Pharmacy & Therapeutics- August 2008 - (Page 471) CASE REPORT: Low-Dose Drotrecogin Alfa in Sepsis LIMITATIONS OF THE STUDY 24 mcg/kg/hour 1.65 1.58 1.55 1.45 INR 1.35 1.25 1.15 1.05 0.95 0.98 1.23 Drotrecogin alfa given Bleeding occurred 1.4 1.28 1.57 18 mcg/kg/hour There were some limitations to our findings. It is possible that the patient might have survived and improved without the use of drotrecogin alfa. As clinicians, we were obligated to offer it to the patient because of his high risk of death resulting from his APACHE II score and two organ failures. Indeed, a clinical trial of low-dose drotrecogin alfa is needed in severely septic patients who cannot tolerate the FDA-approved dosing (24 mcg/kg per hour), as we observed in our case report. CONCLUSION Preclinical and clinical studies led the FDA to set the standard dosing for drotrecogin alfa at 24 mcg/kg per hour for patients with severe sepsis, including those with APACHE II scores above 25.4,9,10,12 As a result of the coffee-ground nasogastric tube output, this dose was discontinued in our patient. After the signs and symptoms of bleeding resolved, the patient received low-dose drotrecogin alfa (18 mcg/kg per hour), because of his high risk of death. Because of this drug’s potent anticoagulant property, increased PT and aPTT levels were also observed during drotrecogin alfa therapy. However, elevated aPTT levels should not be the sole reason for discontinuing drotrecogin alfa therapy, because the drug itself may interact with one-stage coagulation assays of aPTT monitoring. On the basis of our findings in this case report, we concluded that low-dose drotrecogin alfa might be a useful alternative in severely septic patients (i.e., an APACHE II score above 25 and multiorgan failure) who cannot tolerate the FDA-approved dose of 24 mcg/kg per hour. Additional research studies and randomized controlled trials are needed to validate such use. Figure 4 Hematological parameters: International Normal Ratio (INR) levels. HD = hospital day. Drotrecogin alfa resulted in an absolute reduction of mortality by 6%, compared with placebo (24.7% vs. 30.8%, respectively).4,9 However, the ADDRESS study—Administration of Drotrecogin Alfa (Activated) in Early-Stage Severe Sepsis—did not demonstrate the drug’s efficacy in patients with sepsis and a low risk of death (i.e., an APACHE II score below 25 or singleorgan failure). The differences in 28-day mortality rates in the two groups were not statistically significant: 17% of 1,297 patients receiving placebo and 18.5% of 1,316 treated patients (P = 0.34).14 Castelli et al.15 demonstrated an association between PTT levels and drotrecogin alfa therapy. However, because drotrecogin alfa interferes with PTT assays, it is not reliable to monitor only PTT during therapy. In addition, because drotrecogin has a minimal effect on PT, PT is a more reliable laboratory value than PTT for monitoring drug therapy. Given the anticoagulant properties of drotrecogin alfa, the major risk associated with its use is bleeding.3,4,9,11,16 In fact, subanalyses of the PROWESS and ADDRESS clinical trials showed a higher incidence of all-cause mortality with drotrecogin alfa than with placebo in patients with single-organ dysfunction and who had undergone surgery within the previous 30 days. The package insert lists a 3.9% incidence of serious bleeding associated with drotrecogin alfa. A new phase 3 placebo-controlled study (PROWESS– SHOCK), scheduled to begin in 2008 in Europe and the U.S., is expected to provide additional clinical evidence for the efficacy and safety of drotrecogin alfa.17 Even though drotrecogin alfa has been studied in children with severe sepsis, the FDA halted the clinical trial because of a significant increase in intracranial hemorrhage in the treated group when compared with the placebo group.9 Winthrop University Hospital has a strict policy regarding use of drotrecogin alfa in sepsis. All patients must have either (1) APACHE II scores above 25 plus two or more organ failures or (2) three or more organ failures if the APACHE II score is not calculated. Patients must also be currently receiving cardiac pressors (Appendix 1).18 8 18:17 :1 22 7 :4 3: 1 0 6: 2 5 9: 0 14 36 :3 17 1 :1 5 3: 11 45 : 14 30 :4 18 8 : 2 2 57 :4 5 3 11:43 :2 17 5 : 20 0 8 :2 3: 6 10 55 :2 17 9 :5 3 0: 0 3: 9 50 7: 11 27 :5 15 5 :4 0 HD 1 HD 2 HD 3 HD 4 HD 5 HD 6 HD 7 REFERENCES 1. Angus DC, Linde-Zwirble WT, Lidicker J, et al. 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. 2. 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. Crit Care Med 1992;20:864–874. 3. Russell JA. Management of sepsis. N Engl J Med 2006;355(16): 1699–1713. 4. Bernard GR, Vincent JL, Laterre PR, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699–709. 5. Derhaschnig U, Reiter R, Knöbl P, Baumgartner M, et al. Recombinant human activated protein C (rhAPC; drotrecogin alfa [activated]) has minimal effect on markers of coagulation, fibrinolysis, and inflammation in acute human endotoxemia. Blood 2003; 102(6):2093–2098. 6. Schlichting D, McCollam JS. Recognizing and managing severe sepsis: A common and deadly threat. South Med J 2007;100(6): 594–600. 7. Nguyen HB, Rivers EP, Abrahamian FM, et al. Severe sepsis and septic shock: Review of the literature and emergency department management guidelines. Ann Emerg Med 2006;48(1):28–54. 8. Laterre PF, Wittebole X. Clinical review: Drotrecogin alfa (activated) as adjunctive therapy for severe sepsis: Practical aspects at the bedside and patient identification. Crit Care 2003;7:445–450. 9. Xigris (drotrecogin alfa [activated]), package insert. Indianapolis, IN: Eli Lilly; 2007. 10. Bernard GR , Macias WL, Joyce DE, et al. Safety assessment of drotrecogin alfa (activated) in the treatment of adult patients with References continued on page 476 Vol. 33 No. 8 • August 2008 • P&T® 471
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