Outcomes and incidence of bleeding events associated with drotrecogin alfa: a single-centre experience of 440 patients

Introduction

Although drotrecogin alfa activated (DAA) was approved in 2002 for the treatment of severe sepsis, controversy has surrounded this therapy especially with respect to the increased risk of serious bleeding events (SBEs). Recently, there has been further interest in the complications of DAA following a review by Gentry and colleagues suggesting a significantly increased incidence of SBEs and death in those with baseline bleeding precautions [1]. We are one of the largest single-centre users of DAA worldwide and thus are keen to report our experience.

Methods

In 2002 a scoring system, reporting tool, and supporting database were developed to track the outcome of DAA-treated severe sepsis patients in our hospital. This is maintained by the clinical pharmacists and captures data on relative contraindications, adverse events and patient outcome. Classification of data is obtained from the electronic patient record. Any DAA administration outside agreed criteria is recorded and bleeding incidents are reviewed with a consultant intensivist to confirm categorisation into serious or minor.

Results

Four hundred and forty patients, including some enrolled in clinical trials, received DAA in our critical care unit over a 7-year period (2003 to 2009). The mean age was 63 years (range 17 to 92). Four hundred and twenty-eight (97.3%) patients met agreed criteria for treatment. Twelve (2.7%) were treated despite being in single organ failure. Mean organ dysfunction was 3.3 and over 75% of patients had at least three organ failures. The commonest sites of infection were respiratory (56%), abdominal (29%) and urinary tract (4%). The 28-day, critical care and hospital mortalities were 35%, 39% and 46%, respectively. Relative contraindications (CIs) were identified for 38 (8.6%) patients treated with DAA. Of these, 23 (5.2%) had an increased baseline bleeding risk, most commonly thrombocytopenia (2%). Hospital mortality for patients with any CI was 47% (n = 18) and 48% (n = 11) if existing predisposition for bleeding. In the 440 patients, 67 (15%) bleeding events were reported, but only 19 (4%) were considered SBEs (using the definitions from PROWESS [2]). Overall mortality for all bleeding events was 57% and 74% for patients with SBEs. Administration errors occurred in 34 (7.7%) patients, of which three (0.7%) were considered serious. Three hundred and eighteen (72%) patients received DAA for at least 72 hours. Of those who did not complete the course, 81 (66%) died.

Conclusions

We have observed a low incidence of SBEs in patients treated with DAA. As expected, SBEs were associated with a poorer outcome. We firmly believe an established scoring system and monitoring tool has facilitated effective use of DAA whilst minimising associated risks of therapy.