Diuretics and Ultrafiltration in Acute Decompensated HF
Diuretics and Ultrafiltration in Acute Decompensated HF
Loop diuretics inhibit the Na/2Cl/K cotransporter in the thick ascending loop of Henle, resulting in decreased urine sodium and chloride reabsorption with natriuresis and diuresis. The 3 commonly used loop diuretics all work via these same mechanisms, although pharmacologic differences may have clinical importance (Table 1). The greater bioavailability of bumetanide and torsemide may offer more predictable diuresis, and the increased half-life of torsemide in the setting of renal, hepatic, and/or cardiac dysfunction may be advantageous for extended diuresis. The data comparing the loop diuretics are limited to small-scale, chronic HF studies with short follow-up and underuse of contemporary therapy as recently reviewed. These hypothesis-generating studies suggested potential benefits with torsemide compared with furosemide on neurohormonal activation, left ventricular remodeling, and fibrotic changes with resultant reduced hospitalizations, improved symptoms, and potentially reduced mortality. These findings would need to be confirmed in contemporary, adequately powered clinical trials.
Given the need for rapid onset of action, loop diuretics are typically given intravenously for hospitalized ADHF patients. Intravenous (IV) administration of an effective dose furosemide typically results in a diuretic effect within 30 min that peaks at 1 h. In HF, the dose–response curve shifts downward and to the right, thereby necessitating a higher dose to achieve the same effect (Fig. 1). The sigmoid-shaped dose–response relationship demonstrates the importance of attaining a diuretic concentration on the steep part of the curve between the minimal effective dose and dose ceiling. With renal insufficiency, as seen in >50% of ADHF patients, organic anions compete with receptor sites for tubular transporters and further increase dose requirements.
(Enlarge Image)
Figure 1.
Schematic of Dose–Response Curve of Loop Diuretics in Heart Failure Patients Compared With Normal Controls
In heart failure patients, higher doses are required to achieve a given diuretic effect and the maximal effect is blunted.
Although loop diuretics are commonly given by intermittent IV bolus, there are potential benefits of continuous infusion. Continuous infusion results in a more constant delivery of diuretic to the tubule, potentially reducing a post-diuretic "rebound" sodium retention and maintaining more consistent diuresis. Although a meta-analysis suggested greater urine output, shorter length of hospital stay, less renal impairment, and lower mortality rate with continuous infusion compared with intermittent bolus dosing, the recently published DOSE (Diuretic Optimization Strategies Evaluation) trial called these findings into question, as discussed below.
Loop diuretic use in ADHF generally improves dyspnea and decreases ventricular filling pressures (Fig. 2). Loop diuretics may induce the synthesis of prostaglandins with vascular smooth muscle relaxation resulting in renal and pulmonary vasodilation. Although decades of clinical experience suggest that loop diuretics are generally effective at managing congestion in ADHF, recent studies suggested that the lack of adequate decongestion is more common than previously appreciated. The largest ADHF trial to date, the ASCEND-HF (Acute Studies of Clinical Effectiveness of Nesiritide in Subjects with Decompensated Heart Failure) trial (N = 7,141), demonstrated that standard ADHF care resulted in improved dyspnea at 24 h in 66% of patients. The lack of adequate symptom relief with diuretics has been associated with longer hospital stays and increased mortality, underscoring the importance of effective decongestion in improving outcomes in ADHF.
(Enlarge Image)
Figure 2.
Diuretic Mechanisms
Proposed positive and negative effects of loop diuretics as well as sites of action for thiazide diuretics and natriuretic doses of aldosterone antagonists. CHF = congestive heart failure; LV = left ventricular; MR = mitral regurgitation; RAAS = renin-angiotensin-aldosterone system.
Observational studies have shown associations between high doses of loop diuretics and adverse clinical outcomes. These observations are confounded by the fact that patients receiving higher doses of diuretics tend to have greater disease severity or comorbidity, making it impossible to establish whether the relationship between diuretic dose and outcomes is causal. Potential mechanisms for worse outcomes with loop diuretics include stimulation of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system, electrolyte disturbances, and deterioration of renal function (Fig. 2). A recent analysis of the BEST (Beta-blocker Evaluation of Survival Trial) found that worsened mortality in association with high-dose loop diuretics was primarily limited to those patients with elevated blood urea nitrogen, suggesting a role for neurohormonal activation in observed increase mortality with loop diuretics. An animal study using a porcine HF model showed that treatment with furosemide resulted in an increased progression of left ventricular systolic dysfunction.
