PROTECT: LMWH vs. Unfractionated Heparin for VTE Prophylaxis (2011)

“In this large randomized trial, we found that, among medical–surgical critically ill patients, dalteparin was not superior to unfractionated heparin in reducing the incidence of proximal deep-vein thrombosis but did reduce the incidence of pulmonary embolism.”

  • The PROTECT Investigators

1. Publication Details

  • Trial Title: Dalteparin versus Unfractionated Heparin in Critically Ill Patients
  • Citation: The PROTECT Investigators. Dalteparin versus Unfractionated Heparin in Critically Ill Patients. N Engl J Med. 2011;364(14):1305-1315. DOI: 10.1056/NEJMoa1014475
  • Published: April 7, 2011, in The New England Journal of Medicine
  • Author: The PROTECT Investigators
  • Funding: The Canadian Institutes of Health Research and others.

2. Keywords

  • Venous Thromboembolism (VTE), Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), Prophylaxis, Low-Molecular-Weight Heparin (LMWH), Dalteparin, Unfractionated Heparin, Critical Care, Randomized Controlled Trial

3. The Clinical Question

  • In a broad population of critically ill adult patients (Population), is prophylactic dalteparin (a low-molecular-weight heparin) (Intervention) superior to prophylactic unfractionated heparin (UFH) (Comparison) in reducing the incidence of proximal deep-vein thrombosis (DVT) (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Critically ill patients are at a very high risk of developing venous thromboembolism (VTE). Both unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) were widely used for prophylaxis, but LMWH was becoming the standard of care in non-critically ill patients due to its more predictable anticoagulant effect and easier administration.
  • Knowledge Gap: It was unknown if the benefits of LMWH seen in other populations would translate to the critically ill, who have altered drug metabolism and a higher risk of both thrombosis and bleeding. A large, definitive, head-to-head comparison was needed.
  • Proposed Hypothesis: The authors hypothesized that dalteparin would be superior to unfractionated heparin in reducing the incidence of proximal DVT in critically ill patients.

5. Study Design and Methods

  • Design: A large, multicenter, prospective, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 67 intensive care units (ICUs) in 6 countries.
  • Trial Period: Enrollment ran from May 2006 to June 2010.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) admitted to the ICU who were expected to stay for at least 3 days.
    • Exclusion Criteria: Included an admission weight >130 kg, major bleeding, and a contraindication to heparin or blood products.
  • Intervention: Patients received subcutaneous dalteparin (5000 IU) once daily.
  • Control: Patients received subcutaneous unfractionated heparin (5000 IU) twice daily.
  • Management Common to Both Groups: All patients underwent routine screening with compression ultrasonography of the proximal veins of the legs twice weekly.
  • Power and Sample Size: The authors calculated that a sample size of 3750 patients would provide 80% power to detect a 1.5% 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: The incidence of proximal deep-vein thrombosis (DVT) in the legs.
    • Secondary Outcomes: Included the incidence of pulmonary embolism (PE), any VTE (proximal or distal DVT or PE), and 60-day mortality.

6. Key Results

  • Enrollment and Baseline: 3746 patients were randomized (1873 to dalteparin and 1873 to UFH). 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 outcome. Proximal DVT occurred in 96 of 1862 patients (5.1%) in the dalteparin group and in 109 of 1862 patients (5.8%) in the UFH group (p=0.37).
  • Secondary Outcomes: The rate of pulmonary embolism was significantly lower in the dalteparin group (1.3% vs. 2.3%; p=0.01). There was no significant difference in 60-day mortality.
  • Adverse Events: The incidence of major bleeding and heparin-induced thrombocytopenia (HIT) was similar in both groups.

