Transcript Severe Sepsis

Definitions, Epidemiology,
Pathophysiology and
Treatment of Severe Sepsis
1
Severe Sepsis:
A Significant Healthcare Challenge
• Major cause of morbidity and mortality worldwide
— Leading cause of death in noncoronary ICU (US)1
— 11th leading cause of death overall (US)2*
• More than 750,000 cases of severe sepsis
in the US annually3
• In the US, more than 500 patients die
of severe sepsis daily3†
* Based on data for septicemia
†Reflects hospital-wide cases of severe sepsis as defined by infection in the presence of organ dysfunction
1Sands
KE, et al. JAMA 1997;278:234-40.
SL. National Vital Statistics Reports. 1998.
3Angus DC, et al. Crit Care Med 2001;29:1303-10.
2Murphy
2
Sepsis:
ACCP/SCCM Definitions
• Infection
— Inflammatory response to microorganisms, or
— Invasion of normally sterile tissues
• Systemic Inflammatory Response Syndrome (SIRS)
— Core temperature >38C or <36C (>100.4F or <96.8F)
— Elevated heart rate (>90 beats/min)
— Respiratory rate >20 breaths/min or PaCO2 <32 mm Hg or
mechanical ventilation for acute respiratory process
— WBC count >12,000 cells/mm3 or <4,000 cells/mm3 or >10%
immature neutrophils
Bone RC, et al. Chest 1992;101:1644-55.
3
Sepsis:
ACCP/SCCM Definitions (cont)
• Sepsis
— Known or suspected infection, plus
— 2 SIRS criteria
• Severe Sepsis
— Sepsis plus 1 organ dysfunction
— Multiple Organ Dysfunction Syndrome (MODS)
 Altered function of more than one organ in an acutely ill patient
 Homeostasis cannot be maintained without intervention
— Septic Shock
 Sepsis
 Hypotension despite fluid resuscitation
 Perfusion abnormalities
Bone RC, et al. Chest 1992;101:1644-55.
4
Relationship of Infection, SIRS, Sepsis and
Severe Sepsis
Other
Pancreatitis
INFECTION
SEVERE
SEPSIS
SIRS
Trauma
Burns
Adapted from: Bone RC, et al. Chest 1992;101:1644-55.
Opal SM, et al. Crit Care Med 2000;28:S81-2.
5
Severe Sepsis is Common*
Rate per
100,000 Population
300
Incidence
Mortality
250
200
150
100
50
0
Severe Sepsis†
Stroke
Breast Cancer
Lung Cancer
*Calculated data based on information compiled from the American Heart Association, American Cancer Society,
National Center for Health Statistics and the US Census Bureau (1995-1999)
† Severe sepsis mortality rates range from 28%-50% (79/100,000 to 141/100,000 population).
6
Severe Sepsis is Deadly
60
Mortality (%)
50%2
40
34%1
28%3
20
0
Sands KE, et al
Zeni F, et al
Angus DC, et al
1Sands
KE, et al. JAMA 1997;278:234-40.
F, et al. Crit Care Med 1997;1095-100.
3Angus DC, et al. Crit Care Med 2001;29:1303-10.
2Zeni
7
Severe Sepsis is Increasing in Incidence
600
Severe Sepsis Cases
US Population
1,600
500
1,400
1,200
400
1,000
300
800
2001
2025
Total US Population (million)
Sepsis Cases (x103)
1,800
2050
Year
Angus DC, et al. JAMA 2000;284:2762-70.
Angus DC, et al. Crit Care Med 2001;29:1303-10.
8
Severe Sepsis is a Significant
Healthcare Burden
• Sepsis consumes significant healthcare resources
• In a study of patients who contract nosocomial infections,
develop sepsis and survive1:
— ICU stay was prolonged by an additional 8 days
— Additional costs incurred were $40,890/patient
• Estimated annual direct and indirect healthcare costs due
to severe sepsis in the United States exceed $16 billion2
1Pittet
D, et al. JAMA 1994;271:1598-601.
DC, et al. Crit Care Med 2001;29:1303-10.
2Angus
9
Severe Sepsis is a Complex and
Unpredictable Clinical Syndrome
• High mortality rate
• Heterogeneous
patient population
• Unpredictable disease
progression
• Studies indicate that
severe sepsis has
inflammatory,
prothrombotic and
impaired fibrinolytic
components
Angus DC, et al. Crit Care Med 2001;29:1303-10.
Wheeler AP, et al. N Engl J Med 1999;340:207-14.
