DOSE: Diuretic Strategies in Acute Decompensated Heart Failure (2011)

“In patients with acute decompensated heart failure, there were no significant differences in patients’ global assessment of symptoms or in the change in renal function when diuretic therapy was administered by continuous infusion or by bolus injection twice daily or at a high dose or a low dose.”

  • The DOSE Trial Investigators

1. Publication Details

  • Trial Title: Diuretic Strategies in Patients with Acute Decompensated Heart Failure
  • Citation: Felker GM, Lee KL, Bull DA, et al. Diuretic Strategies in Patients with Acute Decompensated Heart Failure. N Engl J Med. 2011;364(9):797-805. DOI: 10.1056/NEJMoa1005419
  • Published: March 3, 2011, in The New England Journal of Medicine
  • Author: G. Michael Felker, M.D., M.H.S.
  • Funding: The National Heart, Lung, and Blood Institute (NHLBI).

2. Keywords

  • Acute Decompensated Heart Failure, Diuretics, Furosemide, Bolus, Continuous Infusion, Randomized Controlled Trial

3. The Clinical Question

  • In patients with acute decompensated heart failure (ADHF) (Population), what is the most effective method of administering loop diuretics? Specifically, is a continuous infusion (Intervention) superior to intermittent boluses (Comparison), and is a high-dose strategy (Intervention) superior to a low-dose strategy (Comparison) in improving patient symptoms and preserving renal function (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Intravenous loop diuretics are a cornerstone of therapy for ADHF to relieve congestion. However, the optimal strategy for their administration was unknown. Some believed a continuous infusion would be more effective and less nephrotoxic than intermittent boluses, while others advocated for high-dose boluses to overcome diuretic resistance.
  • Knowledge Gap: Despite the widespread use of diuretics, there was no high-quality evidence from a large randomized trial to guide clinicians on the best dosing and administration strategy.
  • Proposed Hypothesis: The authors hypothesized that a continuous infusion of furosemide would be superior to intermittent boluses and that a high-dose strategy would be superior to a low-dose strategy for the primary outcomes.

5. Study Design and Methods

  • Design: A multicenter, prospective, 2×2 factorial, randomized, double-blind, controlled trial (used to test the effectiveness of interventions).
  • Setting: 26 medical centers in the United States and Canada.
  • Trial Period: Enrollment ran from August 2008 to September 2010.
  • Population:
    • Inclusion Criteria: Adult patients hospitalized with a primary diagnosis of ADHF who had signs of volume overload and had received at least one dose of an oral loop diuretic before randomization.
    • Exclusion Criteria: Included end-stage renal disease on dialysis, cardiogenic shock (systolic BP < 90 mm Hg), and a serum creatinine > 3.0 mg/dL.
  • Intervention: Patients were randomized in a factorial design to one of four groups for 72 hours:
  • Mode of Delivery: Continuous infusion vs. intermittent boluses every 12 hours.
  • Dose: High dose (2.5 times the prior oral dose) vs. low dose (equivalent to the prior oral dose).
  • Control: The control groups were intermittent boluses and the low-dose strategy.
  • Management Common to Both Groups: All other aspects of heart failure management were at the discretion of the treating clinicians.
  • Power and Sample Size: The authors calculated that a sample size of 308 patients would provide 80% power to detect a clinically meaningful difference in the primary outcomes. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80% is the standard accepted level for clinical trials).
  • Outcomes:
    • Primary Outcome (Efficacy): Patient’s global assessment of symptoms at 72 hours, measured on a visual analog scale.
    • Primary Outcome (Safety): Change in serum creatinine from baseline to 72 hours.
    • Secondary Outcomes: Included change in weight, net fluid loss, and mortality or rehospitalization at 60 days.

