Activated Protein C

OVERVIEW

  • drotrecogin alfa
  • endogenous human protein
  • component of the natural anticoagulant system
  • recombinant glycoprotein with anti-thrombotic, profibrinolytic and anti-inflammatory properties.
  • protein C synthesized in liver

MECHANISM OF ACTION

  • protein C + thrombomodulin on endothelial surface -> activated protein C by thrombin
  • recombinant glycoprotein with anti-thrombotic, profibrinolytic and anti-inflammatory properties.
  • effects:
    1. anti-thrombotic – inhibiting Factor Va and VIII
    2. indirect profibrinolytic – inhibiting plasminogen activator inhibitor-1 (PAI-1) and decreasing generation of activated thrombin-activatable-fibrinolysis-inhibitor
    3. anti-inflammatory – inhibiting TNF production by monocytes and by limiting the thrombin-induced inflammatory responses

DOSE

  • 24mcg/kg/hr (use actual body weight)
  • IV
  • 96 hrs
  • can’t monitor (affects APTT slightly)
  • no dose adjustment for organ dysfunction
  • cost = ~$18,000

INDICATIONS

APC was withdrawn from the market after PROWESS-SHOCK showed it was ineffective. Based on PROWESS, it was previously indicated for:

  • severe sepsis + at least 2 organ failures:
    • CVS – inotropes despite adequate filling
    • RESP – PaO2/FiO2 < 250
    • RENAL – U/O < 0.5mg/kg/hr
    • HAEM – platelets < 80,000
    • META – lactic acidosis (pH < 7.3, lactate > 5)

ADVERSE EFFECTS

  • bleeding (cease 1-2 hrs before procedures, restart 12 hrs after major surgical procedures)
  • increased risk of bleeding if platelets < 30,000 – DVT prophylaxis can be given Evidence – in sepsis there are documented low levels of APC -> associated with increased negative outcomes (increased shock and mortality)
  • improves neutrophil and endothelial interaction -> improves microvascular patency

PROWESS

  • MRCT (2001, NEJM)
  • n = 1690
  • APC vs Placebo in SIRS + at least one organ dysfunction
    -> 6% mortality reduction (more apparent in sicker patients)
    -> no significant rise in bleeding

ENHANCE

  • Multicenter (2005, CCM) – single arm open label
  • n = 2378
    -> similar mortality rates to PROWESS
    -> increased bleeding (ICH)

ADDRESS

  • MRCT (2005, NEJM) – 516 Centers, 34 Countries
    n = 1610
  • Goal = quantify risk of bleeding in those @ low risk of death
    -> serious bleeding: 4% in APC and 2% in Placebo
    -> no role of APC in those at low risk of death

RESOLVE

-> no benefit

PROWESS SHOCK

  • large MCRCT
  • goal = to quantify benefit and risk of use in patients with vasopressor dependent shock
  • Eli Lilly sponsored
    -> no benefit in the APC group

CCC 700 6

Critical Care

Compendium

Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also the Innovation Lead for the Australian Centre for Health Innovation at Alfred Health and Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of two amazing children.

On Twitter, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

Leave a Reply

This site uses Akismet to reduce spam. Learn how your comment data is processed.