By Dr. Mustafa Toma (biography and disclosure) and Dr. Christopher Cheung, (biography and disclosures)
What I did before
Heart failure is one of the most common causes of hospital admissions among patients 65 years and older.(1) The management of acute decompensated heart failure is typically through the administration of loop diuretics, including furosemide, torsemide, and bumetanide. However, prior to the DOSE trial (Diuretic Optimization Strategies Evaluation), evidence supporting the use of loop diuretics was sparse, and the route of administration, dosing, and frequency varied across institutions. Intravenous loop diuretics were the mainstay of therapy, but previous comparisons between low-dose and high-dose strategies suggested increased adverse outcomes with high-dose diuretics, including worsening renal failure and death.(2, 3) These studies were primarily observational and lacked the rigor and prospective design of a randomized controlled trial. Therefore, before the DOSE trial was published, patients admitted with acute decompensated heart failure received low-to-moderate dosages of intravenous diuretics, which may have prolonged their symptoms and hospitalization compared to higher dosages.
What changed my practice
In 2011, Felker et al. published the DOSE study, comparing intravenous low-dose and high-dose loop diuretics, and intermittent bolus and continuous infusion of loop diuretics.(4) The DOSE study was a prospective, randomized, double-blind, double-dummy, controlled trial conducted at 26 institutions across Canada and the United States, and funded by the National Heart, Lung, and Blood Institute. Patients presenting within 24 hours of acute decompensated heart failure, including at least one symptom (ie. dyspnea, orthopnea, edema), and one sign (ie. rales, peripheral edema, ascites, pulmonary congestion on chest radiograph), were enrolled into the study. A history of heart failure requiring oral loop diuretics prior to hospitalization was required, including furosemide (between 80-240 mg daily), or equivalent dosages of torsemide or bumetanide.
Patients were randomized to receive furosemide into four strategies using a 2-by-2 factorial design, including low-dose (intravenous dose equal to daily dose at home) or high-dose (intravenous dose 2.5 times daily dose at home), and intermittent bolus every 12 hours or continuous infusion. The primary efficacy endpoint was the patient’s global assessment of symptoms, measured using a visual-analogue scale, from baseline to 72 hours. The primary safety endpoint was the change in serum creatinine from baseline to 72 hours. The two composite endpoints were: death, re-hospitalization, and emergency room visit within 60 days; and total duration of hospitalization, and death within 60 days after randomization.
308 patients were enrolled in the study with a mean age of 66 years (27% female). There were high rates of medical comorbidities, including heart failure requiring hospitalization within the previous 12 months (74%), renal dysfunction (mean serum creatinine 132.6 umol/L), and systolic dysfunction (mean ejection fraction 35%). In comparing low-dose and high-dose furosemide, the authors found no significance but a trend towards improved efficacy in the high-dose group (patient’s global assessment of symptoms, p=0.06) and no difference in the primary safety endpoint (change in serum creatinine, p=0.21). The high-dose group also demonstrated greater net fluid loss, weight loss, and relief of dyspnea (all secondary endpoints), but a higher proportion of patients developed a transient deterioration of renal function during the first 72 hours. There were no differences in the composite endpoints between the low-dose and high-dose groups. When comparing intermittent bolus with continuous infusion, the authors found no difference in the primary efficacy or safety endpoints, and no differences in the composite and secondary endpoints.