Systemic
Inflammation
Coagulation
Severe
Sepsis
Impaired
Fibrinolysis
10
Inflammation is Activated in Sepsis
14
IL-6 (U/mL)
10
8
6
4
2
0
0
60
120
180
240
300
360
TNF (ng/L)
Endotoxin (ng/L)
12
Minutes after LPS Infusion
Chart adapted from: van Deventer SJ, et al. Blood 1990;76:2520-6.
11
Spectrum of Coagulopathy in Severe Sepsis
Percent of Patients
100
80
60
40
20
0
 Platelets  PTT
 PT
Data from: Yan SB, et al. Chest 2001;120:915-22.
Any One Any Two All Three  Protein C  D-dimers
12
1.2
60
1.0
0.8
0.6
0.4
0.2
50
†
*
*
*
*
*P<.05 vs normal values
†P<.05 vs first day
PAI-1 (ng/mL)
Plasminogen/antiplasmin Ratio
Fibrinolysis is Impaired in Severe Sepsis
40
*
*
*
*
*
30
*
20
*P<.05 vs normal values
10
0
0.0
1
4
7
Time after Hospital Admission (day)
Survivors (n=23)
1
7
Time after Hospital Admission (day)
Nonsurvivors (n=25)
Data from: Lorente JA, et al. Chest 1993;103:1536-42.
4
Normal Values
13
Homeostasis is Unbalanced in Severe Sepsis
FIBRINOLYSIS
COAGULATION
INFLAMMATION
Homeostasis
Carvalho AC, Freeman NJ. J Crit Illness 1994;9:51-75.
Kidokoro A, et al. Shock 1996;5:223-8.
Vervloet MG, et al. Semin Thromb Hemost 1998;24:33-44.
14
Endothelial Dysfunction and
Microvascular Thrombosis
Hypoperfusion/Ischemia
Acute Organ Dysfunction
(Severe Sepsis)
Death
Identifying Acute Organ Dysfunction as a
Marker of Severe Sepsis
Altered
Consciousness
Confusion
Psychosis
Tachycardia
Hypotension
Altered CVP
Altered PAOP
Tachypnea
PaO2 <70 mm Hg
SaO2 <90%
PaO2/FiO2 300
Oliguria
Anuria
 Creatinine
Jaundice
 Enzymes
 Albumin
 PT
Balk RA. Crit Care Clin 2000;16:337-52.
 Platelets
 PT/APTT
 Protein C
 D-dimer
16
Severe Sepsis Therapy:
Conventional Care
•
•
•
•
•
Source control
Antibiotics
Hemodynamic support
Mechanical ventilation
Renal replacement therapy
Wheeler AP, Bernard GR. N Engl J Med 1999;340:207-14.
•
•
•
•
Sedation/analgesia
Adequate nutrition
Hematological support
Other supportive measures
17
Severe Sepsis Therapy:
Numerous Investigational Approaches
• Bacterial product modulators
— Antiendotoxin, bactericidal/permeability-increasing protein
• Anticytokines
— IL-1ra, anti-TNF, sTNF-r
• Antiinflammatory agents
— Glucocorticoids, leukocyte adhesion molecule inhibitors
• Hemostatic agents
— ATIII, TFPI
• Other mechanisms
— iNOS inhibition, antioxidants, thromboxane antagonists,
bradykinin receptor antagonists
Wheeler AP, Bernard GR. N Engl J Med 1999;340:207-14.
