Abstract
BackgroundMeta-analysis of two randomised controlled trials in severe sepsis performed with recombinant human activated protein C may provide further insight as to the therapeutic utility of targeting the clotting cascade in this syndrome.MethodsIn search for relevant studies published, two randomized clinical trials were found eligible.ResultsThe studies, PROWESS and ADDRESS, enrolled a total of 4329 patients with risk ratio (RR) and 95% confidence interval (CI) data for effect on 28-day mortality relative to control treatment of 0.92 (0.83–1.02) suggesting that recombinant human activated protein C is not beneficial in severe sepsis. In PROWESS, 873 of 1690 patients presented with low risk, and 2315 of 2639 patients in ADDRESS as defined by APACHE II score < 25. In this low-risk stratum, no effect of recombinant human activated protein C administration on 28-day mortality was observed. This observation appears to be consistent and homogenous. Heterogeneity between the two studies, however, was seen in patients with APACHE II score ≥ 25 in whom recombinant activated protein C was effective in PROWESS (n = 817; RR 0.71, CI 0.59–0.85) whereas a tendency toward harm was present in ADDRESS (n = 324; RR 1.21, CI 0.85–1.74). Even though the overall treatment effect in this high-risk population was still in favour of treatment with recombinant activated protein C (n = 1141; RR 0.80, CI 0.68–0.94), the observed heterogeneity suggests that the efficacy of recombinant human activated protein C is not robust. Not unlikely, the adverse tendency observed could have become significant with higher statistical power would ADDRESS not have been terminated prematurely.ConclusionThis meta-analysis, therefore, raises doubts about the clinical usefulness of recombinant activated protein C in patients with severe sepsis and an APACHE II score ≥ 25 which can only be resolved by another properly designed clinical trial.
Highlights
Meta-analysis of two randomised controlled trials in severe sepsis performed with recombinant human activated protein C may provide further insight as to the therapeutic utility of targeting the clotting cascade in this syndrome
Because a significant portion of patients included in ADDRESS met inclusion and exclusion criteria of the PROWESS subgroup of patients for whom the current prescription labelling was given, we hypothesized that a meta-analysis of the two clinical trials of Recombinant human activated protein C (rhAPC) in sepsis may provide further insight as to the therapeutic utility of targeting the clotting cascade in this syndrome with rhAPC
PROWESS and ADDRESS investigated the therapeutic effects of rhAPC against placebo in patients with severe sepsis early in their disease and at a dose of 24 μg/kg/hr for a total infusion duration of 96 hours
Summary
Meta-analysis of two randomised controlled trials in severe sepsis performed with recombinant human activated protein C may provide further insight as to the therapeutic utility of targeting the clotting cascade in this syndrome. Recombinant human activated protein C (rhAPC) was approved for use in severely septic patients based on the results of the phase III PROWESS trial [5]. Because a significant portion of patients included in ADDRESS met inclusion and exclusion criteria of the PROWESS subgroup of patients for whom the current prescription labelling was given, we hypothesized that a meta-analysis of the two clinical trials of rhAPC in sepsis may provide further insight as to the therapeutic utility of targeting the clotting cascade in this syndrome with rhAPC
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