Dr. Joseph Esherick Monthly Blog – October 2011
Drotrecogin-alfa (DrotAA) has been an integral part of the care bundle for adult patients hospitalized with severe sepsis or septic shock and a high risk of death since 2002. DrotAA is a synthetic activated Protein C (APC) which has good scientific evidence for why it may be beneficial in patients with severe sepsis and septic shock. Patients with severe sepsis have abnormal activation of their coagulation pathways and inflammatory system and impaired fibrinolysis, which lead to a procoagulant state. Normally, APC acts with Protein S to degrade clotting factors Va and VIIa to promote anticoagulation. However, intrinsic levels of APC are diminished in patients with severe sepsis because of impaired APC synthesis and increased degradation by neutrophil elastases. Therefore, the theory was that a synthetic APC could benefit patients by decreasing the abnormal clotting which occurs in the micro-circulation.
Severe sepsis and septic shock remains an extremely important problem in critical care medicine. More than 200,000 people die of sepsis annually in the United States. When drotrecogin-alfa was initially FDA-approved in 2001, it became the only FDA-approved drug specifically used to treat severe sepsis. The first large trial which studied DrotAA was the PROWESS trial.1 This was an industry-sponsored, double-blind, placebo-controlled, multicenter trial that involved 1690 patients with severe sepsis and a “high risk of death”, which was defined as an APACHE II score of 25 or more...
The trial was stopped early because the mortality reduction from DrotAA exceeded the a priori mortality guidelines for early termination. The 28-day all-cause mortality decreased from 30.8% in the placebo arm to 24.7% in the DrotAA-treated patients (p=0.005). There was a lot of controversy surrounding this trial because the criteria for inclusion and the drug manufacturing process were both changed during the study. As a result, the FDA advisory committee split on the approval for DrotAA in the treatment of severe sepsis. Eli Lilly was extremely aggressive about marketing DrotAA and was able to have it incorporated into the original Surviving Sepsis Campaign Guidelines In 2002.
Subsequent to the PROWESS trial, three sepsis studies were conducted prior to the PROWESS-SHOCK trial to study the efficacy of DrotAA. The ENHANCE (Extended Evaluation of Recombinant Human Activated Protein C) trial in 2001 demonstrated that DrotAA had no mortality benefit if started more than 24h after the onset of severe sepsis.2 The ADDRESS (Administration of Drotrecogin alfa activated in early-stage Severe Sepsis) trial evaluated the efficacy of DrotAA in patients with a low risk of death (single sepsis-induced organ dysfunction or APACHE II score less than 25). There was no mortality benefit seen in the ADDRESS trial.3 The RESOLVE (Researching Severe Sepsis and Organ Dysfunction in Children) trial demonstrated no mortality benefit in children.4 A Cochrane meta-analysis of DrotAA for severe sepsis in adults and children found that DrotAA did not reduce the risk of 28-day mortality in adults, but DrotAA was associated with a higher risk of bleeding.5
In 2008, the Eli Lilly Company agreed to sponsor the PROWESS-SHOCK trial to definitively determine whether DrotAA confers additional benefit for patients with septic shock and a high risk of death.6 This trial included only adult patients with vasopressor-dependent septic shock and either metabolic acidosis, acute kidney injury or hepatic dysfunction. This trial included 1,696 patients and the preliminary analysis of the data have found that the 28-day all cause mortality is statistically the same between the placebo and the DrotAA arms. As a result of these data, the drug manufacturer, Eli Lilly and Co., has voluntarily withdrawn DrotAA from the market.7
The care of patients with septic shock has definitely improved with bundled care, which is summarized by the most recent 2008 Surviving Sepsis Campaign Guidelines.8 These new data would remove DrotAA from the sepsis armamentarium; however, the rest of the treatment bundle still applies. Hopefully, this news does not deter further research in this area as sepsis remains one of the leading killers in the United States.
Joseph Esherick, MD, FAAFP is the Associate Director of Medicine and the Medical ICU Director at the Ventura County Medical Center in Ventura, California. He is also an Associate Clinical Professor of Family Medicine at The David Geffen School of Medicine at UCLA. He received his medical degree from Yale University School of Medicine, New Haven, Connecticut, and completed a family practice residency at the Ventura County Medical Center, Ventura, California. He is board certified in family medicine and the author of the Tarascon Primary Care Pocketbook and the Tarascon Hospital Medicine Pocketbook. He instructs the Hospitalist Procedures course for the National Procedures Institute and is an editorial board member for Tarascon Publishing and for Elsevier’s First Consult.
Dr. Esherick is the author of some of Tarascon Publishing’s best-selling titles including:
The recently published Tarascon Medical Procedures Pocketbook, Tarascon Hospital Medicine Pocketbook and Tarascon Primary Care Pocketbook. Both titles are available in print and mobile (iPhone, Android and Blackberry).
1Bernard GR et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001; 341 (8): 699-709.
2 Vincent JL et al. Drotrecogin alfa treatment in severe 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.
3 AbrahamE et al. Drotrecogin alga (activated) for adults with severe sepsis and a low risk of death. N Engl J Med. 2005; 353 (15): 1332-1341.
4 Nadel S et al. Drotrecogin alfa (activated) in children with severe sepsis: A multicentre phase III randomized controlled trial. Lancet. 2007; 369 (9564): 836-843.
5 Mart-Carvajal A et al. Human recombinant activated protein C for severe sepsis. Cochrane Database Syst Rev. 2008; (1): CD004388.
6 Silva E et al. PROWESS-SHOCK trial: A Protocol Overview and Perspectives. Shock. 2010; 34 (1): 48-53.
7 Shaw G. Eli Lilly Withdraws Xigris for Sepsis. Pharmacy Practice News. 2011; 38: 1-3.
8 Dellinger RP et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Intensive Care Med. 2008; 34(1): 17–60.