Correspondence
Activated Protein C for Severe Sepsis
N Engl J Med 2002; 347:1035-1036September 26, 2002
- Article
To the Editor:
In this issue of the Journal, Warren et al.1 and Siegel2 offer their views on the approval of drotrecogin alfa (activated), or recombinant human activated protein C, for the treatment of severe sepsis. We concur with Dr. Siegel's comments regarding the extensive testing to ensure the potency and consistency of drotrecogin alfa (activated) used in the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial.3 It is fortunate that the master cell bank used to produce the drug administered in the latter portion of the trial will be sufficient to meet clinical needs for several decades.
The PROWESS protocol amendment, which was developed in a blinded fashion very early in the trial and approved by the Food and Drug Administration, clarified the entry criteria as outlined in Table 1Table 1
Amendments to the Entry Criteria for the PROWESS Trial.. Our intent was to enroll patients with a high likelihood of dying from severe sepsis and a low likelihood of dying from other causes. In addition, we wished to exclude patients in whom life support might be curtailed during the 28-day study period.The observed absolute reduction in the risk of death was greatest among the most seriously ill patients, including those with coexisting conditions and advanced age. This is an expected finding with effective treatment of any condition for which the risk of death varies widely. Data from PROWESS on the quartile of the Acute Physiology and Chronic Health Evaluation (APACHE II) score suggest this effect, but as Warren et al. indicate, use of this score in clinical practice is problematic for many reasons. The common technique of predicting the prognosis according to the number of dysfunctional organs showed that the absolute risk reduction for mortality was 1.7 percent (relative risk reduction, 7.8 percent) among patients with a single dysfunctional organ and 7.4 percent (relative risk reduction, 21.8 percent) among those with two or more dysfunctional organs. A large number of subgroups were examined, and only one did not meet the trial definition of subgroup consistency. This was the subgroup containing patients in the lowest interleukin-6 quartile; the treatment benefit for these patients was larger than that for the entire population.
Drotrecogin alfa (activated) has now been administered to more than 2786 patients with severe sepsis in controlled and open-label trials, and overall mortality has been between 25.1 percent and 26.1 percent. We conducted an independent review of all suspected intracranial hemorrhages. The current rate is 0.5 percent (hemorrhages in 13 of the 2786 patients) during the infusion period; 9 of the 13 occurred in patients with a platelet count of less than 30,000 per cubic millimeter, meningitis, or both. Patients with a platelet count of less than 30,000 per cubic millimeter were excluded from the PROWESS trial. The intracranial-hemorrhage rate of 2.5 percent cited by Warren et al. was based on unvalidated data in fewer than 600 patients. Clinicians should not treat patients with contraindications and should avoid treating patients with profound thrombocytopenia, markedly prolonged prothrombin times, or both. The mortality rates reported in the PROWESS trial include any deaths due to bleeding, so that the 6.1 percent absolute benefit with respect to mortality (13 percent for patients with an APACHE II score of more than 25) takes bleeding into account.
Although clinicians can already incorporate level I evidence from PROWESS into their practice to obtain lifesaving benefit for their patients, our understanding of the role of activated protein C in severe sepsis will be enhanced by additional studies, including long-term follow-up studies and studies of children, patients with neutropenia and transplant recipients, and patients at low risk for death as determined in the PROWESS trial.
3 ReferencesE. Wesley Ely, M.D., M.P.H.
Gordon R. Bernard, M.D.
Vanderbilt University School of Medicine, Nashville, TN 37232
wes.ely@vanderbilt. edu Jean-Louis Vincent, M.D., Ph.D.
Erasme University Hospital, 1070 Brussels, Belgium1
Warren HS ,Suffredini AF ,Eichacker PQ ,Munford RS . Risks and benefits of activated protein C treatment for severe sepsis. N Engl J Med 2002;347:1027-1030
Full Text | Web of Science | Medline2
Siegel JP . Assessing the use of activated protein C in the treatment of severe sepsis. N Engl J Med 2002;347:1030-1034
Full Text | Web of Science | Medline3
Bernard GR ,Vincent J-L ,Laterre P-F , et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699-709
Full Text | Web of Science | Medline
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E. W. Ely, D. C. Angus, M. D. Williams, B. Bates, R. Qualy, G. R. Bernard. (2003) Drotrecogin Alfa (Activated) Treatment of Older Patients with Severe Sepsis. Clinical Infectious Diseases 37:2, 187-195
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Siegel, Jay P., . (2002) Assessing the Use of Activated Protein C in the Treatment of Severe Sepsis. New England Journal of Medicine 347:13, 1030-1034
Full Text28
Warren, H. Shaw, , Suffredini, Anthony F., Eichacker, Peter Q., , Munford, Robert S., . (2002) Risks and Benefits of Activated Protein C Treatment for Severe Sepsis. New England Journal of Medicine 347:13, 1027-1030
Full Text
