Anticoagulant therapy in severe sepsis

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PubMed (www.pubmed.gov) for Clinical Trial/Humans/English/Adult

"sepsis" AND ("antithrombin III" OR "protein C" OR "drotrecogin alfa activated" OR "tissue factor pathway inhibitor" OR "tifacogin" OR "heparin")

Activated protein C (APC, drotrecogin alpha activated, DrotAA)

1. Bernard GR et al. N Engl J Med 2001. (1) [level 1b]

• PROWESS (Recombinant human Protein C Worldwide Evaluation in Severe Sepsis)
• randomized, placebo-controlled, phase III clinical trial
• 1690 sepsis patients: recombinant human APC 24 μg/kg/hour for 96 hours (N = 850) versus placebo (N = 840)
• mortality at day 28: 24.7% versus 30.8% (P = 0.005); RR (95% CI): 0.80 (0.69-0.94)
• serious bleeding: 3.5 versus 2.0% (P = 0.06)
• note: the trial was designed to enrol 2280 patients, but was suspended after the second interim analysis because of the mortality difference, according to predefined guidelines.

2. Bernard GR et al. Chest 2004. (2) [level 2b]

• ENHANCE (Extended Evaluation of Recombinant Human Activated Protein C) — US
• single-arm, phase III-B clinical trial
• APC 24 μg/kg/hour for 96 hours (N = 273)
• mortality at day 28: 26.4%
• serious bleeding: 4.0%

3. Vincent JL et al. Crit Care Med 2005. (3) [level 2b]

• ENHANCE (Extended Evaluation of Recombinant Human Activated Protein C)
• Single-arm, phase III-B clinical trial
• APC 24 μg/kg/hour for 96 hours (N = 2375)
• mortality at day 28: 25.3%
• serious bleeding 6.5%

4. Abraham E et al. N Engl J Med 2005. (4) [level 1b]

• ADDRESS (Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis)
• Randomized, placebo-controlled, phase III clinical trial
• APC 24 μg/kg/hour for 96 hours (N = 1316) versus placebo (N = 1297)
• mortality at day 28: 18.5% versus 17.0% (P = 0.34); RR (95% CI): 1.08 (0.92-1.28)
• serious bleeding: 3.9% versus 2.2 % (P = 0.01)
• note: the trial was terminated early because of a low likelihood of meeting the prospectively defined objective of demonstrating a reduction in mortality

5. Wiedermann CJ & KaneiderNC. BMC Emerg Med 2005. (5) [level 1a-]

• meta-analysis of PROWESS (1) and ADDRESS (4)
• sepsis patients with APACHE II score ≥ 25: overall 28-day mortality rate was 30.6% versus 38.3 % (p = 0.007); RR (95% CI): 0.80 (0.68-0.94).
• however, lack of homogeneity; whereas the RR in PROWESS favours APC treatment (RR 0.80, CI 0.68-0.94), in ADDRESS APC seems harmful (RR 1.21, CI 0.85-1.74).
• sepsis patients with APACHE II score < 25: overall 28-day mortality rate was 17.3% vs. 16.8% (P = 0.7); RR (95% CI): 1.03 (0.89-1.20)

Antithrombin III (ATIII)

6. Fourrier F et al. Chest 1993. (6) [level 2b]

• randomized, placebo-controlled, phase II clinical trial
• antithrombin III (90-120 IU/kg loading dose and 90-120 IU/kg over 96 hours) (N = 17) versus placebo (N = 18)
• mortality reduction by 44% (P = 0.22)

7. Eisele B et al. Intensive Care Med 1998. (7) [level 2b]

• randomized, placebo-controlled, phase II clinical trial
• antithrombin III 18,000 IU over 120 hours (N = 20) versus placebo (N = 22)
• mortality at day 30: 25% versus 41%
• 15 % of ATIII treated patients had hemorrhage
• meta-analysis

• 3 European phase II studies (6, 7) (1 RCT not published separately)
• ATIII (N = 60) versus placebo (N = 62)
• mortality at day 30: 35% versus 45 %
• bleeding: not specified

• randomized, placebo-controlled, double-blind, multicenter trial
• ATIII 24,000 IU over 120 hours (N = 60) versus placebo (N = 60)
• mortality at day 30: 50% versus 54%

9. Warren BL et al. JAMA 2001. (9) [level 1b]

• KyperSept Trial
• randomized, placebo-controlled, phase III clinical trial
• ATIII 30,000 IU over 96 hours (N=1161) versus placebo (N = 1155)
• mortality at day 28: 38.9% versus 38.7% (P = 0.94); RR (95% CI): 1.01 (0.91-1.11)
• mortality at day 56 and 90: not different
• mortality rate at day 90 for subgroup of patients not receiving concomitant heparin: 44.9% versus 52.5% (P = 0.03)
• serious bleeding: 10.0 versus 5.7% (P < 0.001)
  

Tissue Factor Pathway Inhibitor (TFPI)

