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.