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
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.
Efficacy- patient’s global assessment of symptoms over a 72hour period
Safety- serum creatinine level change from baseline to 72hours
- 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
- Emergency department visit within 60 days
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
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)
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.