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

Can we Reduce Death Rate with an Antithrombotic, Antiinflammatory and Profibrinolytic agent?

Original Citation

Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699-709.

Overall Study Question

This study had two objectives. The first objective was to determine whether the administration of activated protein C (drotrecogin alfa activated) to patients with early severe sepsis reduced mortality at 28 days as compared with placebo. The second objective was to determine the incidence of adverse events associated with drotrecogin alfa activated. The patients had severe sepsis: documented or suspected infection with 3 or more signs of systemic inflammation and sepsis-induced failure of at least one organ or system that lasted no longer than 24 hours. These last two criteria had to be met within a 24-hour period. Outcome variables were mortality at 28 days and incidence of adverse events.  The intervention was a 96-hour infusion of drotrecogin alfa activated at 24mcg/Kg/hour or a placebo.

Are the Results of the Study Valid?

1. Was assignment of patients randomized?

Yes.  This was a prospective, randomized, double-blind, placebo-controlled multicenter trial involving 1,690 patients (840 received placebo, 850 received drotrecogin alfa activated). Patients were randomized in a 1:1 manner to receive drotrecogin alfa activated or placebo (0.9% saline with or without 0.1% human serum albumin) at each centre.  Block randomization stratified according to site, and all assignments were made through a central randomization centre.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Yes. Of the 1,728 patients who underwent randomization, 1,690 received study drug or placebo. Thirty-eight patients (17 in the placebo group and 21 in the drotrecogin alfa activated group) did not receive either study drug.

3. Were patients, their clinicians, and study personnel ‘blind’ to treatment?

Yes. The patients, investigators and the sponsor were unaware of the patients’ treatment assignment.

4. Were the groups similar at the start of the trial?

The groups were similar in terms of age, race, sex,  APACHE II scores, underlying illness, type of infection (i.e. site and organism ).  A similar number of patients were in shock (70%) or required mechanical ventilation (>70%).

5. Aside from the experimental intervention, were the groups treated equally?

Yes. A blinded review panel judged that the patients were treated equally with respect to appropriate antibiotic treatment.

6. Overall, are the results of the study valid?

Yes.

What were the Results?

1. How large was the treatment effect? 

Mortality at 28 days was 24.7% in the drotrecogin alfa activated group as compared with 30.8% in the placebo group (p=0.005).  Therefore, the administration of drotrecogin alfa activated was associated with a 6.1% absolute risk reduction in mortality at 28 days as compared with placebo.

Prospectively defined subgroup analyses were performed for a number of baseline characteristics, including the APACHE II score, the number of dysfunctional organs or systems, other indicators of severity of disease, sex, age, the site of infection, the type of infection (gram-positive, gram-negative or mixed) and presence or absence of protein C deficiency.  A consistent effect of treatment with drotrecogin alfa was observed amongst all subgroups.

The percentage of patients who had at least one adverse event was similar in both groups; 12.5% in drotrecogin alfa activated vs. 12.1% in the placebo group (p=0.84).  The incidence of serious bleeding was higher in the drotrecogin alfa activated group than in the placebo group (3.5% vs. 2.0% p=0.06).

2. How precise was the estimate of the treatment effect?

The 95% confidence interval for the 6.1% absolute reduction in mortality was 1.9-10.4.

Will the Results Help Me in Caring for My Patients?

1. Can the results be applied to my patient care?

Yes, with careful regard to the inclusion and exclusion criteria used in this study.

2. Were all clinically important outcomes considered?

Yes.

3. Are the likely treatment benefits worth the potential harms and costs?

Yes, for every 17 (actual NNT = 16.39) patients treated, 1 life will be saved.  For every 67 patients treated, 1 patient will suffer from serious bleeding.  The economic cost of drotrecogin alfa activated is not known. Currently this treatment is available in Canada on a compassionate use basis only.

Commentary

This is a very important study that has provided evidence that mortality of select patients with severe sepsis can be reduced with the administration of drotrecogin alfa activated.  The study was very well conducted.  Although the data was not provided, the beneficial effects of this drug were apparently consistent across different subgroups including severity of illness, number of dysfunctional organs/systems and presence or absence of protein C deficiency (80% of patients had protein C deficiency).  In order for patients to benefit from this drug, clinicians need to be alert to the timing of onset of sepsis-induced failure as drotrecogin alfa activated needs to be administered within 24 hours of this criterion.  Depending on the acquisition cost, this study may have important implications for resource allocation within healthcare institutions.

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