Criteria abstracted from The Users' Guide to Medical Literature, from the Health Information Research Unit and Clinical Epidemiology and Biostatistics, McMaster University

Highlighted lines and questions below provide links to the pertinent description of criteria in The EBM User's Guide, now available at the Canadian Centres for Health Evidence

Article Reviewed:

Please visit the new Evidence Based Journal Club Reviews

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

Bernard GR, Vincent JL, Laterre PF, et al.

N Engl J Med 2001;344:699-709. [abstract] [full-text, for subscribers ]

Reviewed by David Vaughn MD, Texas Children's Hospital, Baylor Medical School, Houston TX

Review posted December 20, 2001

---

I. What is being studied?:

The study objective:

This study was designed to evaluate whether the administration of recombinant human activated protein C (drotrecogin alfa activated) would reduce the rate of death from all causes at 28 days in patients with severe sepsis and have an acceptable safety profile.

The study design:

This was an extremely well designed study. It was a randomized, double blind, placebo-controlled trial, conducted at 164 centers in 11 countries, which enrolled 1690 patients over a 2-year period. Two interim analyses were performed after enrolling 760 and 1520 patients by an independent data and safety monitoring board. Provision was made to suspend the study according to a priori guidelines if the analysis indicated that HAPC was significantly more efficacious than placebo.

The patients included:

Patients were eligible for inclusion if they had a known or suspected infection on the basis of clinical data at the time of screening and if they met the following criteria within a 24-hour period: three or more signs of systemic inflammation and the sepsis-induced dysfunction of at least one organ or system that lasted no longer than 24 hours. (Specific definitions provided in Appendix 1 of the paper.) Treatment had to commence within 24 hours after they met the inclusion criteria.

The patients excluded:

Exclusion criteria were very extensive. See appendix 2 of paper for full exclusion criteria. These included:

• Women who were pregnant or breast-feeding,
• Age < 18 yr or weight > 135 kg
• Conditions associated with an increased risk of bleeding, (including thrombocytopenia {Platelet count < 30,000/mm3}, recent surgery or recent gastrointestinal bleed),
• Known hypercoagulable condition including recently documented (within 3 months before the study) or highly suspected deep-vein thrombosis or pulmonary embolism
• Moribund state in which death was perceived to be imminent
• Human immunodeficiency virus infection in association with a last known CD4 count of < 50/mm 3
• History of bone marrow, lung, liver, pancreas, or small-bowel transplantation
• Chronic renal failure
• Recent treatment with unfractionated heparin, low-molecular-weight heparin high dose warfarin, acetylsalicylic acid, thrombolytic therapy, glycoprotein IIb/IIIa antagonists or protein C within 24 hours before the study

The interventions compared:

Comparison was made between the use of recombinant human activated protein C and placebo (0.9% saline with or without 0.1% human serum albumin). HAPC was administered at a dose of 24-mcg/kg body weight/hour (it is not stated whether the drug dose was calculated according to actual or ideal body weight) and placebo was infused at an identical rate for 96 hours. The infusion was halted one hour prior to any surgery or percutaneous procedure, and resumed one to twelve hours later in the absence of any bleeding complications. Other aspects of care were not standardized, including fluid management, inotrope or pressor use, antibiotic therapy or ventilator strategy.

The outcomes evaluated:

The primary evaluated outcome was death at 28 days after commencement of therapy. Secondary outcome measures included the development of major complications, new infection rate and d-dimer and Interleukin-6 levels.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. Randomization was done in a 1:1 manner, through a central randomization center.

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

Was followup complete?

Yes. 1728 patients were randomized. 1690 patients received either study drug or placebo. Those randomized who did not receive either HAPC or placebo (N=38) were excluded because they either had at least one exclusion criterion, they became moribund prior to therapy commencing or because consent to participate was withdrawn. All patients were followed for 28 days. One patient was randomized to receive HAPC but did not receive it. This patient was classified as having died at day 28.

Were patients analyzed in the groups to which they were randomized?

Yes. One patient (see above) was randomized to receive HAPC but did not do so. This patient was classified as having died at 28 days.

Secondary questions:

3. Were patients, health workers, and study personnel "blind" to treatment?

Yes. Patients, caregivers and the study sponsor were blinded to treatment assignment. The infusions were stored in foil wrapped bags. However it is not stated whether the infusion tubing was similarly foil wrapped, or whether there is an obvious difference between the 2 solutions.

