Episode 39- Demystifying the “DOSE” trial


 

Episode Summary:

What dose of diuretics did the “DOSE” trial use in heart failure exacerbations? Was oral bioavailability taken into account?

Show Notes:

Key Points:

Demystifying the ‘DOSE’ trial”:
– The optimal dose and administration strategy of diuretics during heart failure exacerbations remains largely unknown
-The “DOSE” trial enrolled patients into either a “low-dose” strategy (equal to home diuretic dose in furosemide equivalents) or a “high-dose” strategy (home diuretic dose in furosemide equivalents x 2.5) and to either receiving the total dose as a bolus every 12 hours or as a continuous infusion
– For example, if a patient was on 20 mg BID furosemide at home (40 mg daily), they were randomized to receiving either 40 mg IV daily (“low-dose” group) or 100 mg IV daily (“high-dose group). Oral bioavailability was not factored in
– In terms of administration of bolus vs continuous infusion, there were no differences between the two in the primary efficacy end point of patient-reported global assessment of symptoms scores. There was also no difference in the primary safety end point of mean change in creatinine levels or any other secondary efficacy or safety outcomes
– In terms of dosing, there was a non-significantly higher improvement in the primary efficacy endpoint in the “high-dose” group. The “high-dose” group also had greater net fluid loss, weight loss, and relief from dyspnea, but that came with a significantly higher risk of worsening renal function- but note that this was a transient effect that did not lead to any bad outcomes by day 60
– Overall, there was no difference in median length of stay no matter what dose or administration strategy was chosen, nor was there a difference in composite end points that included mortality and rehospitalization
ER-Rx Episode 39

References:

Felker, GM, Lee, KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. NEJM. 2011; 364(9): 797- 805

Transcript:

Hello and welcome to Episode 39 of ER-Rx. Multiple times a day, we get a patient in the ER with a heart failure exacerbation. More often than not, these patients are given diuretics- usually in the form of IV furosemide (Lasix). If they are diuretic-naïve, most will start out with a dose anywhere from 20-40 mg IV. But if the patient is already on oral furosemide at home, how much should we give? Just give their home dose? Some multiple of their home dose? The classic: Age + BUN = the dose you should give (just a joke)? And how should we give it? As a bolus? Or should we jump straight to a continuous infusion?

There is so much conflicting data on this and we have almost no help from clinical guidelines. It’s no surprise that this question has been discussed in the past, and when it is brought up most people also bring up the “DOSE” trial, published almost a decade ago now. The authors of this trial wanted to clear up the uncertainty about dosing and administration of loop diuretics in heart failure exacerbations. They enrolled patients who had a history of heart failure and were on 80 – 240 mg of oral furosemide equivalents prior to study enrollment. Remember that 40 mg of oral furosemide is equal to 20 mg of torsemide or 1 mg of bumetanide. Also remember that 40 mg of oral furosemide is equal to 20 mg IV furosemide.

Patients were randomized to either a “low-dose” strategy or a “high-dose” strategy, and to administration of furosemide by either IV bolus every 12 hours or by continuous IV infusion. The “low-dose” group received a total IV furosemide dose that was equal to their daily home loop diuretic dose in furosemide equivalents, and the “high-dose” group received a dose that was 2.5 times their daily home loop diuretic dose. More on this later. Treatment was continued for up to 72 hours, and at 48 hours the treating physician could adjust the strategy based on response by increasing the dose 50%, maintaining the same strategy, or discontinuing IV treatment and changing to oral diuretics.

In terms of administration of bolus vs continuous infusion, there were no differences between the two in terms of the primary efficacy end point of patient-reported global assessment of symptoms scores. There was also no difference in the primary safety end point of mean change in creatinine levels (mean 0.05 +/- 0.3 mg/dL with boluses vs 0.07 +/- 0.3 mg/dL with CI, p=0.45) or any other secondary efficacy or safety outcomes. Ok, so in the ER, we can go ahead and give furosemide by IV bolus- which makes sense because we don’t usually start an infusion of diuretics in the ER.

How about dosing? There was a non-significantly higher improvement in the primary efficacy endpoint of patient-reported symptoms in the “high-dose” group, and these patients were more likely to change to oral diuretics at 48 hours (31% vs 17%, p< 0.001). The “high-dose” group also had greater net fluid loss, weight loss, and relief from dyspnea, but that came with a significantly higher risk of worsening renal function (an increase in the creatinine level of > 0.3 mg/dL), which occurred in 23% of patients in the “high-dose” group, but only 14% in the “low-dose” group (p=0.04)- but note that this was a transient effect that did not lead to any bad outcomes by day 60.

Overall, there was no difference in median length of stay no matter what dose or administration strategy was chosen, nor was there a difference in composite end points that included mortality and rehospitalization.

So, let’s put this into practice. Let’s say your patient was on 20 mg BID of furosemide at home and is in your ER and you want to diurese. Having listened to this episode you are now even more confident that you can safely give a furosemide IV bolus, but you are trying to figure out which dose to give. You conclude that the “high-dose” strategy may be best for your patient. Since your patient was on a total of 40 mg oral furosemide, the “high-dose” strategy calls for a total daily IV dose of 40 mg x 2.5, or 100 mg- which would be given as 50 mg IV BID. So, the dose your patient would get in the ER is 50 mg IV. Of course, this can be adjusted to other patient factors, but it is a good place to start.

This seems a little high, and this is where the confusion comes in. It’s unclear in the “DOSE” trial if furosemide’s 50% oral bioavailability was taken into account. If so, this patient should actually receive a total of 50 mg IV daily- given as 25 mg IV BID. I spent an embarrassing amount of time trying to figure out if our example patient should get 50 mg IV or 25 mg IV in the ER- since most of the people I talked to also had different answers. I thought I had my answer, and then I emailed the lead author of the “DOSE” trial to see if I was right. According to him, the dosing in the trial was based on numeric values only, and was not adjusted for bioavailability. So, if the patient was on 40 mg of furosemide daily at home, they would get 40 mg IV daily if they were in the “low-dose” group, or 100 mg IV daily if they were in the “high-dose” group. So, even patients in the “low-dose” group received 2x their home diuretic dose if you factor in bioavailability, and the “high-dose” group received a dose that was equivalent to 5x their home dose! Of course, remember that in practice this dose is usually individualized and adjusted based on response.

As always, thank you so much for your time. As part of my New Year’s resolution I decided to make my first Twitter account ever- so please check that out, @errxpodcast. Also, the winner of the prize has been contacted! Congratulations to the lucky winner from Arkansas.


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