THE ROLE OF
ACTIVATED PROTEIN C
IN SEPTIC SHOCK
SEPSIS: suspected/proven infection plus a systemic
inflammatory response syndrome (fever,
tachycardia, tachypnea, leukocytosis)
SEVERE SEPSIS: sepsis with organ dysfunciton
(hypotension, hypoxemia, oliguria, metabolic
acidosis, thrombocytopenia or obtundation)
SEPTIC SHOCK: severe sepsis with hypotension,
despite adequate fluid resuscitation
Sepsis and Coagulation
Sepsis alters the coagulation balance by increasing
procoagulant factors (tissue factor, fibrin), decreasing
anticoagulant factors (protein C and S, antithrombin III
and tissue factor pathway inhibitor) and decreasing
fibrinolysis. This imbalance leads to DIC, microvascular
thrombosis and ultimately, multi-organ failure
Activated protein C inactivates factors Va and VIIIa
(antithrombotic effect) and inhibits the synthesis of
plasminogen-activator inhibitor 1 (profibrinolytic effect)
Activated protein C also has an anti-inflammatory effect
by inhibiting nuclear factor-kB which suppresses
cytokine production (TNF, IL-6) and decreases cellular
Bernard 2001. Proposed actions of activated protein C
Activated protein C and sepsis
Severe sepsis usually produces at least a sub-clinical
coagulopathy evident by an elevated D-dimer and decreased
levels of protein C.
Protein C requires a functioning endothelium for activation.
Severe sepsis leads to the down-regulation of the endothelial
protein C receptor and thrombomodulin, decreasing levels of
activated protein C. There is also decreased synthesis of APC
in the liver and increased consumption due to
Patients admitted with serious infections that did not progress
to shock had higher levels of protein C compared to those
who did develop septic shock (Hesselvik 1991).
Protein C levels are correlated with mortality in patients with
severe sepsis (Yan 2001).
Severe protein C deficiency in patients with septic shock is
associated with early death (Macias 2004).
Established treatments for sepsis
Early goal directed therapy: protocol derived therapy that uses
central venous catheter readings (physiologic parameters) to
dictate therapy including crystalloids, vasopressors, and blood
transfusions. Shown to decrease mortality and decrease
duration of hospitalization (Rivers 2001).
Low tidal volume ventilation: use of low tidal volumes
decreases mortality in septic acute lung injury (Eisner 2001).
Antibiotics: Start broad spectrum antibiotics initially and
narrow coverage when cultures indicate causative pathogen
Activated Protein C? Hypothesis is that supplementation of
coagulation inhibitors could prevent DIC and organ failure and
decrease mortality of severe sepsis
Phase II trial: Bernard et al
Description: A prospective, randomized, placebo-controlled
trial to assess the safety and efficacy of drotecogin alfa
Methods: Dosing and duration of infusion were studied.
Effects of treatment were assessed by markers of
inflammation and coagulopathy including D-Dimer, IL-6,
fibrinogen and platelets along with other clinical markers.
Results: reduction in 28-day all-cause mortality in the high
dose DAA group as compared to placebo. D-dimer and IL-6
levels decreased in a dose-dependent manner with
increasing doses of DAA. The incidence of adverse events
including serious bleeding did not differ between the DAA
and placebo group. Effective and acceptable dose of
recombinant activated protein C (rhAPC) established as 24
um/kg/her for 96 hours.
Phase III trial: PROWESS
Description: randomized, double-blind, placebo-controlled,
multicenter trial with the primary end point of reduction of 28-day
all cause mortality
Methods: 1690 patients with systemic inflammation and organ
failure due to acute infection were enrolled and assigned to an
infusion of DAA or placebo. Exclusion criteria included conditions
with increased risk of bleeding, known hypercoagulable state,
severe thrombocytopenia, pregnancy, cirrhosis, CRF dialysis-
dependent and moribund conditions with low expected survival.
Base-line characteristics of the patients in both groups were
similar with no statistically significant differences.
Results: Enrollment was suspended mid-study when DAA was
found to be more efficacious than placebo. Relative risk
reduction of mortality was 19.4% in the DAA group along with an
absolute risk reduction of 6.1%. Consistent treatment effect of
DAA was observed among all subgroups. There were greater
decreases in D-dimer and IL-6 levels in the DAA group. There
was a higher incidence of serious bleeding in the DAA group vs.
placebo (3.5% vs 2.0%) although limited to the peri-infusion
Bernard 2001. Kaplan-Meier estimates of survival in DAA and placebo groups.
Controversy over protocol
In Nov 2001, the FDA approved the use of rhAPC for treatment
of patients with severe sepsis who have a high risk of death,
but not without some controversy (FDA anti-infective drug
advisory committee was split 10-10 as to whether APC is safe
Midway into the study, the sponsor amended the study
protocol. Changes included:
1. modified entry criteria: shifted population of study towards
patients with less severe underlying disease and more acute
2. new master lot of cells: although extensive in vitro studies
indicated no differences between the old and new
After these changes, there was an improvement of efficacy of
APC vs placebo. However, FDA analysis conclusion was that
changes in efficacy were not 2/2 the changed protocol or new
drug although some remained unconvinced (Warren 2002).
Warren 2002. Line A indicated intro of amended protocol. First analysis occurred at
B, around the time of the new cell group. Second analysis at C.
