Transcript Lindsay Moorman

The Use of Recombinant Human
Activated Protein C for Severe
Sepsis
Presented by: Lindsay Moorman
Advisor: Dr. Hadley
What is Severe Sepsis?
• Severe sepsis – defined by the presence of
both infection and a systemic inflammatory
response which produce organ failure
The Problem
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750,000 Americans suffer from it each year
215,000 die
High mortality rate
Incidence is rising and is expected to exceed
1 million cases by 2010
Physiologic Derangements
Occurring in Severe Sepsis
• Overproduction of inflammatory mediators
– IL-1, IL-6, TNF
• Unopposed microthrombi formation
• Result – organ damage
– Low oxygen perfusion to major organs
– Cytokine-induced apoptosis
General Facts about Protein C
• Made by the liver and circulates as a
zymogen
• Activated by thrombomodulin receptor
• Protein C levels are drastically reduced in
states of sepsis
• Thrombomodulin receptor down regulation
occurs in severe sepsis
Mechanism of Action for rhAPC
• Drastically reduces production of thrombin
• Reduces levels of PAI-1, enhancing tPA’s
actions
• Anti-inflammatory mechanisms
– Reduces cytokine elaboration
– Decreases oxidative damage to endothelial cells
– Blocks endothelial cell apoptosis
The PROWESS Trial
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Placebo-controlled, double-blinded
1690 participants, age 18 or older
Placebo group mortality – 30.8%
rhAPC group mortality – 24.7%
Absolute risk reduction – 6.1%
Ineffective for subgroup with APACHE II
scores less than 24
APACHE II Score
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0-4~4% death rate
5-9~8% death rate
10-14~15% death rate
15-19~25% death rate
20-24~40% death rate
25-29~55% death rate
30-34~75% death rate
over 34~85% death rate
Analysis of the Elderly
Population within the PROWESS
Trial
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Subjects older than 75
Had more underlying disease
Larger absolute risk reduction – 15.5%
For every 6 elderly patients treated, 1
additional life will be saved
ENHANCE Trial
• Open-label, single-arm trial
• 2,375 participants
• Compared mortality results to those of the
PROWESS trial
COMPARISONS
• PROWESS
• ENHANCE
• Mortality rate – 25.3%
• Mortality rate – 24.7%
• Absolute risk reduction 6.1%
• Absolute risk reduction 5.5%
• Ineffective if APACHE II
score of 24 or less
• Ineffective if APACHE II
score of 25 or less
ENHANCE Trial
• Patients treated in less than 24 hours of
organ dysfunction had significantly higher
survival rates, especially among the elderly
Inferences
• rhAPC is most effective in reducing
mortality from severe sepsis in the elderly
• Clinicians must be aware that prompt
treatment can save lives, especially of the
elderly
Recommendations for use of
Xigris (rhAPC)
• Patients with APACHE II scores of 25 or
more
• Infusion lasts 96 hours
Adverse Effects of Xigris
(rhAPC)
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Only side effect is bleeding
Placebo group – 2%
Xigris group – 3.5%
Only seen during infusion period
Contraindications
• Active internal
bleeding
• Hx of hemorrhagic
stroke in last 3 mths
• Hx of intracranial/
intraspinal surgery or
severe head trauma in
last 2 mths
• Trauma with increased
risk of life-threatening
bleeding
• Epidural catheter
• Intracranial neoplasm
• Mass lesion
• Cerebral herniation
Recommendations for use in
Surgical Patients
• d/c 2 hours prior to surgery
• Restart after 12 hours if platelet count is
greater than 30,000
Recommendations for
Concurrent Heparin Use
• XPRESS trial
• No higher incidence of serious bleeding
events
• Slightly higher incidence of minor bleeding
• Heparin doesn’t interfere with efficacy
• Heparin infusion should remain
uninterrupted while Xigris is infused
Recommendations for use in
Patients with DIC
• Study by Dhainaut et al.
• No significant increase in serious bleeding
events
• More efficacious in this population than
patients without DIC
Use in Patients with Borderline
APACHE II Scores
• What if APACHE II score is 23-24?
• Take into account the patients for which
Xigris is most effective:
– Age 50 or older
– Two or more failing organs
– Those who received the drug while in shock
Pediatric Use for Severe Sepsis
• Would it be beneficial with a mortality rate
of 10%?
• RESOLVE trial
– Measured composite time to resolution of organ
failure
– Stopped early due to lack of efficacy
– FDA issued contraindication of Xigris in
children
Pediatric Use for Specific
Subpopulations
• Vincent et al. investigated use in pediatric
conditions associated with high mortality
rates – meningococcemia and Purpura
fulminans (PF)
Pediatric Use in
Meningococcemia and PF
• Retrospective analysis by Vincent et al.
• 119 children
• 4% lower mortality rate for children with
meningococcemia/PF who received
treatment with Xigris than children who
received Xigris and didn’t have these
conditions
Pediatric Use in
Meningococcemia and PF
• Open-label trial conducted by White et al.
• 36 patients with PF-associated
meningococcemia
• Predicted mortality rate – 50%
– With Xigris tx – 8%
• Reduced the need for amputations
Conclusions: What Every
Primary Care Physician Should
Know
• Indicated for use in patients with APACHE II
scores of 25 or more
• This drug is most effective in the elderly, those
with 2 or more dysfunctional organs, and those
who receive Xigris while in shock
• Clinicians should remember that earlier treatment
is better than later treatment
• Xigris may be safely used in the high-risk
populations discussed
Recommendations for Pediatric
Use
• Should only be used off-label when there’s
a threat to life or limb
• Risks/benefits must carefully be weighed
• Should never be used off-label in children
less than 2 months of age
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