How much of the drug should we give? And is it better to dose it continuously or in discrete boluses? These questions are often debated on morning rounds and answered using personal experience, but there has been little evidence to support a particular dose or dosing scheme.
Now, in a rare attempt to study these practical questions, researchers in the prospective, double-blind randomized Diuretic Optimization Strategies Evaluation (DOSE) trial have shown that, at least during the first couple of days of treatment, it doesn’t matter how much you give or how you give it.
In a federally funded study conducted in the United States and Canada by Felker et al, 308 acute heart failure patients were given intravenous furosemide: either as a bolus every 12 hours or as a continuous infusion, at a dose that was either equivalent to the patient’s previous oral dose or two and a half times that dose.
They found that subjects who received continuous infusion of the diuretic fared no better in terms of global symptom assessment or change in serum creatinine than those who received furosemide by bolus.
The study did find that patients on the higher-dose regimens benefited from more fluid loss, weight loss, and relief from shortness of breath and that fewer of them had a serious adverse event. This came at a cost of a transient decline in renal function that was no longer evident at 60 day follow-up. There were no significant differences in these outcomes when comparing the bolus-dose and continuous-infusion regimens.
As NEJM deputy editor John Jarcho notes, the study has a few shortcomings, including the fact that it was designed to look at diuretic management within a narrow time window. However, “it would have been very difficult to randomize patients from the moment they hit the door,” he says. “The message of a trial like this is that, where there’s no evidence base, you have to start somewhere.”
In an accompanying editorial, Greg C. Fonarow of the Ronald Reagan–UCLA Medical Center in Los Angeles writes: “The study by Felker et al. of various dosing strategies for loop diuretics has not solved the problem of the poor prognosis for patients hospitalized with acute decompensated heart failure, nor has it modified the substantial expenditures for this disease. However, this study has introduced the new concept of comparative-effectiveness studies into the field of heart-failure research, high-lighting the importance of acquiring rigorous evidence, even for the most commonly applied interventions.”
What are the implications of using the global symptom assessment scale as the primary efficacy endpoint? Should these results be extrapolated to populations excluded by this study, including those with markedly elevated serum creatinine levels or those with new onset heart failure? How will these results affect your future treatment decisions, if at all?