APC for Lower-Risk Sepsis: Outcomes at One Year
Abstract & Commentary
By Andrew M. Luks, MD, Pulmonary and Critical Care Medicine, University of Washington, Seattle, is Associate Editor for Critical Care Alert.
Dr. Luks reports no financial relationship to this field of study.
Synopsis: In this analysis of follow-up data from the ADDRESS trial, the authors find that use of drotrecogin alpha, as compared to placebo, in patients with severe sepsis who are at low risk of death, did not improve mortality or lead to additional serious adverse events at one year post-hospital discharge.
Source: Laterre PF, et al. Crit Care Med. 2007;35(6)1457-1463.
Several years ago, the PROWESS trial demonstrated a mortality benefit for drotrecogin alfa [activated] (DrotAA; APC) in patients with severe sepsis, and that this benefit was most pronounced in those at high risk of death (ie, APACHE score > 25 or multi-organ dysfunction).1 The ADDRESS trial followed and demonstrated that this benefit was not seen in patients at low risk of death.2 In this study, Laterre and colleagues examine one-year follow-up data from the ADDRESS study to assess the long-term safety and efficacy of DrotAA in this patient population.
There were 2640 patients enrolled in the ADDRESS trial, 1307 in the placebo group, and 1333 in the DrotAA group. Tnjhe authors performed one-year follow-up on all patients who were alive at the end of the 28-day, in-hospital phase of the study. After accounting for those patients who were lost to follow-up or who declined to return surveys and for study sites that did not participate, 1176 subjects from the placebo group and 1200 subjects from the DrotAA group remained and were included in the one-year data analysis. The investigators used mail and telephone surveys and review of medical and public records to obtain data on survival status, cause of death, whether the cause of death was predictable given the patient's underlying condition and serious adverse events thought to be due to DrotAA. Statistical analyses were performed on the intention to treat population. Chi-square tests and Kaplan-Meier analyses were used to compare one-year mortality in the DrotAA and placebo groups for both the entire study population as well as prospectively defined subgroups.
As was noted with 28-day mortality, one-year mortality rates were similar in the DrotAA and placebo groups (34.2% vs 34.0%). No differences in mortality were noted in any of the subgroup analyses. Ninety-two percent of DrotAA patients alive at one year were at home compared to 93% in the placebo group. The majority of in-hospital deaths were attributable to sepsis while those deaths that occurred after discharge were due to other causes. Of note, twice as many DrotAA patients died of cancer as placebo patients, but there is no clear evidence of a causal role in this case. No additional serious adverse events were reported during the one-year follow-up period and none of the post-discharge deaths were felt by the investigators to be due to DrotAA.
In gathering follow-up data on 90% of the patients enrolled in the original ADDRESS trial, Laterre and colleagues provide a useful addition to the growing literature on the use of DrotAA in the management of severe sepsis. In particular, these results provide further evidence that we should not be using the medication in patients at low risk of death, as defined as an APACHE score below 25 and single organ dysfunction. Not only is there no mortality benefit at 28 days but also there is no effect on longer-term outcomes for these patients.
It is further reassuring that even in situations where the medication is used inappropriately (ie, in a patient with a low risk of death) no additional adverse events are observed over the long term that can be attributed to the medication. The authors did observe an unexpected higher incidence of cancer deaths in the DrotAA-treated patients, but it is unclear that the result can actually be linked to the medication. Instead, it likely stems from the fact that more of the DrotAA-treated patients had cancer at the time of enrollment.
The results of this study must be interpreted with some degree of caution, however, as some patients with APACHE scores > 25 or multi-organ dysfunction were included in the trial due to different labeling and indications for DrotAA that existed between the various countries represented in the study.
The results of this study highlight the need for further work to clarify the role of DrotAA in the management of septic patients. After only a single study, the PROWESS Trial demonstrated a modest 6% absolute risk reduction in mortality from severe sepsis; DrotAA became a standard part of many sepsis management protocols. Since that time, a randomized trial in pediatric patients showed no benefit from the medication3 and, as noted above, the ADDRESS trial showed no benefit in patients at low risk for death. No further large randomized trials have been done in patients with a high risk of death to determine whether the results of the PROWESS trial hold up. Such a trial would be useful before we commit to using an expensive medication associated with a higher incidence of severe bleeding.
- Bernard GR, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344(10):699-709.
- Abraham E, et al. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med. 2005;353(13):1332-1341.
- Nadel SB, et al. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet. 2007;369(9564):836-843.