Severe sepsis affects over 750,000 Americans annually and has a high mortality rate. Recombinant human activated protein C (rhAPC), also known as Xigris, reduces inflammation and coagulation in sepsis patients. The PROWESS clinical trial showed a 6.1% reduction in mortality for rhAPC-treated sepsis patients versus placebo. Subsequent trials confirmed rhAPC's effectiveness in reducing mortality, especially for elderly patients and those treated early in disease progression. However, rhAPC use requires careful patient selection due to risk of bleeding and is not recommended for children outside of specific high-risk conditions.

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. COMPARISONS 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

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. Contraindications 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

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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