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 developed proximal DVT between the two groups.
  • Key Statistic(s) Reported: Hazard Ratio (HR) for proximal DVT: 0.92 (95% CI, 0.72 to 1.18; P-value: 0.57).
  • Interpretation of Key Statistic(s):
    • Hazard Ratio (HR):
      • Formula: Conceptually, HR = (Hazard Rate in Intervention Group) / (Hazard Rate in Control Group).
      • Calculation: The paper reports the result as 0.92.
      • Clinical Meaning: An HR of 0.92 suggests a non-significant 8% lower risk of proximal DVT in the dalteparin group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 0.72 to 1.18.
      • Clinical Meaning: Since this range crosses the line of no effect (1.0), it confirms that the result is not statistically significant. Clinically, this means the true effect could range from a 28% benefit to an 18% harm.
    • P-value: The p-value of 0.57 is much higher than the 0.05 threshold, indicating the result is 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 (for the secondary outcome of pulmonary embolism):
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = 2.3% – 1.3% = 1.0%.
      • Clinical Meaning: For every 100 patients treated with dalteparin instead of UFH, 1 additional pulmonary embolism was prevented.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.01 = 100.
      • Clinical Meaning: You would need to treat 100 patients with dalteparin instead of UFH to prevent one additional pulmonary embolism.
  • Subgroup Analyses: No significant differences were found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The very large, multicenter, randomized controlled design with blinded outcome adjudication provided high-quality evidence.
  • Generalizability: The pragmatic design and inclusion of a very large, heterogeneous population of ICU patients make the findings highly generalizable to real-world practice.
  • Statistical Power: The enormous sample size provided definitive power to confidently rule out a modest but clinically important difference in the primary outcome.
  • Patient-Centered Outcomes: The study focused on important patient-centered outcomes, including PE and mortality.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded, which introduces a risk of performance bias.
  • External Validity (Generalizability): The findings are highly generalizable to the broad population of critically ill patients.
  • Other: The trial was technically “negative” for its primary outcome. The positive finding for the secondary outcome of PE, while statistically significant, should be interpreted with some caution. The use of twice-daily UFH in the control arm represents a high standard of care.

10. Conclusion of the Authors

  • The authors concluded that in critically ill patients, prophylaxis with dalteparin was not superior to prophylaxis with unfractionated heparin in preventing proximal DVT.

11. To Summarize

  • Impact on Current Practice: This was a landmark trial that provided definitive evidence that, for the prevention of proximal DVT, LMWH is not superior to twice-daily UFH in a general ICU population.
  • Specific Recommendations:
    • Patient Selection: For the broad population of adult ICU patients requiring VTE prophylaxis.
    • Actionable Intervention: The results suggest that either dalteparin (LMWH) or twice-daily unfractionated heparin are acceptable choices for VTE prophylaxis.
  • What This Trial Does NOT Mean: This trial does NOT mean that LMWH is not a good drug. It only suggests that it is not superior to a well-dosed UFH regimen for DVT prevention.
  • Implementation Caveats: The choice between LMWH and UFH can be guided by other factors, such as the lower incidence of PE with LMWH, ease of administration (once vs. twice daily), and cost, as well as patient-specific factors like renal function.

12. Context and Related Studies

  • Building on Previous Evidence: The PROTECT trial (2011) was designed to provide a definitive answer to the “LMWH vs. UFH” debate in the ICU, a question for which there was previously only weak and conflicting evidence.
  • Influence on Subsequent Research: The definitive neutral finding of this trial has been highly influential in shaping international guidelines, which now generally recommend either LMWH or UFH as acceptable first-line agents for VTE prophylaxis in most critically ill patients.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The optimal VTE prophylaxis strategy in specific high-risk subgroups (e.g., trauma, obesity) remains an area of investigation.
  • Future Directions: Future research is focused on the role of newer anticoagulants and on the optimal duration of VTE prophylaxis after ICU discharge.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a very common and important aspect of routine ICU care.
  • Methods: The very large, multicenter, pragmatic RCT design was appropriate and robust. The main methodological weakness is the open-label design, but the primary outcome was objectively adjudicated.
  • Results: The study reported a clear neutral finding for its primary outcome. The statistically significant reduction in the secondary outcome of pulmonary embolism is an important finding that adds nuance to the overall interpretation.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the primary outcome 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 practice-changing by demonstrating the equivalence of two common strategies, thereby allowing clinicians to make choices based on other factors like cost and convenience.

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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