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