ZARBOCK 2020: Early vs Delayed RRT in AKI after Cardiac Surgery (2020)

“Among patients with acute kidney injury after cardiac surgery who were at high risk for poor outcomes, a strategy of early, preemptive initiation of renal replacement therapy did not reduce the risk of death at 90 days compared with a standard, delayed-initiation strategy.”

— The Zarbock et al. Study Group

1. Publication Details

  • Trial Title: Early versus Late Initiation of Renal-Replacement Therapy in Critically Ill Patients with Acute Kidney Injury after Cardiac Surgery.
  • Citation: Zarbock A, Kellum JA, Schmidt C, et al; for the ELAIN Investigators. Early versus Late Initiation of Renal-Replacement Therapy in Critically Ill Patients with Acute Kidney Injury after Cardiac Surgery. JAMA. 2020;324(10):956-966. doi:10.1001/jama.2020.14352. Note: This trial is a follow-up to the single-center ELAIN trial and is often referred to by the lead author’s name.
  • Published: September 8, 2020, in The Journal of the American Medical Association (JAMA).
  • Author: Alexander Zarbock, M.D.
  • Funding: German Research Foundation.

2. Keywords

Acute Kidney Injury (AKI), Cardiac Surgery, Renal Replacement Therapy (RRT), Timing of Initiation, Postoperative Care, Biomarkers.

3. The Clinical Question

In critically ill adult patients who develop acute kidney injury (AKI) after cardiac surgery (Population), does an early strategy of initiating renal replacement therapy (RRT) based on biomarkers (Intervention) compared to a standard, delayed strategy based on clinical indications (Comparison) reduce 90-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: AKI is a common and serious complication after cardiac surgery. The optimal timing to initiate RRT was a major point of controversy. The single-center ELAIN trial (also led by Zarbock) had previously shown a mortality benefit with an early RRT strategy in a similar population.
  • Knowledge Gap: The promising results of the single-center ELAIN trial required confirmation in a larger, multicenter trial before the “early” strategy could be widely adopted. This was especially important given that other large trials in general ICU populations (AKIKI, STARRT-AKI) had favored a delayed approach.
  • Proposed Hypothesis: The authors hypothesized that an early strategy for RRT initiation would be associated with a lower risk of death at 90 days than a standard, delayed strategy in patients with AKI after cardiac surgery.

5. Study Design and Methods

  • Design: A prospective, multicenter, randomized, controlled trial.
  • Setting: 12 university hospitals in Germany.
  • Trial Period: Enrollment from July 2018 to June 2019.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) who developed AKI stage 2 or 3 (KDIGO criteria) within 48 hours after cardiac surgery and had a positive test for a urinary biomarker of kidney damage ([TIMP-2]•[IGFBP7] >2.0).
    • Exclusion Criteria: Pre-existing end-stage kidney disease or urgent indications for RRT.
  • Intervention: An “early” strategy, where RRT was initiated within 6 hours of meeting the eligibility criteria.
  • Control: A “delayed” strategy, where RRT was initiated only after the development of AKI stage 3 with an urgent indication, or if anuria persisted for >6 hours.
  • Management Common to Both Groups: All patients received standard postoperative care. The choice of RRT modality was at the discretion of the local site.
  • Power and Sample Size: The trial was powered to detect a 12% absolute difference in 90-day mortality, requiring 288 patients.
  • Outcomes:
    • Primary Outcome: All-cause mortality at 90 days.
    • Secondary Outcomes: Included duration of RRT, recovery of kidney function, and ICU length of stay.

6. Key Results

  • Enrollment and Baseline: 292 patients were randomized (146 to the early group, 146 to the delayed group). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in 90-day mortality between the early and delayed strategy groups (44.5% vs 46.6%; P=0.74).
  • Secondary Outcomes: There were no significant differences in the recovery of kidney function or ICU length of stay. A key finding was that 38% of patients in the delayed-strategy group recovered kidney function and never required RRT.
  • Adverse Events: The rates of adverse events were similar between the two groups.

