PROWESS

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Bernard GR, et al. "Efficacy and Safety of Recombinant Human Activated Protein C for Severe Sepsis". The New England Journal of Medicine. 2001. 344(10):699-709.
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Clinical Question

Among patients with severe sepsis, does activated protein C improve survival?

Bottom Line

Among patients with severe sepsis, activated protein C initially seemed to improve survival, but this was not confirmed in the subsequent PROWESS-SHOCK trial.

Major Points

The end-organ dysfunction that accompanies severe sepsis and septic shock is in part mediated by a systemic proinflammatory and procoagulant state, leading to the hypothesis that recombinant human activated protein C (drotrecogin alfa, DrotAA) may improve survival when administered to adults with severe sepsis.

Published in 2001, the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial randomized 1,690 adults with severe sepsis to either DrotAA or placebo. The study was halted early after its second interim analysis revealed a statistically significant survival benefit with DrotAA. In particular, 28-day mortality was 24.7% with DrotAA compared to 30.8% with placebo. Based on this ARR of 6.1%, the NNT to prevent one death at 28 days was estimated at 16. A subgroup analysis demonstrated particular benefits among individuals with more severe critical illness defined as APACHE II score ≥25.

The trial was harshly criticized for 1) its early termination based upon an interim analysis, 2) because the inclusion/exclusion criteria were adjusted mid-protocol to favor less critically ill patients, and 3) because the company altered the manufacturing process for DrotAA mid-protocol.[1] These concerns prompted a split vote among FDA reviewers, with 10 favoring and 10 opposed to the drug's approval. Despite this, the FDA approved DrotAA for use in patients with severe sepsis and a high risk of death, though further studies were requested to evaluate the drug's efficacy and risk profile.

Subsequent trials of DrotAA -- namely ADDRESS, RESOLVE, and ENHANCE -- drew its risk-benefit ratio into question. Most damning was the large, multicenter PROWESS-SHOCK trial, which unequivocally demonstrated that DrotAA conferred no survival benefit in patients with high-risk septic shock. As a result, the FDA withdrew its support of DrotAA in 2011 and Eli Lilly withdrew Xigris from markets worldwide.

Guidelines

Prior to the publication of PROWESS-SHOCK, the Surviving Sepsis Campaign made various recommendations for the use of activated protein C in patients with septic shock. However, the withdrawal of activated protein C from the market obviated the need of the SSC to make specific guideline recommendations.[2]

Design

  • Randomized, double-blind, placebo-controlled trial
  • N=1,690 adults with severe sepsis
    • Drotrecogin alfa (n=850)
    • Placebo (n=840)
  • Setting: 164 centers in 11 countries
  • Enrollment: 1998-2000
  • Analysis: Intention-to-treat
  • Follow-up: 28 days

Population

Inclusion Criteria

  • Severe sepsis, defined as:
    • Known or suspected infection
    • ≥3 signs of SIRS
    • Sepsis-induced organ dysfunction ≤24h
  • Must begin treatment within 24h of meeting study inclusion criteria

Exclusion Criteria

  • Pregnancy or breast-feeding
  • Age <18 years
  • Weight >135 kg
  • Platelets <30,000/mm3
  • Increased risk of bleeding
  • Known hypercoagulable condition
  • Life expectancy <28 days due to uncorrectable medical condition
  • HIV with CD4 count ≤50/mm3
  • Prior bone marrow, lung, liver, pancreas, or small bowel transplant
  • ESRD requiring dialysis
  • Known or suspected portosystemic hypertension, chronic jaundice, cirrhosis, or chronic ascites
  • Acute pancreatitis without source of infection
  • Recent use of more than prophylactic doses of UFH, LMWH, or other anticoagulants

Baseline Characteristics

Demographics:

