1. THE ROLE OF ACTIVATED PROTEIN C IN SEPTIC SHOCK
Helena Yu
Medical Therapeutics
2/2/07

2. Background Sepsis definitions
SEPSIS: suspected/proven infection plus a systemic inflammatory response syndrome (fever, tachycardia, tachypnea, leukocytosis)
SEVERE SEPSIS: sepsis with organ dysfunciton (hypotension, hypoxemia, oliguria, metabolic acidosis, thrombocytopenia or obtundation)
SEPTIC SHOCK: severe sepsis with hypotension, despite adequate fluid resuscitation

3. Background Sepsis and Coagulation
Sepsis alters the coagulation balance by increasing procoagulant factors (tissue factor, fibrin), decreasing anticoagulant factors (protein C and S, antithrombin III and tissue factor pathway inhibitor) and decreasing fibrinolysis. This imbalance leads to DIC, microvascular thrombosis and ultimately, multi-organ failure
Activated protein C inactivates factors Va and VIIIa (antithrombotic effect) and inhibits the synthesis of plasminogen-activator inhibitor 1 (profibrinolytic effect)
Activated protein C also has an anti-inflammatory effect by inhibiting nuclear factor-kB which suppresses cytokine production (TNF, IL-6) and decreases cellular apoptosis

4. Bernard 2001. Proposed actions of activated protein C

5. Background Activated protein C and sepsis
Severe sepsis usually produces at least a sub-clinical coagulopathy evident by an elevated D-dimer and decreased levels of protein C.
Protein C requires a functioning endothelium for activation. Severe sepsis leads to the down-regulation of the endothelial protein C receptor and thrombomodulin, decreasing levels of activated protein C. There is also decreased synthesis of APC in the liver and increased consumption due to microthrombosis.
Patients admitted with serious infections that did not progress to shock had higher levels of protein C compared to those who did develop septic shock (Hesselvik 1991).
Protein C levels are correlated with mortality in patients with severe sepsis (Yan 2001).
Severe protein C deficiency in patients with septic shock is associated with early death (Macias 2004).

6. Background Established treatments for sepsis
Early goal directed therapy: protocol derived therapy that uses central venous catheter readings (physiologic parameters) to dictate therapy including crystalloids, vasopressors, and blood transfusions. Shown to decrease mortality and decrease duration of hospitalization (Rivers 2001).
Low tidal volume ventilation: use of low tidal volumes decreases mortality in septic acute lung injury (Eisner 2001).
Antibiotics: Start broad spectrum antibiotics initially and narrow coverage when cultures indicate causative pathogen
Activated Protein C? Hypothesis is that supplementation of coagulation inhibitors could prevent DIC and organ failure and decrease mortality of severe sepsis

7. Phase II trial: Bernard et al
Description: A prospective, randomized, placebo-controlled trial to assess the safety and efficacy of drotecogin alfa activated (DAA)
Methods: Dosing and duration of infusion were studied. Effects of treatment were assessed by markers of inflammation and coagulopathy including D-Dimer, IL-6, fibrinogen and platelets along with other clinical markers.
Results: reduction in 28-day all-cause mortality in the high dose DAA group as compared to placebo. D-dimer and IL-6 levels decreased in a dose-dependent manner with increasing doses of DAA. The incidence of adverse events including serious bleeding did not differ between the DAA and placebo group. Effective and acceptable dose of recombinant activated protein C (rhAPC) established as 24 um/kg/her for 96 hours.

8. Phase III trial: PROWESS
Description: randomized, double-blind, placebo-controlled, multicenter trial with the primary end point of reduction of 28-day all cause mortality
Methods: 1690 patients with systemic inflammation and organ failure due to acute infection were enrolled and assigned to an infusion of DAA or placebo. Exclusion criteria included conditions with increased risk of bleeding, known hypercoagulable state, severe thrombocytopenia, pregnancy, cirrhosis, CRF dialysis-dependent and moribund conditions with low expected survival. Base-line characteristics of the patients in both groups were similar with no statistically significant differences.
Results: Enrollment was suspended mid-study when DAA was found to be more efficacious than placebo. Relative risk reduction of mortality was 19.4% in the DAA group along with an absolute risk reduction of 6.1%. Consistent treatment effect of DAA was observed among all subgroups. There were greater decreases in D-dimer and IL-6 levels in the DAA group. There was a higher incidence of serious bleeding in the DAA group vs. placebo (3.5% vs 2.0%) although limited to the peri-infusion period.

9. Bernard 2001. Kaplan-Meier estimates of survival in DAA and placebo groups.

10. Controversy over protocol
In Nov 2001, the FDA approved the use of rhAPC for treatment of patients with severe sepsis who have a high risk of death, but not without some controversy (FDA anti-infective drug advisory committee was split as to whether APC is safe and efficacious)
Midway into the study, the sponsor amended the study protocol. Changes included:
1. modified entry criteria: shifted population of study towards patients with less severe underlying disease and more acute infectious illness.
2. new master lot of cells: although extensive in vitro studies indicated no differences between the old and new preparations.
After these changes, there was an improvement of efficacy of APC vs placebo. However, FDA analysis conclusion was that changes in efficacy were not 2/2 the changed protocol or new drug although some remained unconvinced (Warren 2002).

11. Warren 2002. Line A indicated intro of amended protocol
Warren Line A indicated intro of amended protocol. First analysis occurred at B, around the time of the new cell group. Second analysis at C.