18
Conclusions:
Epidemiology, Pathophysiology and Conventional Therapy


Sepsis + acute organ dysfunction = severe sepsis
Severe sepsis is common, deadly and consumes
significant healthcare resources
— >750,000 cases/year in the United States
— Mortality of 28% to 50% despite conventional care
— In the United States, the costs of severe sepsis exceed
$16 billion

Severe sepsis is more than just inflammation
— Coagulopathy, evidenced by increased D-dimers and
decreased Protein C levels, is almost universal
— Patients have impaired fibrinolysis
19
Conclusions:
Epidemiology, Pathophysiology and Conventional Therapy (cont)

The origin of multiple organ dysfunction syndrome
(MODS) in severe sepsis is multifactorial in origin
but includes disordered hemostasis and endothelial
dysfunction

The development of interventions to reduce mortality in
life-threatening severe sepsis has remained an unmet
need until recently
20
The Role of Endogenous
Activated Protein C in
Severe Sepsis
21
The Protein C System
• The Protein C system is essential in restoring homeostasis
in patients with severe sepsis. Components include:
— Protein C: An inactive precursor of Activated Protein C
— Activated Protein C: An endogenous modulator with antithrombotic,
antiinflammatory and profibrinolytic properties
— Thrombomodulin: An endothelial cell protein. The thrombomodulin/thrombin
complex is required for activation of Protein C
— Protein S: A cofactor for endogenous Activated Protein C activity
22
The Role of Endogenous Activated Protein C
in Patients with Severe Sepsis
Tissue Factor
PAI-1
Prevention of activation
Inactivation
Monocyte
Factor Va
Inactivation
Activated
Protein C
THROMBIN
Neutrophil
Inhibition
Activated Protein C
Factor VIIIa
IL-6
IL-1
TNF-
Inhibition
Activated Protein C
COAGULATION
CASCADE
Endothelium
Inflammatory Response
to Infection
Suppressed
fibrinolysis
TAFI
Fibrin
IL-6
Tissue Factor
Inactivation
Activated Protein C
Thrombotic Response
to Infection
Fibrin clot
Fibrinolytic Response
to Infection
23
Endogenous Activated Protein C Restores
Homeostasis in Patients with Severe Sepsis
Activated Protein C
 COAGULATION
 INFLAMMATION
 FIBRINOLYSIS
Homeostasis
Carvalho AC, et al. J Crit Illness 1994;9:51-75.
Kidokoro A, et al. Shock 1996;5:223-8.
Vervloet MG, et al. Semin Thromb Hemost 1998;24:33-44.
24
Conclusions:
The Role of Endogenous Activated Protein C in Severe Sepsis


Endogenous Activated Protein C is a key element in the body’s
response to severe sepsis
Endogenous Activated Protein C has the following properties:
— Antiinflammatory
— Antithrombotic
— Profibrinolytic

In the presence of sepsis-associated endothelial dysfunction, the
body may be unable to convert significant amounts of
endogenous Protein C to Activated Protein C; consequently,
patients are unable to benefit from the properties of endogenous
Activated Protein C
25
The Development of
Drotrecogin Alfa (Activated)
26
Drotrecogin Alfa (Activated):
Indications
• Drotrecogin alfa (activated) is indicated for the reduction of
mortality in adult patients with severe sepsis (sepsis
associated with acute organ dysfunction) who have a high
risk of death (eg, as determined by APACHE II*)
• Efficacy has not been established in adult patients with
severe sepsis and lower risk of death. Safety and efficacy
have not been established in pediatric patients with
severe sepsis
* APACHE (Acute Physiology and Chronic Health Evaluation). For more information
on using the APACHE II scoring system, please see
http://www.sfar.org/scores2/scores2.html
See important safety information in this presentation.
27
Scientific Basis for the Development of
Recombinant Human Activated Protein C
• Severe sepsis is an inflammatory and prothrombotic
state with impaired fibrinolysis
• Endogenous Activated Protein C is a regulator of
inflammation, coagulation and fibrinolysis
• Levels of endogenous Protein C are low in patients
with severe sepsis and are associated with an
adverse outcome
• Sepsis is a complex syndrome that can lead to
acute organ dysfunction and death
• Sepsis exerts a significant clinical and economic burden
28
The Development of Drotrecogin
Alfa (Activated)
1960s: Antithrombotic activity of Activated Protein C identified
1980s: Human Protein C purified
1980s: Lilly commits to the development of recombinant human Activated
Protein C
1994: Phase 1 studies begin
1996-1998: Phase 2 trial
1998-2000: PROWESS trial
2000: Drotrecogin alfa (activated) designated as the generic name
2001: Xigris accepted as the proprietary name for drotrecogin alfa
(activated)
2001: Xigris approved for marketing by the US FDA
Xigris is a trademark of Eli Lilly and Company.
