Results of the PROWESS-SHOCK trial, as well as a 2012 Cochrane review, seem to have resolved the controversy related to efficacy of recombinant human activated protein C (rhAPC). However, discussion continues, as the May issue of Critical Care Medicine examines observational data from the Surviving Sepsis Campaign to analyze the association between treatment with rhAPC and outcomes among patients with severe sepsis. Casserly et al completed this study before the release of the PROWESS-SHOCK results.

Of the 15,022 subjects at 165 hospitals included in the Surviving Sepsis Campaign database, 6.7 % (n=1009) received rhAPC. Those patients were more likely to have pneumonia or abdominal infections, while patients who did not receive the drug were more likely to have urinary tract infections. Patients who received rhAPC also were more likely to have a higher degree of baseline acute organ dysfunction and to require mechanical ventilation.

After adjusting for multiple confounders, patients who received rhAPC had statistically significantly lower in-hospital mortality according to a multivariable logistic regression analysis (odds ratio, 0.76; 95% confidence interval, 0.66-0.86; P<0.001). Propensity score matching was used to validate the risk adjusted multivariate regression model, and the results were similar. Patients with thrombocytopenia and coagulopathy also were found to have lower, and statistically significant, adjusted risks of hospital mortality.

In October 2011, drotrecogin alfa (activated) [Xigris] manufacturer Eli Lilly and Company withdrew rhAPC from the market and announced the discontinuation of all other ongoing clinical trials. While further discussions about rhAPC might be considered moot, it is worth noting that previous rigorously conducted clinical trials occasionally have yielded discordant results compared to observational, “real-life” investigations. This particular study is hampered by several limitations, including confounding by indication, since patient demographic data were not available. Moreover, data about bleeding complications were not available. As with any observational trial, unmeasured confounders might also explain differences in measured outcomes.

The recent moratorium on the use of rhAPC appears to represent yet another failure of immunomodulatory agents to impact outcomes for critically ill patients with sepsis; however, the infrequent use of rhAPC, in selected populations, was found to be associated with a significant improvement in adjusted hospital mortality in this study. One important finding from this trial is that implementation programs, such as the Surviving Sepsis Campaign, have the potential to change clinical practice. Though rhAPC was rarely used overall, its use did increase over time once rhAPC was endorsed by Surviving Sepsis Campaign. 

Concise Critical Appraisal is a regular feature authored by SCCM member Samuel M. Galvagno Jr., DO. Each installment highlights journal articles most relevant to the critical care practitioner.