Diuretic Strategies in Patients with Acute Decompensated Heart Failure

Felker GM, Lee KL, Bull DA et al.

New England Journal of Medicine: 2011. 364 (9) 797-805

Aim of study

Provide prospective data to guide the use of loop diuretics in acute decompensated heart failure

Design and location

Prospective, double-blind, randomized trial

Multi-centre: The Heart Failure Clinical Research Network- regional clinical centres and associated hospitals in United States and Canada

Methodology

308 patients admitted with acute decompensated heart failure randomised to receive IV furosemide administered either as a:

-bolus dosing every 12 hours at low dose (IV equivalent to patient’s oral dose)

-bolus dosing every 12 hours at high dose (IV equivalent to 2.5 x patient’s oral dose)

-continuous infusion at a low dose (IV equivalent to patient’s oral dose)

-continuous infusion at a high dose (IV equivalent to 2.5 x the patient’s oral dose).

Physician guided dose adjustments could be made at 48hours- increase 50%, maintain or switch to oral.

Primary Outcomes

Efficacy- patient’s global assessment of symptoms over a 72hour period

Safety- serum creatinine level change from baseline to 72hours

Secondary Outcomes

  • Change in weight
  • Freedom from congestion at 72 hours
  • Change in bivariate vector of creatinine and weight at 72 hours
  • Dyspnea VAS AUC over 48 and 72 hours
  • Change in Creatinine at 24, 48, 96 hours, day 7 (or discharge) and 60 days
  • Change in Cystatin C at 72 hours, Day 7 (or discharge) and 60 days
  • Persistent/Worsening Heart Failure
  • Development of cardio-renal syndrome (CRS)
  • Treatment Failure
  • Net fluid loss over 72 hours
  • Time from randomization to discharge of index hospitalization
  • Days hospitalized for heart failure or deceased in 60 days from randomization
  • Changes in circulating biomarkers at 72 hours, day 7 (or discharge) and 60 days

Clinical end points

  • Death
  • Rehospitalisation
  • Emergency department visit within 60 days

Statistics

Analysis according to intention-to-treat principle

Comparison of mode groups and dose groups

Linear model- continuous end points

Logistic regression- binary end points

Cox model and Kaplan-Meier curves for time to event end points

Results

308 patients, mean age 66 years, 27% female, mean ejection fraction was 35%, mean Cr 132.6, mean BNP 7439

  • Bolus vs continuous infusion- no significant difference in primary or secondary outcomes, however:
    • Bolus patients more likely to require dose increase at 48 hours (21% vs 11%)
  • Low-dose vs high-dose not associated with significant difference in primary endpoints, however:
    • High-dose patients more likely to change to oral at 48 hours (31% vs 17%)
    • Low-dose patients more likely to require 50% increase at 48hours (24% vs 9%)
  • High-dose furosemide resulted in greater fluid loss, weight loss and patient reported relief from dyspnea than low dose (secondary end points)
  • Higher proportion of patients on high-dose met the end point of worsening renal function (‘treatment failure’) during the 72hour period than low dose
    • Although at 60 days there was no difference between the study groups
  • Clinical events:
    • Fewer patients in high-dose group experienced serious adverse events (37% vs 50%)
    • More cases of renal failure with continuous infusion than bolus (11 vs 8), but more with low-dose than high (12 vs 7)

Conclusions/Discussions

No significant difference between administration as a bolus or continuous infusion, or low-dose vs high-dose in terms of the safety and efficacy co-primary end-points.

High-dose administration is associated with greater relief of dyspnea, greater fluid loss, weight loss and fewer adverse events, despite higher incidence of ‘treatment failure’ (serum Cr >26.5 in 72hours).

Stated Limitations from the study

  • Population had severe heart failure- how does this translate to newly diagnosed HF or those with modest diuretic requirements?
  • Intention-to-treat analysis but option for treatment adjustment at 48hours
  • Co-administration with vasopressors/inotropes- important consideration in ITU setting

Discussion from Journal Club

Touched on BMJ article recommendations:

‘How to prescribe loop diuretics in oedema’. Anisman et al. BMJ 2019;364:l359

– Pharmacokinetics- ‘on’ or ‘off’, no gradual effect. Therapeutic threshold for patient can be predicted by eGFR and proteinuria

-Variable dose prescribing is not favourable- if the threshold has been surpassed, use that dose repeatedly. No further diuresis from doses above threshold, no ‘mild diuresis’ from those below

-If requiring titratable response, use other diuretic class

In ITU furosemide is used to achieve fluid balance, not just in context of heart failure- so comes with different considerations.

Summary by Dr A Sira. Journal Club Meeting 01 October 2020.

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