What I do now
The DOSE trial provided good insight into the dosage and frequency for administering loop diuretics in patients presenting with acute decompensated heart failure. Prior to DOSE, evidence for the management of acute decompensated heart failure was sparse and primarily observational; management depended primarily on expert opinions and institutional practice patterns. Since the publication of the DOSE trial, we now know that there is no significant difference between intravenous low-dose and high-dose loop diuretics, with respect to efficacy and safety. Secondary endpoints, such as reduced dyspnea, in the high-dose group may edge the clinician towards using a higher dose of furosemide, with confidence that safety outcomes, including renal dysfunction and the composite endpoints, remain unaffected. Administering the patient’s home diuretic dose intravenously is also a viable option with equivalent efficacy. The equivocal results between bolus and continuous infusions suggest no significant advantage to either route, and is therefore up to the preference of the prescribing physician. The authors also hypothesize that the continuous placebo infusion, as part of the double-dummy protocol, increased the time in which patients were supine and enhanced the diuresis in the bolus group, resulting in equivocal results.(4)
Although the DOSE study did not show clear-cut results towards either low-dose or high-dose loop diuretics, or intermittent bolus or continuous infusion, it provides strong prospective evidence for the management of acute decompensated heart failure. In patients presenting to hospital with signs and symptoms of acute decompensated heart failure, we recommend giving at least 1 and up to 2.5 times their home dose of loop diuretic intravenously to manage their symptoms of congestion. We do not recommend routine infusions of loop diuretic as there is likely no benefit, although there may remain certain situations in which an infusion may be considered. For the volume-overloaded outpatient, one could consider doubling the home dosage of loop diuretic for 3-5 days, followed by clinical and volume status re-assessment. Lack of improvement or deterioration should prompt referring the patient for hospital admission. Many previous studies in acute decompensated heart failure have not yielded positive results (ie. OPTIME-CHF, EVEREST, and ASCEND-HF), and perhaps the DOSE study serves as a reminder about the importance of diuresis in what is fundamentally a hypervolemic physiologic state.(5-7) Recent studies may suggest a role for novel agents in acute decompensated heart failure (ie. serelaxin in RELAX-AHF), but the jury is still out on these new therapies.(8)
Conclusion
In patients presenting with acute decompensated heart failure and previously on oral loop diuretics at home, there is no difference between low-dose and high-dose furosemide, or bolus and continuous infusions, on the patient’s global assessment of symptoms and changes in serum creatinine at 72 hours. Patients prescribed higher doses may have an earlier resolution of symptoms, but are at risk of a transient worsening of renal function, and should have their serum creatinine monitored closely. Physicians can prescribe intravenous loop diuretics with confidence that their decision is evidence-based, efficacious, and safe.
References
- Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics–2014 update: a report from the American Heart Association. Circulation. 2014 Jan 21;129(3):e28-e292. (View with CPSBC or UBC)
- Butler J, Forman DE, Abraham WT, et al. Relationship between heart failure treatment and development of worsening renal function among hospitalized patients. Am Heart J. 2004 Feb;147(2):331-8. (View with CPSBC or UBC)
- Hasselblad V, Gattis Stough W, Shah MR, et al. Relation between dose of loop diuretics and outcomes in a heart failure population: results of the ESCAPE trial. Eur J Heart Fail. 2007 Oct;9(10):1064-9. (View with CPSBC or UBC)
- Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med. 2011 Mar 3;364(9):797-805. (View)
- Cuff MS, Califf RM, Adams KF, et al. Short-term intravenous milrinone for acute exacerbation of chronic heart failure. JAMA. 2002 Mar 27;287(12):1541-47. (Request from CPSBC or view with UBC)
- Konstam MA, Gheorghiade M, Burnett JC, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST outcome trial. JAMA. 2007;297(12):1319-1331. (Request from CPSBC or view with UBC)
- O’Connor CM, Starling RC, Hernandez AF, et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med. 2011;365:32-43. (View)
- Teerlink JR, Cotter G, Davidson BA, et al. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomized, placebo-controlled trial. Lancet. 2013;381:29-39. (View with CPSBC or UBC)
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This goes against what is trending in Emergency Medicine
From EMDocs: http://www.emdocs.net/furosemide-treatment-acute-pulmonary-edema/
“There’s minimal or no role for the administration of loop diuretics early in the management of APE. The majority of patients aren’t volume overloaded.”
And here: http://socmob.org/2013/04/evidence-based-management-of-acute-heart-failure-forget-lmnop-think-pond/
These authors de-emphasize the importance of loop diuretic treatment over nitrates and NIPPV
Creatinine level: to what level will you allow the creatinine to escalate on diuresis, before you reduce the dose?
20 or 30 % from baseline, or a specific number?
