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Drug Evaluation

Drotrecogin alfa (activated; Xigris®): an effective and cost-efficient treatment for severe sepsis

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Pages 15-26 | Published online: 09 Jan 2014

References

  • American College of Chest Physicians/ Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Grit. Care. Med. 20, 864–874 (1992).
  • Levy M, Fink M, Marshall J etal. 2001 SCCM/ESICM/ACCP/ATS/SIS International sepsis definitions conference. Grit. Care Med. 31, 1250–1256 (2003).
  • Angus D, Linde-Zwirble W, Lidicker J, Clermont G, Carcillo J, Pinsky M. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Grit. Care Med 29, 1303–1310 (2001).
  • •Population- based (northeastern USA) study of incidence and cost of severe sepsis.
  • Martin G, Mannino D, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979–2000. N Engl. J. Med 348, 1546–1554 (2003).
  • •Population-based (Continental USA) study of the changing incidence and outcome of sepsis.
  • Brun-Buisson C, Doyon F, Carlet J eta]. Incidence, risk factors, and outcome of severe sepsis and septic shock in adults. A multicenter prospective study in intensive care units. French ICU Group for Severe Sepsis. JAMA 274, 968–974 (1995).
  • Friedman G, Silva E, Vincent J-L. Has the mortality rate of septic shock changed with time? Grit. Cate Med 26, 2078–2086 (1998).
  • Salvo I, de Cian W, Musicco M et al. The Italian SEPSIS study: preliminary results on the incidence and evolution of SIRS, sepsis, severe sepsis, and septic shock. Int. Care Med. 21 (Suppl 2), S244–249 (1995).
  • Sands K, Bates D, Lanken P eta]. Epidemiology of sepsis syndrome in 8 academic medical centers. Academic Medical Center Consortium Sepsis Project Working Group. JAIVIA 278, 234–40 (1997).
  • Zeni F, Freeman B, Natanson C. Anti- inflammatory therapies to treat sepsis and septic shock: a reassessment. Grit. Care Med 25, 1095–1100 (1997).
  • •Reviews the imrnunomodulatory therapies including pooled analyses on outcome.
  • Heyland D, Hopman W Coo H, Tranmer J, McColl M. Long-term health-related quality of life in survivors of sepsis. Short Form 36: a valid and reliable measure of health related quality of life. Grit. Cate Med 28, 3599–3605 (2000).
  • Herridge M, Cheung A, Tansey C eta]. One-year outcome in survivors of the acute respiratory distress syndrome. N Engl. I Med 348, 683–693 (2003).
  • Graf J, Koch M, Dujardin R, Kersten A, Janssens U. Health-related quality of life before, 1 month after, and 9 months after intensive care in medical cardiovascular and pulmonary patients. Grit. Care Med 31, 2163–2169 (2003).
  • Davidson T, Caldwell E, Curtis J, Hudson L, Sterling K. Reduced quality of life in survivors of acute respiratory distress syndrome compared with critically ill control patients. 161/11A 281, 354–360 (1999).
  • Ziegler E, Fisher CJ, Sprung C et al Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin. A randomized double-blind, placebo-controlled trial. The HA-1A Sepsis Study Group. N Engl. J. Med 324,429–36 (1991).
  • McCloskey E, Straube R, Sanders C, Smith S, Smith C. Treatment of septic shock with human monoclonal antibody HA-1A. A randomized, double-blind, placebo-controlled trial. CHESS Trial Study Group. Ann Intern. Med 121,1–5 (1994).
  • Laupland K. Polyclonal intravenous immunoglobulin for the prophylaxis and treatment of infection in critically ill adults. Can. Infect. Dis. 13,100–106 (2002).
  • Greenman R, Schein R, Martin M et al A controlled clinical trial of E5 murine monoclonal IgM antibody to endotoxin in the treatment of gram-negative sepsis. The XOMA Sepsis Study Group. JAIVIA 266, 1097–1102 (1991).
  • Angus D, Birmingham M, Balk R eta]. E5 murine monoclonal antiendotoxin antibody in gram negative sepsis: a randomized controlled trial. E5 Study Investigators. PIMA 283,1723–1730 (2000).
  • Calandra T, Glauser M, Schellekens J, Verhoef J. Treatment of gram-negative septic shock with human IgG antibody to Escherichia coli J5: a prospective, double-blind, randomized trial. j Infect. Dis. 158, 312–319 (1988).
