Diuretic Optimization Strategies Evaluation in Acute Heart Failure - DOSE

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.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Anticoagulation Management and Atrial Fibrillation, Atrial Fibrillation/Supraventricular Arrhythmias, Statins, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

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


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