The Use of Recombinant Human Activated Protein C for Severe Sepsis

1. The Use of Recombinant Human Activated Protein C for Severe Sepsis Presented by: Lindsay Moorman Advisor: Dr. Hadley

2. What is Severe Sepsis? • Severe sepsis – defined by the presence of both infection and a systemic inflammatory response which produce organ failure

3. The Problem • 750,000 Americans suffer from it each year • 215,000 die • High mortality rate • Incidence is rising and is expected to exceed 1 million cases by 2010

4. Physiologic Derangements Occurring in Severe Sepsis • Overproduction of inflammatory mediators • IL-1, IL-6, TNF • Unopposed microthrombi formation • Result – organ damage • Low oxygen perfusion to major organs • Cytokine-induced apoptosis

5. General Facts about Protein C • Made by the liver and circulates as a zymogen • Activated by thrombomodulin receptor • Protein C levels are drastically reduced in states of sepsis • Thrombomodulin receptor down regulation occurs in severe sepsis

6. Mechanism of Action for rhAPC • Drastically reduces production of thrombin • Reduces levels of PAI-1, enhancing tPA’s actions • Anti-inflammatory mechanisms • Reduces cytokine elaboration • Decreases oxidative damage to endothelial cells • Blocks endothelial cell apoptosis

7. The PROWESS Trial • Placebo-controlled, double-blinded • 1690 participants, age 18 or older • Placebo group mortality – 30.8% • rhAPC group mortality – 24.7% • Absolute risk reduction – 6.1% • Ineffective for subgroup with APACHE II scores less than 24

8. APACHE II Score • 0-4~4% death rate • 5-9~8% death rate • 10-14~15% death rate • 15-19~25% death rate • 20-24~40% death rate • 25-29~55% death rate • 30-34~75% death rate • over 34~85% death rate

9. Analysis of the Elderly Population within the PROWESS Trial • Subjects older than 75 • Had more underlying disease • Larger absolute risk reduction – 15.5% • For every 6 elderly patients treated, 1 additional life will be saved

10. ENHANCE Trial • Open-label, single-arm trial • 2,375 participants • Compared mortality results to those of the PROWESS trial

11. PROWESS Mortality rate – 25.3% Absolute risk reduction - 6.1% Ineffective if APACHE II score of 24 or less ENHANCE Mortality rate – 24.7% Absolute risk reduction - 5.5% Ineffective if APACHE II score of 25 or less COMPARISONS

12. ENHANCE Trial • Patients treated in less than 24 hours of organ dysfunction had significantly higher survival rates, especially among the elderly

13. Inferences • rhAPC is most effective in reducing mortality from severe sepsis in the elderly • Clinicians must be aware that prompt treatment can save lives, especially of the elderly

14. Recommendations for use of Xigris (rhAPC) • Patients with APACHE II scores of 25 or more • Infusion lasts 96 hours

15. Adverse Effects of Xigris (rhAPC) • Only side effect is bleeding • Placebo group – 2% • Xigris group – 3.5% • Only seen during infusion period

16. Active internal bleeding Hx of hemorrhagic stroke in last 3 mths Hx of intracranial/ intraspinal surgery or severe head trauma in last 2 mths Trauma with increased risk of life-threatening bleeding Epidural catheter Intracranial neoplasm Mass lesion Cerebral herniation Contraindications

17. Recommendations for use in Surgical Patients • d/c 2 hours prior to surgery • Restart after 12 hours if platelet count is greater than 30,000

18. Recommendations for Concurrent Heparin Use • XPRESS trial • No higher incidence of serious bleeding events • Slightly higher incidence of minor bleeding • Heparin doesn’t interfere with efficacy • Heparin infusion should remain uninterrupted while Xigris is infused

19. Recommendations for use in Patients with DIC • Study by Dhainaut et al. • No significant increase in serious bleeding events • More efficacious in this population than patients without DIC

20. Use in Patients with Borderline APACHE II Scores • What if APACHE II score is 23-24? • Take into account the patients for which Xigris is most effective: • Age 50 or older • Two or more failing organs • Those who received the drug while in shock

21. Pediatric Use for Severe Sepsis • Would it be beneficial with a mortality rate of 10%? • RESOLVE trial • Measured composite time to resolution of organ failure • Stopped early due to lack of efficacy • FDA issued contraindication of Xigris in children

22. Pediatric Use for Specific Subpopulations • Vincent et al. investigated use in pediatric conditions associated with high mortality rates – meningococcemia and Purpura fulminans (PF)

25. Pediatric Use in Meningococcemia and PF • Retrospective analysis by Vincent et al. • 119 children • 4% lower mortality rate for children with meningococcemia/PF who received treatment with Xigris than children who received Xigris and didn’t have these conditions

26. Pediatric Use in Meningococcemia and PF • Open-label trial conducted by White et al. • 36 patients with PF-associated meningococcemia • Predicted mortality rate – 50% • With Xigris tx – 8% • Reduced the need for amputations

27. Conclusions: What Every Primary Care Physician Should Know • Indicated for use in patients with APACHE II scores of 25 or more • This drug is most effective in the elderly, those with 2 or more dysfunctional organs, and those who receive Xigris while in shock • Clinicians should remember that earlier treatment is better than later treatment • Xigris may be safely used in the high-risk populations discussed

28. Recommendations for Pediatric Use • Should only be used off-label when there’s a threat to life or limb • Risks/benefits must carefully be weighed • Should never be used off-label in children less than 2 months of age

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