  • Alejandria M, Lansang M, Dans L, Mantaring J. Intravenous immunoglobulins for treating sepsis and septic shock. Coch. Data. Syst. Rev CD001090 (2003).
  • Bone R, Fisher CJ, Clemmer T, Slotman G, Metz C, Balk R. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N. Engl. Med 317,653–658 (1987).
  • KLastersky J, Cappel R, Debusscher L. Effectiveness of pmethasone in management of severe infections. A double-blind study. N Engl. J. Med 284, 1248–1250 (1971).
  • Lucas C, Ledgerwood A. The cardiopulmonary response to massive doses of steroids in patients with septic shock. Arch Surg. 119,537–541 (1984).
  • Luce J, Montgomery A, Marks J, Turner J, Metz C, Murray J. Ineffectiveness of high-dose methylprednisolone in preventing parenchymal lung injury and improving mortality in patients with septic shock. Am. Rev. Resp. Dis. 138, 62–68 (1988).
  • Schumer W Steroids in the treatment of clinical septic shock. Ann. Sing 184, 333–341 (1976).
  • Sprung C, Caralis P, Martial E etal. The effects of high-dose corticosteroids in patients with septic shock. A prospective, controlled, study. N Engl. J. Med 311, 1137–1143 (1984).
  • Cronin L, Cook D, Carlet J eta]. Corticosteroid treatment for sepsis: a critical appraisal and meta-analysis of the literature. Grit. Cam Med 23,1430–1439 (1995).
  • Lefering R, Neugebauer E. Steroid controversy in sepsis and septic shock: a meta-analysis. Grit. Care Med 23, 1294–1303 (1995).
  • Bernard G, Reines H, Halushka P etal Prostacyclin and thromboxane A2 formation is increased in human sepsis syndrome. Effects of cyclooxygenase inhibition. Am. Rev Rep. Dis. 144, 1095–1101 (1991).
  • Bernard G, Wheeler A, Russell J et al The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group. N Engl. J. Med. 336,912–918 (1997).
  • Haupt M, Jastremski M, Clemmer T, Metz C, Cons G. Effect of ibuprofen in patients with severe sepsis: a randomized, double-blind, multicenter study. The Ibuprofen Study Group. Grit. Care Med 19, 1339–1347 (1991).
  • Abraham E, Anzueto A, Gutierrez G etal Double-blind randomised controlled trial of monoclonal antibody to human tumor necrosis factor in treatment of septic shock. NORASEPT Study Group. Lancet 351, 929–933 (1998).
  • Abraham E, Glauser M, Butler T et al p55 Tumor necrosis factor receptor fusion protein in the treatment of patients with severe sepsis and septic shock. A randomized controlled multicenter trial. Ro 45–2081 Study Group. JAIVIA 277, 1531–1538 (1997).
  • Abraham E, Laterre P-F, Garbino J et al Lenercept Study Group. Lenercept (p55 tumor necrosis factor receptor fusion protein) in severe sepsis and early septic shock: a randomized, double-blind, placebo-controlled, multicenter Phase III with 1342 patients. Grit. Cam Med 29, 503–510 (2001).
  • Abraham E, Wunderink R, Silverman H et al Efficacy and safety of monoclonal antibody to human tumor necrosis factor a in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. TNF-a MAb Sepsis Study Group. JAIVIA 273,934–941 (1995).
  • Cohen J, Carlet J. INTERSEPT an international, multicenter, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor-a in patients with sepsis. International Sepsis Trial Study Group. Grit. Care Med 24,1431–1440 (1996).
  • Conway E, Rosenberg R. Tumor necrosis factor suppresses transcription of the thrombomodulin gene in endothelial cells. Mol Cell Biol. 8, 5588–5592 (1988).
  • Dhainaut J-F, Vincent J-L, Richard C etal CDP571, a humanized antibody to human tumor necrosis factor-a: safety, pharmacokinetics, immune response, and influence of the antibody on cytokine concentrations in patients with septic shock. CPD571 Sepsis Study Group. Grit. Cam Med 23,1461–1469 (1995).
  • Exley A, Cohen J, Buurman W et al Monoclonal antibody to TNF in severe septic shock. Lancet 335, 1275–1277 (1990).
