REVIEW URRENT C OPINION

An update in the management of acute decompensated heart failure Ronnen Maze and Haissam Haddad

Purpose of review This review will provide an overview of recent advances in the management of acute decompensated heart failure, focusing on major publications from the past few years. Recent findings There have been several publications investigating different strategies in the management of acute decompensated heart failure. Trials have investigated the role of ultrafiltration, diuretic infusions and recombinant B-type natriuretic peptide for the treatment of these patients. Summary In patients with acute decompensated heart failure, the use of ultrafiltration in place of diuretics, diuretic infusions, and B-type natriuretic peptide has not shown benefit in recent trials. Unfortunately, there have been no major advances in the management of patients with acute decompensated heart failure. Keywords decompensated heart failure, diuretics, ultrafiltration

INTRODUCTION Heart failure remains a major public health issue, with over 650 000 new cases diagnosed annually in the United States [1]. There are over 1 000 000 hospital admissions annually for acute decompensated heart failure (ADHF) [2]. The cornerstone of therapy for patients with ADHF remains diuresis and treatment directed at the underlying cause of decompensation. Yet, despite aggressive therapy, the morbidity and mortality associated with ADHF remain high. Patients admitted for ADHF have a high rate of readmission – 50% at 6 months [3], and high in-hospital (4%) and 1-year mortality rates approaching 30% [4]. Despite several recent advances in the management of chronic heart failure [5], the poor outcomes in patients presenting with ADHF are concerning. Several recent trials have addressed new strategies for the management of ADHF. These strategies include the use of ultrafiltration as an alternative to diuresis, diuretic infusions, and recombinant B-type natriuretic peptide (BNP). This review provides an overview and update of the latest evidence for the management of ADHF.

ULTRAFILTRATION Loop diuretics are the foundation of therapy in patients with ADHF [6]. Yet, due to limitations www.co-cardiology.com

associated with the use of diuretics, including diuretic resistance, electrolyte abnormalities and renal dysfunction, the use of ultrafiltration as an alternative strategy has been investigated for several years. The Ultrafiltration versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Congestive Heart Failure (UNLOAD) study [7], published in 2007, randomized 200 patients with ADHF to ultrafiltration or intravenous diuretics. The trial demonstrated a greater reduction in weight (5.0  3.1 vs. 3.1  3.5 kg; P ¼ 0.001) and net fluid loss (4.6 vs. 3.3 l; P ¼ 0.001) at 48 h in the ultrafiltration group. Moreover, at 90 days, there was a reduction in repeat hospitalizations in patients randomized to ultrafiltration. Given these beneficial effects of ultrafiltration, the strategy was further tested in patients with cardiorenal syndrome (defined as an increase in the serum creatinine level of at least 0.3 mg per deciliter within 12 weeks before or 10 days after Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada Correspondence to Dr Haissam Haddad, MD, FRCPC, FACC, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y 4W7, Canada. Tel: +1 613 761 5165; fax: +1 613 761 5212; e-mail: hhaddad @ottawaheart.ca Curr Opin Cardiol 2014, 29:180–184 DOI:10.1097/HCO.0000000000000038 Volume 29  Number 2  March 2014

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Management of acute decompensated heart failure Maze and Haddad

KEY POINTS  ADHF remains a major cause of morbidity and mortality despite many recent advances in the therapy of chronic heart failure.  The optimal mode of administration of intravenous diuretics remains unknown.  The role for ultrafiltration in the management of ADF has not been clearly elucidated in recent trials and further research is needed.  Nesiritide is not associated with significant symptom improvement or clinical benefits in patients with ADHF.

the index admission for heart failure) in the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial [8 ]. This study hypothesized that increasing diuretic use in patients with acute cardiorenal syndrome may contribute to further worsening of renal function, a phenomenon that may be avoided by the use of ultrafiltration. This study randomized 188 patients with ADHF, worsened renal function and persistent congestion to a strategy of intravenous diuretics (titrated to maintain urine output of 3–5 l/day) or ultrafiltration. The primary endpoint was change from baseline in serum creatinine level and body weight, assessed at 96 h. The study showed a worsening of renal function at 96 h in the ultrafiltration group as compared with the pharmacologic group, with mean change in creatinine level of þ0.23 þ 0.70 mg/dl in the ultrafiltration group and 0.04 þ 0.53 mg/dl in the pharmacologic group (P ¼ 0.003). This increased creatinine was not associated with greater weight loss, as no difference was observed in the degree of weight loss at 96 h between &&

Creatinine increase (mg/dl) 1.0 0.8 Ultrafiltration (N–92) Weight loss (lb) –20 –18 –16 –14 –12 –10 –8 Pharmacologic therapy (N–94)

0.6 0.4 0.2 0.0 –6

–4

–2

P–0.003

0

–0.2

Weight gain (lb)

–0.4 –0.6

–0.8 Creatinine decrease (mg/dl)

FIGURE 1. Changes in creatinine and weight at 96 h. Ellipses represent 95% confidence regions. Reproduced with permission from [8 ]. &&

the two treatment groups (Fig. 1). At 96 h and at day 7 or hospital discharge, there were no betweengroup differences in scores on the dyspnea and global well being visual analog scale, a secondary endpoint of the study. No significant difference was noted in the rates of death or rehospitalization of 60 days. Furthermore, adverse events were more common in the ultrafiltration group over the 60-day follow-up period (72 vs. 57%; P ¼ 0.003). This was due to a higher incidence of kidney failure, bleeding complications and intravenous catheterrelated complications. Although ultrafiltration remains an important modality of fluid removal in patients who are refractory to diuretic therapy, its use as an alternative to diuretics requires further investigation. Current guidelines recommend ultrafiltration therapy as a class IIb indication for patients who have not responded to initial medical therapy [9]. An ongoing trial, the Aquapheresis Versus Intravenous Diuretics and Hospitalizations for Heart Failure (AVOID-HF, ClinicalTrials. gov NCT01474200), is currently recruiting patients to further evaluate the role of ultrafiltration in the management of patients with ADHF.

DIURETIC THERAPY Diuretic therapy – particularly loop diuretics – remains the cornerstone of therapy for patients with ADHF. Current guidelines recommend the prompt use of intravenous diuretics in patients admitted with evidence of significant volume overload [9]. Yet, there is a lack of prospective data to guide the optimal administration of this drug class to patients. The Diuretic Optimization Strategies Evaluation (DOSE-HF) trial was conducted to prospectively compare administration of intravenous diuretic therapy via bolus dosing or continuous infusion [10]. This study randomized 308 patients with ADHF to receive intravenous furosemide administered either through bolus dosing every 12 h or via continuous infusion. Each group was further stratified to either a low-dose (equivalent to patient’s previous oral dose) or high-dose (2.5 times the previous oral dose) regimen. The trial had two co-primary endpoints. The primary efficacy endpoint was patients’ global assessment of symptoms, whereas the primary safety endpoint was the change in serum creatinine at 72 h. The study found no significant difference between the treatment groups in the primary efficacy or the primary safety endpoint (Fig. 2). High-dose intravenous infusion (as compared with low-dose infusion) was associated with greater relief of dyspnea and increased diuresis at the expense of

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Heart failure

dosing of furosemide. A randomized trial (Clinical Trials. Gov NCT00904488) is ongoing comparing the combination of an oral thiazide diuretic (metolazone) and intravenous bolus dosing of furosemide with continuous infusion furosemide. Certainly, further research is needed to identify the optimal use of intravenous furosemide and combination diuretic regimens in patients with ADHF.

