A randomized controlled trial of loop diuretics was published in NEJM two weeks ago. The trial involved 308 patients, from 26 clinical sites. The details are below:
Prospective double-blind randomized controlled trial (intention to treat analysis)
Enrollment within 24 hrs of admission with ADHF
Clinical diagnosis of heart failure
History of chronic heart failure and receipt of an oral loop diuretic for at least 1 month before hospitalization, at a dose between 80 mg and 240 mg daily in the case of furosemide (or equivalent loop diuretic)
Serum creatinine > 3mg/dL
IV vasodilators or IV inotropic agents
2 x 2 factorial design; 1:1:1:1 randomization, stratified on centre
High dose (2.5 x home diuretic dose) vs low dose (home oral dose)
Continuous vs bolus dosing (every 12 hours) of loop diuretics
At 48 hours, the treating doctors could increase the dose by 50% (remaining blinded), make no changes (remaining blinded) or change to open-label oral diuretics
Efficacy – global assessment of symptoms from baseline to 72 hours
Safety – change in serum creatinine from baseline to 72 hours
As these were co-primary endpoints, p<0.025 for each was required>
There were no significant differences in the either the primary efficacy or safety endpoints
between continuous vs bolus dose, nor between high vs low dose diuretics.
The patients in the high-dose group had greater relief of dyspnoea and had higher net fluid loss; however, this was offset by a greater increase in serum creatinine after 72 hours.
This is the first major trial examining the efficacy of loop diuretics in modern-day treatment of acute decompensated heart failure. It certainly is thought provoking in terms of its clinical applications and generalizability. Perhaps the first thing to note is that it excludes the sickest patients - those that need inotropes or vasodilators - patients who may be most likely to benefit from aggressive diuresis.
The use of a visual-analogue scale as a measure of symptoms seems a little hard to interpret as a primary efficacy endpoint of diuretic therapy – the editorial suggested it may be too insensitive also.
From a dosing point of view – it does not appear that subjects were given a bolus before a continuous infusion was started, something that we were always taught to do. In the bolus group, another point we were told during training is that 12 hour intervals may be too long – when a threshold dose of a loop diuretic is reached, the frequency of dosing should be increased in order to exert maximum effect. Again, major evidence is lacking for these proposed dosing strategies.
Although not powered to examine mortality, there were no differences in outcomes between the various strategies. A total of 130 patients died, were re-hospitalized or required an ED visit within 60 days. This really hits home that a lot more work is required to improve the outcomes of this patient subgroup. I’m sure this trial will receive a lot of attention from experts in the field and invite further research ideas.