Updates on role of human recombinant activated protein C in patients with sepsis and severe sepsis: Changed scenario after PROWESS SHOCK trial

Sir,

In the previous publication in Indian Journal of Anesthesia, the role of human recombinant activated protein C in sepsis and severe sepsis has been discussed.[1]

Initially, there was great confusion regarding the use of activated protein C (APC) in sepsis. PROWESS (recombinant human activated protein C world wide evaluation in severe sepsis) trial[2] conducted in July 1998 was a multi-center, randomized, double blind, placebo-controlled trial of 1690 patients with severe sepsis. Results of the trial clearly indicated that one in every five patients who would have died was saved with Drotrecogin alfa treatment, added to best treatment of care. Then use of this drug started judiciously in patients with septic shock worldwide till results of other trials were declared.

Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) trial completed in 2005 found no significant difference in 28-day mortality (17% placebo versus 18.5% APC, ρ=0.34) with the use of APC. On the contrary, risk of serious bleeding was increased (2.4% with APC and 1.2% with placebo during infusion period).[3]

Researching Severe Sepsis and Organ Dysfunction in Children (RESOLVE) trial with 240 children getting APC and 237 children getting placebo submitted its report in 2007. In this trial too, 28-day mortality rate was not improved significantly (placebo 17.5% versus APC 17.7%, ρ=0.39). Unlike previous studies, risk of bleeding was equal for placebo and APC (6.8% placebo and 6.7% APC, ρ=0.97).[4]

Cochrane Database, which submitted its review in 2008, did not found any significant reduction in 28-day mortality in adults who were given APC. However, risk of bleeding was increased.[5]

So, Food and drug association (FDA) recommended another multi center, placebo controlled, trial to determine the efficacy of APC, named PROWESS-SHOCK trial.[6] PROWESS-SHOCK was started in 2008 and submitted its report in March 2011. Its results have been published recently in 2011. PROWESS-SHOCK trial included 1,696 patients with severe sepsis and septic shock. The inclusion criteria were the following: (1) At least two of the four systemic inflammatory response syndrome criteria (2) Clear evidence of infection (3) Received IV resuscitation of ≥30 mL/kg administered 4 h before or after initiation of vasopressor therapy (4) Continuous requirement of at least one of four vasopressors for at least 4 h (5) Hypoperfusion (renal, acidosis, hepatic) (6) Drotrecogin initiated within 24 h of shock onset. The 28-day mortality was greater in patients receiving drotrecogin alfa (n=846, 26.4%) as compared with the placebo arm (n=834, 24.2%). The difference was not significant statistically (P=0.31). Mortality was not improved even in patients with severe protein C deficiency. During infusion, serious bleeding was not identified.[7]

After results of PROWESS-SHOCK trial, the scenario has been changed completely. APC was withdrawn from the market on Oct 25, 2011. In response to the removal of Drotrecogin alfa (activated), also referred to as rhAPC, in all markets following results of the PROWESS-SHOCK study, the Surviving Sepsis Campaign withdraws its suggestions for use of rhAPC as stated in “Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock.[8,9]

We can take a lesson from the failed PROWESS trial that single study is not sufficient in confirming the treatment benefits especially in complex disease like sepsis. And the search continues for an ideal agent in the management of sepsis.