  • Fisher CJ, Agosti J, Opal S etal Treatment of septic shock with the tumor necrosis factor receptor: FC fusion protein. The solube TNF Receptor Sepsis Study Group. N. Engl. Med 334,1697–1702 (1996).
  • Fisher CJ, Opal S, Dhainaut J-F etal Influence of an anti-tumor necrosis factor monoclonal antibody on cytokine levels in patients with sepsis. The CB0006 Sepsis Syndrome Study Group. Grit. Care Med 21,318–327 (1994).
  • Reinhart K, Wiegand-Lohnert C, Grimminger F etal Assessment of the safety and efficacy of the monoclonal anti-tumor necrosis factor antibody-fragment MAK 195F in patients with sepsis and septic shock: a multicenter, randomized, placebo-controlled, dose-ranging study. Grit. Care Med 24,733–742 (1996).
  • Saravolatz L, Wherry J, Spooner C etal Clinical safety, tolerability, and pharmacokinetics of murine monoclonal antibody to human tumor necrosis factor-a. Infect. Dis. 169,214–217 (1994).
  • Fisher CJ, Slotman G, Opal S et al Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: a randomized, open-label, placebo-controlled multicenter trial. The IL-1RA Sepsis Syndrome Study Group. Grit. Care Med 22,12–21 (1994).
  • Opal S, Fisher CJ, Dhainaut J-F etal Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a Phase III randomized doubleblind placebo-controlled multicenter trial. Crit. Cam Med 25,1115–1124 (1997).
  • Fein A, Bernard G, Criner G eta]. Treatment of severe systemic inflammatory response syndrome and sepsis with a novel bradykinin antagonist, deltibant (CP-0127). Results of a randomized, double-blind, placebo-controlled trial. CP-0127 SIRS and Sepsis Study Group. JAIVIA 277, 482–487 (1997).
  • Dhainaut J-F, Tenaillon A, Le Tulzo Y eta]. Platelet-activating factor receptor antagonist BN 52021 in the treatment of severe sepsis: a randomized, double-blind, placebo-controlled, multicenter clinical trial. BN 52021 Sepsis Study Group. Grit. Cam Med. 22, 1720–1728 (1994).
  • Cohen J, Guyatt G, Bernard G et al UK Medical Research Council International Working Party. New strategies for clinical trials in patients with sepsis and septic shock. Grit. Care Med. 29, 880–886 (2001).
  • Nasraway SJ. Sepsis research: we must change course. Grit. Cam Med. 27,427–430 (1999).
  • Bernard G, Vincent J-L, Laterre P-F et al Efficacy and safety of recombinant activated human protein C for severe sepsis. N. Engl. Med. 344, 699–709 (2001).
  • ••The results of the Phase III study ofdrotrecogin alfa activated (DAA) in patients with severe sepsis.
  • Banks S, Gerstenberger E, Eichacker P, Natanson C. Long-term cost effectiveness of drotrecogin alfa (activated): an unanswered question. Grit. Cate Med. 31, 308–309 (2003).
  • •Short editorial identifying some issues on the representativeness of the Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study population, and identifying some concerns in economic evaluations of DAA.
  • Chalfin D, Teres D, Rapoport J. A price for cost-effectiveness: implications for recombinant human activated protein C (rhAPC). Crit, Cate Med 31,306–308 (2003).
  • Cohen H, Welage L. Strategies to optimize drotrecogin a (activated) use: guidelines and therapeutic controveries. Phalmacotherapy22, S223—S235 (2002).
  • Dasta J, Cooper L. Impact of drotrecogin alfa (activated) on resourse use and implications for reimbursement. Phalmacotherapy22, S206—S215 (2002).
  • Eichacker P, Natanson C. Recombinant human activated protein C in sepsis: inconsistent trial results, an unclear mechanism of action, and safety concerns resulted in labeling restrictions and the need for phase IV trials. Cats Cam Med, 31, S94—S96 (2003).
  • •Short contrarian opinion on the data supporting adoption of DAA as a standard of care. Part of a supplement focusing on severe sepsis and DAA.
  • Thompson, C. High-cost sepsis drug forces pharmacists to weigh patients' future. Am. Health-Syst. Pharm. 59, 692–697 (2002).
