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Drotrecogin alfa (activated): real-life use and outcomes for the UK
Kathryn M Rowan1, Catherine A Welch, Emma North
1Intensive Care National Audit & Research Centre, Tavistock House, Tavistock Square, London WC1H 9HR, UK. kathy.rowan@icnarc.org
Insights
Drotrecogin alfa (activated) use in severe sepsis showed effectiveness in patients with multiple organ failure, aligning with PROWESS study findings. Treatment appeared less effective in less severe cases.
Area of Science:
- Critical Care Medicine
- Pharmacology
- Sepsis Research
Background:
- The Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study demonstrated significant mortality reduction with Drotrecogin alfa (activated; DrotAA).
- Drotrecogin alfa (activated) was approved for severe sepsis treatment following the PROWESS trial results.
Purpose of the Study:
- To conduct an audit of Drotrecogin alfa (activated) use in critical care units.
- To describe DrotAA utilization patterns and assess its effectiveness in a real-world setting.
- To compare DrotAA effectiveness using nonrandomized methods against established trial data.
Main Methods:
- An audit of Drotrecogin alfa (activated) infusions was performed across England, Wales, and Northern Ireland.
- Data from 1,292 DrotAA infusions were linked to national case mix and outcome data.
- Nonrandomized comparisons, including individually-matched and propensity-matched controls, were used to assess effectiveness.
Main Results:
- Drotrecogin alfa (activated) was administered to patients with severe sepsis, often with three or more organs failing.
- Crude hospital mortality was high (45%), with 8.1% experiencing serious adverse events, primarily bleeding.
- Effectiveness estimates were consistent with PROWESS, particularly when DrotAA was initiated within 24 hours and in patients with severe disease (≥3 organs failing).
Conclusions:
- Drotrecogin alfa (activated) use was observed in approximately 1 in 16 severe sepsis admissions with two or more organ failures.
- Nonrandomized effectiveness estimates corroborated PROWESS findings, suggesting benefit in severely ill patients.
- Drotrecogin alfa (activated) demonstrated limited effectiveness in patients with less severe sepsis presentations.
Introduction:
In March 2001, the results of the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study were published, which indicated a 6.1% absolute reduction in 28-day mortality. Drotrecogin alfa (activated; DrotAA) was subsequently approved for use in patients with severe sepsis.
Methods:
In December 2002, critical care units in England, Wales and Northern Ireland were invited to participate in an audit of DrotAA. Data for each infusion of DrotAA were linked to case mix and outcome data from a national audit. Use of DrotAA was described and a nonrandomized comparison of effectiveness was conducted.
Results:
1,292 infusions of DrotAA were recorded in 112 units; 61% commenced during the first 24 hours in the unit. The majority (77%) of patients had three or more organs failing; lung (42%) and abdomen (40%) were the most common primary sites of infection. Crude hospital mortality was high (45%); at 28 days, only 18% had left acute hospital and 19% were still in the unit. For 30%, the full 96-hour infusion was not completed; 24% of infusions were interrupted; 8.1% experienced one or more serious adverse events, of which 77% were serious bleeding events. Of eight relative risks estimated from individually-matched (0.75 to 0.85) and propensity-matched (0.82 to 0.90) controls, seven were consistent with the results of PROWESS. Restricting the analysis to patients receiving DrotAA during the first 24 hours resulted in larger treatment effects (relative risks 0.62 to 0.81). For all matches, similar patterns were seen across subgroups. No effect of DrotAA was seen for two organs failing or lower severity scores, compared with a significant mortality reduction for three or more organs failing or higher severity scores.
Conclusion:
Use of DrotAA was approximately one in 16 for admissions meeting the definition for severe sepsis and with two or more organs failing. Patients receiving DrotAA were younger and more severely ill but were less likely to have serious conditions in their past medical history. Nonrandomized estimates for the effectiveness of DrotAA were consistent with the findings of PROWESS. DrotAA appeared not to be effective in patients with less severe disease.
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