29
Drotrecogin Alfa (Activated):
Properties
• Recombinant form of human Activated Protein C
• Produced by an established human cell line
possessing the complementary DNA for the inactive
human Protein C zymogen
• May variably prolong the APTT
30
Conclusions:
The Development of Drotrecogin Alfa (Activated)
• Drotrecogin alfa (activated) is a recombinant form of
human Activated Protein C
• Derivation of the name:
— Cogin = family of coagulation inhibitors
— Alfa = first form of the recombinant molecule
— Activated = the molecule is the activated form of
recombinant human Protein C
31
The PROWESS
(Recombinant Human
Activated Protein C
Worldwide Evaluation in
Severe Sepsis) Trial:
Overview
32
PROWESS Study Description
Design
–
–
–
Randomized, double-blind, placebo-controlled trial of drotrecogin
alfa (activated)
164 sites in 11 countries
1690 patients (age 18-96 years)
Population—Severe Sepsis
–
–
–
Presence of a known or suspected infection
Evidence of a systemic response to the infection (3 or more SIRS criteria)
At least one sepsis-associated organ dysfunction of no longer
than 24 hours duration
Treatment Arms
–
–
All patients received conventional care (1:1 randomization)
1:1 randomization to drotrecogin alfa (activated) 24 µg/kg/hr or
placebo for 96 hours
Bernard GR, et al. N Engl J Med 2001;344:699-709.
33
Organ Dysfunction in the PROWESS
Clinical Trial
Respiratory
PaO2/FiO2 250 in the presence of other
dysfunctional organs/systems or 200
if lung dysfunction alone
Cardiovascular
Arterial systolic BP 90 mm Hg or
MAP 70 mm Hg for 1 hour despite
adequate fluid resuscitation, adequate
intravascular volume status or use of
vasopressors
Renal
Urine output <.5 mL/kg/hr
despite adequate fluid resuscitation
Hematologic
Platelets <80,000/mm3 or decreased by 50%
in preceding 3 days
Unexplained
metabolic acidosis
pH 7.3 or base deficit 5.0 mmol/L
associated with plasma lactate level
>1.5 times the upper limit of normal
Bernard GR, et al. N Engl J Med 2001;344:699-709.
34
PROWESS Study Design
24 hrs to meet inclusion
criteria and obtain consent
Start of study agent
infusion
Assessment of
28-day all-cause
mortality
Average time from first
acute organ
dysfunction to start of
drug was 17 hrs
Conventional Patient Care
24 hrs from meeting
inclusion criteria to
start of study agent
Bernard GR, et al. N Engl J Med 2001;344:699-709.
End of 96-hr infusion of study agent
35
Summary of PROWESS Main
Exclusion Criteria*
* Details
•
Platelet count <30,000/mm3
•
Certain medications associated with increased bleeding risk
(eg, therapeutic heparin, warfarin, thrombolytics, glycoprotein
IIb/IIIa inhibitors)
•
Increased risk of bleeding (eg, surgery within 12 hours, GI bleed
within 6 weeks, risk of CNS bleed, trauma patients at risk of
bleeding [significant contusion or injury to vascular organ],
portosystemic hypertension)
•
Moribund patients expected to die within 24 hours
•
Patients expected to die from comorbidities within 28 days
•
Pregnancy or breastfeeding
•
HIV positive, with most recent CD4 count ≤50/mm3
•
Chronic dialysis
•
Bone marrow, lung, liver, pancreas or small-bowel transplant
of additional exclusion criteria not presented on the slide are specified in the reference article.
Bernard GR, et al. N Engl J Med 2001;344:699-709.
36
PROWESS Study Stopped for Efficacy by
Independent DSMB at 2nd Interim Analysis
Interim 1
October 1999
Stage 1
Stage 2
Placebo
n=380
n=380
Drotrecogin alfa
(activated)
n=380
n=380
Interim 2
June 2000
Number of patients
Efficacy stopping
rules
Bernard GR, et al. New Engl J Med 2001;344:699-709.
n=760
n=1520
N=1728
P≤.0002
P≤.0118
July 26, 2000
last patient visit
37
Patient Disposition in PROWESS
Placebo
N=1728
patients enrolled
n=857
randomized
n=17
not treated
Drotrecogin alfa
(activated)
n=871
randomized
n=21
not treated
n=840 treated
n=850 treated
n=840 completed
protocol
n=850 completed
protocol
Bernard GR, et al. N Engl J Med 2001;344:699-709.
38
PROWESS Demographics Were
Well Balanced
Placebo
n=840 (%)
Drotrecogin alfa
(activated)
n=850 (%)
Total
N=1690 (%)
Mean age (years)
60.6
60.5
60.5
Mean weight (kg)
75.0
74.8
74.9
353 (42.0)
487 (58.0)
373 (43.9)
477 (56.1)
726 (43.0)
964 (57.0)
689 (82.0)
151 (18.0)
695 (81.8)
155 (18.2)
1384 (81.9)
306 (18.1)
Gender
Male
Female
Racial origin
Caucasian
Non-Caucasian
Bernard GR, et al. N Engl J Med 2001;344:699-709.
