A 42-year old woman presents to the intensive care unit in septic shock from an untreated urinary tract infection.
When her blood pressure does not respond to fluids, the team moves quickly. She’s soon intubated and a central line is placed to administer norepinephrine. Despite early initiation of broad-spectrum antibiotics, her vasopressor requirements continue to escalate.
Most who’ve spent time in the ICU have cared for a similar patient: young, previously healthy, heading toward end-organ failure and death in the setting of overwhelming infection. Indeed, despite advances in management of critical illness, the rate of death from severe sepsis ranges from 30 to 50 percent.
Our artillery is relatively limited. Until recently, this is a patient for whom we’d consider recombinant human activated protein C – drotrecogin alfa (activated), DrotAA, or Xigris. But this was a drug that was expensive and the data as to its efficacy and safety were mixed. However, the PROWESS-SHOCK study published in this week’s NEJM presents the data showing DrotAA to have no significant effect on all-cause mortality among patients with septic shock. Based on these data in October of 2011, the drug’s manufacturers pulled DrotAA from the market worldwide.
The study, “Drotrecogin Alfa (Activated) in Adults with Septic Shock,” puts to rest questions that have surrounded DrotAA since its FDA approval in 2001. The initial trial of DrotAA, the Prospective Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study, had enrolled nearly 2,000 patients with severe sepsis and was stopped early for efficacy when investigators found a risk reduction in mortality from 30.8 percent to 24.7 percent in the group treated with DrotAA.
A subgroup analysis from the study suggested that the greatest benefit of DrotAA – which was also tied to increased bleeding in the intervention arm – was seen in the sickest patients, specifically those with APACHE scores (a system for grading severity of illness upon ICU admission higher numbers means sicker patients) greater than 25. On this basis, the Food and Drug Administration approved DrotAA for patients with severe sepsis at “high risk of death.” Given its pro-coagulant activity, the drug was contraindicated in those at increased risk for bleeding.
At the time, some experts objected to approval of a drug based on a subgroup analysis from a major trial and plans were made to continue to study the drug to resolve ongoing questions. Thus, the PROWESS-SHOCK study was designed to address these remaining doubts regarding when and how to use DrotAA for patients with severe sepsis.
This study enrolled almost 1,700 patients with septic shock from sites worldwide from 2008 to 2011, out of nearly 30,000 assessed for eligibility. Those in shock who could begin study treatment within 24 hours after pressors were started, received DrotAA or placebo for 96 hours.
The patients enrolled had a high burden of illness. More than two thirds had dysfunction of three or more organs, with mean APACHE scores of 25.2 in the DrotAA group and 25.5 in the placebo group. In both groups, the most common sources of infection were lung, abdomen and urinary tract. Similar proportions received glucocorticoids and anticoagulants.
The primary outcome, death from any cause 28 days after randomization, was no better in the DrotAA group than in those receiving placebo; 26.4% of those in the DrotAA group died, compared to a 24.2% mortality in the placebo group. Similarly, rates of death at 90 days showed no statistically significant difference, although there was a trend toward higher mortality in the DrotAA group. The lack of benefit from DrotAA was consistent in predefined subgroups, even those with a higher risk of death.
Why was this result so different from the earlier PROWESS study? In their discussion, the authors note that they are unable to offer an explanation for the inconsistency, but do mention that their results fall in line with the negative studies following PROWESS.
In an accompanying editorial, infectious disease specialists Richard Wenzel and Michael Edmond write that despite certain limitations, this study should “end any further pursuit of a niche for DrotAA in the treatment of sepsis…This setback should inspire a redoubling of efforts to seek new approaches to treatment that are based on a more crystalline view of the biology of sepsis.”
Until those new approaches come to fruition then, we will continue to treat our ICU patients in septic shock with the treatments that have at least some evidence of improved outcomes: rapid administration of fluids, early antibiotics and vasopressors to maintain her blood pressure, low-dose glucocorticoids and low-tidal volume ventilation should she develop acute respiratory distress syndrome.
Hopefully, for this 42-year old woman, these interventions will be enough.