According to a meta-analysis published in the July issue of the magazine Lancet Infectious Diseases, which included 9 controlled clinical trials and 16 trials in a group and covering a total of 47,223 patients, as well as 20 safety analyzes with the participation of 8,245 other patients, a significant reduction in hospital mortality was revealed with the use of activated drotrekogin alpha. Analysis also showed an increased risk of severe bleeding while using this medication.

The new data are consistent with the results of the randomized double-blind placebo-controlled trial PROWESS (placebo-controlled study Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis), based on which the drug was approved for use. in the United States in 2001 and in Europe in 2002 g.

However, given the concern that the drug is not effective in patients with less severe sepsis and in children, the researchers conducted a second clinical trial, PROWESS-SHOCK. The results of this clinical study were not in favor of the drug and, ultimately, Eli Lilly recalled the drug to the market in October 2011.

Activated drotrecogin alpha or activated recombinant human protein C is a substance with anticoagulant, anti-inflammatory and fibrinolytic effects. The main mechanism of its action is considered to be activation of receptor 1 signaling, mediated by the activation of protein C endothelial receptors by proteinase, which provides a cytoprotective effect on endothelial cells.

In a recent report that included the results of a 10-year analysis, it was shown that among patients treated with drotrekogin alfa, mortality had decreased by 18% compared to the control group (relative risk [RR], 0.822, 95% confidence interval [CI] 0.779-0.867, P less than 0.0001). The rate of reduction in mortality coincided with that obtained in the PROWESS study (RR 0.851, 95% CI 0.740-0.979), but was lower than in the patients included in the PROWESS study, whose disease was more severe (RR 0.708, 95% CI 0.590-0.849).

Additional benefits of drotrecogin alpha have been identified following a meta-regression analysis with regard to improved mortality control (P = 0.01) and more severe disease (P = 0, 04).

Studies in a group have shown that the nosocomial mortality in patients treated with drotrecogin alfa is 41% (95% CI 35-48%), which exceeds this indicator according to the PROWESS study - 31% (95% CI 27 -36%, P less than 0.0001).

Meanwhile, in patients receiving drotrecogin alfa, severe bleeding occurred in 5.6% of cases (95% CI 4.5-6.9%), which was higher than the level found in the PROWESS study (3.5%, 95% CI 2.5–5.0%, P = 0.003), however, its value was close to that of the indicator in patients with severe illness included in the PROWESS study (P = 0.073).

The authors concluded that the risk of severe bleeding with drotrekogin alpha was higher in clinical practice than with a pre-registration study, which may be explained by the use of a drug in violation of the instructions, and not by treating patients with a more severe course of the disease. The results of this drug efficacy study are consistent with data from the PROWESS study, not PROWESS-SHOCK.

Compared to the patient population of the PROWESS study, drotrekogine alfa was used in more severe patients and was associated with a higher risk of bleeding, but did not show high efficacy. Although these data do not have a high level of evidence, many scientists believe that much can be learned from similar studies conducted in actual clinical practice.

It should be noted that the current death rate from sepsis is unacceptable, therefore new drugs are urgently needed to treat sepsis, while some researchers are asking questions: after excluding this drug, some patients have have they been denied effective treatment? Shouldn't we remember patients who may benefit from the prescription of this medication?

Researchers need to focus on key lessons from drotrecogin alfa, including the assumption that the goal of treating sepsis alone is an inadequate approach to develop new treatment strategies to improve disease outcomes in a very heterogeneous group of patients.

Sepsis is a dreaded disease, the number of which, according to rough estimates, reaches only a quarter of a million people a year in the United States. This indicator exceeds the mortality rate of the four most common types of oncopathology in the United States, and the number of victims of sepsis worldwide is expected to reach one million. However, very few studies are devoted to the treatment of this disease.

Some scientists doubt that the present study could change anything regarding the future drug drotrekogin alfa.

The main problem with any meta-analysis is the need for statistical processing of the data at a certain level, which complicates the interpretation of their results. Such an analysis is significantly different from a randomized controlled trial, where you can get a clear answer: yes or no. In this case, the authors did an excellent job of selecting the studies included in the analysis, which allowed us to make the study fair and impartial.

Thus, according to a meta-analysis, it was found that a number of patients participating in the studies benefited from the use of drotrekogin alpha.