  • Age: 60.6 years
    • <60 years: 43.6%
    • <65 years: 53.5%
    • <75 years: 78.5%
  • Male: 58.0%
  • White: 82.0%
  • Comorbidities:
    • HTN: 35.0%
    • MI: 14.4%
    • CHF: 9.0%
    • DM: 22.4%
    • Pancreatitis: 3.9%
    • Liver disease: 2.6%
    • COPD: 26.1%
    • Cancer: 18.8%
    • Recent trauma: 5.1%
  • Recent surgical history:
    • Elective surgery: 6.2%
    • Emergent surgery: 21.2%
    • No history of surgery: 72.6%
  • APACHE II score: 25.0
  • Mechanical ventilation: 77.5%
  • Shock: 71.7%
    • Use of any vasopressor: 75.5%
    • Use of dobutamine: 13.5%
  • Number of dysfunctional organs or systems:
    • 0: 0%
    • 1: 24.2%
    • 2: 32.5%
    • 3: 25.0%
    • 4: 13.8%
    • 5: 3.6%
  • Time from first organ dysfunction to study agent infusion: 17.4h

Disease characteristics:

  • Site of infection:
    • Lung: 53.6%
    • Abdomen: 19.9%
    • Urinary tract: 10.2%
    • Other: 16.3%
  • Positive blood culture: 32.5%
  • Gram stain of bacterial pathogen:
    • Purely gram-negative: 23.3%
    • Purely gram-positive: 25.1%
    • Mixed: 13.9%
    • Unconfirmed: 5.4%
    • Culture negative or not obtained: 32.5%
  • Organism type:
    • Gram-positive:
      • S. aureus: 14.4%
      • Other staphylococcal species: 6.2%
      • S. pneumoniae: 11.3%
      • Other streptococcal species: 9.2%
      • Enterococcus species: 6.5%
      • Other gram-positive: 3.0%
    • Gram-negative:
      • E. coli: 17.4%
      • Klebsiella species: 6.8%
      • Pseudomonas species: 5.1%
      • Enterobacter species: 4.2%
      • Haemophilus influenzae: 4.2%
      • Bacteroides species: 3.0%
      • Other gram-negative: 10.2%
    • Fungus:
      • Candida albicans: 1.7%
      • Other candida species: 5.0%
      • Yeast: 1.1%
      • Other fungus: 0.8%

Laboratory values:

  • D-dimer: 4.15 µg/mL
  • IL-6: 484 pg/mL
  • Protein C activity: 50%
  • Protein C deficiency: 79.8%

Interventions

  • 1:1 assignment, stratified by site to one of two groups:
    • DrotAA 24 µg/kg/hr for 96 hours
    • Placebo (saline +/- 0.1% albumin) for 96 hours
  • Treatment was stopped for interventions like percutaneous procedures (1 hour before and after) and major surgery (1 hour before and 12 hours after)
  • Critical care management by treatment center's direction
  • Patients followed forward for 28 days
  • Labs (eg, D-dimer and IL-6) at baseline, daily for the first week, day 14, and day 28

Outcomes

Primary Outcomes

28-day mortality
24.7% vs. 30.8% (RR 0.80; 95% CI 0.69-0.84; P=0.005)

Secondary Outcomes

None specified.

Subgroup Analysis

Prespecified subgroup analyses demonstrated consistent benefit of DrotAA regardless of APACHE II score, number of dysfunctional organs, sex, age, site of infection, type of infection, and presence or absence of protein C deficiency.

Adverse Events

≥1 serious adverse event
12.5% vs. 12.1% (P=0.84)
Serious bleeding event
3.5% vs. 2.0% (P=0.06)
Thrombotic events
2.0% vs. 3.0% (P=0.20)

Criticisms

  • Industry-sponsored study
  • Early study termination
  • Inclusion/exclusion criteria were adjusted mid-protocol to favor less critically ill patients
  • Manufacturing process for DrotAA was altered mid-protocol

Funding

Supported by Eli Lilly, for whom multiple authors were either employees, consultants, or stakeholders.

Further Reading

  1. Warren HS, et al. N Engl J Med 2002; 347:1027-1030
  2. Dellinger RP, et al. Surviving Sepsis Campaign: InternationalGuidelines for Management of Severe Sepsisand Septic Shock: 2012. Critical Care Medicine. 2013;41(2):580-637.