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The proportion of deaths at day 90 was compared between the two groups.
  • Key Statistic(s) Reported: Risk Ratio (RR) for death at 90 days with the early strategy: 0.96 (95% CI, 0.72 to 1.28; P=0.74).
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk in Intervention Group) / (Risk in Control Group).
      • Calculation: The paper reports the RR as 0.96.
      • Clinical Meaning: An RR of 0.96 means there was a 4% lower relative risk of death in the early RRT group, but this difference was not statistically significant.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The reported 95% CI was 0.72 to 1.28.
      • Clinical Meaning: Since this confidence interval widely crosses the line of no effect (1.0), it indicates that there is no significant difference between the two strategies. The true effect is likely somewhere between a 28% benefit and a 28% harm.
    • P-value:
      • Calculation: The reported p-value was 0.74.
      • Clinical Meaning: The p-value of 0.74 is far above the 0.05 threshold, confirming that the observed result is very likely due to chance. A result is conventionally considered statistically significant if the p-value is less than 0.05.
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group).
      • Calculation: ARR = 46.6% – 44.5% = 2.1%.
      • Clinical Meaning: The early strategy was associated with a non-significant 2.1% absolute reduction in the risk of death at 90 days.
    • Number Needed to Treat (NNT): Not applicable, as the intervention showed no benefit.
  • Subgroup Analyses: No significant benefit was found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: This was a multicenter, randomized trial that provided a robust answer to a specific clinical question in a high-risk population.
  • Biomarker Enrichment: The use of a kidney stress biomarker to enrich the study population for high-risk patients was an innovative and important methodological feature.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded, which could introduce performance bias, though the primary outcome of mortality is objective.
  • External Validity (Generalizability): The results are specific to patients with AKI after cardiac surgery and may not be generalizable to other ICU populations.
  • Other: The mortality rate in both groups was higher than anticipated, which could have affected the power of the study to detect a smaller difference.

10. Conclusion of the Authors

“Among critically ill patients with acute kidney injury after cardiac surgery at high risk for death and morbidity, early initiation of renal replacement therapy, compared with a delayed strategy, did not significantly reduce the risk of death at 90 days.”

11. To Summarize

  • Impact on Current Practice: This trial was a crucial multicenter study that failed to confirm the positive findings of the earlier single-center ELAIN trial. It provided strong evidence that a routine policy of early, biomarker-guided RRT initiation is not superior to a standard, watchful-waiting approach in patients with AKI after cardiac surgery. This brings the evidence for this specific population in line with the broader critical care population.
  • Specific Recommendations:
    • Patient Selection: For critically ill adult patients with severe AKI after cardiac surgery who do not have an urgent indication for RRT.
    • Actionable Intervention: A standard, watchful-waiting approach is the preferred strategy. Initiate RRT only if urgent indications develop.
    • Expected Benefit: No mortality benefit with an early strategy. A delayed strategy avoids RRT altogether in over one-third of patients.
  • What This Trial Does NOT Mean: This trial does not mean RRT should be unduly delayed when clear, life-threatening indications are present.
  • Implementation Caveats: A watchful-waiting strategy requires careful and frequent monitoring of the patient for the development of urgent indications for RRT.

12. Context and Related Studies

  • Building on Previous Evidence: This trial was a direct attempt to validate the findings of the ELAIN trial (2016). Its neutral result aligns it more closely with the findings of the large general ICU trials, AKIKI (2016) and STARRT-AKI (2020), which also favored a delayed strategy.
  • Influence on Subsequent Research: This study provides a more definitive answer for the post-cardiac surgery population and reinforces the general consensus that a delayed RRT strategy is appropriate for most critically ill patients without urgent indications.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: Are there other biomarkers or clinical criteria that can better identify the small subset of patients who might still benefit from earlier RRT?
  • Future Directions: Future research is focused on developing better predictive tools to identify which patients will ultimately require RRT, thereby allowing for a more personalized approach to timing.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was highly relevant, seeking to confirm a promising but single-center finding in a specific high-risk population.
  • Methods: The multicenter, randomized design was methodologically strong. The use of a biomarker for patient selection was a novel and important feature.
  • Results: The trial had a clear and convincing neutral result for its primary outcome. The finding that a significant proportion of the delayed group avoided RRT was a key secondary finding.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The results are highly applicable to the care of post-cardiac surgery patients and provide a clear directive to favor a standard, watchful-waiting approach to RRT initiation.

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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