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					        THE ROLE OF
                 Helena Yu
       Medical Therapeutics
Sepsis definitions
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
  activated (DAA)
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
    and efficacious)
   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
       infectious illness.
       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
    of death
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).
Economic considerations
   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)
Mannis 2002.
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)
Works Cited
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
   Med 2001;344:699-709.
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;
   32[Suppl]: S534-S541.
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.
Works Cited
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

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