Bernard GR, Vincent JL, Laterre PF et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. New England Journal of Medicine 2001; 344: 699-709.
RHH Journal Club. May 16th, 2013. Dr Matt Smith
Full-text article (if available)
Does administration of drotrecogin alfa activated (APC) reduce the rate of death in patients with severe sepsis and have an acceptable safety profile?
- Multicentre, double blind; Randomised Controlled Trial.
- 164 centres across 11 countries from July 1998 through to June 2000.
Eligible if: 1) known or suspected infection 2) met SIRS criteria 3) sepsis-induced dysfunction of at least one organ system within 24 hours of enrolment.
Exclusions: Pregnancy or breast feeding, weight >135 kg, platelets <30,000, conditions that increased risk of bleeding, known hypercoagulable condition, lack of consent or advance directive, not expected to survive 28d, HIV, prior transplant, CRF, portosystemic hypertension, pancreatitis, other study; or contra-indicated drug
Block randomization to administration of APC or placebo (1:1) – 0.9% saline.
Infusions of APC (24microg/kg/h) or placebo from foil wrapped bags were run for total of 96h.
Patients followed for 28 days after infusion start or until death.
Blood samples obtained for D-dimer, IL-6, and antibodies against APC during this time.
Other ITU interventions not standardised.
- Primary outcome:
Death from any cause, assessed 28 days after initiation of infusion.
Trial designed to enroll 2280 patients with planned interim analyses at 760 and 1520 patients.
- Secondary outcomes:
None formally specified, but incidence of serious adverse events (particularly serious bleeding) reported, plus pre-specified subgroup analyses by demographics, APACHE-II score, laboratory variables, microbiological cultures, development of anti-APC antibodies.
- Did groups start with a similar prognosis? – Pragmatically, yes (75% patients with at least 2 organ system failure and chest or abdominal sepsis)
- Numbers involved: Enrollment suspended at second interim analysis (1728/2280 randomisations) as apparent difference in mortality rate exceeded a priori guideline (not disclosed) for stopping the trial.
- Randomisation – “made through a central randomisation centre” – method not disclosed
- Blinded? – Yes.
- Intention to treat principle applied? – Yes.
- Confounding factors considered? – Yes (e.g. similar numbers received >90% of the intended infusion when taking into account invasive procedures)
- Follow up complete? Only to 28 days after enrolment (a significant number of ITU patients stay >28d!)
Primary outcome: 28-day mortality 24.7% vs. 30.8% (RR 0.80; 95% CI 0.69-0.84; P=0.005)
Adverse event data: ≥1 serious adverse event 12.5% vs. 12.1% (P=0.84). Serious bleeding event 3.5% vs. 2.0% (P=0.06). Thrombotic events 2.0% vs. 3.0% (P=0.20)
Take home message/application of this research: “Treatment with drotrecogin alfa activated significantly reduces mortality in patients with severe sepsis and may be associated with an increased risk of bleeding.”
This trial informed the use of the drug Xigris (APC) for a number of years in the UK, along with its inclusion in the Surviving Sepsis Guidelines. An absolute mortality reduction of 6% could potentially save thousands of lives per year! (NNT approx. 17). FDA approval in the US was however a split vote. Criticisms arose due to the study being sponsored by the pharmaceutical industry (along with many trial players being connected to Eli Lilly), the early termination of the study, some inclusion/exclusion criteria being adjusted mid-protocol and the manufacturing process for APC also being altered mid-trial. On the basis of the published data (which appears to confer a reasonable degree of validity) the drug was used in Europe for a certain, more critically ill subset of patients with severe sepsis. Further trials of the drug were, however, to follow…