Activated Protein C
Dr John Griffiths DICM MRCP FRCA MA
Focus on the physiological role of activated protein C
In vivo activated protein C (APC) is an important mediator of the body’s response to sepsis as it possesses antithrombotic, anti-fibrinolytic and anti-inflammatory properties. APC inactivates clotting factors Va and VIIIa, thereby preventing the generation of thrombin. Inhibition of thrombin formation decreases inflammation by inhibiting platelet activation, neutrophil recruitment and mast-cell degranulation. APC has direct anti-inflammatory properties by blocking the production of the pro-inflammatory cytokines tumour necrosis factor, interleukin-1 and interleukin-6 and limiting the adhesion of immune cells to endothelium. APC also exerts an anti-apoptotic effect that may contribute to the suppression of inflammation. Furthermore, activated protein C enhances fibrinolysis by inhibiting plasminogen-activator-inhibitor type 1 (PA-1).
Focus on the PROWESS Trial
Recombinant human activated protein C (rhAPC, drotrecogin alfa) has been developed and is the first anti-inflammatory agent that has proved effective in the treatment of sepsis. The PROWESS study is the first trial to demonstrate a therapeutic benefit of targeting the inflammatory response in sepsis. The trial was a randomised, double-blind, placebo-controlled multicentre trial. Patients were admitted to the trial if they had a known or clinically suspected infection plus three of more signs of systemic inflammation and the sepsis-induced dysfunction of at least one organ or system (Table 1). Patients had to begin treatment within twenty-four hours of meeting the inclusion criteria. Patients were randomised to receive either placebo or rhAPC. The trial was stopped early because of the mortality difference between the two groups at the second interim analysis. The administration of rhAPC resulted in a 19.4% reduction in the relative risk of death within the first 28 days of commencement of the study drug, and in an absolute risk reduction of 6.1%. The number to treat in order to save one additional life was 16. The survival benefit was greatest in those with the highest degree of critical illness, as defined by Acute Physiology and Chronic Health Evaluation (APACHE II) Scores ≥ 25, where an absolute mortality reduction of 13% was produced. A major risk associated with the use of rhAPC is bleeding. The incidence of serious bleeding in the PROWESS study (intrcranial haemorrhage, a life-threatening bleeding episode, or a requirement for 3 or more units of blood) was higher in the rhAPC group than in placebo group (3.5% versus 2.0%) during the infusion of the study drug. There was fatal intracranial haemorrhage in 2 patients in the treatment group and in 1 patient in the placebo group. Serious bleeding, however, occurred in both the treatment and the placebo group primarily in patients with a high baseline risk of haemorrhage.
Hence, the contraindications for the use of rhAPC include:
There were no other complications attributed to the use of rhAPC. The data regarding efficacy and safety of rhAPC have been subsequently confirmed in the ENHANCE US trial.
- APPT> 120 seconds
- INR > 3.
- Platelet count < 30000×109/l
- Gastrointestinal ulceration
- Trauma, surgery within the last 12 hours
- Epidural catheters
- Chronic severe liver disease
- Intracranial pathology
Table 1. Summary of inclusion criteria of PROWESS Trial
Known or suspected infection, evidenced by at least one of the following:
- white cells in a normally sterile body fluid; perforated viscous
- radiographic evidence of pneumonia in association with the production of purulent sputum
- a syndrome associated with a high risk of infection (e.g., ascending cholangitis).
MODIFIED SIRS CRITERIA
At least three of the following four criteria:
- a core temperature of ≥38°C or ≤36°C
- a heart rate of ≥90 beats/min, except in patients with a medical condition known to increase the heart rate or those receiving treatment that would prevent tachycardia
- a respiratory rate of ≥20 breaths/min or a PaCO2 of ≤mm Hg or the use of mechanical ventilation for an acute respiratory process
- a white-cell count of ≥12,000/mm3 or ≤4,000/mm3 or a differential count showing > 10 percent immature neutrophils
CRITERIA FOR DYSFUNCTIONAL ORGANS OR ORGAN SYSTEMS*
At least one of the following five criteria:
- Cardiovascular system dysfunction: arterial systolic blood pressure ≤90 mm Hg or mean arterial pressure ≤ 70 mm Hg for at least 1 hour despite adequate fluid resuscitation, adequate intravascular volume status or the use of vasopressors in an attempt to maintain a systolic blood pressure of ≥90mm Hg or mean arterial pressure of ≥70mm Hg.