  • Warren H, Suffredini A, Eichacker P, Munford R. Risks and benefits of activated protein C treatment for severe sepsis. N Engl. Med. 347, 1027–1030 (2002).
  • ••Opinion article identifying concerns in thePROWESS study. Part of three articles published in the same issue of the New England Journal of Medicine on DAA. It was countered by the article by Siegel in the same issue.
  • Dhainaut J-F, Yan S, Cariou A, Mira J. Soluble thrombomodulin, plasma-derived unactivated protein C, and recombinant human activated protein C in sepsis. Grit. Care Med. 30, S318—S324 (2002).
  • Esmon C. Cell mediated events that control blood coagulation and vascular injury. Ann Rev. Cell Biol. 9, 1–16 (1993).
  • Esmon C. The protein C pathway. Grit. Cam Med. 28(Suppl), S44—S48 (2000).
  • Esmon C. Protein C anticoagulant pathway and its role in controlling microvascular thrombosis and inflammation. Grit. Cam Med. 29, S48—S51 (2001).
  • Esmon C. Inflammation and thrombosis. j Thromb. I-Lemost. 1, 1343–1348 (2003).
  • Grinnel B, Hermann R, Yan S. Human protein C inhibits selectin mediated cell adhesion: role of unique fucosylated oligosaccharide. Clycobiology4, 221–226 (1994).
  • Grinnel B, Joyce D. Recombinant human activated protein C: a system modulator of vascular function for treatment of severe sepsis. Grit. Cam Med. 29, S53—S60 (2001).
  • Hack C, Zeeleder S. The endothelium in sepsis: source of and a target for inflammation. Grit. Care Med. 29, S21—S27 (2001).
  • Nimah M, Brilli R. Coagulation dysfunction in sepsis and multiple organ system failure. Grit. Cam Clin. 19, 441–458 (2003).
  • Riewald M, Ruf W Science review: role of coagulation protease cascades in sepsis. Grit. Care7, 123–129 (2003).
  • Levi M, de Jonge E, van der Poll T Rationale for restoration of physiological anticoagulant pathways in patients with severe sepsis and disseminated intravascular coagulation. Grit. Care Med. 29, S90—S94 (2001).
  • Faust S, Levin M, Harrison O eta]. Dysfunction of endothelial protein C activation in severe meningococcal sepsis. N. Eng. Med. 345, 408–416 (2001).
  • ••Describes the pathogenesis of purpurafulminans and the key role of the protein C pathway.
  • Abraham E, Reinhart K, Opal S et al Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis. A randomized controlled trial. JAIVIA 290, 238–247 (2003).
  • Abraham E, Reinhart K, Svoboda P etal Assessment of the safety of recombinant tissue factor pathway inhibitor in patients with severe sepsis: a multicenter, randomized, placebo-controlled, single-blind, dose-escalation study. Grit. Care Med. 29, 2081–2089 (2001).
  • Warren B, Eid A, Singer P eta]. High dose antithrombin III in severe sepsis: a randomized controlled trial. JAIVIA 286, 1869–1878 (2001).
  • Powars D. Acquired purpura fulminans in meningococcemia: association with acquired deficiencies of proteins C and S. N. Eng. Med. 317, 571–572 (1987).
  • Brandtzaeg P, Sandset P, Joo G, Ovstebo R, Abildgaard U, Kierulf P. The quantitative association of plasma endotoxin, antithrombin, protein C, extrinsic pathway inhibitor and fibrinopeptide A in systemic meningococcal disease. Thromb. Res. 55, 459–470 (1989).
  • Leclerc F, Hazelzet J, Jude B eta]. Protein C and S deficiency in severe infectious purpura of children: a collaborative study of 40 cases. Int. Cam Med. 18, 202–205 (1992).
  • Madden R, Gill J, Marlar R. Protein C and S levels in two patients with acquired purpura fulminans. BE J. 1-Lematol. 75, 112–117 (1990).
  • Marlar R, Endres-Brooks J, Miller C. Serial studies of protein C and its plasma inhibitor in patients with disseminated intravascular coagulation. Illood66, 59–63 (1985).
  • Sheth S, Carvalho A. Protein C and S alterations in acutely ill patients. Am. j Hematol 36, 14–19 (1991).
  • Roman J, Velasco F, Fernandez eta]. Protein C, protein S, and C4b-binding protein in neonatal severe infection and septic shock. I Perinat. Med. 20, 111–116 (1992).