6. Key Results

  • Enrollment and Baseline: 308 patients were randomized. The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome:
    • Mode of Delivery: There was no significant difference in the primary efficacy outcome (symptom assessment) or the primary safety outcome (change in creatinine) between the continuous infusion and intermittent bolus groups.
    • Dose: There was no significant difference in the primary efficacy outcome (symptom assessment) or the primary safety outcome (change in creatinine) between the high-dose and low-dose groups.
  • Secondary Outcomes: Patients in the high-dose group had significantly greater net fluid loss and weight loss. However, they also had a higher incidence of transient worsening of renal function. There were no significant differences in 60-day mortality or rehospitalization rates for either comparison.
  • Adverse Events: The incidence of adverse events was similar across all groups.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcomes were analyzed using analysis of covariance (ANCOVA).
  • Primary Outcome Analysis: The primary outcomes were comparisons of the mean change in symptom scores and creatinine between the groups.
  • Key Statistic(s) Reported: The key statistics were the mean changes and the associated P-values for the primary outcomes.
  • Interpretation of Key Statistic(s):
    • P-value: The p-values for all primary outcome comparisons were well above the 0.05 threshold, indicating that the results were not statistically significant and very likely due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the trial was neutral, ARR and NNT are not applicable.
  • Subgroup Analyses: No significant differences were found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, double-blind, factorial design was of high quality and allowed two important clinical questions to be answered efficiently.
  • Generalizability: The inclusion of 26 diverse medical centers increases the applicability of the findings.
  • Statistical Power: The study was adequately powered for its primary outcomes.
  • Patient-Centered Outcomes: The study included the important patient-centered outcome of symptom assessment, in addition to physiological measures.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was well-conducted with a low risk of bias.
  • External Validity (Generalizability): The study population was a relatively stable group of ADHF patients and did not include those with severe renal failure or cardiogenic shock, limiting the generalizability of the findings to these sicker populations.
  • Other: The duration of the intervention was limited to 72 hours.

10. Conclusion of the Authors

  • In patients with acute decompensated heart failure, there were no significant differences in patient-reported symptoms or renal function with either a continuous vs. bolus infusion strategy or a high-dose vs. low-dose diuretic strategy.

11. To Summarize

  • Impact on Current Practice: This was a landmark trial that provided strong evidence that, for most patients with ADHF, the specific method of diuretic administration (bolus vs. infusion) is less important than achieving adequate diuresis. It also clarified the trade-offs of a high-dose strategy (better decongestion at the cost of transient renal dysfunction).
  • Specific Recommendations:
    • Patient Selection: For adult patients hospitalized with acute decompensated heart failure.
    • Actionable Intervention: The results suggest that either a continuous infusion or intermittent bolus strategy is acceptable. A high-dose strategy can be used to achieve more rapid decongestion, but clinicians should be prepared to monitor for and accept a transient rise in creatinine.
  • What This Trial Does NOT Mean: This trial does NOT mean that diuretic dosing is unimportant. It suggests that for the initial 72 hours, there is no single superior strategy for all patients.
  • Implementation Caveats: The key to diuretic therapy remains tailoring the dose and strategy to the individual patient’s response and clinical status, with careful monitoring of fluid balance, symptoms, and renal function.

12. Context and Related Studies

  • Building on Previous Evidence: The DOSE trial (2011) was designed to provide a definitive answer to a question that had been debated for years based on smaller, less conclusive studies and physiological reasoning.
  • Influence on Subsequent Research: The neutral findings of this trial have been highly influential in shaping heart failure guidelines, which now emphasize a more flexible, individualized approach to diuretic therapy rather than a rigid, one-size-fits-all protocol.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The optimal diuretic strategy in patients with severe renal dysfunction or cardiogenic shock remains an area of investigation.
  • Future Directions: Future research is focused on identifying which patients might benefit most from a high-dose or continuous infusion strategy and on developing novel therapies to overcome diuretic resistance.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a very common and fundamental aspect of heart failure management.
  • Methods: The multicenter, double-blind, factorial RCT design was of high quality and efficient. The patient population was representative of a general ADHF population.
  • Results: The study reported clear neutral findings for both of its primary comparisons. The secondary findings provided important insights into the trade-offs of a high-dose strategy.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The high external validity of this pragmatic trial means its findings are broadly applicable. This is a classic example of a high-quality “negative” trial that was profoundly practice-changing by providing strong evidence that a more complex or aggressive strategy is not superior to a simpler one, thereby supporting a more individualized approach to care.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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