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    DOSE Trial 2011

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    DOSE Trial 2011

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    DOSE Trial 2011

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    of 5

    Diuretic Optimization Strategies Evaluation in

    Acute Heart Failure - DOSE


    Mar 02, 2011

    Author/Summarized by Dharam J. Kumbhani, MD, SM, FACC


    Author:
    Summary Reviewer: Deepak L. Bhatt, MD, MPH, FACC, MBA
    Trial Sponsor: National Heart, Lung, and Blood Institute Heart
    Failure Clinical Research Network
    Date Presented: 01/01/2010
    Date Published: 01/01/2011
    Date Updated: 03/02/2011
    Original Posted Date: 03/02/2011

    References
    Description:

    Although intravenous (IV) diuretics are routinely used in clinical practice, the
    optimal dosage and route of administration are not well understood. In addition,
    observational studies have demonstrated worsening creatinine and clinical
    outcomes with higher dose of furosemide. Accordingly, the DOSE study sought to
    evaluate the safety and efficacy of different strategies for diuretic dosing in
    patients with acute decompensated heart failure (ADHF).
    Hypothesis:
    The DOSE study sought to evaluate the safety and efficacy of two strategies for
    furosemide dosing in patients with ADHF: 1) route of administration (Q12 hour
    bolus vs. continuous infusion), and 2) dosing (low intensification to 1x oral dose
    vs. high intensification to 2.5x oral dose).
    Study Design

    Factorial

    Patients Enrolled: 308


    Mean Follow Up: 60 days
    Mean Patient Age: Median age: 66 years
    Female: 27
    Mean Ejection Fraction: 35
    Patient Populations:

    ≥18 years old


    Prior clinical diagnosis of HF with daily home use of oral loop diuretic for at
    least 1 month
    Daily oral dose of furosemide ≥80 mg and ≤240 mg (or equivalent)
    Identified within 24 hours of hospital admission
    HF defined by at least one symptom and one sign
    Anticipated need for IV loop diuretics for at least 48 hours
    Willingness to provide informed consent
    Exclusions:

    Received or planned IV vasoactive treatment (inotropes, vasodilators) or ultra-


    filtration therapy for HF
    Systolic blood pressure <90 mm Hg
    Serum creatinine >3.0 mg/dl at baseline or renal replacement therapy
    BNP <250 ng/ml or NT-proBNP <1000 mg/ml (if measured for clinical purposes)
    Acute coronary syndrome within 4 weeks
    Anticipated need for coronary angiography or other procedures requiring IV
    contrast
    Primary Endpoints:

    Efficacy:

    Patient Global Assessment by VAS over 72 hours using AUC


    Safety:

    Change in creatinine from baseline to 72 hours


    Secondary Endpoints:

    Change in weight over 24, 48, 72, and 96 hours


    Freedom from signs and symptoms of congestion at 72 hours
    Bivariate vector of change in creatinine and weight at 72 hours
    Dyspnea VAS AUC over 24, 48, and 72 hours
    Change in serum creatinine at 24, 48, and 96 hours, day 7 (or discharge), and
    day 60
    Change in cystatin C at 72 hours, day 7 (or discharge), and day 60
    Persistent or worsening HF
    Development of worsening renal function (increase in creatinine >0.3 mg/dl at
    any time during initial 72 hours)
    Treatment failure (persistent HF, worsening renal failure, or death)
    Index hospitalization length of stay
    Death, rehospitalization, or emergency department visit within 60 days
    Drug/Procedures Used:

    Patients were randomized in a 2 x 2 factorial design to either Q12 hour bolus


    versus continuous infusion, or low intensification to 1x oral dose versus high
    intensification to 2.5x oral dose of furosemide. About 48 hours after
    randomization, patients could be changed over to oral diuretics, continued on
    same strategy, or undergo a 50% increase in dose, as deemed appropriate.
    Concomitant Medications:

    Angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (64%),


    beta-blockers (83%), aldosterone antagonists (28%)
    Principal Findings:

    A total of 308 patients were randomized in a 2 x 2 factorial fashion. The mean


    ejection fraction was 35 ± 18%, with a baseline furosemide dose of 131 mg/day.
    About 57% of the patients had ischemic cardiomyopathy, 53% had atrial
    fibrillation or atrial flutter, and 51% had diabetes. The mean systolic blood
    pressure was 119 mm Hg, with a mean heart rate of 78 bpm. Mean sodium was
    138 mg/dl, and mean creatinine was 1.6 mg/dl. The mean N-terminal B-type
    natriuretic peptide (NT-proBNP) was 7439 pg/ml.
    There was no difference between Q12 dosing and continuous infusion of
    furosemide on the visual analog scale (VAS) area under the curve (AUC) (4236 vs.
    4373, p = 0.47). Change in creatinine was also similar (0.05 vs. 0.07 mg/dl, p =
    0.45). Secondary endpoints such as net volume loss (4237 vs. 4249 ml, p = 0.89), %
    treatment failure (38% vs. 39%, p = 0.88), change in weight at 72 hours (-6.8 vs. 8.1
    lbs, p = 0.20), dyspnea VAS AUC at 72 hours (4456 vs. 4699, p = 0.36), and length
    of stay (5 vs. 5 days, p = 0.97) were similar between the two arms. The incidence
    of a composite of death, rehospitalization, or emergency department visit was
    similar between the two arms (hazard ratio [HR] 1.15, 95% confidence interval [CI]
    0.83-1.60, p = 0.41).

    For the low and high intensification of furosemide dosing analysis, there was no
    difference on the VAS AUC (4171 vs. 4430, p = 0.06). Change in creatinine was also
    similar (0.04 vs. 0.08 mg/dl, p = 0.21). Secondary endpoints such as net volume
    loss (3575 vs. 4899 ml, p = 0.001), change in weight at 72 hours (-6.1 vs. 8.7 lbs, p
    = 0.011), and dyspnea VAS AUC at 72 hours (4478 vs. 4688, p = 0.04) were
    significantly worse in the low intensification arm, as compared with the high
    intensification arm, respectively.

    Other outcomes such as length of stay (6 vs. 5 days, p = 0.55), and % treatment
    failure (37% vs. 40%, p = 0.56) were similar between the two arms. The % of
    patients with increase in creatinine of >0.3 mg/dl within 72 hours was lower in the
    low intensification arm (14% vs. 23%, p = 0.04). However, this was transient, since
    there was no overall change in creatinine or cystatin C between the two groups.
    There was also no difference between the two groups in serum creatinine over
    the 60 day follow-up period. The incidence of a composite of death,
    rehospitalization, or emergency department visit was similar between the two
    arms (HR 0.83, 95% CI 0.60-1.16, p = 0.28).
    Interpretation:

    The results of the DOSE trial illustrate that there is no difference in global
    symptom relief, as assessed by the VAS AUC, or change in renal function, with a
    Q12 versus continuous infusion, or low versus high intensification of furosemide
    dosing. Further, continuous dosing was not associated with an improvement in
    any of the secondary outcomes assessed, including net diuresis, weight loss, or
    treatment failure. On the other hand, high intensification (2.5x oral dose) of
    furosemide was associated with a significant improvement in net diuresis, weight
    loss, and symptom relief, as compared with low intensification. Changes in
    creatinine noted in the high intensification arm were transient.

    These results are important, and aim to address two important clinically relevant
    questions regarding the use of diuretics in patients with ADHF. One of the
    limitations is that the study protocol permitted change in congestive heart failure
    (CHF) medications 48 hours after randomization, based on clinical response. This
    could have biased the results towards the null. An analysis of outcomes at 48
    hours may be helpful to address this issue. Also, these results are applicable to
    patients with chronic CHF, who did not require inotropes or intravenous
    vasodilators, and who were on moderate to high doses of diuretic at baseline.
    References:

    Felker GM, Lee KL, Bull DA, et al., on behalf of the NHLBI Heart Failure Clinical
    Research Network. Diuretic strategies in patients with acute decompensated heart
    failure. N Engl J Med 2011;364:797-805.

    Presented by Dr. G. Michael Felker at the ACC.10/i2 Summit, Atlanta, GA, March
    2010.

    Keywords: Follow-Up Studies, Diuresis, Blood Pressure, Creatinine, Sodium Potassium


    Chloride Symporter Inhibitors, Furosemide, Vasodilator Agents, Cardiomyopathies, Confidence
    Intervals, Natriuretic Peptide, Brain, Treatment Failure, Area Under Curve, Weight Loss, Body
    Weight, Diuretics, Dyspnea, Heart Rate, Visual Analog Scale, Heart Failure, Peptide Fragments,
    Atrial Fibrillation, Informed Consent, Cystatin C, Diabetes Mellitus, Atrial Flutter

    © 2024 American College of Cardiology Foundation. All rights reserved.

    Last Updated August 2019

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