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Table 1 Summary of clinical trials with drotrecogin alfa (activated) in severe sepsis

From: Clinical trials in severe sepsis with drotrecogin alfa (activated)

Study

Patients (n)

Study type

Main findings

Comments

Adults

    

   Phase II [1]

131

RCT

Reduction in D-dimer and interleukin-6 plasma levels with DrotAA; reduction in 28-day all-cause mortality (not significant); no difference in bleeding events

Dose-finding study; optimal dose defined as 24 μg/kg per hour; benefit more pronounced in high-risk patients

   PROWESS [2]

1,690

RCT

Significant reduction in 28-day, all-cause mortality; faster resolution of organ dysfunction; consistent survival benefit in more than 70 subgroups; reduced ospital and 3 month mortality

Increased survival benefit in patients at high risk for death; no benefit in single organ dysfunction and low APACHE II score; increased incidence of serious bleeding events

   ENHANCE [11]

2,378

Open label

Similar 28-day, all-cause mortality compared with PROWESS; earlier intervention associated with improved outcome (<24 hours)

Increased incidence of bleeding events compared with PROWESS

   ADDRESS [12]

2,640

RCT

No difference in 28-day and hospital all-cause mortality in patients at low risk for death

Increased incidence of bleeding events; no increased incidence in ICH

   XPRESS [13]

1,994

RCT

Concomitant heparin does not increase 28-day mortality; heparin prophylaxis should not be discontinued before DrotAA

Small increase in nonserious bleeding; prophylactic heparin reduces incidence of ischaemic stroke

Children

    

   Phase Ib [14]

83

Open label

Safety and pharmacokinetic/pharmacodynamic study; pharmacokinetics/pharmacodynamics similar to adults

Safety similar to adults

   RESOLVE [15]

477

RCT

No difference in time to organ failure resolution; no difference in 28-day mortality; no difference in the incidence of serious bleeding events

More ICH in children younger than 60 days in DrotAA arm

  1. ADDRESS, Administration of Drotrecogin alfa (activated) in early stage Severe Sepsis; APACHE, Acute Physiology and Chronic Health Evaluation; DrotAA, drotecogin alfa (activated); ENHANCE, Extended Evaluation of Recombinant Human Activated Protein C; ICH, intracerebral haemorrhage; PROWESS, Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis; RCT, randomized controlled trial; RESOLVE, REsearching severe Sepsis and Organ dysfunction in children: a gLobal perspective; XPRESS, Xigris and Prophylactic hepaRin Evaluation in Severe Sepsis.