Dallas steatosis index, hepatic steatosis index, non-alcoholic fatty liver disease fibrosis score and Fibrosis-4 score were calculated to assess steatosis and fibrosis risk. Changes from baseline in scores were examined by mixed model repeated measures and their associations with cardiorenal outcomes and mortality by Cox regression. RESULTS: At baseline, 73% and 84% of participants had high steatosis risk by Dallas steatosis index and hepatic steatosis index, whereas 23% and 4% had a high risk of advanced fibrosis by non-alcoholic fatty liver disease fibrosis score and Fibrosis-4 score. Percentages of people at high steatosis risk slightly decreased with empagliflozin only, whereas empagliflozin did not improve percentages of individuals at high fibrosis risk over time compared with placebo. The high risk of advanced fibrosis at baseline related to higher risk for cardiovascular events. Effects of empagliflozin on cardiorenal and all-cause mortality outcomes were consistent across all risk groups. CONCLUSIONS: Empagliflozin may reduce steatosis but not fibrosis risk in individuals with type 2 diabetes and cardiovascular disease. The improvements in cardiorenal outcomes and mortality associated with empagliflozin therapy appear to be independent of steatosis and fibrosis risk.

Empagliflozin Improves Cardiovascular and Renal Outcomes in Heart Failure Irrespective of Systolic Blood Pressure.

BACKGROUND: Empagliflozin reduces the risk of cardiovascular death or heart failure (HF) hospitalization in patients with reduced ejection fraction. Its interplay with systolic blood pressure (SBP) is not known. OBJECTIVES: The goal of this study was to evaluate the interplay of SBP and the effects of empagliflozin in EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction). METHODS: Study patients (N = 3,730) were randomly assigned to groups according to SBP at baseline (<110 mm Hg, n = 928; 110-130 mm Hg, n = 1,755; >130 mm Hg, n = 1,047). This study explored the influence of SBP on the effects of empagliflozin on cardiovascular death or HF hospitalization (primary outcome), as well as on total HF hospitalizations, rate of decline in estimated glomerular filtration rate, renal outcomes, and empagliflozin's effects and significance on SBP. RESULTS: Over a median of 16 months considering only patients receiving placebo, baseline SBP and the risk of cardiovascular death or hospitalization for HF (P trend = 0.0015) were inversely related. Corrected for placebo, a slight early increase was observed in SBP at <110 mm Hg, no change at 110-130 mm Hg, and a slight reduction at >130 mm Hg. These between-group differences were of borderline significance (P for interaction trend = 0.05-0.10) after 4 and 12 weeks but were not significant later. SBP at baseline did not influence the effect of empagliflozin to reduce the risk of HF events or renal endpoints. When treated with empagliflozin, patients with SBP <110 mm Hg did not have an increased rate of symptomatic hypotension. CONCLUSIONS: Empagliflozin was effective and safe, with no meaningful interaction between SBP and the effects of empagliflozin in the EMPEROR-Reduced trial. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).

Dabigatran versus Warfarin for Acute Venous Thromboembolism in Elderly or Impaired Renal Function Patients: Pooled Analysis of RE-COVER and RE-COVER II.

Management of acute venous thromboembolism (VTE) with anticoagulants in elderly patients and those with chronic kidney disease poses special challenges. The RE-COVER and RE-COVER II trials showed that dabigatran 150 mg twice daily was as effective as warfarin over 6 months in preventing recurrent VTE, with a lower bleeding risk. We now assess the effects of old age and renal impairment (RI) on pooled trial outcomes in 5,107 patients: 4,504 aged <75 years and 603 aged ≥75 years. The primary efficacy outcome was symptomatic VTE/VTE-related death. Safety outcomes were centrally adjudicated major bleeding events (MBEs), MBEs or clinically relevant non-major bleeding events (MBEs/CRBEs) and any bleeds. Baseline renal function was categorized as normal, mild RI or moderate RI. A total of 3,698 had normal renal function and 1,100 and 237 had mild and moderate RI, respectively (23 patients with severe RI and 49 with missing creatinine clearance data were not included). For dabigatran, VTE/VTE-related death decreased from 3.1% (normal renal function) to 1.9% for mild RI and to 0.0% for moderate RI. For warfarin, the event rates were 2.6, 1.6 and 4.1%, respectively. Overall, major bleeding increased with increasing RI (p = 0.0037) and with age (p = 0.4350), with no apparent difference between the dabigatran and warfarin patients. Dabigatran shows better efficacy than warfarin in RI and in the elderly patients, probably because of an increase in the concentration of dabigatran. However, bleeding risk increases with both dabigatran and warfarin in the presence of RI.