DOSE

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Felker GM, et al. "Diuretic strategies in patients with acute decompensated heart failure". The New England Journal of Medicine. 2011. 364(9):797-805.
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Clinical Question

Among patients with acute decompensated HF, how do continuous vs. intermittent and low- vs. high-dose IV loop diuretics compare in symptom improvement and impairment of renal function at 72 hours?

Bottom Line

Among patients with acute decompensated HF, high-dose loop diuretics are associated with better symptom improvement than low-dose loop diuretics at the cost of some renal impairment, while continuous diuretic infusions are no better than intermittent diuretic boluses.

Major Points

Loop diuretics are central to the treatment of acute decompensated HF. Compared to intermittent boluses, continuous infusions of loop diuretics achieve more constant plasma levels of diuretic, which theoretically may protect against the adverse hemodynamic and renal effects of intermittent diuretic boluses. As a result, continuous infusions became en vogue, although no randomized trial had demonstrated the benefit of continuous infusions over intermittent boluses of diuretic.[1] The ideal dosage of loop diuretic also remains in question, with some providers using double or triple a patient's home dose and others preferring to start with the patient's home dose and gradually uptitrating to achieve euvolemia.

The 2011 Diuretic Optimization Strategies Evaluation (DOSE) trial randomized 308 patients with acute decompensated HF in a 2x2 factorial design to intermittent vs. continuous and low-dose (home dose) vs. high-dose therapy (2.5x home dose) with IV loop diuretics. Patients were mostly male (74%), white (73%), and older (mean age 66 years), with moderate-severe LV systolic dysfunction (baseline EF 35%) on loop diuretics at a dose equivalent to furosemide 134mg/day. At 72 hours, there was no statistically significant difference in global symptom assessment between intermittent or continuous arms, or between low- or high-dose arms, although there was a trend towards superiority of high- over low-dose therapy (P=0.06). More patients in the high-dose arm had an increase in creatinine >0.3 mg/dL at 72 hours compared to the low-dose arm (P=0.04), but there was no significant difference in rates of renal failure at 60 days (4% vs. 9%). There was a nonsignificant trend towards reduced hospitalization (27% vs. 36%) in high-dose vs. low-dose groups.

Although it did not reach statistical significance, the main result of DOSE was the demonstration of a trend towards more rapid symptom improvement with high-dose compared to low-dose diuretic therapy. This trend, and lack of a statistically significant difference, led others to criticize the study's selection of the global symptom assessment as its primary outcome,[2] as it may be too subjective and insufficiently sensitive to detect small differences in symptoms between groups. When more objective outcomes were used, high-dose diuretic therapy consistently bested low-dose therapy; this is seen in the study's secondary endpoints of proportion free of congestion (18% vs. 11%), 72-hour weight loss (3.9 vs. 2.8 kg), and 72-hour fluid loss (4.9 vs. 3.6 L), all of which favored high-dose therapy. These objective improvements occurred despite the higher rates of thiazide use among patients in the low-dose arm (15% vs. 8%). It is not known whether low-dose diuretic therapy necessitated the use of additional thiazides or whether this was a chance occurrence (P=0.06). It is possible that the rates of renal dysfunction and electrolyte abnormalities observed in the low-dose arm were driven in part by the increased use of thiazides. (Thiazides are, at least anecdotally, associated with more renal dysfunction and electrolyte abnormalities.[3])

The question of intermittent versus continuous infusions of diuretic remains, however, as there was no difference in efficacy when comparing these two first-line strategies. Current practice is generally to use intermittent diuretic boluses, and AHA/ACC guidelines recommend transitioning to a continuous infusion only if the patient's congestion is refractory to intermittent boluses. DOSE did not investigate aggressive step-up therapy as was used in the loop diuretic arm of the CARRESS-HF trial (2012), and thus the question remains unanswered.

Guidelines

AHA/ACCF Heart Failure (2013, adapted)[4]

  • Patients with HF in the hospital and significant fluid overload should be promptly treated with IV loop diuretics (class I, level B)
    • If on chronic loop diuretics, initial IV dose should equal or exceed the chronic dose and may be given continuously or as boluses with titration for symptom relief, reduction in volume excess, and avoidance of hypotension (class I, level B)
    • If inadequate relief of symptoms, it's reasonable to increase the dose of IV loop diuretics or add a second diuretic like a thiazide (class IIa, level B)
    • Low-dose dopamine infusion can be considered in addition to loop diuretics to improve diuresis and preserve renal perfusion and function (class IIb, level B)

Design

  • Multicenter, randomized, double-blind, 2x2 factorial, comparative trial
  • N=308
    • Bolus (n=156) vs. continuous (n=152)
    • Low-dose (n=151) vs. high-dose (n=157)
  • Setting: 26 centers in the US and Canada
  • Enrollment: 2008-2009
  • Follow-up: 60 days
  • Analysis: Intention-to-treat
  • Primary outcomes:
    • Global assessment of symptoms from baseline to 72 hours
    • Change in creatinine from baseline to 72 hours

Population

Inclusion Criteria

  • ADHF presentation in prior 24 hours
  • History of chronic HF without any specific EF requirement
  • Furosemide 80-240 mg PO daily (or equivalent loop diuretic) for ≥1 month

Exclusion Criteria

  • SBP <90 mmHg
  • Creatinine >3 mg/dL
  • Requiring inotropes (other than digoxin) or vasodilators

Baseline Characteristics

From the bolus group.