APC for which patients
FDA approved APC for treatment of patients with an APACHE
II score of ≥ 25. Treatment benefit of APC increased with the
risk of death.
APACHE II score was the best predictor of survival benefit from
activated protein C compared to other measures of risk and
severity. Benefit of APACHE score is that it assesses severity
of acute process along with other risk factors such as age and
preexisting health status. However, the APACHE score was not
intended to be used as a selection criteria. It was developed to
predict a patient’s risk of dying in the ICU over a 24 hr period.
APACHE score in reality is in flux as physiologic parameters
change over time. Furthermore, there is intra and inter-
observer variability in designated scores among experienced
ICU physicians as high as 10-20% (Polderman 2001).
Warren 2002. Mortality and bleeding according to APACHE II quartiles
APC for which patients
After FDA approval of APC in adults with severe sepsis and a
high risk of death (APACHE>25), the FDA required another study
evaluating APC in patients with severe sepsis and low risk of
Abraham et al conducted a double-blind, placebo controlled,
multicenter study in patients with severe sepsis with low risk of
death (defined by APACHE<25) with the primary end point of all-
cause mortality at 28 days.
The study was terminated early as there was no statistically
significant differences in 28 day mortality between placebo and
APC. In addition, there was a higher incidence of serious
bleeding in the APC group vs placebo both in the peri-infusion
period and the entire 28 day study period.
With no beneficial treatment effect and an increased rate of
bleeding in the treatment group, the study concluded that APC
should not be used in patients with severe sepsis, with a low risk
Abraham 2005. Kaplan-Meier estimates of survival in DAA and placebo groups.
Other Concerns with PROWESS
Study population: There is some concern as to whether the
PROWESS study population is representative of the total
population of patients with sepsis in hospitals and consequently
whether the study results can be generalized. 80% of patients in
the study were living at home prior to hospitalization, 50% were
admitted with respiratory failure and all patients who had organ
failure for >24 hrs were excluded from the study.
Bleeding risk: Incidence of severe bleeding complications may
increase when APC is used in less controlled environments.
During open-label APC use after the trial, 2.5% of patients had
an intracranial hemorrhage as compared to 0.2% of patients who
received APC during the trial (Warren 2002).
DAA is an expensive therapy, costing an average of 6,800
dollars per therapeutic course resulting in reluctance to use DAA
in certain populations.
An economic analysis was done, and the average cost per life-
year gained by treating patients with APC was $27,936 (Mannis
The study concluded that activated protein C is relatively cost
effective when targeted to patients with severe sepsis, with an
APACHE>25, and a reasonable life expectancy.
In addition, cost effectiveness ratios of APC are similar to or
better than other widely accepted therapies including organ
transplantation, dialysis, and implanted cardiac debrillators
Angus 2003. Comparison of APC with other widely used interventions
Activated Protein C reduces mortality in patients
with severe sepsis with a high risk of death
Treatment of severe sepsis with APC is cost
effective when targeted to patients with severe
sepsis, high risk of death with a reasonable life
Activated protein C has not shown efficacy and in
addition is not cost effective in patients with severe
sepsis with low risk of death (APACHE<25)
Abraham E, Laterre P-F, Garg R, et al. Drotrecofin alfa (activated) for adults
with severe epsis and low risk of death. N Engl J Med 2005;353:1332-
Angus DC, Linde-Zwirble HT, Clermont G. Cost-effectiveness of drotrecogin
alfa (activated) in the treatment of severe sepsis. Critical Care Med 2003
Bernard GR, Vincent J-L, Laterre P-F, et al. Efficacy and safety of
recombinant human activated protein C for severe sepsis. N Engl J
Eisner MD, Thompson T, Hudson LD, et al. Efficacy of low tidal volume
ventilation in patients with different clinical risk factors for acute lung
injury and the acute respiratory distress syndrome. Am J Repis Crit Care
Med 2001; 164:231-6.
Fourrier F. Recombinant human activated protein C in the treatment of
severe sepsis: An evidence-based review. Crit Care Med 2004;
Hesselvik JF, Malm J, Dahlback B, et al. Protein C, protein S, C4b-binding
protein in severe infection and septic shock. Thromb Haemost
Macias WL, Nelson DR. Severe protein C deficiency predicts early death in
severe sepsis. Crit Care Med 2004;32(Suppl):S229-332.
Mannis BJ, Lee H, Doig CJ, et al. An economic evaluation of activated
protein C treatment for severe sepsis. N Engl J Med 2002;347:993-
Polderman KH, Jorna EM, Girbes AR. Intra-observer variability in
APACHE II scoring. Intensive Care Med 2001;27:1550-2.
Rice TW, Bernard G. Drotrecogin alfa (activated) for the treatment of
severe sepsis and septic shock. Am J Med Sci 2004; 328(4):205-
Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the
treatment of severe sepsis and septic shock. N Engl J Med
Russell JA. Management of sepsis. J Engl J Med 2006;355:1699-713.
Siegel JP. Assessing the use of activated protein C in the treatment of
severe sepsis. N Engl J Med 2002;347:1030-1034.
Warren HS, Suffredini AF, Eichacker PQ, Munford RS. Risks and
benefits of activated protein C treatment for severe sepsis. N Engl
J Med 2002;347:1027-1030.
Yan SB, Helterbrand JD, Hartman DL, et al. Low levels of protein C are
associated with poor outcomes in severe sepsis. Chest