  • Mesters R, Helterbrand J, Utterback B etal Prognostic value of protein C concentrations in neutropenic patients at high risk of severe septic complications. Grit. Cam Med. 28, 2209–2216 (2000).
  • Yan S, Helterbrand J, Hartman D, Wright T, Bernard G. Low levels of protein C are associated with poor outcome in severe sepsis. Chest 120,915–922 (2001).
  • Ware L, Fang X, Matthay M. Protein C and thrombomodulin in human acute lung injury. AIR I Physiol 285, L514—L521 (2003).
  • Aoki N, Matsuda T, Saito H etal A comparative prospective double-blind randomized trial of activated protein C and unfractionated heparin in the treatment of disseminated intravascular coagulation. Int. 1-Lematol 75,540–547 (2002).
  • Clarke R, Johnston J, Mayne E. Meningococcal septicemia: treatment with protein C concentrate. Int. Care Merl 26, 471–473 (2000).
  • Ettingshausen C, Veldman A, Beeg T, Schneider W, Jager G, Kreuz W Replacement therapy with protein C concentrate in infants and adolescents with meningococcal sepsis and purpura fulminans. Sem. Thromb. Hem. 25, 537–541 (1999).
  • Fijen C, Derkx B, Kuijper E eta]. Fulminant meningococcal septic shock in a boy with combined inherited properidin and protein C deficiency. Cl/n. Exp. Immunol 102,290–296 (1995).
  • Gerson W, Dickerman J, Bovill E, Golden E. Severe acquired protein C deficiency in purpura fulminans associated with disseminated intravascular coagulation: treatment with protein C concentrate. Pediatrics 91,418–422 (1993).
  • Hazelzet J, de Kleijn E, de Groot R. Endothelial protein C activation in meningococcal sepsis. N Engl. I Merl 345, 1776–1777 (2001).
  • Kreuz W, Veldman A, Escuriola- Ettingshausen C, Schneider W Beeg T Protein-C concentrate for meningococcal purpura fulminans. Lancet 351,986–987 (1997).
  • Leclerc F, Cremer R, Leteurtre S, Martinot A, Fourier C. Protein C concentrate and recombinant tissue plasminogen activator in meningococcal septic shock. Crit. Care Med. 28, 1694–1697 (2000).
  • Rintala E, Kauppila M, Seppala O-P et al Protein C substitution in sepsis-associated purpura fulminans. Grit. Care Med. 28, 2373–2378 (2000).
  • Rivard G, David M, Farrell C, Schwarz H. Treatment of purpura fulminans in meningococcemia wiht protein C concentrate. j Perliatc 126,646–652 (1995).
  • Smith O, White B, Vaughan D etal Use of protein-C concentrate, heparin, heamodiafiltration in meningococcus-induced purpura fulminans. Lancet 350, 1590–1593 (1997).
  • Bernard G, Ely E, Wright T etal. Safety and dose relationship of recombinant human activated protein C for coagulopathy in severe sepsis. Grit. Care Merl 29,2051–2059 (2001).
  • ••Phase II data on DAA in severe sepsis.
  • Cook D, Heyland D, Marshall J. The Canadian Critical Care Trials Group. On the need for observational studies to design and interpret randomized trials in ICU patients: a case study in stress ulcer prophylaxis. Int. Care Merl 27,347–354 (2001).
  • Padkin A, Rowan K, Black N. Using high quality clinical databases to complement the results of randomized controlled trials: the case of recombinant human activated protein C. BE Med. 1. 323,923–926 (2001).
  • Ely E, Laterre P-F, Angus D etal Drotrecogin alfa (activated) adminstration across clinically important subgroups of patients with severe sepsis. Cr/t. Care Merl 31,12–19 (2003).
  • •Subgroup analyses of the PROWESS dataset.
  • Vincent J-L, Angus D, Artigas A et al Effects of drotrecogin alfa (activated) on organ dysfunction in the PROWESS trial. Grit. Care Merl 31,834–840 (2003).
  • Ely E, Angus D, Williams M, Bates B, Qualy R, Bernard G. Drotrecogin alfa (activated) treatment of older patients with severe sepsis. CID37,187–195 (2003).