Of particular interest is the association of higher diuretic dosing with worsening renal function (WRF) during ADHF hospitalization because WRF characterized by changes in creatinine and/or estimated glomerular filtration rate has been shown to be a predictor of poor outcomes. More recent data from several studies, however, have suggested that transient WRF during acute HF therapy may not affect post-discharge outcomes. Given that persistent congestion is itself a predictor of both WRF and adverse outcomes, it would appear that transient WRF may be a reasonable trade-off in exchange for better decongestion. Understanding the optimal balance between the benefits of decongestion and the potential adverse effects of diuretics served as the rationale for the DOSE trial.
There is limited evidence to guide diuretic use as reflected in practice guidelines in which diuretic therapy is given a class I recommendation with a level of evidence based on expert opinion. The recently published DOSE trial is the largest prospective, double blind, randomized ADHF trial to evaluate initial diuretic strategies. Using a 2 × 2 factorial design, the DOSE trial randomized 308 ADHF patients to IV furosemide given as twice-daily boluses or continuous infusion and to either a low dose (IV dose numerically equivalent to the patient's oral dose) or a high dose (2.5 times oral dose given intravenously) strategy. There was no significant difference in either of the co-primary endpoints of global assessment of symptoms (Fig. 3A) or change in serum creatinine over 72 h with diuretic administration by bolus or continuous infusion or with a low- versus a high-dose strategy. However, patients randomized to the higher dose strategy had more favorable outcomes with regard to several secondary measures, including relief of dyspnea, change in weight, and net fluid loss. These potential benefits were balanced by greater changes in renal function (Fig. 3B). Although the mean change in creatinine from baseline to 72 h was not significantly different between the low- and high-dose strategy, the high-dose approach was associated with a significantly higher proportion of patients experiencing transient WRF (increase in creatinine >0.3 mg/dl). Despite these changes in renal function, the higher dose group had fewer serious adverse events and no evidence of worse 60-day outcomes. Taken as a whole, the data suggest that higher doses of diuretics are likely to be more efficacious in relieving congestion than a low-dose strategy, at the cost of transient WRF that does not appear to have long-term consequences.
(Enlarge Image)
Figure 3.
Patients' Global Assessment of Symptoms (VAS) During the 72-h Study Treatment Period and Changes in Serum Creatinine Over Time
(A) Patients' global assessment of symptoms was quantified as the area under the curve (AUC) of serial assessments from baseline to 72 h. Mean (± SD) AUCs are shown for the group that received a low dose of the diuretic compared with the group that received a high dose. (B) The mean change in serum creatinine level over the course of the study is shown for the group that received a low dose of the diuretic compared with the group that received a high dose. VAS = visual analog scale.
Loop Diuretics in ADHF
Pharmacology
Loop diuretics inhibit the Na/2Cl/K cotransporter in the thick ascending loop of Henle, resulting in decreased urine sodium and chloride reabsorption with natriuresis and diuresis. The 3 commonly used loop diuretics all work via these same mechanisms, although pharmacologic differences may have clinical importance (Table 1). The greater bioavailability of bumetanide and torsemide may offer more predictable diuresis, and the increased half-life of torsemide in the setting of renal, hepatic, and/or cardiac dysfunction may be advantageous for extended diuresis. The data comparing the loop diuretics are limited to small-scale, chronic HF studies with short follow-up and underuse of contemporary therapy as recently reviewed. These hypothesis-generating studies suggested potential benefits with torsemide compared with furosemide on neurohormonal activation, left ventricular remodeling, and fibrotic changes with resultant reduced hospitalizations, improved symptoms, and potentially reduced mortality. These findings would need to be confirmed in contemporary, adequately powered clinical trials.
Given the need for rapid onset of action, loop diuretics are typically given intravenously for hospitalized ADHF patients. Intravenous (IV) administration of an effective dose furosemide typically results in a diuretic effect within 30 min that peaks at 1 h. In HF, the dose–response curve shifts downward and to the right, thereby necessitating a higher dose to achieve the same effect (Fig. 1). The sigmoid-shaped dose–response relationship demonstrates the importance of attaining a diuretic concentration on the steep part of the curve between the minimal effective dose and dose ceiling. With renal insufficiency, as seen in >50% of ADHF patients, organic anions compete with receptor sites for tubular transporters and further increase dose requirements.
(Enlarge Image)
Figure 1.
Schematic of Dose–Response Curve of Loop Diuretics in Heart Failure Patients Compared With Normal Controls
In heart failure patients, higher doses are required to achieve a given diuretic effect and the maximal effect is blunted.
Although loop diuretics are commonly given by intermittent IV bolus, there are potential benefits of continuous infusion. Continuous infusion results in a more constant delivery of diuretic to the tubule, potentially reducing a post-diuretic "rebound" sodium retention and maintaining more consistent diuresis. Although a meta-analysis suggested greater urine output, shorter length of hospital stay, less renal impairment, and lower mortality rate with continuous infusion compared with intermittent bolus dosing, the recently published DOSE (Diuretic Optimization Strategies Evaluation) trial called these findings into question, as discussed below.