- Renal dysfunction: urine output <0.5 ml/kg of body weight/hr for 1 hour, despite adequate fluid resuscitation
- Respiratory-system dysfunction: PaO2:FiO2 ratio ≤250 in the presence of other dysfunctional organs or systems or ≤200 if only dysfunctional organ system
- Haematological dysfunction: the platelet count had to be <80,000/mm3 or to have decreased by 50 percent in the 3 days preceding enrolment
- Unexplained metabolic acidosis: pH ≤7.30 or base deficit ≥5.0 mmol/litre in association with a plasma lactate level >1.5 times the upper limit of the normal value for the reporting laboratory
* The first sepsis-induced organ or system dysfunction had to develop within 24 hours before study enrollment
Focus on the use of activated protein C in sepsis
The rationale behind infusing APC is that in sepsis, conversion of protein C to the activated form is inhibited by down-regulation of thrombomodulin, leading to decreased effective concentrations. Nearly ninety percent of trial patients demonstrated APC deficiency. The effects of rhAPC on long-term survival in the PROWESS trial have recently been reported. In all patients (92% follow-up rate), hospital survival was higher with rhAPC than with placebo. After 3 months this treatment effect was lost and survival rates became similar in the two groups. Only the subgroup with APACHE scores ≥ 25 maintained a significantly higher survival rate up to 2.5 years. In fact, rhAPC given to less severely ill patients was associated with an increased mortality at 1 year follow-up.
Focus on the ADDRESS trial
The results of the ADDRESS trial, which was designed to examine the effects of rhAPC on survival in patients with severe sepsis who were at low risk of death as defined by APACHE II scores < 25 or single-organ failure, were reported recently. The ADDRESS trial was stopped early because 28-day mortality and in-hospital mortality were statistically the same in the group receiving rhAPC as in the placebo group.
Focus on the cost of activated protein C
The cost of a course of rhAPC is high (around £5000, depending on body weight). The cost per quality-adjusted life year (QALY), however, is only modest - up to £11,000 per QALY. This cost- effectiveness is similar to that of newer thrombolytic agents used for the treatment of myocardial infarction. In September 2004 the National Institute of Clinical Excellence (NICE) sanctioned the use of rhAPC for the treatment of adult patients who have severe sepsis and two or more organ failure as have the guidelines of the recent ‘Surviving Sepsis Campaign.
Key learning points
- Patients with severe sepsis and two or more organ failures should be considered for treatment with rhAPC
- Recombinant activated protein C increases the risk of serious bleeding events
- It is imperative that every patient being considered for treatment with rhAPC must be carefully selected using appropriate exclusion criteria
Key References Bone RC, Grodzin CJ, Balk RA. Chest 1997;112:235-43.
Sepsis: a new hypothesis for pathogenesis of the disease process.
Bernard GR, Vincent JL, Laterre PF et al. N Engl J Med 2001; 344: 699-709.
Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) Study Group. Efficacy and safety of recombinant human activated protein C for severe sepsis.
Ely EW, Laterre PF, Angus DC et al. Crit Care Med 2003; 31 (1): 12-19
PROWESS investigators. Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis.
Angus DC, Laterre PF, Helterbrand JD et al. Crit Care Med 2004; 32 (11): 2199-206.
The effect of drotrecogin alfa (activated) on long-term survival after severe sepsis.
National Institute for Clinical Excellence http://www.nice.org.uk/pdf/TA084guidance.pdf
Drotrecogin alfa (activated) for severe sepsis. Technology appraisal 84 September 2004.
Dellinger RP, Carlet JM et al. Crit Care Med 2004;32(3):858-873.
Surviving sepsis campaign guidelines for management of severe sepsis and septic shock.
Bernard GR, Margolis BD, Shanies HM et al. Chest 2004; 125 (6): 2206-216.
Extended evaluation of recombinant human activated protein C United States Trial (ENHANCE US).
Davies A, Ridley S, Hutton J et al. Anaesthesia 2005; 60 (2): 155-162.
Cost effectiveness of drotrecogin alfa (activated) for the treatment of severe sepsis in the United Kingdom.