BLOOD COAGULATION AND INFLAMMATION IN SEPSIS. A NEW CHALLENGE. Antonio Artigas Critical Center Sabadell Hospital Autonomous University of Barcelona

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1 BLOOD COAGULATION AND INFLAMMATION IN SEPSIS. A NEW THINKING AND THERAPEUTIC CHALLENGE Antonio Artigas Critical Center Sabadell Hospital Autonomous University of Barcelona

2 SEVERE SEPSIS PATHOPHYSIOLOGY Microvascular dysfunction Inflammation Coagulation Fibrinolysis Hypoperfusion/hypoxia Microvascular thrombosis Endothelial dysfunction Organ dysfunction Global tissue hypoxia Direct tissue damage

3 Roles of ATIII, APC, and TFPI in Coagulation

4 Arg AntiThrombin III Heparin binding site Ser

5 Anti-Thrombin III A serine proteasee inhibitor-inactivates thrombin and compo onents of the intrinsic, extrinsic, and common clotting system Stimulates prostacyclin synthesis in endothelial cells - limits platelet aggregation Attenuates TNF generation via PGI-induced C AMP production

6 KyberSept Study Design double- Randomized, placebo-controlled, blind trial in severe sepsis More than 200 centers participating worldwide, to recruit 2,300 patients High dose intravenous AT III (30,000 IU) given within 4 days

7 Survival time until day 91 - ITT population Surviva al (%) Time on study (days) Placebo (N=1157 censored=603) AT III (N=1157 censored=630) Warren et al. JAMA 286: ,2001.

8 Model for TFPI Binding to Factor VIIa/TF on the Cell Membrane

9 OPTIMIST Study Double-blind, placebo-controlledphase 3 clinical trial multi-center, Patients with severe sepsis 245 hospitals in 17 countries, in North America, Europe, and Israel Tifacogin (TFPI) (0.025 mg/kg/hr for 96 hours) or placebo Primary efficacy population: INR > 1.2 Secondary safety population: INR < 1.2 Primary endpoint: 28 day all cause mortality Planned enrollment of 1950 patients (1750 with INR > 1.2, 200 with INR < 1.2)

10 Mean TFPI Levels at Hours (Patients with Baseline INR >/= 1.2) 175 P-value <.001* Mean TFPI Level (ng g/ml) +/- 1 SE (n = 781) Placebo (n=792) tifacogin

11 Lack of Effect of TFPI on 28 Day All-Cause Mortality Abraham et al. JAMA 290: ,2003.

12 TFPI IN SEVERE SEPSIS Abraham et al. JAMA 290: ,2003.

13 TFPI IN SEVERE SEPSIS Abraham et al. JAMA 290: ,2003.

14 Relationship between Heparin Use and Mortality Placebo INR > 1.2 tifacogin INR < 1.2 P Placebo tifacogin P Heparin (n=) % Mortality 29.8 % 34.0 % % 12.3% 0.23 No Heparin (n=) % Mortality 42.7 % 34.6% % 11.1% 0.18

15 CAPTIVATE STUDY 28-day all-cause mortality (Per-protocol & Optimal Cohort) Per Protocol Optimal Cohort 28-day Mortality (% %) 15 14,8 13, N=721 N=687 Tifacogin Placebo 15 12,7 11,2 10 Per-Protocol (PP): patients with clinical evaluation committee (CEC) confirmed or possible CAP, met severe CAP criteria at baseline, no clinically significant protocol deviations, minimal study drug infusion time. Optimal Cohort : PP patients with confirmed CAP, acceptable antimicrobial therapy, and did not have only a non-bacterial infection. 28-day Mortality (% %) 5 0 N=569 N=545 Tifacogin Placebo

16 CAPTIVATE STUDY 28-day all-cause mortality by disease characteristics (ITT) TFP mg/kg/h TFP mg/kg/h Placebo 28-day all-cause mortality (%) major 1 major CAP severity 0 major 3 minor 0 major 2 minor

17 Severe Protein C Deficiency at Baseline is Associated with Early Death P C > 8 0 % ( N = ) P C = % ( N = ) P C < = 4 0 % ( N = ) Survival Rate (%) p < D a y s Kaplan-Meier estimates of mortality within the PROWESS placebo group

18 Proposed Pathways for APC Activity PAI-1 Mosnier LO, et al. Blood Nov 16

19 APC effects on the Neutrophil Neutrophils have protein C receptors. Sturn et al. Blood.2003:102: 1499 APC inhibits neutrophil chemotaxis. Feistritzer et al. JACI. 2003, 112:375 APC does not modify neutrophil respiratory burst, bacterial phagocytosis or apoptosis. Nick et al. Blood 2004, 104:3878. Neutrophil

