Efficacy and Safety of Recombinant Human Activated Protein C for Severe Sepsis
This review may be edited
Posted By: Gordon S. Doig
Posted Date: March 6th, 2001
Title: Efficacy and Safety of Recombinant Human Activated Protein C for Severe Sepsis
Authors: Bernard, Vincent et al
Reference: NEJM vol 344, March 8, 2001
Link: Click here for a direct link to the paper. A password may be required for access to fulltext.
Abstract: Background. Drotrecogin alfa (activated), or recombinant human activated protein C, has antithrombotic, antiinflammatory, and profibrinolytic properties. In a previous study, drotrecogin alfa activated produced dose-dependent reductions in the levels of markers of coagulation and inflammation in patients with severe sepsis. In this phase 3 trial, we assessed whether treatment with drotrecogin alfa activated reduced the rate of death from any cause among patients with severe sepsis.
Methods. We conducted a randomized, double-blind, placebo-controlled, multicenter trial. Patients with systemic inflammation and organ failure due to acute infection were enrolled and assigned to receive an intravenous infusion of either placebo or drotrecogin alfa activated (24 g per kilogram of body weight per hour) for a total duration of 96 hours. The prospectively defined primary end point was death from any cause and was assessed 28 days after the start of the infusion. Patients were monitored for adverse events; changes in vital signs, laboratory variables, and the results of microbiologic cultures; and the development of neutralizing antibodies against activated protein C.
Results. A total of 1690 randomized patients were treated (840 in the placebo group and 850 in the drotrecogin alfa activated group). The mortality rate was 30.8 percent in the placebo group and 24.7 percent in the drotrecogin alfa activated group. On the basis of the prospectively defined primary analysis, treatment with drotrecogin alfa activated was associated with a reduction in the relative risk of death of 19.4 percent (95 percent confidence interval, 6.6 to 30.5) and an absolute reduction in the risk of death of 6.1 percent (P=0.005). The incidence of serious bleeding was higher in the drotrecogin alfa activated group than in the placebo group (3.5 percent vs. 2.0 percent, P=0.06).
Conclusions. Treatment with drotrecogin alfa activated significantly reduces mortality in patients with severe sepsis and may be associated with an increased risk of bleeding.
Are the Results Valid?
1. Was the assignment of patients to treatments randomized? ( Was allocation concealment maintained?)
Yes. The study was 'block randomized' according to study site with all assignments being made by a central randomization center.
2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?
2a. Was followup complete?
Yes. ALL patients except 1 were followed for 28 days. The single patient who was 'lost to follow up' was attributed as 'dead' for the intention to treat analysis (this is the most conservative assumption).
2b. Were patients analyzed in the groups to which they were randomized?
Yes. The primary intention to treat analysis was conducted based on randomization group (there were no cross-overs). The primary intention to treat analysis can be found at the bottom of Table 4.
3. Were patients, health workers, and study personnel blind to treatment?
Yes. The study is described as a 'double-blind, placebo controlled trial'. Presumably the use of a placebo resulted in blinding of the 1) patient, 2) the health care team and 3) the study coordinator/outcome assessor.
4. Were the groups similar at the start of the trial?
Yes. Table 1 does not reveal any significant differences with respect to demographics, severity of illness, preexisting conditions, or medical interventions.
5. Aside from the experimental intervention, were the groups treated equally?
Unknown. Although the authors do not explicitly report supportive care received by each group (need for ventilation, inotrope support, antibiotic usage etc) they do report serious adverse events. There was a higher frequency of 'serious bleeding' in the active intervention arm (2% vs. 3.5%, p=0.06). It is also intersting to note that the authors do not report length of hospital or ICU stay.
What are the Results?
1. How large was the treatment effect?
The primary intention to treat analysis (includes ALL patients randomized) reports an absolute decrease in 28 day mortality of 6.5% (31.1% vs. 24.8%, p=0.003)
2. How precise was the estimate of the treatment effect?
The 95% confidence interval for the estimate of absolute 28 day mortality benefit extends from 2% to 11%.
Will the Results Help Me In Caring For My Patients?
1. Can the results be applied to my patient care?
This is most likely a landmark trial (first successful trial in the field of sepsis). IF the product is used on ONLY patients who explicitly satisfy the study entry criteria, it is reasonable to assume that your own patients will benefit in the same way the trial participants did.
2. Were all clinically important outcomes considered?
No. It is unfortunate that the authors do not report hospital or ICU length of stay. I can only hope this will be released in subsequent publications. It would also be extrememly interesting to see long term quality of life outcomes on this study group.
3. Are the likely treatment benefits worth the potential harms and costs?
At this time we are unable to judge this question. When we have full costing information (includes cost of drug PLUS cost of increased length of stay), we will be better able to make an informed decision. We can only hope that the combined cost per quality adjusted life year saved is in line with other currently accepted interventions.

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Efficacy and Safety of Recombinant Human Activated Protein C for Severe Sepsis

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