Efficacy
Loop diuretic use in ADHF generally improves dyspnea and decreases ventricular filling pressures (Fig. 2). Loop diuretics may induce the synthesis of prostaglandins with vascular smooth muscle relaxation resulting in renal and pulmonary vasodilation. Although decades of clinical experience suggest that loop diuretics are generally effective at managing congestion in ADHF, recent studies suggested that the lack of adequate decongestion is more common than previously appreciated. The largest ADHF trial to date, the ASCEND-HF (Acute Studies of Clinical Effectiveness of Nesiritide in Subjects with Decompensated Heart Failure) trial (N = 7,141), demonstrated that standard ADHF care resulted in improved dyspnea at 24 h in 66% of patients. The lack of adequate symptom relief with diuretics has been associated with longer hospital stays and increased mortality, underscoring the importance of effective decongestion in improving outcomes in ADHF.
(Enlarge Image)
Figure 2.
Diuretic Mechanisms
Proposed positive and negative effects of loop diuretics as well as sites of action for thiazide diuretics and natriuretic doses of aldosterone antagonists. CHF = congestive heart failure; LV = left ventricular; MR = mitral regurgitation; RAAS = renin-angiotensin-aldosterone system.
Safety
Observational studies have shown associations between high doses of loop diuretics and adverse clinical outcomes. These observations are confounded by the fact that patients receiving higher doses of diuretics tend to have greater disease severity or comorbidity, making it impossible to establish whether the relationship between diuretic dose and outcomes is causal. Potential mechanisms for worse outcomes with loop diuretics include stimulation of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system, electrolyte disturbances, and deterioration of renal function (Fig. 2). A recent analysis of the BEST (Beta-blocker Evaluation of Survival Trial) found that worsened mortality in association with high-dose loop diuretics was primarily limited to those patients with elevated blood urea nitrogen, suggesting a role for neurohormonal activation in observed increase mortality with loop diuretics. An animal study using a porcine HF model showed that treatment with furosemide resulted in an increased progression of left ventricular systolic dysfunction.
Of particular interest is the association of higher diuretic dosing with worsening renal function (WRF) during ADHF hospitalization because WRF characterized by changes in creatinine and/or estimated glomerular filtration rate has been shown to be a predictor of poor outcomes. More recent data from several studies, however, have suggested that transient WRF during acute HF therapy may not affect post-discharge outcomes. Given that persistent congestion is itself a predictor of both WRF and adverse outcomes, it would appear that transient WRF may be a reasonable trade-off in exchange for better decongestion. Understanding the optimal balance between the benefits of decongestion and the potential adverse effects of diuretics served as the rationale for the DOSE trial.
The DOSE Trial
There is limited evidence to guide diuretic use as reflected in practice guidelines in which diuretic therapy is given a class I recommendation with a level of evidence based on expert opinion. The recently published DOSE trial is the largest prospective, double blind, randomized ADHF trial to evaluate initial diuretic strategies. Using a 2 × 2 factorial design, the DOSE trial randomized 308 ADHF patients to IV furosemide given as twice-daily boluses or continuous infusion and to either a low dose (IV dose numerically equivalent to the patient's oral dose) or a high dose (2.5 times oral dose given intravenously) strategy. There was no significant difference in either of the co-primary endpoints of global assessment of symptoms (Fig. 3A) or change in serum creatinine over 72 h with diuretic administration by bolus or continuous infusion or with a low- versus a high-dose strategy. However, patients randomized to the higher dose strategy had more favorable outcomes with regard to several secondary measures, including relief of dyspnea, change in weight, and net fluid loss. These potential benefits were balanced by greater changes in renal function (Fig. 3B). Although the mean change in creatinine from baseline to 72 h was not significantly different between the low- and high-dose strategy, the high-dose approach was associated with a significantly higher proportion of patients experiencing transient WRF (increase in creatinine >0.3 mg/dl). Despite these changes in renal function, the higher dose group had fewer serious adverse events and no evidence of worse 60-day outcomes. Taken as a whole, the data suggest that higher doses of diuretics are likely to be more efficacious in relieving congestion than a low-dose strategy, at the cost of transient WRF that does not appear to have long-term consequences.
(Enlarge Image)
Figure 3.
Patients' Global Assessment of Symptoms (VAS) During the 72-h Study Treatment Period and Changes in Serum Creatinine Over Time
(A) Patients' global assessment of symptoms was quantified as the area under the curve (AUC) of serial assessments from baseline to 72 h. Mean (± SD) AUCs are shown for the group that received a low dose of the diuretic compared with the group that received a high dose. (B) The mean change in serum creatinine level over the course of the study is shown for the group that received a low dose of the diuretic compared with the group that received a high dose. VAS = visual analog scale.
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