  • Demographics: Age 66.2 years, male 74%, white race 73%
  • Health data: SBP 118 mmHg, HR 76 BPM, O2 saturation 96%, JVD ≥8 cm H2O 91%, orthopnea 92%
  • PMH: ICM 58%, a fib or a flutter 54%, DM 52%
  • PSH: ICD 40%
  • Medications: ACE-inhibitor or ARB 67%, BB 85%, aldosterone antagonist 27%,
    • Furosemide or equivalent dose: 134 mg/day
  • HF data:
    • LVEF: 35%
    • HF hospitalization in prior year: 74%
  • Laboratory: Na 138 mg/dL, BUN 37 mg/dL, creatinine 1.5 mg/dL, NT-proBNP 7,308 pg/mL, cystatin C 1.6 mg/L

Interventions

  • Randomized to a group:
    • Low-dose bolus: Home dose of diuretic converted to IV equivalent, divided in two administrations daily
    • Low-dose infusion - Home dose of diuretic converted to IV equivalent, administered continuously
    • High-dose bolus - 2.5x home dose of diuretic converted to IV equivalent, divided in two administrations daily
    • High-dose infusion - 2.5x home dose of diuretic converted to IV equivalent, administered continuously
  • Each group had a matching placebo
  • At 48 hours the diuretics could be modified by the clinician to 50% increase in dose, maintenance of current intervention, or change to open-label oral diuretics
  • At 72 hours all interventions became open-label

Outcomes

Comparisons are
    Bolus vs. continuous
    Low-dose vs. high-dose

Primary Outcomes

Area under the curve (AUC), global visual assessment of symptoms (VAS) from baseline to 72 hours
4236 vs. 4373 (P=0.47)
4171 vs. 4430 (P=0.06)
Change in creatinine from baseline to 72 hours
+0.05 vs. +0.07 mg/dL (P=0.45)
+0.04 vs. +0.08 mg/dL (P=0.21)

Secondary Outcomes

AUC for dyspnea from baseline to 72 hours
4456 vs. 4699 (P=0.36)
4478 vs. 4668 (P=0.04)
No congestion at 72 hours
14% vs. 15% (P=0.78)
11% vs. 18% (P=0.09)
Weight change at 72 hours
-6.8 vs. -8.1 lbs (P=0.20)
-6.1 vs. -8.7 lbs (P=0.01)
Net fluids at 72 hours
-4,237 vs. -4,249 mL (P=0.89)
-3,575 vs. -4,899 mL (P=0.01)
NT-proBNP change at 72 hours
-1,316 vs. -1,773 pg/mL (P=0.44)
-1,194 vs. -1,882 pg/mL (P=0.06)
Persistent or worsening HF
25% vs. 23% (P=0.78)
26% vs. 22% (P=0.40)
Treatment failure
38% vs. 39% (P=0.88)
37% vs. 40% (P=0.56)
Change in creatinine >0.3 mg/dL
17% vs. 19% (P=0.64)
14% vs. 23% (P=0.04)
Hospital stay
5 vs. 5 days (P=0.97)
6 vs. 5 days (P=0.55)
Alive, out of hospital
51 vs. 51 days (P=0.36)
50 vs. 52 days (P=0.42)
All-cause mortality, rehospitalization, or ED visit
HR for continuous infusion 1.15 (95% CI 0.83-1.60; P=0.41)
HR for high-dose 0.83 (95% CI 0.60-1.16; P=0.28)

Adverse Events

Statistics not given except where noted.

Any
44% vs. 44% (P=0.92)
50% vs. 38% (P=0.03)
Severe
23% vs. 24% (P=0.80)
25% vs. 23% (P=0.75)
Cardiac
28% vs. 25%
30% vs. 22%
Renal/urinary
5% vs. 8%
9% vs. 4%

Criticisms

  • Dosing may have been too low, especially in those with renal dysfunction, with goal weight loss of 5 to 10%[2]
  • Effective diuresis triggers neurohormonal reflexes, which may be associated with development of associated symptoms and may obscure the global assessment[2]
  • No cost analysis[2]

Funding

  • National Heart, Lung, and Blood Institute grants
  • Authors with multiple financial disclosures

Further Reading

  1. Fonarow GC. "Editorial: Comparative effectiveness of diuretic regimens." The New England Journal of Medicine. 2011;364(9):877-878.
  2. 2.0 2.1 2.2 2.3 Various authors. "Correspondence: Diuretic Strategies in Patients with Acute Heart Failure." N Engl J Med. 2011; 364:2066-2069.
  3. Rosenberg J, et al. "Combination therapy with metolazone and loop diuretics in outpatients with refractory heart failure: an observational study and review of the literature." Cardiovasc Drugs Ther. 2005;19(4):301-6.
  4. Yancy CW, et al. "2013 ACCF/AHA guideline for the management of heart failure." Circulation. 2013;128:e240-e327.