39
Common Sources of Infection in PROWESS
Placebo
n=840 (%)
Drotrecogin alfa
(activated)
n=850 (%)
Lung
450 (53.6)
456 (53.6)
906 (53.6)
Intra-abdominal
167 (19.9)
170 (20.0)
337 (19.9)
86 (10.2)
85 (10.0)
171 (10.1)
137 (16.3)
139 (16.4)
276 (16.3)
Urinary tract
Other*
Total
N=1690 (%)
*Includes blood, skin, central nervous system, cardiovascular system,
reproductive system, bones and joints, etc.
Bernard GR, et al. N Engl J Med 2001;344:699-709.
40
Type of Infection and Gram Stain Class
in PROWESS
Placebo
n=840 (%)
At least one positive
bacterial culture1
At least one positive
blood culture2
Fungal (+ culture)1
Drotrecogin alfa
(activated)
n=850 (%)
Total
N=1690 (%)
567 (67.5)
562 (66.1)
1129 (66.8)
273 (32.5)
278 (32.7)
551 (32.6)
64 (7.6)
72 (8.5)
136 (8.0)
Type of Gram Stain Class of Bacterial Pathogen2
Pure Gram +
211 (25.1)
219 (25.8)
430 (25.4)
Pure Gram -
196 (23.3)
185 (21.8)
381 (22.5)
Mixed Gram
117 (13.9)
133 (15.6)
250 (14.8)
Other*
316 (37.6)
313 (36.8)
629 (37.2)
*Includes
1Data
unconfirmed, culture negative or not obtained
on file, Eli Lilly and Company
GR, et al. N Engl J Med 2001;344:699-709.
2Bernard
41
PROWESS Patients Were Evenly Distributed
by APACHE II Score at Study Entry
Placebo
n=840 (%)
Drotrecogin alfa
(activated)
n=850 (%)
Total
N=1690 (%)
Preinfusion APACHE II Score1
Mean
24.95
24.58
24.77
Range
3 - 50
5 - 53
3 - 53
218 (25.6)
218 (25.6)
204 (24.0)
210 (24.7)
433 (25.6)
440 (26.0)
366 (21.7)
451 (26.7)
Preinfusion APACHE II Quartile2
1st
2nd
3rd
4th
1Bernard
2Data
215 (25.6)
222 (26.4)
162 (19.3)
241 (28.7)
GR, et al. N Engl J Med 2001;344:699-709.
on file, Eli Lilly and Company
42
PROWESS Patients Were Evenly Distributed
by Number of Dysfunctional Organ Systems
Placebo
n=840 (%)
Drotrecogin alfa
(activated)
n=850 (%)
Total
N=1690 (%)
Number of Organ Failure Entry Criteria Met
0
0 (0)
1 (0.1)
1 (0.1)
1
203 (24.2)
215 (25.3)
418 (24.7)
2
3
4
5
273 (32.5)
218 (26.0)
116 (13.8)
30 (3.6)
270 (31.8)
214 (25.2)
119 (14.0)
31 (3.6)
543 (32.1)
432 (25.6)
235 (13.9)
61 (3.6)
Bernard GR, et al. N Engl J Med 2001;344:699-709.
43
Most PROWESS Subjects Had
Sepsis-Induced Coagulopathy
Biomarkers
Normal Range
% Patients Abnormal
Procoagulant Activity
D-dimer (mg/L)
TAT* (µg/L)
FI.2† (nmol/L)
Anticoagulant Activity
Protein C activity
Protein S activity
AT-III activity
0 - .39
1.0 - 4.1
.44 - 1.10
99.7‡
95.5‡
77.5‡
81 - 173%
60 - 155%
80 - 120%
87.6§
77.8§
81.7§
* TAT = Thrombin-antithrombin complex
† F1.2 = Prothrombin fragment 1.2
‡ Percentage of patients with values higher than the upper limit of normal
§ Percentage of patients with values lower than the lower limit of normal
Data on file, Eli Lilly and Company
44
Inflammation and Microvascular Dysfunction
Were Very Common in PROWESS
Biomarkers
Global Coagulation Tests
Platelet count (mm3)
PT (s)
APTT (s)
Proinflammatory Marker
IL-6 (pg/mL)
Endothelial Dysfunction
sTM (ng/mL)
Antifibrinolytic Activity
PAI-1 activity (AU/mL)
Normal Range
% Patients Abnormal
140 - 400 x103
10.6 - 14.5
21 - 39
30.6†
93.4*
63.1*
.38 - 10.1
98.5*
18 - 53
72.0*
4 - 37.8
44.0*
* Percentage of patients with values higher than the upper limit of normal
† Percentage of patients with values lower than the lower limit of normal
Data on file, Eli Lilly and Company
45
Summary of Baseline Characteristics
in PROWESS
• Baseline characteristics for the two treatment groups
were similar
• In the overall PROWESS population:
— Pulmonary and intra-abdominal sources were the most common
sites of infection
— The types of infection were similar in both groups
— The population was homogenous with respect to evidence of
systemic inflammation and coagulopathy
Bernard GR, et al. N Engl J Med 2001;344:699-709.
