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APC was withdrawn from the market after PROWESS-SHOCK showed it was ineffective.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

References and Links