10. Abraham E et al. JAMA 2003. (10) [level 1b]

• OPTIMIST (Optimized Phase III Tifacogin in Multicenter International Sepsis Trial)
• randomized, placebo-controlled, phase III clinical trial
• TFPI 25 mcg/kg/hour for 96 hours (N = 880) versus placebo (N = 874)
• mortality at day 28: 34.2% versus 33.9% (P = 0.75); RR (95% CI): 1.01 (0.89-1.15)
• serious bleeding: 6.5% versus 4.8% for high INR (P = 0.13); 6.0% versus 3.3% for low INR (P = 0.37)
• note: the trial was performed in 2 stages: stage 1 included only patients with high INR (≥ 1.2, N = 1987), in stage 2 also lower INR (< 1.2) patients were included (N = 201); major analyses were restricted to the high INR group.
• note: analysis of the first 722 patients demonstrated mortality rates favoring tifacogin: 38.9% vs. 29.1% (P < 0.006).

Comment

Strategies aiming at restoration of physiological anticoagulant pathways, such as administration of antithrombin (ATIII), tissue factor pathway inhibitor (TFPI), and activated protein C (APC), have been performed in patients with severe sepsis/septic shock in the past few years. Although phase II studies on infusion of AT or TFPI showed promising results, both strategies proved to be ineffective in reducing mortality in two large, randomized, placebo-controlled phase III studies (KyberSept (9) and OPTIMIST (10)).

To date, only APC has shown to improve survival of patients with severe sepsis, more specifically, those with high risk of death (APACHE II score ≥ 25) (1). Patients with low risk of death do not seem to benefit from APC (4). Treatment of severe sepsis patients with APC should be done with precaution, excluding those with low risk of death or high risk of bleeding.

There is no evidence that ATIII and TFPI (tifacogin) are beneficial to patients with severe sepsis. There is one ongoing trial exploring the beneficial effects of TFPI in critically ill patients with severe community-acquired pneumonia: the CAPTIVATE study is a randomized, placebo-controlled, phase 3 clinical trial that is expected to enroll approximately 2,100 patients at approximately 200 centers in 16 countries (http://www.clinicaltrials.gov; identifier NCT00084071); many of these patients may have (pneumo-)sepsis.

Both Warren et al. (9) and Abraham et al. (10) suggest interactions with ATIII and TFPI, respectively, with heparin; showing trends of increased survival in ATIII or TFPI treated patients who did not have concomitant heparin. Recruitment for the phase 4 trial investigating effects of heparin prophylaxis co-administration during APC treatment has recently been completed (http://www.clinicaltrials.gov; identifier NCT00049777); results are expected soon.

1. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699-709.
2. Bernard GR, Margolis BD, Shanies HM, Ely EW, Wheeler AP, Levy H, Wong K, Wright TJ. Extended evaluation of recombinant human activated protein C United States Trial (ENHANCE US): a single-arm, phase 3B, multicenter study of drotrecogin alfa (activated) in severe sepsis. Chest 2004;125:2206-2216.
3. Vincent JL, Bernard GR, Beale R, Doig C, Putensen C, Dhainaut JF, Artigas A, Fumagalli R, Macias W, Wright T et al. Drotrecogin alfa (activated) treatment in severe sepsis from the global open-label trial ENHANCE: further evidence for survival and safety and implications for early treatment. Crit Care Med 2005;33:2266-2277.
4. Abraham E, Laterre PF, Garg R, Levy H, Talwar D, Trzaskoma BL, Francois B, Guy JS, Bruckmann M, Rea-Neto A et al. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med 2005;353:1332-1341.
5. Wiedermann CJ, KaneiderNC. A meta-analysis of controlled trials of recombinant human activated protein C therapy in patients with sepsis. BMC Emerg Med 2005;5:7.
6. Fourrier F, Chopin C, Huart JJ, Runge I, Caron C, Goudemand J. Double-blind, placebo-controlled trial of antithrombin III concentrates in septic shock with disseminated intravascular coagulation. Chest 1993;104:882-888.
7. Eisele B, Lamy M, Thijs LG, Keinecke HO, Schuster HP, Matthias FR, Fourrier F, Heinrichs H, Delvos U. Antithrombin III in patients with severe sepsis. A randomized, placebo-controlled, double-blind multicenter trial plus a meta-analysis on all randomized, placebo-controlled, double-blind trials with antithrombin III in severe sepsis. Intensive Care Med 1998;24:663-672.
8. Baudo F, Caimi TM, de Cataldo F, Ravizza A, Arlati S, Casella G, Carugo D, Palareti G, Legnani C, Ridolfi L et al. Antithrombin III (ATIII) replacement therapy in patients with sepsis and/or postsurgical complications: a controlled double-blind, randomized, multicenter study. Intensive Care Med 1998;24:336-342.
9. Warren BL, Eid A, Singer P, Pillay SS, Carl P, Novak I, Chalupa P, Atherstone A, Penzes I, Kubler A et al. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 2001;286:1869-1878.
10. Abraham E, Reinhart K, Opal S, Demeyer I, Doig C, Rodriguez AL, Beale R, Svoboda P, Laterre PF, Simon S et al. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA 2003;290:238-247.