PROWESS: Drotrecogin Alfa (Activated) in Severe Sepsis (2001)

“Treatment with drotrecogin alfa activated reduced the 28-day mortality rate from 30.8 percent in the placebo group to 24.7 percent in the drotrecogin alfa activated group, a relative reduction in the risk of death of 19.4 percent (P=0.005).”

  • The PROWESS Study Group

1. Publication Details

  • Trial Title: Efficacy and Safety of Recombinant Human Activated Protein C for Severe Sepsis
  • Citation: Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344(10):699-709. DOI: 10.1056/NEJMoa002152
  • Published: March 8, 2001, in The New England Journal of Medicine
  • Author: Gordon R. Bernard, M.D., on behalf of the PROWESS Study Group
  • Funding: Eli Lilly.

2. Keywords

  • Sepsis, Septic Shock, Activated Protein C, Drotrecogin Alfa (Activated), Xigris, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with severe sepsis (Population), does treatment with drotrecogin alfa (activated) (Intervention) compared to placebo (Comparison) reduce 28-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Severe sepsis was known to involve a complex interplay of inflammation and coagulation. Activated protein C is an endogenous protein with both anticoagulant and anti-inflammatory properties, and its levels are depleted in patients with severe sepsis.
  • Knowledge Gap: It was hypothesized that replacing activated protein C with a recombinant form, drotrecogin alfa (activated), could modulate the harmful host response and improve survival. This novel therapeutic approach had shown promise in pre-clinical studies but required validation in a large, definitive randomized controlled trial.
  • Proposed Hypothesis: The authors hypothesized that drotrecogin alfa (activated) would be superior to placebo in reducing 28-day mortality in patients with severe sepsis.

5. Study Design and Methods

  • Design: A multicenter, international, prospective, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: 164 medical centers in 11 countries.
  • Trial Period: Enrollment ran from July 1998 to June 2000.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with a presumed or proven infection and evidence of a systemic inflammatory response, plus sepsis-induced dysfunction of at least one organ system for no more than 24 hours.
    • Exclusion Criteria: Included a high risk of bleeding, pregnancy, moribund status, and recent use of heparin.
  • Intervention: Patients received a continuous intravenous infusion of drotrecogin alfa (activated) at a dose of 24 µg/kg/hr for a total of 96 hours.
  • Control: Patients received a matching intravenous placebo.
  • Management Common to Both Groups: All other aspects of sepsis management were at the discretion of the treating clinicians according to standard practice at the time.
  • Power and Sample Size: The authors calculated that a sample size of 1680 patients would be required to have 90% power to detect a 20% relative risk reduction in 28-day mortality. (Power is a study’s ability to find a real difference between treatments if one truly exists; 90% power means the study had a 90% chance of detecting the specified effect, which is considered very high).
  • Outcomes:
    • Primary Outcome: All-cause mortality at 28 days.
    • Secondary Outcomes: Included organ dysfunction scores and the incidence of serious bleeding.

6. Key Results

  • Enrollment and Baseline: 1690 patients were randomized (850 to drotrecogin alfa and 840 to placebo). The groups were well-matched at baseline.
  • Trial Status: The trial was stopped early by the data and safety monitoring board after a pre-planned interim analysis showed a significant mortality benefit in the intervention group.
  • Primary Outcome: 28-day mortality was significantly lower in the drotrecogin alfa group: 210 of 850 patients (24.7%) died, compared with 259 of 840 patients (30.8%) in the placebo group (p=0.005).
  • Secondary Outcomes: Patients in the drotrecogin alfa group had a greater improvement in cardiovascular and respiratory organ dysfunction scores.
  • Adverse Events: The incidence of serious bleeding was higher in the drotrecogin alfa group during the infusion period (2.0% vs. 1.0%), but this difference was not statistically significant.

