An 'Ignominious End' for a Landmark Sepsis Trial

The Saga of rhAPC

Greg Martin, MD


October 08, 2012

Drotrecogin Alfa (Activated) in Adults With Septic Shock

Ranieri VM, Thompson BT, Barie PS, et al
N Engl J Med. 2012;366:2055-2064


The saga of recombinant human activated protein C (rhAPC), also known as drotrecogin alfa, activated (DrotAA) or Xigris®, has come to an ignominious end. The efficacy and safety of rhAPC for the treatment of patients with septic shock has long been questioned.[1,2] Eli Lilly, with input from the European Medicines Agency, decided several years ago to conduct another phase 3 trial examining the outcomes of sepsis patients treated with rhAPC, as a condition for continued market availability of the drug.[3,4]

Primarily on the basis of data from the original licensure trial (PROWESS), DrotAA was long considered to be most effective when the severity of sepsis was at its highest. This new phase 3 trial, PROWESS-SHOCK, was designed to compare rhAPC with placebo in critically ill patients with septic shock.

PROWESS-SHOCK was a randomized, double-blind, placebo-controlled, multicenter trial that enrolled 1697 patients with septic shock and compared rhAPC and placebo for 96 hours of treatment. The primary outcome was death from any cause at 28 days; secondary outcomes included 90-day mortality.

At 28 days, 26.4% of patients in the rhAPC group and 24.2% in the placebo group had died, yielding a relative risk for death of 1.09 (95% confidence interval [CI], 0.92-1.28; P = .31). At 90 days, the respective proportions were 34.1% vs 32.7% (relative risk, 1.04; P = .56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74-1.17; P = .54).

Rates of death at 28 and 90 days did not significantly differ in other predefined subgroups. Serious bleeding during the treatment period occurred in 1.2% and 1.0% of patients at 28 and 90 days, respectively (P = .81). The investigators concluded that rhAPC treatment does not reduce the risk for death at either 28 or 90 days after onset of septic shock.


DrotAA was the first drug of its kind to demonstrate an effective pharmacologic treatment for sepsis.[5] In practice, however, the treatment seemed to show less efficacy and a higher risk for bleeding than in the PROWESS trial. Over the years, concerns also arose about rationing of the drug and underutilization in a growing population of critically ill patients, owing to its high cost.[6]

Immediately after the analysis of study data and before this publication, Eli Lilly announced that it was withdrawing the drug from the worldwide market and terminating production. This decision effectively ended the saga of rhAPC, including any further research and development. Although some studies, including 2 published very recently,[7,8] have suggested that rhAPC may work in specific groups of patients with sepsis, withdrawal of the drug for general use in sepsis is unfortunately appropriate.