CARRESS-HF: Ultrafiltration in Acute Decompensated Heart Failure (2012)

“In patients with acute decompensated heart failure, cardiorenal syndrome, and persistent congestion, a strategy of stepped pharmacologic therapy was superior to a strategy of ultrafiltration for the preservation of renal function at 96 hours, with no significant difference in weight loss.”

  • The CARRESS-HF Investigators

1. Publication Details

  • Trial Title: Ultrafiltration in Decompensated Heart Failure with Cardiorenal Syndrome
  • Citation: Bart BA, Goldsmith SR, Lee KL, et al. Ultrafiltration in Decompensated Heart Failure with Cardiorenal Syndrome. N Engl J Med. 2012;367(24):2296-2304. DOI: 10.1056/NEJMoa1210357
  • Published: December 13, 2012, in The New England Journal of Medicine
  • Author: Bradley A. Bart, M.D.
  • Funding: National Heart, Lung, and Blood Institute (NHLBI).

2. Keywords

  • Acute Decompensated Heart Failure, Cardiorenal Syndrome, Ultrafiltration, Diuretics, Randomized Controlled Trial

3. The Clinical Question

  • In patients with acute decompensated heart failure, persistent congestion, and worsening renal function (Population), is a strategy of ultrafiltration (Intervention) superior to a stepped pharmacologic (diuretic) strategy (Comparison) for the primary composite outcome of change in serum creatinine and change in weight at 96 hours (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The management of acute decompensated heart failure with volume overload and worsening renal function (cardiorenal syndrome) is a major clinical challenge. High doses of loop diuretics, the standard therapy, can sometimes be ineffective and may further worsen renal function. Ultrafiltration, a mechanical method of fluid removal, was a promising alternative that could remove isotonic fluid without the neurohormonal activation associated with diuretics.
  • Knowledge Gap: While physiologically appealing, there was no high-quality evidence from a large randomized trial to determine if ultrafiltration was truly superior to a strategy of aggressive, protocol-guided diuretic therapy in this high-risk patient population.
  • Proposed Hypothesis: The authors hypothesized that a strategy of ultrafiltration would be superior to a stepped pharmacologic strategy in preserving renal function and achieving greater weight loss.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 25 medical centers in the United States and Canada.
  • Trial Period: Enrollment ran from June 2008 to January 2012.
  • Population:
    • Inclusion Criteria: Adult patients hospitalized with acute decompensated heart failure, with evidence of persistent congestion and worsening renal function (a rise in creatinine of at least 0.3 mg/dL).
    • Exclusion Criteria: Included a systolic blood pressure <90 mm Hg, a need for inotropes or mechanical ventilation, and end-stage renal disease.
  • Intervention: Patients were treated with ultrafiltration at a rate of 200 ml per hour.
  • Control: Patients were treated with a stepped pharmacologic protocol, which involved escalating doses of intravenous loop diuretics and the addition of other diuretics like metolazone and dopamine as needed.
  • Management Common to Both Groups: Both strategies were protocol-guided with the goal of relieving congestion.
  • Power and Sample Size: The authors calculated that a sample size of 188 patients would provide 88% power to detect a significant difference in the primary composite outcome. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80-90% is considered standard).
  • Outcomes:
    • Primary Outcome: A composite of the change in serum creatinine and the change in body weight, both assessed at 96 hours after randomization.
    • Secondary Outcomes: Included patient-reported symptoms, rates of rehospitalization, and mortality at 60 days.

