Findings cast doubt on sepsis drug withdrawal

By Eleanor McDermid

A meta-analysis of clinical trial and real-world data suggests that drotrecogin alfa (activated) may in fact reduce mortality in patients with severe sepsis.

The findings are in line with the original placebo-controlled Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial, which led to the drug's approval, but conflict with those of the follow-up PROWESS SHOCK study, after which drotrecogin alfa (activated) was withdrawn because of perceived lack of efficacy.

The current analysis includes nine clinical trials with 41,401 patients (not including the PROWESS trials), but also 16 prospective or retrospective cohort studies, including 5822 patients.

In a commentary accompanying the study in The Lancet Infectious Diseases, Jean-Louis Vincent (Université Libre de Bruxelles, Belgium) says: "Although these data might not represent the highest levels of evidence, many of us (including me) maintain that we can learn a lot from such real-life studies."

The meta-analysis, by Andre Kalil (University of Nebraska Medical Center, Omaha, USA) and Steven LaRosa (Beverly Hospital, Massachusetts, USA), shows a higher serious bleeding rate than that reported in PROWESS, at 5.6% versus 3.5%, although the team attributes most of this difference to off-label use.

However, there was a significant 18% reduction in in-hospital mortality among patients treated with drotrecogin alfa (activated) versus controls. This was similar to the benefit reported in PROWESS, and the overall result did not change when the researchers added the PROWESS and PROWESS SHOCK findings to their analysis. The result also held in sensitivity analyses accounting for factors including the trial design and whether the trial was sponsored by the drotrecogin alfa (activated) manufacturer.

However, adding the PROWESS SHOCK data resulted in significant heterogeneity, "which raises questions about the comparability between this new trial and PROWESS," say Kalil and LaRosa.

Vincent notes several barriers to producing new drugs for sepsis patients. "Industry knows that the authorities might now request two positive studies before a drug is licensed for marketing, making development costs even higher than before and possibly not worth the risk."

But he stresses that research in this area should still be pursed. "The death rate from sepsis is unacceptable and new drugs are needed urgently," he says. "Researchers need to focus on the key lessons learned from drotrecogin alfa (activated), including the notion that targeting of 'sepsis' itself is an inadequate approach to the development of therapies to improve outcomes in this heterogeneous group of patients."

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