20 Biologic Activities of activated Protein C Anti-thrombotic Inactivation of Va and VIIIa Pro-fibrinolytic Inactivation of PAI-1 Protease Mediated Activity Anti-inflammatory Direct effects on circulating leukocytes Macrovascular and microvascular effects apc-epcr-par interactions apc-epcr-s1p interactions EPCR (ie, apcr) Mediated Activity

21 Drotrecogin alfa (activated) Mechanism of Action in 2006 Endothelial cell surface Fibrin degradation Blood stream Coagulation cascade PAI-1 Throm bin APC Decreased Neutrophil Chemotaxis Fibrin/platelet aggregation PARs Throm bin Throm bom odulin APC EPCR T ransactivation S-1 P-1 PAR-1 Cell activation Rac/R ho C ytoskeleton re-arrangem ent Vascular barrier function

22 Define relative role of thrombin inhibition vs. directed cell signaling by APC K193E onnticoagulant utant L8W Anticoagulant mutant Grinnell et al, Lilly Research Laboratories, In Press JASN

23 Modulation of systemic hemodynamics by APC in the rat endotoxin model is PAR-1 dependent MAP (mmh Hg) * # # MAP (mm Hg) * 80 Sham Control APC K193E (30 µg/kg) 80 Sham Control L8W 30 µg/kg L8W 100 µg/kg LPS LPS

24 The dual functions of APC modulate distinct anti-inflammatory pathways in the renal microvasculature Prothombinase L8W Thrombin APC PAR -1 Signa al K193E Pro- inflammatory/ Vascular activation IL-6 IL-18 ACE-1 Anti- inflammatory/ Vascular protection Adhesion inos ADM

25 MICROCIRCULATORY DYSFUNCTION Normal Volunteer Sublingual Microscopy Patient with septic shock HR = 120, MAP 60, PAOP 16, Cardiac Index = 3.5, SVO2 = 68% On norepinephrine and dopamine Am J Respir Crit Care Med 2002;166;98-104

26 Effects of Xigris on microvascular perfusion t initiation of therapy N=20 Capillary perfusion, % BASE BASE + 4 H P<0.01 vs base

27 Phase III : PROWESS Study : 28-day Survival 0.30 Morta ality Rate Placebo 0.15 DrotA AA Log rank : p = d 14d 21d Days from Start of Infusion 28d G. Bernard et al., NEJM 2001

28 PROWESS and ADDRESS: Comparison of Mortality Rates PROWESS Overall Single OD APACHE II <25 ADDRESS Overall Mortality Rate P-value N Drot PLA Relative Risk of Death (Point Estimate and 95% CI)

29 Russell JA Crit Care Med 2006;35:1-5

30 Primary objective of RPCs in patients with vasopressor-dependent Septic Shock PROWESS Shock APROACCHS Randomized, double blind, placebo control trial to determine whether when compared with placebo, treatment with recombinant human activated protein C reduces 28-day all-cause mortality in adult patients with persistent septic shock. Randomized, double blind, placebo control, factorial assignment trial aims at com-paring the efficacy (90- day all-cause mortality) of recombinant human activated protein C to that of low dose of corticosteroids and at investigating the interaction between these drugs in adult with persistent septic shock

31 Intervention of RPCs in patients with vasopressor-dependent Septic Shock PROWESS Shock APROACCHS 1 st arm : placebo 1 st arm : placebos 2 nd arm : recombinant human activated 2 nd arm : hydrocortisone + protein C fludrocortisone and placebo 3 rd arm : recombinant human activated protein C and placebo 4 th arm : recombinant human activated protein C and hydrocortisone + fludrocortisone

32 Estimated enrollment of RPCs in patients with vasopressor-dependent Septic Shock PROWESS Shock APROACCHS Estimated enrollment : 1500 pts (option to enroll 2000 if aggregate mortality < 750 pts) Interim analyses (1/3: safety; 2/3: efficacy (<.001 & >250 deaths) Estimated 28-dy mortality : 31.5% Study start date : march 2008 Estimated study completion date: march 2011 Estimated Enrollment: 1280 pts (320 pts per arm) Estimated 90day-mortality : 45% Study start date : march 2008 Estimated study completion date: march 2011

33 CONCLUSIONS Microvascular dysfunction is common in severe sepsis and results in tissue hypoxia. Clinical trials with agents that interrupt coagulation cascades are negative with one exception rhapc. rhapc has additional mechanisms of action independent of effects of coagulation that may explain clinical efficacy. New RCT in septic shock are necessary to confirm rhapc clinicall efficacy.