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Aims Renal failure is a major challenge in treating heart failure ( HF) patients. HF medication may deteriorate renal function, but the impact thereof on outcome is unknown. We investigated the effects of HF medication on worsening renal function ( WRF) and the relationship to outcome. Methods and results This post-hoc analysis of TIME-CHF ( NT-proBNP-guided vs. symptom-guided management in chronic HF) included patients with LVEF ≤45% and ≥1 follow-up visit ( n = 462). WRF III was defined as a rise in serum creatinine ≥0.5 mg/ dL (i.e. 44.2 µmol/L) at any time during the first 6 months. Four classes of medication were considered: loop diuretics, beta-blockers, renin-angiotensin system ( RAS)-blockers, and spironolactone. Functional principal component analysis of daily doses was used to comprehend medication over time. All-cause mortality after 18 months was the primary outcome. Interactions between WRF, medication, and outcome were tested. Patients with WRF III received on average higher loop diuretic doses ( P = 0.0002) and more spironolactone ( P = 0.02), whereas beta-blockers ( P = 0.69) did not differ and lower doses of RAS-blockers were given ( P = 0.09). There were significant interactions between WRF III, medicationn and outcome. Thus, WRF III was associated with poor prognosis if high loop diuretic doses were given ( P = 0.001), but not with low doses ( P = 0.29). The opposite was found for spironolactone (poor prognosis in the case of WRF III with no spironolactone, P <0.0001; but not with spironolactone, P = 0.31). Beta-blockers were protective in all patients ( P <0.001), but most in those with WRF III ( P <0.05 for interaction). RAS-blockade was associated with improved outcome ( P = 0.006), irrespective of WRF III. Conclusion Based on this analysis, it may be hypothesized that high doses of loop diuretics might have detrimental effects, particularly in combination with significant WRF, whereas spironolactone and beta-blockers might be protective in patients with WRF. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to evaluate whether biomarkers reflecting pathophysiological pathways are different between heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF) and whether the prognostic value of biomarkers is different in HFpEF vs. HFrEF., Methods and Results: A total of 458 HFrEF (LVEF ≤40%) and 112 HFpEF (LVEF ≥50%) patients aged ≥60 years with NYHA class ≥II from TIME-CHF were included. Endpoints are 18-month overall and HF hospitalization-free survival. After correction for baseline characteristics that differed between the HF types, i.e. age, gender, body mass index, systolic blood pressure, cause of HF, and AF, HFpEF patients exhibited higher soluble interleukin 1 receptor-like 1 [ST2; 37.6 (28.5-54.7) vs. 35.7 (25.6-52.2), P = 0.02], high sensitivity C-reactive protein (hsCRP; 8.54 (3.39-25.86) vs. 6.66 (2.42-15.39), P = 0.01), and cystatin-C [1.94 (1.57-2.37) vs. 1.75 (1.39-2.12), P = 0.01]. In contrast, HFrEF patients exhibited higher NT-proBNP [2142 (1473-4294) vs. 4202 (2239-7411), P < 0.001], high sensitivity troponin T [hsTnT; 27.7 (16.8-48.0) vs. 32.4 (19.2-59.0), P = 0.03], and haemoglobin [124 (110-135) vs. 134 (122-145), P < 0.001]. In addition to these clinical characteristics, NT-proBNP, haemoglobin, cystatin-C, hsTnT, and ST2 improved the area under the curve from 0.86 (0.82-0.89) to 0.91 (0.87-0.94; P < 0.001) for discriminating HFpEF from HFrEF. There were no significant interactions between HFpEF and HFrEF when considering the prognostic value of the investigated biomarkers (P > 0.10 for both endpoints), except for cystatin-C which had less prognostic impact in HFpEF (P < 0.01)., Conclusion: Biomarker levels suggest a different amount of activation of several pathophysiological pathways between HFpEF and HFrEF. No important differences in the prognostic value of biomarkers in HFpEF vs. HFrEF were found except for cystatin-C, and for NT-proBNP in the NT-proBNP-guided study arm only, both of which had less prognostic value in HFpEF., Trial Registration: ISRCTN43596477., (© 2015 The Authors European Journal of Heart Failure © 2015 European Society of Cardiology.)