Impact of worsening renal function related to medication in heart failure

Abstract

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.

Heart Failure Increases the Risk of Adverse Renal Outcomes in Patients With Normal Kidney Function

“…29, 30 Further contributing to potential renal damage are recurrent episodes of acute kidney injury 31 and potential direct nephrotoxicity of medications received during the course of HF. 32 Much less is known about the effects of HF on long-term kidney function in patients with normal eGFR, but the above mentioned pathophysiologic changes postulated to cause poorer renal outcomes in those with preexisting CKD could also be instrumental in engendering new onset kidney damage and incident CKD. It is thought that the elevated renal G-Protein Coupled Receptor – G protein βγ (GPCR-Gβγ) signaling and endothelin system expression seen in heart failure may cause renal tissue damage, fibrosis and inflammation, which can manifest as acute renal failure and cardiorenal syndrome 2.…”

Spironolactone Treatment and Effect on Survival in Chronic Heart Failure Patients with Reduced Renal Function: A Propensity-Matched Study

“…Likewise, Vardeny et al [21] demonstrated a favorable effect of spironolactone on survival in HF patients with reduced eGFR despite worsening renal function. On the other hand, worsening renal function following the use of high-dose loop diuretics was associated with increased mortality [24]. Given the beneficial effect of spironolactone on survival in HF patients despite decreased eGFR, one could hypothesize that some reduction in renal function with spironolactone should be accepted and should not lead to discontinuation of treatment.…”

Evaluation of kidney function throughout the heart failure trajectory – a position statement from the Heart Failure Association of the European Society of Cardiology

“…Particularly in the setting of heart failure with reduced ejection fraction (HFrEF), the treatment benefits of the neurohormonal blockers strongly outweigh the accompanying WRF, which itself is more an intra‐renal haemodynamic reflection of neurohormonal blockade and not necessarily a signal of direct renal injury (pseudo‐WRF) . Yet, misinterpretation of these changes still results in inappropriate discontinuation of decongestive or neurohormonal blocker therapy in clinical practice . Paradoxically, patients with baseline CKD (who are at higher risk for WRF) might actually benefit the most in absolute terms of treatment with neurohormonal blockers, as the presence of CKD is associated with a higher event rate …”

“…Despite the direct epidemiologic link between changes in renal function and outcome, a thorough knowledge on the pathophysiologic contributors of renal function changes during AHF is essential. Not all changes in eGFR are equal, and appropriate interpretation is essential to improve heart failure care …”

“…While some of these changes are merely a reflection of an appropriate renal response, others might indicate renal injury . The misinterpretation of these alterations might result in inappropriate discontinuation of disease‐modifying heart failure therapies, premature discontinuation of decongestive therapies, or ongoing renal injury . This position paper provides an overview about the evaluation and interpretation of kidney function throughout the heart failure trajectory.…”