Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis.
OBJECTIVE
To assess the effects of drotrecogin alfa (activated) therapy, a recombinant human activated protein C, across clinically relevant subpopulations in a randomized, phase 3, placebo-controlled study of patients with severe sepsis (recombinant human activated protein C worldwide evaluation in severe sepsis [PROWESS]).


METHODS
Univariate and multivariable analysis of prospectively defined subgroups from the PROWESS study.


METHODS
A total of 164 medical centers in 11 countries.


METHODS
A total of 1,690 patients with severe sepsis.


RESULTS
We report observed 28-day mortality rates for drotrecogin alfa (activated) and placebo patients for subgroups prospectively defined by demographic data, surgical status, type and site of infection, and clinical and biochemical measures of disease severity. We performed subgroup analyses to explore the consistency of the mortality benefit observed in the overall population and performed tests for both quantitative and qualitative interactions. To examine the magnitude of the treatment benefit with drotrecogin alfa (activated) across the underlying predicted risk of mortality spectrum, we used stepwise logistic regression on PROWESS placebo patients to generate a predicted risk of mortality model that simultaneously included many clinical and biochemical markers of mortality risk. Because drotrecogin alfa (activated) has anticoagulant properties, we also present analyses of bleeding and thrombotic events. Actual mortality rates were lower with drotrecogin alfa (activated) compared with placebo for nearly all prospectively defined subgroups. Both univariate and multivariable regression analyses showed a consistent relative risk reduction in 28-day mortality rates for drotrecogin alfa (activated). Larger absolute risk reductions were found with drotrecogin alfa (activated) in patients with a higher baseline predicted risk of mortality, and actual mortality rates were lower with drotrecogin alfa (activated) in all subgroups defined by disease severity measures where a > or = 20% placebo mortality was observed. Although discriminatory power was limited by few observed events, the increased absolute risk of experiencing a serious bleeding event with treatment did not seem to vary according to the baseline predicted risk of mortality.


CONCLUSIONS
The administration of drotrecogin alfa (activated) to patients with severe sepsis was associated with a significant survival benefit that tended to increase with higher baseline likelihood of death. Current data suggest that the increased risk of bleeding does not vary according to likelihood of death.
Ely
E Wesley
EW
Division of Allergy, Pulmonary and Critical Care Medicine, Tennessee Valley Veteran's Affairs Geriatric Research Education and Clinical Center, Vanderbilt University School of Medicine, Nashville 37232-8300, USA. wes.ely@vanderbilt.edu
Laterre
Pierre-François
PF
Angus
Derek C
DC
Helterbrand
Jeffrey D
JD
Levy
Howard
H
Dhainaut
Jean-François
JF
Vincent
Jean-Louis
JL
Macias
William L
WL
Bernard
Gordon R
GR
D018806:APACHE; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000890:Anti-Infective Agents / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011486:Protein C / Q000009:adverse effects / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use*; D012307:Risk Factors; D018805:Sepsis / Q000188:drug therapy* / Q000401:mortality; D015996:Survival Rate
D000890:Anti-Infective Agents; D011486:Protein C; D011994:Recombinant Proteins; C421124:drotrecogin alfa activated