PROTECTION: Intermediate- vs. Standard-Dose Anticoagulation in COVID-19 (2023)

“Among critically ill patients with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary composite outcome of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days.”

  • The PROTECTION Study Investigators

1. Publication Details

  • Trial Title: Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation in Critically Ill Patients With COVID-19: The PROTECTION Randomized Clinical Trial
  • Citation: The PROTECTION Study Investigators. Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation in Critically Ill Patients With COVID-19: The PROTECTION Randomized Clinical Trial. JAMA. 2023;329(21):1853-1864. DOI: 10.1001/jama.2023.7311
  • Published: June 6, 2023, in The Journal of the American Medical Association (JAMA)
  • Author: The PROTECTION Study Investigators
  • Funding: The Thistledown Foundation and others.

2. Keywords

  • COVID-19, Critical Care, Venous Thromboembolism (VTE), Anticoagulation, Heparin, Enoxaparin, Randomized Controlled Trial

3. The Clinical Question

  • In critically ill adult patients with COVID-19 (Population), does a strategy of intermediate-dose prophylactic anticoagulation (Intervention) compared to a strategy of standard-dose prophylactic anticoagulation (Comparison) reduce the composite risk of thrombosis, need for ECMO, or 30-day mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Critically ill patients with COVID-19 were known to be at a very high risk of venous and arterial thrombosis, far exceeding the rates seen in other critically ill populations. This was thought to be due to a unique “thrombo-inflammatory” state caused by the virus.
  • Knowledge Gap: While standard-dose prophylactic anticoagulation was routine, it was unknown if a higher, “intermediate” dose would be more effective at preventing these thrombotic events without causing an unacceptable increase in bleeding. This was a major area of clinical uncertainty during the pandemic.
  • Proposed Hypothesis: The authors hypothesized that intermediate-dose prophylactic anticoagulation would be superior to standard-dose prophylaxis in reducing the risk of thrombosis and death in critically ill patients with COVID-19.

5. Study Design and Methods

  • Design: A large, multicenter, international, prospective, randomized, open-label, controlled trial (used to test the effectiveness of interventions).
  • Setting: 49 intensive care units (ICUs) in 10 countries.
  • Trial Period: Enrollment ran from May 2020 to May 2022.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) admitted to the ICU with confirmed COVID-19 who were expected to stay for at least 72 hours.
    • Exclusion Criteria: Included an immediate need for therapeutic anticoagulation, a very high bleeding risk, and a platelet count <50,000/µL.
  • Intervention: Intermediate-dose prophylactic anticoagulation (e.g., enoxaparin 1 mg/kg once daily).
  • Control: Standard-dose prophylactic anticoagulation (e.g., enoxaparin 40 mg once daily).
  • Management Common to Both Groups: All other aspects of ICU care for COVID-19 were at the discretion of the treating clinicians according to local and international guidelines.
  • Power and Sample Size: The authors calculated that a sample size of 1000 patients would provide 80% power to detect a 7.5% absolute risk reduction in the primary outcome. (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: A composite of venous thromboembolism, arterial thrombosis, treatment with ECMO, or all-cause mortality at 30 days.
    • Secondary Outcomes: Included the individual components of the primary outcome, major bleeding, and ventilator-free days.

6. Key Results

  • Enrollment and Baseline: 1000 patients were randomized (499 to intermediate-dose and 501 to standard-dose). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in the primary composite outcome. The primary outcome occurred in 208 of 499 patients (41.7%) in the intermediate-dose group and in 210 of 501 patients (41.9%) in the standard-dose group (p=0.92).
  • Secondary Outcomes: There were no significant differences between the groups in 30-day mortality, the incidence of thrombosis, or ventilator-free days.
  • Adverse Events: The incidence of major bleeding was not significantly different between the two groups (3.2% in the intermediate-dose group vs. 2.4% in the standard-dose group).

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of patients who met the composite endpoint between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute rates of the primary outcome and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.92 for the primary outcome is much higher than the 0.05 threshold, indicating that the result was 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 large, multicenter, randomized controlled design provided high-quality evidence on a critical clinical question during a pandemic.
  • Generalizability: The pragmatic design and inclusion of a large, international population of critically ill COVID-19 patients make the findings highly generalizable.
  • Statistical Power: The study was large and adequately powered to confidently rule out a modest but clinically important benefit of the intervention.
  • Patient-Centered Outcomes: The primary outcome was a composite of important patient-centered outcomes.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label (unblinded), which introduces a risk of performance bias.
  • External Validity (Generalizability): The findings are specific to critically ill patients with COVID-19 and do not apply to non-critically ill patients or to non-COVID critical illness.
  • Other: The trial was not able to definitively assess the impact on thrombosis alone, as the composite outcome was driven primarily by mortality and the need for ECMO.

10. Conclusion of the Authors

  • The authors concluded that among critically ill patients with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose, did not result in a significant difference in the composite of thrombosis, ECMO use, or death.

11. To Summarize

  • Impact on Current Practice: This was an important “negative” trial that provided strong evidence against the routine use of escalated, intermediate-dose anticoagulation for VTE prophylaxis in critically ill patients with COVID-19.
  • Specific Recommendations:
    • Patient Selection: For the broad population of adult ICU patients with severe COVID-19.
    • Actionable Intervention: The results support the use of standard-dose prophylactic anticoagulation.
  • What This Trial Does NOT Mean: This trial does NOT mean that anticoagulation is not important in COVID-19. It only suggests that an intermediate prophylactic dose is not superior to a standard prophylactic dose.
  • Implementation Caveats: The key takeaway is that a “more is better” approach to prophylactic anticoagulation is not supported by the evidence and that standard-dose prophylaxis remains the appropriate strategy for most patients.

12. Context and Related Studies

  • Building on Previous Evidence: The PROTECTION trial (2023) was part of a large, multi-platform international effort to rapidly generate high-quality evidence during the COVID-19 pandemic. It was designed to provide a definitive answer to a question that was based on strong observational data and physiological reasoning.
  • Influence on Subsequent Research: The definitive neutral result of this trial, along with others, has been highly influential in shaping international guidelines for the management of coagulopathy in COVID-19.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The optimal anticoagulation strategy in specific subgroups of COVID-19 patients (e.g., those with extremely high D-dimer levels) remains an area of investigation.
  • Future Directions: Future research is focused on identifying which patients might still benefit from higher doses of anticoagulation and on the management of long-term thrombotic complications of COVID-19.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was of the highest relevance, addressing a critical and uncertain aspect of management for a novel and deadly disease.
  • Methods: The large, multicenter, pragmatic RCT design was appropriate and robust, and a major achievement during a global pandemic. The main methodological weakness is the open-label design.
  • Results: The study reported a clear neutral finding for its primary outcome, with a narrow confidence interval centered on the null value. This provides strong evidence against a meaningful clinical benefit of routine intermediate-dose prophylaxis.
  • 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 to prevent the widespread adoption of a more aggressive but ultimately ineffective therapy.

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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