Change in 0.15 creatinine (mg/dl) P = 0.45

P = 0.21

0.10 0.08 0.07 0.05

0.05 0.04

RECOMBINANT B-TYPE NATRIURETIC PEPTIDE

se do

se do w Lo

H ig h

ou tin u

C on

Bo

lu s

s

0.00

FIGURE 2. Mean change in serum creatinine at 72 h. Reproduced with permission from [10].

an increase in serum creatinine at 72 h. High-dose furosemide was associated with greater net fluid loss, weight loss and relief from dyspnea. These effects came at the expense of an increased proportion of patients meeting the prespecified secondary safety endpoint of worsening renal function. Finally, neither mode (bolus vs. infusion) nor dosing (low-dose vs. high-dose) of furosemide was associated with improvement in the composite endpoint of death, rehospitalization or emergency department visit at 60 days of follow-up (Fig. 3). In summary, this study failed to show a benefit for intravenous continuous infusion furosemide compared with bolus dosing of the drug in patients with ADHF. Despite this, there may be a physiologic basis for the use of a continuous infusion regimen in patients with tenuous hemodynamics and in patients with venous congestion that may be refractory to conventional, bolus

Bolus vs. continuous infusion Proportion 1.0

Low-dose vs. high-dose strategy Proportion 1.0

Hazard ratio with continuous infusion, 1.15 (95% CI, 0.83–1.60)

0.9

Hazard ratio with high-dose strategy, 0.83 (95% CI, 0.60–1.16)

0.9

P = 0.41

0.8

Nesiritide, a recombinant BNP, was approved by the US Food and Drug Administration in 2001 for use in patients with decompensated heart failure to relieve dyspnea, presumably via a reduction in pulmonary capillary wedge pressure. Research subsequently demonstrated a worsening renal function and increased rate of early death associated with the use of nesiritide. The use of nesiritide is currently a class IIB indication as adjunctive therapy for the relief of dyspnea in patients admitted with ADHF [9]. The Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial was conducted to investigate the role of nesiritide, in addition to standard care, in patients with ADHF [11]. The study randomized 7141 patients who were hospitalized with ADHF to receive either nesiritide or placebo for 24–168 h. All patients received standard-of-care heart failure therapy otherwise. Outcomes included rates of selfreported dyspnea at 6 and 24 h, rehospitalization for heart failure or death from any cause at 30 days, and renal dysfunction. The trial failed to show any difference in the rate of death or rehospitalization for heart failure at 30 days (Table 1). Additionally, self-reported dyspnea, although numerically improved, did not meet

P = 0.28

0.8

0.7

0.7

0.6

0.6 Continuous

0.5 0.4

Low dose

0.5 Bolus

0.4

0.3

0.3

0.2

0.2

0.1

0.1

0.0

High dose

0.0 0

10

20

30

40

50

60

Days

0

10

20

30

40

50

60

Days

FIGURE 3. Kaplan–Meier curves for the clinical composite endpoint of death, rehospitalization, or emergency department visit. Reproduced with permission from [10]. CI, confidence interval. 182

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Management of acute decompensated heart failure Maze and Haddad Table 1. Primary and secondary clinical endpoints and safety endpoints through day 30 (ASCEND-HF)a

Endpoint

Nesiritide (N ¼ 3496)

Placebo (N ¼ 3511)

Percentage-point difference or odds ratio (95% CI)

P value

321/3423 (9.4)

345/3413 (10.1)

0.7 (2.1 to 0.7)

0.31

Primary clinical endpoints Death from any cause or rehospitalization for heart failure – no./total no. (%) Death from any cause

126/3490 (3.6)

141/3499 (4.0)

0.4 (1.3 to 0.5)

Rehospitalization for heart failure

204/3422 (6.0)

208/3411 (6.1)

0.1 (1.2 to 1.0)

147/3459 (4.2)

165/3462 (4.8)

0.6 (1.5 to 0.5)

0.30

20.9  6.9

20.7  7.1

0.2 (–0.13 to 0.53)

0.16

372/3423 (10.9)

402/3415 (11.8)

0.9 (2.4 to 0.6)

0.24

Death from cardiovascular causes – no./total no. (%)

112/3498 (3.2)

124/3509 (3.5)

0.3 (1.2 to 0.5)

0.44

Sudden death from cardiac causes – no./total no. (%)

19/3324 (0.6)

16/3327 (0.5)

0.1 (0.3 to 0.4)

0.61

930/3498 (26.6)

538/3509 (15.3)

11.3 (9.4 to 13.1)

An update in the management of acute decompensated heart failure.

This review will provide an overview of recent advances in the management of acute decompensated heart failure, focusing on major publications from th...
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