6. Key Results

  • Enrollment and Baseline: 188 patients were randomized (94 to ultrafiltration and 94 to pharmacologic therapy). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: The stepped pharmacologic strategy was superior to ultrafiltration for the primary composite outcome.
    • Creatinine: The mean serum creatinine level increased by 0.23 mg/dL in the ultrafiltration group, whereas it decreased by 0.04 mg/dL in the pharmacologic-therapy group (p=0.003).
    • Weight Loss: There was no significant difference in weight loss between the two groups (a mean of 5.5 kg in the ultrafiltration group vs. 5.7 kg in the pharmacologic-therapy group).
  • Secondary Outcomes: There were no significant differences between the groups in patient-reported symptoms, rehospitalization rates, or 60-day mortality.
  • Adverse Events: The incidence of serious adverse events was significantly higher in the ultrafiltration group (72% vs. 57%), driven primarily by a higher rate of renal failure.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The components of the primary outcome were analyzed using t-tests.
  • Primary Outcome Analysis: The primary outcome was a comparison of the mean changes in creatinine and weight between the two groups.
  • Key Statistic(s) Reported: The key statistics were the mean changes and the associated P-values for the two components of the primary outcome.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.003 for the difference in the change in creatinine is well below the 0.05 threshold, indicating a highly statistically significant difference in favor of the pharmacologic-therapy group (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the trial showed harm with the intervention, NNT is not applicable. The key clinical impact is the finding of a higher rate of serious adverse events with ultrafiltration.
  • Subgroup Analyses: No significant subgroup analyses were reported.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, controlled design provided high-quality evidence on an important clinical question.
  • Generalizability: The inclusion of 25 diverse medical centers increases the applicability of the findings.
  • Statistical Power: The study was adequately powered for its primary outcome.
  • Patient-Centered Outcomes: The study included important patient-centered outcomes like symptoms and rehospitalization rates, in addition to the primary physiological endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label (unblinded), which introduces a risk of performance bias.
  • External Validity (Generalizability): The specific stepped-care pharmacologic protocol was very aggressive and may not be representative of “usual care” in all centers. The ultrafiltration protocol was also fixed at 200 ml/hr and may not represent the optimal way to deliver this therapy.
  • Other: The primary outcome was a composite of a lab value (creatinine) and a clinical measure (weight), which can sometimes be difficult to interpret.

10. Conclusion of the Authors

  • In patients with acute decompensated heart failure and cardiorenal syndrome, the use of a stepped pharmacologic-therapy algorithm was superior to ultrafiltration for the preservation of renal function and was associated with fewer adverse events.

11. To Summarize

  • Impact on Current Practice: This was a major practice-changing trial that provided strong evidence against the routine use of ultrafiltration in this patient population and demonstrated the effectiveness of an aggressive, protocol-guided diuretic strategy.
  • Specific Recommendations:
    • Patient Selection: For adult patients with acute decompensated heart failure, persistent congestion, and worsening renal function.
    • Actionable Intervention: A stepped pharmacologic strategy, involving escalating doses of loop diuretics and the addition of other diuretics as needed, should be the first-line approach.
  • What This Trial Does NOT Mean: This trial does NOT mean that ultrafiltration has no role in the management of heart failure. It may still be a useful rescue therapy for patients who are truly refractory to all forms of diuretic therapy.
  • Implementation Caveats: The success of the pharmacologic strategy in this trial was dependent on a structured, aggressive, and protocolized approach to diuretic administration.

12. Context and Related Studies

  • Building on Previous Evidence: The CARRESS-HF trial (2012) was designed to provide a definitive answer to the question of ultrafiltration’s role, which had been raised by smaller, less conclusive studies.
  • Influence on Subsequent Research: The definitive negative result of this trial has led to a significant decline in the routine use of ultrafiltration for cardiorenal syndrome and has reinforced the importance of optimizing medical therapy first.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The optimal way to deliver ultrafiltration (e.g., slower rates, different timing) in patients who are truly diuretic-refractory remains an area of investigation.
  • Future Directions: Future research is focused on identifying which specific patients might still benefit from ultrafiltration and on developing novel pharmacologic therapies for cardiorenal syndrome.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a common and difficult clinical problem.
  • Methods: The multicenter RCT design was appropriate. The main methodological weakness is the open-label design. A key strength was the use of a highly structured and aggressive diuretic protocol in the control arm, which represented a true test of medical therapy versus a mechanical approach.
  • Results: The study reported a clear and statistically significant difference in its primary outcome, favoring the pharmacologic-therapy arm. The finding of increased serious adverse events in the ultrafiltration group is a critical safety signal.
  • 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 to the management of cardiorenal syndrome in most hospital settings.

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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