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By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
The FDA recently approved the first biologic treatment for severe sepsis. Drotrecogin alfa (activated), a glycoprotein serine protease produced by genetic engineering, has the same amino acid sequence as human plasma-derived Activated Protein C. It appears to have antithrombotic, anti-inflammatory, and profibrinolytic action in patients with sepsis. Drotrecogin alfa will be marketed by Lilly as Xigris.
Drotrecogin is indicated for the reduction of mortality in adult patients with sepsis associated with acute organ failure (ie, severe sepsis) who have a high risk of mortality.1 In the clinical study, risk of mortality was determined by acute physiology and chronic health evaluation score (APACHE II).
Drotrecogin should be infused intravenously at a rate of 24 µg/kg/h of a total of 96 hours.
It is supplied as 5 mg and 20 mg single-use vials. The lyophilized powder should be stored under refrigeration and protected from light.1
In patients with systemic inflammation and organ failure due to acute infection, drotrecogin was associated with a absolute reduction in the risk of death of 6.1% (24.7% vs 30.8%) 28 days after the start of infusion.2
Bleeding is the most common adverse effect of drotrecogin. The incidence of serious bleeding (eg, intracranial hemorrhage, life-threatening bleeding) compared to placebo was 3.5% vs. 2.0%.2 Patients at risk for bleeding should be evaluated on a risk to benefit basis. Drotrecogin is contraindicated in patients with active internal bleeding, recent hemorrhagic stroke or intracranial or intraspinal surgery, severe head trauma, other trauma associated with an increased risk of life-threatening bleeding, presence of an epidural catheter, or intracranial neoplasm, mass lesion, or evidence of cerebral herniation.1
There is currently no evidence to suggest that patients with severe sepsis but with a lower risk of death would benefit from drotrecogin.1
Sepsis is the systemic inflammatory response to infection. Severe sepsis is sepsis associated with organ dysfunction, hypoperfusion, or hypotension.3,4 The sequelae of sepsis are the result of interplay between the inflammatory cascade and the coagulation cascade. Protein C is one of the body’s defenses against thrombosis. It possesses antithrombotic, anti-inflammatory, and profibrinolytic effects. Data indicate that protein C deficiency might be predictive of death associated with sepsis.5-7 The safety and efficacy of drotrecogin, which is a genetically engineered version of naturally occurring Activated Protein C, was demonstrated in Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial and was the basis for the approval of the agent.2 Patients were eligible for the trial if they had a known or suspected infection and the following criteria within a 24-hour period: 3 or more signs of systemic inflammation and sepsis-induced dysfunction of at least 1 organ or system that lasted no longer than 24 hours. Signs of systemic inflammation are temperature ³ 38°C or £ 36°C, heart rate ³ 90 bpm, respiratory rate ³ 20 breaths/min or PaCO2 £ 32 mm Hg, or WBC count ³ 12,000/mm3 or £ 4000/mm3 or > 10% immature neutrophils. Patients in the trial had an average APACHE II score of 25, more than 73% were on mechanical ventilation and more than 70% were in shock. Time to initiation of antibiotics was within 48 hours. Patients at risk for bleeding disorders, those not expected to survive 28 days, those treated with drugs such as heparin, anticoagulants, or antiplatelet agents, and others with suppressed immune systems were excluded. Eight hundred and forty (840) were assigned to placebo and 850 to drotrecogin (24 µg/kg/h ´ 96 h). Baseline characteristics were generally comparable except there were more patients in the placebo groups on mechanical ventilation (77.6% vs 73.3%). Drotrecogin, administered no later than 24 hours after meeting study inclusion criteria resulted in an absolute reduction in risk of all-cause 28-day mortality of 6.1% (24.7% vs 30.8%, P = 0.005). Treatment with drotrecogin resulted in lower plasma D-dimer levels, and greater decreases in serum interleukin-6 levels, indicators of antithrombotic and anti-inflammatory activity, respectively. Those who received drotrecogin also appeared to have greater numbers of vasopressor and ventilator-free days.8,9 The results also suggest that patients with a greater number of organ failures had a greater absolute risk reduction in mortality, although the study was not sufficiently powered to distinguish these potential differences.9 Protein C levels may not be a predictor of drotrecogin success in this population. Serious bleeding was higher in the drotrecogin group compared to placebo (3.5% vs 2.0%, P = 0.06). Neutralizing antibodies against drotrecogin were not detected.
Drotrecogin is expensive with a wholesale cost of $6800 per patient.
It is estimated that about 750,000 cases of severe sepsis occur each year in the United States with about a 30% mortality.10 The hospital cost is estimated at $17 billion and more than $22,000 per case. Drotrecogin alfa (activated) is the first agent approved to treat severe sepsis. Balancing the cost and benefit of this agent will be a challenge for decision makers. Based on the study results, 1 life would be saved for about every 16 patients treated with drotrecogin. This translates to about $108,800 per life saved. If the PROWESS entry criteria are generally accepted, the number of treated patients could be substantial. Padkin et al indicated that 28% of all intensive care admissions met the criteria.11
The role will ultimately be determined as clinicians gain broader experience.
1. Xigris Product Information. Eli Lilly and Company. November 2001.
2. Bernard GR, et al. N Engl J Med. 2001;344:699-709.
3. Muckart DJ, Bhagwanjee S. Crit Care Med. 1997;25: 1789-1795.
4. American College of Chest Physicians/Society of Critical Care Medicine. Crit Care Med. 1992;20:864-874.
5. Yan SB, et al. Chest. 2001;120:915-922.
6. Fisher CJ, et al. Crit Care Med. 2000;28(suppl 9): S49-S56.
7. Mesters RM, et al. Crit Care Med. 2000;28:2209-2216.
8. Angus DC, et al. Crit Care Med. 2000;28(suppl):A48.
9. Salmaan K, et al. Pharmacotherapy. 2001;21(11): 1389-1402.
10. Angus DC, et al. Crit Care Med. 2001;29:1303-1310.
11. Padkin A, et al. BMJ. 2001;323:923-926.
Dr Elliott is the Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. Dr Elliott is Editor-in-Chief of The Physician's Therapeutics & Drug Alert.