Changes in Renal Function During Hospitalization and Soon After Discharge in Patients Admitted for Worsening Heart Failure in the Placebo Group of the EVEREST Trial

Study Questions:

What impact does admission for renal function or the development of worsening renal function (WRF) during a heart failure (HF) admission have on post-discharge and long-term patient outcomes?


This was a subanalysis of 2,061 patients enrolled into the placebo arm of EVEREST, a randomized controlled trial of the selective vasopressin-2 receptor antagonist tolvaptan, administered to patients hospitalized with HF. All patients had a left ventricular ejection fraction <40% and signs of volume overload. Worsening renal function was defined as an increase in serum creatinine of ≥0.3 mg/dl during the in-hospital (randomization to discharge or day 7) or post-discharge (discharge or day 7 to 4 weeks post-discharge) period. The primary outcomes of interest were: 1) all-cause mortality, and 2) the composite endpoint of cardiovascular (CV) mortality or HF rehospitalization during the period of follow-up.


Of the 2,021 patients with HF, 8.5% had a high-normal baseline estimated glomerular filtration rate (eGFR) (≥90 ml/min/1.73 m2), 39% low-normal (60-89.9 ml/min/1.73 m2), 44% moderately reduced (30-59.9 ml/min/1.73 m2), and 7.8% severely reduced (<30 ml/min/1.73 m2) baseline eGFR. Older age, lower body weight, lower systolic blood pressure, lower serum sodium, and higher B-type natriuretic peptide (BNP) were associated with poorer baseline renal function. WRF occurred in 13.8% of patients during the hospitalization and 11.9% of patients after discharge. Compared to baseline measurements, patients with WRF had lower blood pressures, body weight, and logBNP after discharge than those without WRF. On multivariate analysis, neither baseline eGFR nor in-hospital WRF were significantly associated with all-cause mortality (all p > 0.05), although trends were noted. Patients with WRF after discharge did experience a significantly higher mortality (hazard ratio [HR], 1.60; 95% confidence interval [CI], 1.21-2.13). Patients with moderate (HR, 1.51; 95% CI, 1.07-2.13) and severe (HR, 1.88; 95% CI, 1.21-2.92) renal dysfunction at baseline had a higher risk of CV death/HF hospitalization than those with high-normal baseline renal function. Likewise, patients who developed WRF during the in-hospital stay and after discharge had a 1.32 (95% CI, 1.07-1.63) and 1.43 (95% CI, 1.13-1.80) higher risk of CV death/HF hospitalization, respectively.


The authors concluded that the use of WRF as an outcome measure in HF clinical trials should be re-evaluated since it is associated with both favorable (lower BNP, weight loss) and adverse clinical indicators in HF.


This is an interesting analysis of the impact of renal function on HF outcomes. The authors argue that use of in-hospital WRF as a clinical trial endpoint may be poorly discriminative of adverse HF long-term outcomes. Because patients with in-hospital WRF have greater weight loss and lower BNPs by discharge, they hypothesize that inpatient WRF reflects arterial underfilling due to fluid fluxes instigated by greater diuresis. In contrast, WRF after discharge had a stronger association with adverse outcome. Many mechanisms can be at play when HF patients develop renal compromise-reduced renal perfusion due to low cardiac index or high central venous pressures, intravascular volume depletion due to rapid diuresis, initiation or titration of angiotensin-converting enzyme inhibitors, and exposure to renal toxins (dyes, antibiotics) during an inpatient stay. Trends were noted when assessing the impact of in-hospital WRF on overall survival, and in-hospital WRF had a significant correlation with adverse CV outcomes. Thus, the potential for an association between WRF and adverse outcome should not be dismissed, regardless of pathophysiologic mechanism. Finally, the criterion of a 0.3 mg/dl bump in serum creatinine as a marker of WRF should be re-examined since the association between creatinine and outcome is not linear.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Follow-Up Studies, Kidney Function Tests, Weight Loss, Heart Failure, Diuresis, Glomerular Filtration Rate, Hospitalization, Benzazepines, Natriuretic Peptide, Brain

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