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activated protein C
activated protein C
activated protein C
activated protein C
activated protein C
activated protein C
activated protein C
activated protein C
activated protein C
activated protein C
activated protein C
activated protein C
activated protein C
activated protein C
activated protein C
activated protein C
activated protein C
activated protein C
activated protein C
activated protein C
activated protein C
activated protein C
activated protein C
activated protein C
activated protein C
activated protein C
activated protein C
activated protein C
activated protein C
activated protein C
activated protein C
activated protein C
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activated protein C


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  • 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
    • Mortality rate – 25.3%
    • Absolute risk reduction - 6.1%
    • Ineffective if APACHE II score of 24 or less
    • 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)‏
  • 23.  
  • 24.  
  • 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
    • Andreoli TE, Carpenter CC, Griggs RC, Loscalzo J, editors. Cecil essential of medicine. 6 th edition. Philadelphia: W.B. Saunders Company; 2004.
    • Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001; 29(7): 1303-1310.
    • Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001 March 8; 344(10): 699-709.
    •   Dalton HJ. Recombinant activated protein C in pediatric sepsis. Pediatr Infect Dis J. 2003 August; 22(8): 743-45.
    • Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004; 32(3):858-873.
    • Dhainaut JF, Yan SB, Joyce DE, Pettila V, Basson B, Brandt JT, Sundin DP, Levi M. Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation. J Thromb Haemost. 2004; 2:1924-33.
    • Eichacker PQ, Danner RL, Suffredini AF, Cui X, Natanson C, Magnuson WG. Reassessing recombinant human activated protein C for sepsis: Time for a new randomized controlled trial. Crit Care Med. 2005; 33(10): 2426-2428.
    • Eli Lilly and Company, Sepsis Overview. Available at:
    • , Accessed on 2005 October 3.
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    • Ely EW, Angus DC, Williams MD, Bates B, Qualy R, Bernard GR. Drotrecogin alfa (activated) treatment of older patients with severe sepsis. Clin Infect Dis. 2003 July 15; 37:187-195.
    • Esmon CT. Protein C anticoagulant pathway and its role in controlling microvascular thrombosis and inflammation. Crit Care Med. 2001 Jul 01; 29 Suppl 7: S48-51.
    • Fein AM, Abraham EM, Balk RA, Bernard GR, Bone RC, Dantzker DR, Fink MP, editors. Sepsis and Multiorgan Failure. Baltimore: Williams & Wilkins; 1997.
    • Girard TD, Opal SM, Ely EW. Insights into severe sepsis in older patients: from epidemiology to evidence-based management. Clin Infect Dis. 2004 Mar 01; 40: 719-727.
    • Giroir BP. Recombinant human activated protein C for the treatment of severe sepsis: is there a role in pediatrics? Curr Opin Pediatr. 2003; 15:92-96.
    • Grinnell BW, Joyce D. Recombinant human activated protein C: A system modulator of vascular function for treatment of severe sepsis. Crit Care Med. 2001; 29 Suppl 7: S53-61.
    • Kerr M. Drotrecogin plus heparin efficacious for adults with severe sepsis. Available at:
    • http://www. medscape .com/ viewarticle /521768 , Accessed on 2006 February 2.  
    • Kumar V, Abbas AK, Fausto N, editors. Robbins and Cotran Pathological Basis of Disease. 7 th ed. Philadelphia: Elsevier Inc.; 2005.
    • Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med. 2003 April; 31(4): 1250-56.
    • Liaw PCY, Esmon CT, Kahnamoui K, Schmidt S, Kahnamoui S, Ferrell G, et al. Patients with severe sepsis vary markedly in their ability to generate activated protein C. Blood. 2004 December 15; 104(13): 3958-3964.
    • McLeay AM. Drotrecogin alfa: A role in emergency department treatment of severe sepsis? Emerg Med Australas. 2004; 16:324-335.
  • 31.
    • Shapiro NI, Howell M, Talmor D. A blueprint for a sepsis protocol. Acad Emerg Med. 2005; 12(4): 352-359.
    • Society of Critical Care Medicine, Press Room: Sepsis Guide. Available at:
    • http://www. sccm .org/press_room/sepsis_guide.asp , Accessed on 2005 October 3.
    • Taylor A FB Jr., Chang A, Esmon CT, et al. Protein C prevent the coagulopathic and lethal effect of E. coli infusion in the baboon. J Clin Invest. 1987; 79:918-925
    • Taylor B FB Jr., Stearns-Kurosawa DJ, Kurosawa S, et al. The endothelial cell protein C receptor aids in host defense against Escherichia coli sepsis. Blood. 2000; 95:1680-1686. 
    • U.S. Food and Drug Administration A , A catalog of FDA approved drug products. Label and Approval history for Xigris. Label approved on 6/23/05. Available at:
    • , Accessed on 2005 October 3.
    • U.S. Food and Drug Administration B , The FDA Safety Information and Adverse Event Reporting Program. 2005 Safety Alert: Xigris [drotrecogin alfa (activated)]. Available at: , Accessed on 2006 February 3.
    • Vincent JL A , Carlet J, Opal SM, editors. The Sepsis Text. Boston: Kluwer Academic Publishers; 2002.
    • Vincent JL B , Bernard GR, Beal R, Doig C, Putensen C, Dhainaut JF, Artigas A, Fumagalli R, Macias W, Wright T, Wong K, Sundin DP, Turlo MA, Janes J. Drotrecogin alfa (activated treatment in sever sepsis from the global open-label trial ENHANCE: Further evidence for survival and safety and implications for early treatment. Crit Care Med. 2005; 33(10): 2266-2277.
    • Vincent JL C , Nadel S, Kutsogiannis DJ, Noel Gibney RT, Yan SB, Wyss VL, Bailey JE, Mitchell CL, Sarwat S, Shinall SM, Janes JM. Drotrecogin alfa (activated) in patients with severe sepsis presenting with purpura fulminans, meningitis, or meningococcal disease: a retrospective analysis of patients enrolled in recent clinical studies. Crit Care. 2005; 9(4): R331-R343.
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    •   Warren HS, Suffredini AF, Eichacker PQ, Munford RS. Risks and Benefits of Activated Protein C Treatment for Severe Sepsis. N Engl J Med. 2002 September 26; 347(13):1027-1030.
    • Watson RS, Carcillo JA, Linde-Zwirble WT, Clermont G, Lidicker J, Angus DC. The epidemiology of severe sepsis in children in the United States. American Journal of Respiratory and Critical Care Medicine. 2003; 167: 695-701.
    • White B, Livingstone W, Murphy C, Hodgson A, Rafferty M, Smith OP. An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia. Blood. 2000 December 1; 96(12): 3719-3724.
    • Yan SB, Helterbrand JD, Hartman DL, Wright TJ, Bernard GR. Low levels of protein C are associated with poor outcome in severe sepsis. Chest. 2001 September; 120(3): 915-922.