12. APC for which patients
FDA approved APC for treatment of patients with an APACHE II score of ≥ 25. Treatment benefit of APC increased with the risk of death.
APACHE II score was the best predictor of survival benefit from activated protein C compared to other measures of risk and severity. Benefit of APACHE score is that it assesses severity of acute process along with other risk factors such as age and preexisting health status. However, the APACHE score was not intended to be used as a selection criteria. It was developed to predict a patient’s risk of dying in the ICU over a 24 hr period. APACHE score in reality is in flux as physiologic parameters change over time. Furthermore, there is intra and inter-observer variability in designated scores among experienced ICU physicians as high as 10-20% (Polderman 2001).

13. Warren 2002. Mortality and bleeding according to APACHE II quartiles

14. APC for which patients
After FDA approval of APC in adults with severe sepsis and a high risk of death (APACHE>25), the FDA required another study evaluating APC in patients with severe sepsis and low risk of death
Abraham et al conducted a double-blind, placebo controlled, multicenter study in patients with severe sepsis with low risk of death (defined by APACHE<25) with the primary end point of all-cause mortality at 28 days.
The study was terminated early as there was no statistically significant differences in 28 day mortality between placebo and APC. In addition, there was a higher incidence of serious bleeding in the APC group vs placebo both in the peri-infusion period and the entire 28 day study period.
With no beneficial treatment effect and an increased rate of bleeding in the treatment group, the study concluded that APC should not be used in patients with severe sepsis, with a low risk of death

15. Abraham 2005. Kaplan-Meier estimates of survival in DAA and placebo groups.

16. Other Concerns with PROWESS
Study population: There is some concern as to whether the PROWESS study population is representative of the total population of patients with sepsis in hospitals and consequently whether the study results can be generalized. 80% of patients in the study were living at home prior to hospitalization, 50% were admitted with respiratory failure and all patients who had organ failure for >24 hrs were excluded from the study.
Bleeding risk: Incidence of severe bleeding complications may increase when APC is used in less controlled environments. During open-label APC use after the trial, 2.5% of patients had an intracranial hemorrhage as compared to 0.2% of patients who received APC during the trial (Warren 2002).

17. Economic considerations
DAA is an expensive therapy, costing an average of 6,800 dollars per therapeutic course resulting in reluctance to use DAA in certain populations.
An economic analysis was done, and the average cost per life-year gained by treating patients with APC was $27,936 (Mannis 2002).
The study concluded that activated protein C is relatively cost effective when targeted to patients with severe sepsis, with an APACHE>25, and a reasonable life expectancy.
In addition, cost effectiveness ratios of APC are similar to or better than other widely accepted therapies including organ transplantation, dialysis, and implanted cardiac debrillators (Angus 2003)

18. Mannis 2002.

19. Angus 2003. Comparison of APC with other widely used interventions

20. Conclusions
Activated Protein C reduces mortality in patients with severe sepsis with a high risk of death (APACHE>25)
Treatment of severe sepsis with APC is cost effective when targeted to patients with severe sepsis, high risk of death with a reasonable life expectancy
Activated protein C has not shown efficacy and in addition is not cost effective in patients with severe sepsis with low risk of death (APACHE<25)

21. Works Cited
Abraham E, Laterre P-F, Garg R, et al. Drotrecofin alfa (activated) for adults with severe epsis and low risk of death. N Engl J Med 2005;353:
Angus DC, Linde-Zwirble HT, Clermont G. Cost-effectiveness of drotrecogin alfa (activated) in the treatment of severe sepsis. Critical Care Med 2003 Jan;31(1):1-11.
Bernard GR, Vincent J-L, Laterre P-F, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:
Eisner MD, Thompson T, Hudson LD, et al. Efficacy of low tidal volume ventilation in patients with different clinical risk factors for acute lung injury and the acute respiratory distress syndrome. Am J Repis Crit Care Med 2001; 164:231-6.
Fourrier F. Recombinant human activated protein C in the treatment of severe sepsis: An evidence-based review. Crit Care Med 2004; 32[Suppl]: S534-S541.
Hesselvik JF, Malm J, Dahlback B, et al. Protein C, protein S, C4b-binding protein in severe infection and septic shock. Thromb Haemost 1991;65:126-9.
Macias WL, Nelson DR. Severe protein C deficiency predicts early death in severe sepsis. Crit Care Med 2004;32(Suppl):S

22. Works Cited
Mannis BJ, Lee H, Doig CJ, et al. An economic evaluation of activated protein C treatment for severe sepsis. N Engl J Med 2002;347:
Polderman KH, Jorna EM, Girbes AR. Intra-observer variability in APACHE II scoring. Intensive Care Med 2001;27:
Rice TW, Bernard G. Drotrecogin alfa (activated) for the treatment of severe sepsis and septic shock. Am J Med Sci 2004; 328(4):
Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:
Russell JA. Management of sepsis. J Engl J Med 2006;355:
Siegel JP. Assessing the use of activated protein C in the treatment of severe sepsis. N Engl J Med 2002;347:
Warren HS, Suffredini AF, Eichacker PQ, Munford RS. Risks and benefits of activated protein C treatment for severe sepsis. N Engl J Med 2002;347:
Yan SB, Helterbrand JD, Hartman DL, et al. Low levels of protein C are associated with poor outcomes in severe sepsis. Chest 2001;120: