STARRT-AKI: Standard vs. Accelerated RRT in AKI (2020)

“In a large, multicenter, randomized trial, we found that an accelerated strategy for the initiation of renal-replacement therapy in critically ill patients with acute kidney injury did not decrease mortality at 90 days as compared with a standard strategy.”

— The STARRT-AKI Investigators

1. Publication Details

  • Trial Title: Standard versus Accelerated Initiation of Renal-Replacement Therapy in Acute Kidney Injury.
  • Citation: The STARRT-AKI Investigators. Standard versus Accelerated Initiation of Renal-Replacement Therapy in Acute Kidney Injury. N Engl J Med. 2020;383(3):240-251. doi:10.1056/NEJMoa2000741.
  • Published: July 16, 2020, in The New England Journal of Medicine.
  • Author: The STARRT-AKI Investigators for the Canadian Critical Care Trials Group, the Australian and New Zealand Intensive Care Society Clinical Trials Group, and the United Kingdom Critical Care Research Group.
  • Funding: Canadian Institutes of Health Research; National Health and Medical Research Council of Australia; and others.

2. Keywords

Acute Kidney Injury (AKI), Renal Replacement Therapy (RRT), Continuous Renal Replacement Therapy (CRRT), Sepsis, Critical Illness, Timing of Initiation.

3. The Clinical Question

In critically ill patients with severe acute kidney injury (Population), does an accelerated strategy of initiating renal replacement therapy (RRT) within 12 hours (Intervention) compared to a standard, watchful-waiting strategy (Comparison) reduce all-cause mortality at 90 days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Acute kidney injury (AKI) is common in critically ill patients and is associated with high mortality. Renal replacement therapy (RRT) is a life-saving intervention, but the optimal time to start it was a major point of clinical equipoise.
  • Knowledge Gap: Previous trials (like AKIKI and ELAIN) had conflicting results regarding the timing of RRT initiation. It was unclear if an “early” (accelerated) start improved survival by preventing complications of AKI, or if a “late” (standard) start avoided the risks and costs of an invasive therapy in patients who might recover kidney function spontaneously. A large, definitive trial was needed.
  • Proposed Hypothesis: The authors hypothesized that an accelerated strategy for RRT initiation would be associated with a lower risk of death at 90 days than a standard strategy.

5. Study Design and Methods

  • Design: A prospective, multicenter, international, open-label, randomized, controlled trial.
  • Setting: 168 intensive care units (ICUs) in 15 countries.
  • Trial Period: Enrollment from October 2015 to September 2019.
  • Population:
    • Inclusion Criteria: Adult critically ill patients (≥18 years) with severe AKI (KDIGO stage 2 or 3) for whom the treating clinician had determined that RRT was not urgently required but was uncertain about the optimal timing.
    • Exclusion Criteria: Urgent indications for RRT (e.g., severe hyperkalemia, severe acidosis), pre-existing end-stage kidney disease, or prior RRT.
  • Intervention: An accelerated strategy, where RRT was to be initiated as soon as possible and within 12 hours after the patient met eligibility criteria.
  • Control: A standard strategy, where RRT was discouraged unless an urgent indication developed or AKI persisted for more than 72 hours.
  • Management Common to Both Groups: The choice of RRT modality (intermittent or continuous) and all other aspects of ICU care were at the discretion of the local clinical team.
  • Power and Sample Size: The trial was powered to detect a 6.5% absolute difference in 90-day mortality, requiring 2866 patients.
  • Outcomes:
    • Primary Outcome: All-cause mortality at 90 days.
    • Secondary Outcomes: Included RRT dependence among survivors at 90 days, duration of RRT, ICU and hospital length of stay, and adverse events.

6. Key Results

  • Enrollment and Baseline: 2927 patients were included in the final analysis (1465 in the accelerated-strategy group, 1462 in the standard-strategy 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 accelerated and standard strategy groups (43.9% vs 43.7%; P=0.92).
  • Secondary Outcomes: Among survivors at 90 days, more patients in the accelerated-strategy group were still dependent on RRT (10.4% vs 6.0%). Patients in the accelerated-strategy group also had a longer median duration of RRT.
  • Adverse Events: Adverse events related to RRT (e.g., hypotension, hypophosphatemia) were more common in the accelerated-strategy group.

