Impact of short-acting loop diuretic doses and cardiac sympathetic nerve abnormalities on outcomes of patients with reduced left ventricular function

Abstract

Recent studies reported that high doses of short-acting loop diuretics are associated with poor outcomes in patients with heart failure (HF). Short-acting loop diuretics have been shown to activate the renin-angiotensin system (RAS) and have no favorable effects on cardiac sympathetic nervous system (SNS) activity. The goal of this study is to investigate the relationship between daily doses of furosemide and the outcomes of patients with left ventricular dysfunction (LVD) from the viewpoint of cardiac SNS abnormalities using iodine-123-labeled metaiodobenzylguanidine ( 123 l-MIBG) myocardial scintigraphy. We enrolled 137 hospitalized patients (62.5 ± 14.2 years old, 103 men) with LVEF < 45% who underwent 123 l-MIBG myocardial scintigraphy. A delayed heart-to-mediastinum ratio (delayed HMR) was assessed using 123 l-MIBG scintigraphy. Cardiac events were defined as cardiac death or re-hospitalization due to the deterioration of HF. Cox proportional hazard analysis was used to identify predictors of cardiac events. Cardiac events occurred in 57 patients in a follow-up period of 33.1 ± 30 months. In a multivariate Cox proportional hazard analysis, delayed HMR and furosemide doses were identified as independent predictors of cardiac events ( P = .0042, P = .033, respectively). Inverse probability of treatment weighting Cox modeling showed that the use of furosemide (≥40 mg /day) was associated with cardiac events with a hazard ratio of 1.96 ( P = .003). In the Kaplan-Mayer analysis, the cardiac event-free survival rate was significantly lower in patients treated with high doses of furosemide (≥60 mg/day vs 40–60 mg/day vs <40 mg/day, the Log-rank test P < .0001). In a receiver-operating characteristic (ROC) analysis, the cut-off value for cardiac events was 40 mg/day of furosemide. The cardiac event-free rate was significantly lower in patients with delayed HMR <1.8 (median value) and receiving furosemide ≥40 mg/day than in other patients (the Log-rank test P < .0001). Significant differences in cardiac event rates according to furosemide doses among patients with delayed HMR <1.8 were observed among patients without β-blocker therapy ( P = .001), but not among those with β-blocker therapy ( P = .127). The present results indicate that a relationship exists between higher doses of furosemide and poor outcomes. The prognosis of HF patients with severe cardiac SNS abnormalities receiving high-dose short-acting loop diuretics is poor.

Toxicity, Side Effects, and Furosemide Interactions in Therapy of Heart Failure Patients (Systematic Review)

“…Research conducted by Tyler P. Rasmussen et al and Hisamitsu Onitsuka et al also demonstrated that renal function worsened in furosemide-treated patients. 16,19 In the study of Tyler P. Rasmussen et al it was found that furosemide cause AKI, and in this study female patients suffered from AKI more than men (p = 0.0081). 19 Based on the results of the study of Hisamitsu Onitsuka et al, patients treated with furosemide 40mg per day, had low serum sodium (P<0.0001) and eGFR (P=0.011).…”

“…Based on the results of data synthesis, it was found that the side effects of furosemide therapy in the treatment of heart failure patients were in the form of electrolyte disturbances, such as 11,12,13,14,15,16 : hyponatremia 11,14 ; hypokalemia 12,14,17 ; dan hypomagnesemia 12 , heart rhythm disturbances 12,15 , worsening of kidney function and worsening of AKI 11,12,13,18,16,19 , which were characterized by an increase in BUN; creatinine; and decreased GFR; hypotension 20 , an increase in plasma renin 11 , as well as an increased risk of bone fragility that can lead to fracture. 21,22 The incidence of hypochloremia, hypocalcemia, and dehydration in the study hypothesis, was not identified by the reviewed journals.…”

“…19 Based on the results of the study of Hisamitsu Onitsuka et al, patients treated with furosemide 40mg per day, had low serum sodium (P<0.0001) and eGFR (P=0.011). 16 Study about side effects of furosemide and bone fragility and fracture 21,22 has also been performed (Figure 4), both in children and the elderly. Research by Ji Haeng Heo et al Regarding the effect of furosemide on children with heart disease, it was shown that there were 75 patients receiving furosemide treatment with fractures out of a total sample of 978 patients on furosemide therapy, where the incidence was higher than 2934 patients who did not receive furosemide therapy with a significant relationship (P < .001).…”

Predictors of bleeding events in acute decompensated heart failure patients with antithrombotic therapy: AURORA study

“…Higher doses of loop diuretics have been shown to activate the renin‐angiotensin system. 15 , 16 Further, angiotensin II signalling augments the expression of Ang‐2, a proangiogenic signal, which activates angiogenesis in the presence of vascular endothelial growth factor. 17 Finally, an arteriovenous malformation caused by angiogenesis can cause GI bleeding.…”

Modulation of Urate Transport by Drugs

“…It has also been suggested that activation of the RAS and hyperosmolarity may lead to overexpression of URAT1 [ 141 ]. A similar scenario can be envisioned for loop diuretics, since they also activate the RAS [ 142 , 143 ]. Although the overexpression of URAT1 upon treatment with diuretics has not been documented in public databases, upregulation of the sodium–hydrogen exchanger NHE3 upon increased angiotensin II has been reported [ 144 ].…”