Mecklai A, Subacius H, Konstam MA, et al.
J Am Coll Cardiol HF 2016;published online ahead of print

Background

Heart failure (HF) patients often experience congestive signs and symptoms, despite treatment with chronic diuretic therapy [1]. Common causes include excess dietary sodium intake, altered gastrointestinal absorption of oral diuretic agents, decreased secretion of loop diuretic agents into the nephron, comorbid renal insufficiency, and glomerular and renal tubular changes that limit the increase in fractional sodium excretion in response to loop diuretic agents [2,3]. In these cases, the diuretic therapy can be adjusted to increase renal sodium and water excretion and achieve euvolemia [4,5].
However, the effects of higher diuretic agent doses on clinical outcomes of HF patients remain uncertain. Data on the one hand show an association between higher dose diuretic agents and greater risk for adverse clinical outcomes [6,7], and on the other hand between higher diuretic agent doses and improved survival in hospitalized HF patients [8]. 
These conflicting data led to the hypothesis that the relationship between diuretic agent dose and clinical outcomes might differ according to the clinical response to diuretic therapy, which can be assessed based on the post-treatment volume status of the patient (presence or absence of clinical signs and symptoms of congestion at hospital discharge).
This study tested this hypothesis, with a post hoc analysis to determine the association between short-term in-hospital diuretic agent use and post-discharge 30-day clinical outcomes in 3037 patients discharged with and without signs of persistent congestion in the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study With Tolvaptan) trial. The EVEREST trial was a randomised, double-blind, placebo-controlled trial comparing the safety and efficacy of tolvaptan, a selective vasopressin-2 receptor antagonist, versus matching placebo, in addition to standard care, in patients hospitalised for worsening of HF [9,10].   

Main results

• Among patients with average diuretic agent dose <160 mg/day, there was no association between diuretic agent dose and the 30-day risk for the combined outcome event: HR for log-linear analysis of diuretic agent dose: 1.09; 95%CI: 0.90-1.33; P=0.37.
• Among patients with average diuretic agent doses ≥160 mg/day, there was a significant association between diuretic agent dose and 30-day risk for the combined outcome event: HR for log-linear analysis of diuretic agent dose: 1.22; 95%CI: 1.05-1.42; P= 0.001.
• In univariate analysis, subjects exposed to high-dose diuretic agents (≥160 mg/day) had a higher risk for the combined outcome compared with subjects exposed to low-dose diuretic agents: 18.9% vs. 10.0%; HR: 2.00; 95%CI: 1.64-2.46; P<0.0001.
• After adjustment for pre-specified covariates of disease severity, the association between diuretic agent dose and outcomes was not significant: HR: 1.11; 95%CI: 0.89-1.38; P=0.35.
• Study treatment allocation (tolvaptan vs. placebo) did not modify the association between diuretic agent dose and outcomes (P-interaction=0.26).
• 69% of patients had little or no congestion at hospital discharge. Congestion status at hospital discharge did not modify the association between diuretic agent exposure and the combined endpoint (P-interaction=0.84).

Conclusion

Based on a post hoc analysis of the EVEREST study in patients who were hospitalised due to worsening of HF, the short-term diuretic agent exposure during hospital treatment was not an independent predictor of 30-day all-cause mortality and HF re-hospitalisation in multivariate analysis. Moreover, the congestion status at discharge did not alter the association between diuretic agent dose and clinical outcomes.
Find this article online at JACC Heart Failure

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