Not really the scope of your article, but not to be seen in isolation, should we not use an ACE inhibitor, and or a vasodilator ex Nitro in the acute setting, before embarking on flogging the horse, say 30 min before the diuretic?
Take home message:
Doubling of the home dose for a few days, monitoring the clinical and lab outcome.
Also changing the po / home dose to the same mg but IVI on admission.
Thanks
As mentioned earlier, we are getting further away from using diuretics as the mainstay of therapy for acute heart failure. Nitrates and BIPAP appear to be much more effective and diuretics mainly serve to disrupt renal function. I think the fact that there were minimal differences between the low dose group and the high dose group in the DOSE trial supports this. Diuretics should be used with caution in these patients!
My understanding is that IV furosemide works faster but not better than PO. I use for acute decompensated, but once 02 saturation and dyspnea improve I change to oral. (Hospitalist)
It seems incredible that such a study has not been done previously. I can well recall arguments between residents in my training hospital more than 40 years ago about this matter, with strong feelings on both sides.
RESPONSE TO DOSE TRIAL COMMENTS:
RESPONSE #1
Dear Dr. Mitchell,
We thank you for reviewing our article and your comments. Regarding your discussion point regarding loop diuretics, we have reviewed the articles that you linked and certainly agree that the management of acute pulmonary edema may require non-invasive positive pressure ventilation and nitrates. This is usually dictated by the severity of the presentation – patients with severe respiratory distress may benefit from non-invasive positive pressure ventilation.
However, in patients presenting with decompensated heart failure due to acute-on-chronic fluid overload, these patients will likely benefit from diuretic therapy. The 2013 ACCF/AHA Guidelines recommend prompt treatment with intravenous loop diuretics for patients admitted with HF and evidence of significant fluid overload. These guidelines are available here: http://circ.ahajournals.org/content/128/16/e240.long
RESPONSE #2
Dear Dr. Le Roux,
We thank you for reviewing our article and your comments. Typically for diuresis, we will consider dose adjustment when there is evidence of an acute kidney injury or signs of hypovolemia suggestive of over-aggressive diuresis. The Acute Kidney Injury Network (AKIN) defines an acute kidney injury as a percentage increase in serum creatinine more than 50% from baseline, or an absolute increase of more than 26 µmol/L. However, patients with chronic volume overload and impaired renal function at baseline may also require a larger dose of intravenous diuretics to facilitate diuresis.
Nitrates (ie. nitroglycerin) can be considered as an adjuvant to diuretic therapy for symptomatic relief of dyspnea in patients admitted with acute decompensated heart failure. This is discussed in detail in the 2013 ACCF/AHA Guidelines, available here: http://circ.ahajournals.org/content/128/16/e240.long.
Regarding ACE inhibitors, we typically initiate these agents once the decompensated heart failure has been managed. The use of ACE inhibitors combined with diuretics can increase the likelihood for precipitating an acute kidney injury. Also, patients presenting with decompensated heart failure often already have an element of acute kidney injury as well (ie. cardiorenal syndrome). Certainly, ACE inhibitors are critical in the long-term management of patients with heart failure with reduced ejection fraction.
RESPONSE #3
Dear Dr. Turner,
We thank you for reviewing our article and your comments. Please see above for our response to a similar comment. Non-invasive positive pressure ventilation and diuretics all have role in decompensated heart failure, depending on the severity of presentation. The 2013 ACCF/AHA Guidelines are available here: http://circ.ahajournals.org/content/128/16/e240.long
RESPONSE #4
Dear Dr. Moher,
We thank you for reviewing our article and your comments. Certainly, intravenous furosemide may be necessary in patients with acute decompensated heart failure as their profound tissue edema can impair gastrointestinal absorption of oral furosemide. We agree with your management – once these patients are stabilized, they should be transitioned to oral furosemide.
RESPONSE #5
Dear Dr. Toews,
We thank you for reviewing our article and your comments. This is certainly a very interesting study, just published in the NEJM a few years ago. How the times have changed!
Thank you for your comments,
Christopher Cheung and Dr. Mustafa Toma