PROWESS-SHOCK

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Ranieri VM, et al. "Drotrecogin Alfa (Activated) in Adults with Septic Shock". The New England Journal of Medicine. 2012. 366(22):2055-2064.
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Clinical Question

Among patients with septic shock, does activated protein C decrease mortality?

Bottom Line

Among patients with septic shock, activated protein C provides no mortality benefit at 28 or 90 days.

Major Points

The end-organ dysfunction that accompanies severe sepsis and septic shock is in part mediated by a systemic proinflammatory and procoagulant state. Since activated protein C promotes fibrinolysis and inhibits thrombosis, it was hypothesized that recombinant human activated protein C (drotrecogin alfa, DrotAA) may improve survival when administered to patients with severe sepsis. This was initially tested in the 2001 PROWESS trial, which demonstrated a survival benefit among patients with severe sepsis randomized to DrotAA (28-day mortality of 24.7% vs. 30.8% with placebo). Subgroup analyses suggested the greatest benefit occurred in patients with a high risk of death (ie, APACHE II scores ≥25).[1][2][3] As a result, the FDA approved DrotAA for use only in patients with severe sepsis and a high risk of death, and requested further studies to evaluate DrotAA among less critically ill patients.

The ADDRESS trial evaluated DrotAA in less critically ill patients with severe sepsis, while the RESOLVE trial evaluated DrotAA in children with severe sepsis.[4] Both trials were stopped early for a lack of efficacy. The ENHANCE trial was an open-label study to evaluate safety for those who met entry criteria for PROWESS, and demonstrated a bleeding rate of 5.5%, higher than that of the original PROWESS trial.

The conflicting data from these subsequent studies led to the Prospective Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis and Septic Shock (PROWESS-SHOCK) trial, which randomized 1,664 patients with septic shock and high risk of death to either DrotAA or placebo. The mean APACHE II score was 25; most patients had a lactic acidosis that persisted despite aggressive fluid resuscitation; and effectively all patients had multiorgan dysfunction. However, at an interim efficacy analysis, rates of 28-day mortality were similar between the two groups (26.4% vs. 24.2%). After years of inconsistent results, PROWESS-SHOCK was the final nail in the coffin for Xigris, Eli Lilly's trade name for DrotAA. In 2011, Eli Lilly announced a voluntary withdrawal of Xigris from markets worldwide, and the FDA withdrew its approval of the drug in the United States.

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.[5]

Design

  • Multicenter, double blind, parallel design, randomized, placebo-controlled trial
  • N=1,664 patients with sepsis
    • DrotAA (n=842)
    • Placebo (n=822)
  • Setting: 208 sites in multiple continents
  • Enrollment: 2008-2010
  • Analysis: Intention-to-treat
  • Follow-up: 90 days

Population

Inclusion Criteria

  • Age ≥18 years
  • Infection requiring IV antibiotics
  • ≥2 SIRS criteria
  • Septic shock, defined as:
    • At least 30 mL/kg IV fluids
    • ≥1 vasopressor for ≥4h
    • Continuing vasopressor requirements through time of randomization with goal SBP of 90 mmHg or MAP of 65 mmHg
    • Hypoperfusion in the prior 36 hours, defined as ≥1 of:
      • Metabolic acidosis, defined as base deficit of at least 5 mmol/L, bicarbonate <18 mmol/L, lactate >2.5 mmol/L
      • Urine output <0.5 mL/kg/h for an hour or a 50% increase of creatinine from baseline
      • Acute hepatic dysfunction with AST or ALT >500 IU/dL or bilirubin >2 g/dL

Exclusion Criteria

  • Coexisting diseases with a high risk of death (eg, metastatic cancer)

Baseline Characteristics

Data from the DrotAA group. Both groups similar except where otherwise noted.

Demographics:

  • Age: 63.4 years
  • Male: 57.7%
  • Caucasian: 87.0%
  • Comorbidities:
    • Alcoholism: 14.2%
    • CAD: 13.4%
    • CHF: 5.7%
    • Chronic liver disease: 3.5%
    • COPD: 15.2%
    • CKD: 9.9%
    • DM: 22.3%
    • HTN: 45.1%
    • Immunodeficiency: 6.0%
    • Malignancy: 17.3%
    • Pancreatitis: 3.5%
    • Stroke: 5.7%
    • Thrombophilia: 0.0% vs. 0.5% (P=0.045)
    • VTE: 3.7%
  • Number of baseline dysfunctional organs:
    • 1: 2.2%
    • 2: 13.5%
    • 3: 32.5%
    • 4: 38.4%
    • 5: 13.3%
  • Time between first vasopressor and study drug infusion: 17.2h
  • APACHE II score: 25.2
  • Recent surgery: 37.1%
  • Corticosteroid for septic shock: 51.3%
  • Mechanical ventilation: 81.8%
  • Renal replacement therapy: 14.2%
  • ARDS: 26.4%
  • Heparin: 43.9%
  • Severe protein C deficiency: 40.4%
  • Prior DM: 22.2%
  • Prior immunodeficiency: 6.0%
  • Prior malignancy: 17.0%

