The effect of drotrecogin alfa (activated) on long-term survival after severe sepsis.
OBJECTIVE
To determine long-term survival for subjects with severe sepsis enrolled in the previous multiple-center trial (PROWESS) of drotrecogin alfa (activated) (DrotAA) vs. placebo.


METHODS
Retrospective, cross-sectional, blinded follow-up of subjects enrolled in a previous randomized, controlled trial.


METHODS
One hundred sixty-four tertiary care institutions in 11 countries.


METHODS
The 1,690 subjects with severe sepsis enrolled and treated with study drug in PROWESS, of whom 1,220 were alive at 28 days (the end of the original PROWESS follow-up).


METHODS
DrotAA (n = 850), 24 mug/kg/hr for 96 hrs, or placebo (n = 840).


RESULTS
Long-term survival data were collected. We had follow-up information on 100% of subjects at 28 days, 98% at hospital discharge, 94% at 3 months, and 93% at 1 yr. The longest follow-up was 3.6 yrs. Hospital survival was higher with DrotAA vs. placebo (70.3% vs. 65.1%, p = .03). There was no statistically significant difference in duration of survival time or in landmark survival rates in subjects who received DrotAA compared with those who received placebo (median duration of survival = 1113 days vs. 846 days for DrotAA vs. placebo, p = .10; landmark survival rates for DrotAA vs. placebo, 66.1% vs. 62.4% at 3 months [p = .11], 62.2% vs. 60.3% at 6 months [p = .44], 58.9% vs. 57.2% at 1 yr [p = .49], and 52.6% vs. 49.3% at 2(1/2) yrs [p = .21]). There was a significant interaction (p = .0008) between treatment assignment and baseline Acute Physiology and Chronic Health Evaluation (APACHE) II scores, suggesting qualitative differences in treatment effect with severity of illness. Subjects with APACHE II >/=25 had better survival time with DrotAA (median duration of survival: 450 vs. 71 days, p =.0005). Survival rates were also higher at landmark time points (DrotAA vs. placebo, 58.9% vs. 48.4% at 3 months [p = .003], 55.2% vs. 45.3% at 6 months [p = .005], 52.1% vs. 41.3% at 1 yr [p = .002], and 45.6% vs. 33.8% at 2(1/2) yrs [p = .001]). In the APACHE II <25 group there was no significant difference in survival time or survival rates at landmark time points except at 1 yr (DrotAA vs. placebo, 65.5% vs. 72.0% at 1 yr, p = .04).


CONCLUSIONS
The acute survival benefit observed in subjects with severe sepsis who received DrotAA persists to hospital discharge. The survival benefit loses statistical significance thereafter. Post hoc analysis suggests the effect of DrotAA varies by APACHE II score with improved long-term survival in subjects with APACHE II scores >/=25 but no benefit in those with lower scores.
Angus
Derek C
DC
Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Laterre
Pierre-Francois
PF
Helterbrand
Jeff
J
Ely
E Wesley
EW
Ball
Daniel E
DE
Garg
Rekha
R
Weissfeld
Lisa A
LA
Bernard
Gordon R
GR
D018806:APACHE; D000203:Activities of Daily Living; D000328:Adult; D000368:Aged; D000890:Anti-Infective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D003430:Cross-Sectional Studies; D004311:Double-Blind Method; D005260:Female; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D005500:Follow-Up Studies; D017052:Hospital Mortality; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure / Q000382:microbiology; D016016:Proportional Hazards Models; D011486:Protein C / Q000494:pharmacology / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D012189:Retrospective Studies; D018401:Sample Size; D018805:Sepsis / Q000150:complications / Q000188:drug therapy* / Q000401:mortality*; D016019:Survival Analysis; D015996:Survival Rate; D013997:Time Factors; D016896:Treatment Outcome
D000890:Anti-Infective Agents; D005343:Fibrinolytic Agents; D011486:Protein C; D011994:Recombinant Proteins; C421124:drotrecogin alfa activated