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed.
  • Statistical Tests Used: The primary outcome was analyzed using a mixed-effects logistic regression model.
  • Primary Outcome Analysis: The proportion of deaths at day 90 was compared between the two groups.
  • Key Statistic(s) Reported: Relative Risk (RR) for death at 90 days: 1.00 (95% CI, 0.93 to 1.09; P=0.92).
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR): An RR of 1.00 indicates no difference in the risk of death between the two strategies.
    • Confidence Interval (CI): The 95% CI is narrow and centered around 1.0, providing a precise estimate of no effect.
    • P-value: The p-value of 0.92 confirms the lack of a statistically significant difference.
  • Clinical Impact Measures: Not applicable as no benefit was shown for the primary outcome.
  • Subgroup Analyses: There was no significant benefit for the accelerated strategy in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: This was a very large, international, multicenter, randomized trial that provided a robust answer to a critical clinical question.
  • Generalizability: The pragmatic design and inclusion of a large number of diverse ICUs worldwide make the findings highly generalizable.
  • Patient-Centered Outcomes: The primary outcome of 90-day mortality is a strong, patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label (unblinded), which is a potential source of bias, though the primary outcome of mortality is objective.
  • External Validity (Generalizability): The trial enrolled patients for whom the clinician was already uncertain about timing, so it may not apply to patients with clear urgent indications for RRT.
  • Other: A significant proportion (38%) of patients in the standard-strategy group never required RRT, highlighting the potential for renal recovery with a watchful approach.

10. Conclusion of the Authors

“In this trial involving critically ill patients with acute kidney injury, an accelerated strategy for the initiation of renal-replacement therapy did not result in a lower risk of death at 90 days than a standard strategy.”

11. To Summarize

  • Impact on Current Practice: This trial was a landmark study that has largely settled the debate on the timing of RRT initiation. It provides strong evidence against a routine policy of “early” RRT for all patients with severe AKI. It supports a more conservative, watchful-waiting approach, which avoids exposing a substantial number of patients who will recover on their own to an unnecessary and potentially harmful invasive procedure.
  • Specific Recommendations:
    • Patient Selection: For critically ill adult patients with severe AKI 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 (e.g., severe metabolic derangements) or if kidney function fails to recover.
    • Expected Benefit: No mortality benefit with an accelerated strategy. A standard strategy avoids RRT altogether in over one-third of patients and is associated with a lower risk of RRT dependence among survivors.
  • What This Trial Does NOT Mean: This trial does not mean RRT should be unduly delayed when clear, life-threatening indications are present. The “standard” arm still involved prompt initiation of RRT when it became necessary.
  • 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: STARRT-AKI was the largest and most definitive trial on this topic, designed to resolve the conflicting findings of earlier, smaller trials like ELAIN (2016) (which favored early RRT) and AKIKI (2016) (which favored a delayed strategy).
  • Influence on Subsequent Research: The results of STARRT-AKI are largely consistent with those of AKIKI and have solidified the evidence base in favor of a more conservative approach to RRT initiation. It is now considered the definitive trial in this area and heavily influences international guidelines.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: Are there specific subgroups of patients with AKI (e.g., based on biomarkers or etiology) who might still benefit from an accelerated approach?
  • 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 of fundamental importance in critical care nephrology, addressing a common, high-stakes clinical decision.
  • Methods: The large, multicenter, international RCT design was methodologically robust and is the major strength of the trial.
  • Results: The trial had a clear and convincing neutral result for its primary outcome. The secondary findings of increased RRT dependence and adverse events in the accelerated group represent an important signal of potential harm with a routine “early” strategy.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The results are highly applicable to the global ICU community and provide a clear directive to favor a standard, watchful-waiting approach to RRT initiation in the absence of urgent indications.

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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