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 death between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute mortality rates and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.005 for the primary outcome is well below the 0.05 threshold, indicating that the observed difference in mortality is highly statistically significant and very unlikely to be 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 = 30.8% – 24.7% = 6.1%.
      • Clinical Meaning: For every 100 patients with severe sepsis treated with drotrecogin alfa, about 6 additional deaths were prevented at 28 days.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.061 = 16.4, which is rounded down to 16.
      • Clinical Meaning: You would need to treat 16 patients with drotrecogin alfa to prevent one additional death.
  • Subgroup Analyses: A post-hoc subgroup analysis suggested that the benefit was greatest in the sickest patients (those with an APACHE II score ≥ 25).

8. Strengths of the Study

  • Study Design and Conduct: The large, multicenter, randomized, double-blind, placebo-controlled design is the gold standard for minimizing bias and provided high-quality evidence.
  • Generalizability: The inclusion of 164 diverse centers across 11 countries increases the external validity of the findings.
  • Statistical Power: The study was large and adequately powered, and found a significant effect.
  • Patient-Centered Outcomes: The primary outcome of 28-day mortality is a robust and patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was well-conducted with a low risk of bias.
  • External Validity (Generalizability): The benefit appeared to be concentrated in the sickest patients, raising questions about its efficacy in patients with less severe sepsis.
  • Other: The trial was stopped early for benefit, which can sometimes lead to an overestimation of the true treatment effect. The trial was funded by the manufacturer of the drug, which represents a potential conflict of interest. The increased bleeding risk, while not statistically significant, was a notable safety concern.

10. Conclusion of the Authors

  • The authors concluded that treatment with drotrecogin alfa (activated) significantly reduces mortality in patients with severe sepsis and should be considered as a new therapeutic option.

11. To Summarize

  • Impact on Current Practice: This was a landmark trial that led to the FDA approval of drotrecogin alfa (Xigris), the first and only drug ever approved specifically for the treatment of severe sepsis. It was widely adopted into international guidelines. However, the drug was later voluntarily withdrawn from the market by the manufacturer after a follow-up trial (PROWESS-SHOCK) in a less sick population failed to confirm a survival benefit.
  • Specific Recommendations:
    • Patient Selection: At the time, the results supported its use in adult patients with severe sepsis at high risk of death.
    • Actionable Intervention: Administer drotrecogin alfa (activated) as a 96-hour infusion.
    • Expected Benefit: This intervention was shown to prevent approximately one death for every 16 patients treated.
  • What This Trial Does NOT Mean: As later evidence showed, this trial did NOT mean that drotrecogin alfa was a “magic bullet” for all septic patients.
  • Implementation Caveats: The key takeaway from the entire history of this drug is the critical importance of post-marketing surveillance and confirmatory trials, especially for drugs approved based on a single trial that was stopped early.

12. Context and Related Studies

  • Building on Previous Evidence: The PROWESS trial (2001) was the first major trial to show a survival benefit for a specific, targeted anti-inflammatory/anticoagulant therapy in sepsis.
  • Influence on Subsequent Research: The positive but controversial findings of this trial led to a decade of debate and further research. The subsequent PROWESS-SHOCK trial (2012) was designed as a confirmatory trial in a population with a lower risk of death. When it failed to show a benefit, the drug was withdrawn from the market.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The key unresolved question from the PROWESS era is why the benefit seen in the initial trial was not replicated in the confirmatory trial.
  • Future Directions: The failure of drotrecogin alfa to ultimately prove its benefit has shifted the focus of sepsis research away from broad, untargeted anti-inflammatory agents and towards more personalized approaches aimed at identifying specific patient phenotypes that might respond to targeted immunomodulatory therapies.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was of the highest relevance, testing a novel, targeted therapy for a devastating disease with no specific treatments.
  • Methods: The large, multicenter, double-blind RCT design was of high quality. The main methodological points for discussion are the early stopping for benefit and the industry funding.
  • Results: The study reported a statistically significant and clinically meaningful mortality benefit (NNT of 16).
  • Conclusions and Applicability: The authors’ conclusion was a fair reflection of their data. The trial is a landmark in the history of sepsis research, not only for its initial positive result but also for the crucial lessons learned from its subsequent failure to be confirmed. It serves as a powerful case study in the complexities of drug development, the importance of confirmatory trials, and the dangers of over-interpreting the results of a single, industry-sponsored study that was stopped early for benefit.

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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