  • Opal S, Garber G, LaRosa S eta]. Systemic host responses in severe sepsis analyzed by causative microorganism and treatment effects of drotrecogin a (activated). CID 37,50–88 (2003).
  • Anti-infective Advisory Committee. FDA briefing document: drotrecogin a (activated) (Recombinant activated protein C. Food and Drug Administration, 2001. (2003).
  • Bernard G, Macias W, Joyce D, Williams M, Bailey J, Vincent J-L. Safety assessment of drotrecogin 2003 (activated) in the treatment of adult patients with severe sepsis. Grit. Care 7,155–163 (2003).
  • •A pooled analysis of safety of DAA from patients enrolled in PROWESS and ENHANCE (to date).
  • Wheeler A, Doig C, Wright T, Wong K, Vincent J-L, Bernard G. Baseline characteristics and survival of adult severe sepsis patients treated with drotrecogin alfa (activated) in a global, single-arm, open-label trial (ENHANCE). Chest 124, S91 (2003).
  • Vincent J-L, Light B, Wright T, Wong K, Johnson G, Bernard G. Global ENHANCE results indicate organ function improvement with drotrecogin alfa (activated) in severe sepsis patients. Chest 124, S103 (2003).
  • Beale R, Wright T, Wong K, Vincent J-L, Bernard G. Safety of drotrecogin a (activated) in adult patients with severe sepsis: comparison of global ENHANCE to PROWESS. Chest 124, S102 (2003).
  • Manns B, Lee H, Doig C, Johnson D, Donaldson C. An economic evaluation of activated protein C treatment for severe sepsis. N Engl. I Merl 347,993–1000 (2002).
  • ••First economic evaluation of DAA using apopulation-based cohort of patients and with actual costs and outcomes during 3 years of follow-up.
  • Angus D, Linde-Zwirble W, Clermont G et al Cost-effectiveness of drotrecogin a (activated) in the treatment of severe sepsis. Grit. Care Merl 31,1–11 (2003).
  • ••Economic evaluation of DAA using dataon a subset of patients enrolled in PROWESS.
  • Fowler R, Hill-Popper M, Stasinos J, Sanders G, Garber A. Cost-effectiveness of recombinant human activated protein C and the influence of severity of illness in the treatment of patients with severe sepsis. Grit. Care 18,181–191 (2003).
  • Guidelines for management information systems in Canadian health services organizations. Canadian Institute for Health Information, Ottawa, Canada. (1999).
  • Angus D, Musthafa A, Clermont G etal Quality-adjusted survival in the first year after the acute respiratory distress syndrome. Am j Respir. Grit. Care Merl 163,1389–1394 (2001).
  • Fryback D, Dasbach E, Klein R eta]. The Beaver Dam Health Outcomes Study: initial catalog of health-state quality factors. Med. Dec. Making-13, 89–102 (1993).
  • Launois R, Riou-Franca L, Guidet B, Aergeter P, Meshaka P, Pinton P. Cost effectiveness analysis of drotrecogin a (activated) as a treatment for severe sepsis. Int. Care Merl 28, S161 (2002).
  • Neilson A, Schneider H, Chinn C, Clouth J, Burchadi, H. Cost-effectiveness of drotrecogin alfa (activated) for the treatment of severe sepsis in Germany. Int. Cate Med 28, S161 (2002).
  • Davies A, Hutton J, Ridley, S, Chinn C, Barber B. Cost-effectiveness of drotrecogin alfa (activated) in treating severe sepsis in the UK. Int. Care Med. 28, S161 (2002).
  • Siegel J. Assessing the use of activated protein C in the treatment of severe sepsis. N. Engl. J. Med 347,1030–34 (2002).
  • ••A commentary and rebuttal to Warren [57] on the design and conduct of PROWESS, and the review by the Anti-Infectives Committee Advisory Board. Dr. Siegel is the Director of the Center for Biologics Evaluation and Research at the Food and Drug Administration.
  • Burchadi H, Jegers M, Goedee J, Leititis J. Benchmarking in the ICU: the measurement of costs and outcome to analyze efficiency and efficacy. In: Evaluating Critical Cam: Using Health Services Research to Improve Quality Sibbald W, Bion J (Eds). 222–243 Springer, NY, USA (2001).
  • Hill B. The environment and disease: association and causation. Proc. Royal Soc. Med. 58,295–300 (1965).

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