Anticoagulant modulation of inflammation in severe sepsis

Table 1 Previous trials of anticoagulant therapy in severe sepsis

Ref.	Year	Inclusion criteria	n	Design	Therapy	Primary outcome	Treatment	Control	P value
AT
Warren et al[27] (Kybersept)	2001	Severe sepsis	2314	Phase 3 RCT	AT 30000 IU × 96 h or placebo	Mortality	450/115 (38.9%)	446/1157 (38.7%)	0.94
Gando et al[29]	2013	Sepsis	60	Prospective randomized	AT 30 IU/kg × 72 h or placebo	DIC recovery (%) on day 3	16/30 (53.3%)	6/30 (20%)	0.015
Tagami et al[30]	2014	Sepsis-associated DIC in severe pneumonia	4388	Retrospective, propensity matched	AT 1500 IU/d	Mortality	890/2194 (40.6%)	270/2194 (44.2%)	0.02
rAPC
Bernard et al[33] (Prowess trial)	2001	Severe sepsis	1690	Phase 3 RCT	APC 24 μg/kg per hour × 96 h or placebo	Mortality	210/850 (24.7%)	259/840 (30.8%)	0.005
Vincent et al[35] (Enhance trial)	2005	Severe sepsis	2378	Prospective single arm multicenter	APC 24 μg/kg per hour × 96 h	Mortality	25.30%	NA	NA
Abraham et al[36] (Address trial)	2005	Severe sepsis with APACHE < 25	2613	Phase 3 RCT	APC 24 μg/kg per hour × 96 h or placebo	Mortality	243/1316 (18.5%)	220/1297 (17%)	0.34
Ranieri et al[37] (Prowess shock)	2012	Septic shock	1680	Phase 3 RCT	APC 24 μg/kg per hour × 96 h or placebo	Mortality	223/846 (26.4%)	202/834 (24.2%)	0.31
Rimmer et al[38]	2012	Severe sepsis with septic shock	933	Retrospective, 2:1 propensity matched	APC 24 μg/kg per hour × 96 h	Mortality	180/311 (34.7%)	254/622 (40.8%)	0.05
Thrombomodulin
Saito et al[43]	2007	DIC associated with hematologic malignancy or infection	234	Phase 3 RCT	Thrombomodulin 0.06 mg/kg × 6 d or heparin 8 U/kg per hour × 6 d	DIC recovery (%) on day 7	74/112 (66.1%) (thrombomodulin)	56 (49.9%) (heparin)	0.027
Vincent et al[44]	2013	Sepsis with DIC	741	Phase 2 RCT	Thrombomodulin 0.06 mg/kg × 6 d or placebo	Mortality	66/371 (17.8%)	80/370 (21.6%)	0.273
Heparin
Jaimes et al[47] (HETRASE study)	2009	Sepsis	317	RCT	Heparin 500 U/h × 7 d or placebo	LOS	12 d (median)	12.5 d (median)	0.976
rTFPI
Abraham et al[49]	2001	Severe sepsis	210	Phase 2 RCT	rTFPI 0.025 or 0.05 mg/kg per hour × 96 h or placebo	Mortality	43/141 (30%)	26/69 (38%)	0.3
Abraham et al[50] (OPTIMIST trial)	2003	Severe sepsis	1754	Phase 3 RCT	rTFPI 0.025 mg/kg per hour × 96 h or placebo	Mortality	301/880 (34.2%)	296/874 (33.9%)	0.88
Wunderink et al[52] (CAPTIVATE trial)	2011	Severe sepsis with community acquired pneumonia	2102	Phase 3 RCT	rTFPI 0.025 mg/kg per hour × 96 h or placebo	Severity adjusted 28 d mortality	185/955 (19.4%)	178/914 (19.5%)	0.56

RCT: Randomized controlled trial; LOS: Length of stay; APC: Activated protein C; DIC: Disseminated intravascular coagulation; TFPI: Tissue factor pathway inhibitor; AT: Anti-thrombin; NA: Not available.