Christian Brun-Buisson, MD
Does drotrecogin alfa (activated) (DrotAA) reduce mortality in patients with septic shock?
Randomized placebo-controlled trial (Prospective Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis and Septic Shock [PROWESS-SHOCK] study). ClinicalTrials.gov NCT00604214.
Blinded* (patients, clinicians, investigators, and sponsors).
208 sites in Europe, North and South America, Australia, New Zealand, and India.
1697 patients ≥ 18 years of age (mean age 63 y, 56% men) who had sepsis (infection and ≥ 2 signs of systemic inflammation), shock (norepinephrine, ≥ 5 µg/min, or equivalent dose of another vasopressor for ≥ 4 h, and crystalloid, ≥ 30 mL/kg body weight, or equivalent colloid volume within 8 h of vasopressor initiation), and evidence of hypoperfusion; were refractory to vasopressor weaning; and began the study drug ≤ 24 hours after the first dose of a vasopressor. Patients with coexisting illness at high risk for death were excluded.
IV DrotAA (Xigris, Eli Lilly), 24 µg/kg body weight/h for 96 hours (n = 852), or placebo (0.9% saline) (n = 845). If study infusions were interrupted for procedures, they continued to day 6 to complete the 96-hour infusion.
Primary outcome was 28-day mortality. Secondary outcomes included 90-day mortality, serious adverse events, and bleeding events. 1500 patients were needed to detect a 7% absolute reduction from 35% in 28-day mortality (80% power, α = 0.05); sample size was increased to 1696 because mortality rate after recruitment of 750 patients was 28%.
98% at 90 days (intention-to-treat analysis).
DrotAA did not reduce mortality at 28 or 90 days (Table). Risk for nonserious bleeding events during treatment was higher with DrotAA (Table).
Drotrecogin alfa (activated) did not reduce mortality at 28 or 90 days in patients with septic shock.
Drotrecogin alfa (activated) (DrotAA) vs placebo in patients with septic shock†
†NS = not significant; other abbreviations defined in Glossary. RRI, NNH, and CI calculated from control event rates and relative risks in article.
‡During treatment period.
Brun-Buisson C. Drotrecogin alfa (activated) did not reduce mortality at 28 or 90 days in patients with septic shock. Ann Intern Med. 2012;157:JC2–11. doi: 10.7326/0003-4819-157-4-201208210-02011
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Published: Ann Intern Med. 2012;157(4):JC2-11.
Multi-Organ Failure and Sepsis, Pulmonary/Critical Care.
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