Laboratory data:

  • aPTT: 61.5 sec
  • PT: 20.8 sec
  • PAI-1: 179.8 U/mL
  • Creatinine: 177.9 µmol/L (2.0 mg/dL)
  • Lactate: 3.3 mmol/L
  • Platelets >100: 75.2%

Resuscitation:

  • CVP 11.7 mmHg
  • IV fluids 24h prior to vasopressors: 3.6L
  • IV fluids from vasopressor to study drug infusion: 5.5L
  • Dopamine: 12 (range 8-16) µg/kg/min
  • Epinephrine: 18 (8-33) mcg/min
  • Norepinephrine: 24 (13-46) µg/min
  • Phenylephrine: 105 (29-160) µg/min
  • Vasopressin: 0.04 (0.03-0.04) U/min

Disease characteristics:

  • Primary site of infection:
    • Lung: 43.4%
    • Abdomen: 30.9%
    • Urinary tract: 11.4%
    • Skin: 5.6%
    • Other: 8.7%
  • Positive blood cultures: 31.7%
  • Community-acquired infection: 76.9%
  • Organism identified: 73.2% vs. 68.0% (P=0.02)
  • Organism sensitive to chosen antibiotics: 84.1%
  • Time from antibiotics to initiation of vasopressor: 2.5 hours
  • Source control of infection: 90.8%

Interventions

  • Randomized to receive DrotAA 24 ug/kg/hr for 96 hours or placebo for 96 hours
  • Assessment of APACHE II score
  • Assessment of Sequential Organ Failure Assessment (SOFA) score from 0 (best) to 4 (worst)

Outcomes

Comparisons are DrotAA vs. placebo.

Primary Outcomes

28-day mortality
26.4% vs. 24.2% (RR 1.09; 95% CI 0.92-1.28; P=0.31)

Secondary Outcomes

90-day mortality
34.1% vs. 32.7% (RR 1.04; 95% CI 0.90-1.19; P=0.56)
SOFA score at day 7
Cardiovascular: no difference
Respiratory: no difference
Renal: no difference
Coagulation: no difference
Liver: no difference

Subgroup Analysis

No significant differences in any subgroup, including:

  • APACHE II class
  • Organs failing
  • Surgeries
  • ARDS
  • Length of delay of initiation of vasopressor infusion
  • Protein C level
  • Glucocorticoid use
  • Heparin use
  • Baseline SOFA for coagulation

Adverse Events

Any serious event by day 28
14.3% vs. 11.5% (RR 1.23; 95% CI 0.96-1.59; P=0.11)
Any bleeding event during treatment period
Non-serious: 8.6% vs. 4.8% (RR 1.80; 95% CI 1.23-2.61; P=0.002)
Serious: 1.2% vs. 1.0% (RR 1.25; 95% CI 0.49-3.15; P=0.81)
Any cerebral hematoma, cerebral hemorrhage, subarachnoid hemorrhage, hemorrhagic stroke by day 28
0.4% vs. 0.4% (RR 1.00; 95% CI 0.20-4.90; P=1.00)

Criticisms

  • Did not study coagulation- or inflammation-related markers with infusion of the medication as was performed with previous trials

Funding

By Eli Lilly, the manufacturer of Xigris (drotrecogin alfa). Authors with multiple conflicts of interest.

Further Reading

  1. Concurrent editorial in NEJM
  2. FDA safety podcast transcript
  3. Intensive Care Medicine: Design, conduct, analysis and reporting of a multi-national placebo-controlled trial of activated protein C for persistent septic shock
  4. ADDRESS Trial for patients with sepsis and low risk of death
  5. Dellinger RP, et al. Surviving Sepsis Campaign: InternationalGuidelines for Management of Severe Sepsisand Septic Shock: 2012. Critical Care Medicine. 2013;41(2):580-637.