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

Yes. There was no significant difference between the 2 groups in demographic variables, preexisting illness, history of recent surgery, Apache score, requirement for mechanical ventilation, a diagnosis of shock, need for pressor or inotropes or number of dysfunctional organs. There was no difference between the 2 groups in time to commencement of therapy.

There was no significant difference between the 2 groups in terms of infection focus and type of organism isolated. Baseline measures of coagulation and inflammatory activity (D-dimers, Interleukin-6) were similar. There was no difference between the 2 groups in the incidence of protein C deficiency.

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

Unknown. A blinded review committee determined that appropriate anti-microbial therapy was administered in > 90% of patients in each group within 48 hours of the diagnosis of sepsis and continued for at least 5 days or until the patient died. However there was no standardized therapeutic protocol for other aspects of critical care management and the authors do not report any difference in management.

III. What were the results?

1. How large was the treatment effect?

Substantial. Mortality was 30.8% in the control group compared to 24.7% in the experimental group. This equates to a 6.1% absolute risk reduction in mortality (95% confidence intervals 1.9-10.4%); and a relative risk reduction of 20% in patients treated with HAPC (95% confidence intervals 6-31%). These figures did not differ essentially when the groups were analyzed on an intention to treat basis; that is all individuals randomized to placebo or HAPC were considered to have received these agents, regardless of whether they actually did so.

In addition, sub-group analyses were defined prospectively. These sub-groups were defined according to sex, age, illness severity, Apache II score, type and site of infection and presence or absence of PC deficiency. According to the authors (data was only shown for the protein C deficiency analysis) there was no difference in outcome when these sub-groups were analyzed.

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

These estimates were quite precise. The 95% confidence intervals for reduction in absolute mortality ranged between 1.9-10.4% suggesting a positive benefit for patients treated with HAPC. Moreover, the 95% confidence intervals for relative risk reduction were 6-31%, again suggesting a significant positive benefit for those treated with HAPC.

IV. Will the results help me in caring for my patients?

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

Not exactly in so far as this study was confined to patients aged 18 and older. However it is reasonable to assume that HAPC should have similar beneficial effects in children with severe sepsis. There are a number of case series describing improved outcomes in septic children treated with protein C (note that these studies did not use a recombinant form; rather a purified protein C concentrate was administered) (1). A pediatric study is currently underway which aims to determine the safety profile of HAPC.

In addition, it is extremely encouraging that these data suggest that HAPC is beneficial in sepsis due to multiple organisms. This is in contrast to numerous studies in which the beneficial effects of a drug were confined to patients infected with a particular organism. The fact that there was no difference in outcome in the various sub-group analyses (see above) is also very encouraging.

2. Were all clinically important outcomes considered?

No. Although the primary outcome analyzed was appropriate (mortality), other important outcome variables, which may be critical in determining the cost benefit analysis of this drug, were not included. These include duration of ICU stay, pressor requirement, and ventilator days. However this study was not intended to assess these outcome measures.

A secondary outcome, measurement of D-dimer levels, which are a measure of the degree of disseminated intravascular coagulation (DIC), were markedly lower in the group which received HAPC for at least 7 days following the commencement of the infusion. This suggests that the use of HAPC in severe sepsis is associated with a reduced risk of DIC.

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

When analyzed by effect on mortality, it is clear that HAPC is beneficial and should be used in patients who fulfill the inclusion criteria. As noted above, it is impossible to assign a dollar based cost benefit analysis with current information.

A similar percentage of patients in each group experienced an adverse event. However more patients receiving HAPC experienced a major bleeding complication, a result that almost reached statistical significance (3.5% vs. 2.0%; p=0.06). This becomes important when one notes that many patients with risk factors for bleeding were excluded a priori. In clinical practice, patients with pre-existing hemorrhage tendencies may also be those most at risk of developing septic shock. In both groups, those who experienced a bleeding complication had an identifiable risk factor for bleeding. The use of heparin did not appear to further increase the risk of bleeding in patients receiving HAPC. However it does not appear that the study was designed to analyze the contribution of independent risk factors to the development of complications. In summary, HAPC should be used in adult patient with severe sepsis. Data from a pediatric study is awaited with great interest.

References

1. Smith OP, White B, Vaughan D, Rafferty M, Claffey L, Lyons B, Casey W. Use of protein-C concentrate, heparin, and haemodiafiltration in meningococcus-induced purpura fulminans. Lancet 1997;350(9091):1590-3. [abstract]

Comments

Back to the EB Journal Club Index