OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

ANNOTATED BIBLIOGRAPHY

References updated: 08 January 2018

• Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, et al.; Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344: 699-709. [PubMed: 11236773]

  (Among 1690 patients with severe sepsis with organ failure who were treated with drotrecogin alfa or placebo infusions for 96 hours, 28 day all-cause mortality was lower with drotrecogin than placebo [24.7% vs 30.8%]; important side effects included serious bleeding episodes [3.5% vs 2.0%], but "there were no other safety concerns...on the basis of assessments of organ dysfunction, vital signs, serum chemical data, or hematologic data").
• Bernard GR, Margolis BD, Shanies HM, Ely EW, Wheeler AP, Levy H, Wong K, Wright TJ; Extended Evaluation of Recombinant Human Activated Protein C United States Investigators. Extended evaluation of recombinant human activated protein C United States Trial (ENHANCE US): a single-arm, phase 3B, multicenter study of drotrecogin alfa (activated) in severe sepsis. Chest 2004; 125: 2206-16. [PubMed: 15189943]

  (Among 273 adults with severe sepsis with organ failure treated with drotrecogin alfa infusions, the 28 day mortality rate was 26.4% and serious bleeding episodes [the only serious adverse event attributed to drug] occurred in 4%; no mention of serum enzyme elevations or hepatotoxicity).
• Abraham E, Laterre PF, Garg R, Levy H, Talwar D, Trzaskoma BL, François B, et al; Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) Study Group. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med 2005; 353: 1332-41. [PubMed: 16192478]

  (Among 2613 patients with severe sepsis but a "low risk of death" who were treated with drotrecogin alfa or placebo infusions for 96 hours, 28 day mortality was similar in both groups [18.5% vs 17%] while serious bleeding episodes were more frequent with drotrecogin [2.4% vs 1.2%]; no mention or serum enzyme elevations or hepatotoxicity).
• Payen D, Sundin DP, Nelson DR, Williams MD. Analysis of efficacy and safety of drotrecogin alfa (activated) in surgical patients, using an international integrated database. Surgery 2007; 142: 426-7. [PubMed: 17723900]

  (Among 1659 patients with severe sepsis following surgery who participated in 5 clinical studies of drotrecogin alfa vs placebo, serious bleeding episodes were more common with drotrecogin than placebo [4.9% vs 0.5%], but were rarely fatal).
• Laterre PF, Abraham E, Janes JM, Trzaskoma BL, Correll NL, Booth FV. ADDRESS (ADministration of DRotrecogin alfa [activated] in Early stage Severe Sepsis) long-term follow-up: one-year safety and efficacy evaluation. Crit Care Med 2007; 35: 1457-63. [PubMed: 17452935]

  (Among 2640 patients who received drotrecogin alfa or placebo infusions for an episode of "early stage" severe sepsis with organ failure [Abraham 2005], one year follow up was available on 2376 at which time mortality rates were similar [34.2% vs 34%]).
• Payen D, Sablotzki A, Barie PS, Ramsay G, Lowry S, Williams M, Sarwat S, et al. International integrated database for the evaluation of severe sepsis and drotrecogin alfa (activated) therapy: analysis of efficacy and safety data in a large surgical cohort. Surgery 2007; 141: 548-61. [PubMed: 17431957]

  (Retrospective analysis using a large integrated database on patients with severe sepsis after surgery who received drotrecogin alfa found that serious adverse events were more common with drotrecogin than placebo [7.5% vs 6.3%] as were severe bleeding episodes [4.9% vs 0.5%]; no mention of liver related adverse events).
• Nadel S, Goldstein B, Williams MD, Dalton H, Peters M, Macias WL, Abd-Allah SA, et al.; REsearching severe Sepsis and Organ dysfunction in children: a gLobal perspective (RESOLVE) study group. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet 2007; 369 (9564): 836-43. [PubMed: 17350452]

  (Among 477 children with severe sepsis and organ failure treated with infusions of drotrecogin alfa vs placebo for 96 hours, 28 day mortality [17.2% vs 17.5%] and rates of severe bleeding [6.7% vs 6.8%] were similar and "the overall safety profile [was] acceptable"; no mention of serum enzyme elevations or hepatotoxicity).
• Dhainaut JF; INDEPTH Clinical Evaluation Committee. International integrated database for the evaluation of severe sepsis (INDEPTH): clinical evaluation committee report on the safety of drotrecogin alfa (activated) therapy. Curr Med Res Opin 2008; 24: 1187-97. [PubMed: 18348744]

  (Among 4459 patients with severe sepsis enrolled in studies of drotrecogin alfa vs placebo and analyzed in an integrated database, total serious adverse event rates were similar [13.2% vs 13.8%], while serious bleeding episodes more frequent with drotrecogin than placebo [5.6% vs 2.0%] and arterial thrombotic events less common with drotrecogin [1.8% vs 2.9%]).
• Woodward B, Cartwright M. Safety of drotrecogin alfa (activated) in severe sepsis: data from adult clinical trials and observational studies. J Crit Care 2009; 24: 595-602. [PubMed: 19327331]

  (Review of safety analyses of 2 controlled and 4 open label trials of drotrecogin alfa in severe sepsis from the sponsor focuses upon serious bleeding episodes and does not discuss serum enzyme elevations or hepatotoxicity).
• Poole D, Bertolini G, Garattini S. Errors in the approval process and post-marketing evaluation of drotrecogin alfa (activated) for the treatment of severe sepsis. Lancet Infect Dis 2009; 9: 67-72. [PubMed: 19095197]

  (Analysis of the approval of drotrecogin alfa in the US and Europe points out that the approval was based upon analysis of subgroups of patients in the initial single trial in patients with severe sepsis and organ failure).
• Steingrub JS, Cheatham ML, Woodward B, Wang HT, Effron MB; XEUS Investigators. A prospective, observational study of Xigris Use in the United States (XEUS). J Crit Care 2010; 25: 660. [PubMed: 20435433]

  (Among 548 adults with severe sepsis treated with drotrecogin alfa in clinical practices, 28 day mortality was 36.7% and the rate of serious bleeding episodes 3.1%; no mention of serum enzyme elevations or hepatotoxicity).
• Kalil AC, LaRosa SP. Effectiveness and safety of drotrecogin alfa (activated) for severe sepsis: a meta-analysis and metaregression. Lancet Infect Dis 2012; 12: 678-86. [PubMed: 22809883]

  (Systematic review of literature [9 controlled trials and 20 open label studies] on drotrecogin alfa therapy of severe sepsis concludes that drotrecogin treatment was associated with a reduction in hospital mortality).
• Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Finfer S, Gårdlund B, et al; PROWESS-SHOCK Study Group. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med 2012; 366: 2055-64. [PubMed: 22616830]

  (Among 1697 patients with septic shock treated with drotrecogin alfa or placebo infusions for 96 hours, 28 day mortality was similar in both groups [26.4% vs 24.7%], while serious adverse events were more frequent with drotrecogin [14.3% vs 11.5%] as was serious bleeding [8.6% vs 4.8%]; rates of hepatic failure were similar in both groups).
• Holder AL, Huang DT. A dream deferred: the rise and fall of recombinant activated protein C. Crit Care 2013; 17: 309. [PMC free article: PMC3672523] [PubMed: 23509922]

  (Commentary on Ranieri [2012] concludes that "drotrecogin should no longer be recommended in sepsis guidelines as a standard of care").
• Annane D, Timsit JF, Megarbane B, Martin C, Misset B, Mourvillier B, Siami S, et al.; APROCCHSS Trial Investigators. Recombinant human activated protein C for adults with septic shock: a randomized controlled trial. Am J Respir Crit Care Med 2013; 187: 1091-7. [PubMed: 23525934]

  (Among 411 patients with septic shock treated with drotrecogin alfa, corticosteroids, both or placebos, 90 day mortality was the same for the regimens with or without drotrecogin [47.6% vs 46.3%] as were the rates of serious adverse events [53.8% vs 54.7%] and serious bleeding [12,5% vs 14.3%]; no mention of serum enzyme elevations or hepatotoxicity).
• Miranda CJ, Mason JM, Babu BI, Sheen AJ, Eddleston JM, Parker MJ, Pemberton P, Siriwardena AK. Twenty-four hour infusion of human recombinant activated protein C (Xigris) early in severe acute pancreatitis: The XIG-AP 1 trial. Pancreatology 2015; 15: 635-41. [PubMed: 26547592]

  (Among 19 patients with severe acute pancreatitis treated with drotrecogin alfa infusions for 24 hours, 28 day mortality was slightly but not significantly higher than that of historical controls [11% vs 5%] and treated patients had no serious bleeding episodes; no mention of serum enzyme elevations or hepatotoxicity).