46
The PROWESS
(Recombinant Human
Activated Protein C
Worldwide Evaluation in
Severe Sepsis) Trial:
Results
47
Drotrecogin Alfa (Activated) Significantly
Reduced Mortality in PROWESS
Primary Analysis Results
35
2-sided P-value .005
Adjusted relative risk reduction 19%
Mortality (%)
30
6% Absolute
reduction in
mortality
31%
25
25%
20
15
Placebo
(n=840)
10
Drotrecogin
alfa
(activated)
(n=850)
5
See important safety information in this presentation.
Bernard GR, et al. N Engl J Med 2001; 344:699-709.
48
Drotrecogin Alfa (Activated) Significantly
Reduced Mortality in PROWESS (cont)
Percent Survivors
100
90
Drotrecogin alfa (activated)
(n=850)
80
Placebo
(n=840)
6% Absolute
mortality
difference
70
P=.006 (stratified log-rank test)
0
0
7
14
21
28
Days from Start of Infusion to Death
See important safety information in this presentation.
Bernard GR, et al. N Engl J Med 2001;344:699-709.
49
Mortality Reduction by Gender and
Ethnic Origin in PROWESS
Overall
Male
Drotrecogin alfa
n
(activated) Placebo
964
24.3%
31.0%
Female
726
25.2%
30.6%
1384
24.5%
31.1%
306
25.8%
29.8%
Gender
Origin
Caucasian
Non-Caucasian
|
|
|
|
|
-50 -40 -30 -20 -10
|
|
0 10
|
20
Relative Risk (%)
See important safety information in this presentation.
Data on file, Eli Lilly and Company
50
Mortality Reduction by Infectious Agent
in PROWESS
Pure Gram +
Drotrecogin alfa
n
(activated) Placebo
430
22.8%
32.7%
Pure Gram -
381
24.3%
28.6%
Mixed
Gram +/-
250
21.8%
26.5%
556
25.6%
32.5%
Overall
No bacteria
isolated
|
|
|
|
|
|
|
|
|
-50 -40 -30 -20 -10 0 10 20 30
Relative Risk (%)
See important safety information in this presentation.
Data on file, Eli Lilly and Company
51
Mortality Reduction by Baseline APACHE II
Scores in PROWESS
Overall Population
N=1690
Absolute Reduction
in Mortality
Overall Population
6%
Relative Risk Reduction
in Mortality
19% (P=.005)
Baseline APACHE II Score*
Quartiles 3 & 4
13%
29%
Quartiles 1 & 2
0%
1%
* Of measures used, the APACHE II score was most
effective in classifying patients by risk of death and by
likelihood of benefit from drotrecogin alfa (activated).
See important safety information in this presentation.
52
Mortality Reduction by Number of
Dysfunctional Organs in PROWESS
Other important indicators of risk or severity also supported an
association between likelihood of drotrecogin alfa (activated)
benefit and risk of death.
Number of
Dysfunctional Organ
Systems at Baseline
Absolute Reduction
in Mortality
Relative Risk Reduction
in Mortality1
4
11%
22%
3
2
8%
5%
24%
20%
1
2%
8%
See important safety information in this presentation.
1Data
on file, Eli Lilly and Company
53
Mortality Reduction Regardless of Protein C
Level in PROWESS
• Mortality reductions were observed in patients with and without normal
Protein C levels
• There is no scientific basis to assay Protein C levels to determine
candidates for drotrecogin alfa (activated) therapy
Overall
Protein C
Drotrecogin alfa
n
(activated) Placebo
1379
25.7%
32.1%
195
15.6%
26.7%
Low levels
Normal levels
|
|
|
|
|
|
|
|
|
-50 -40 -30 -20 -10 0 10 20 30
Relative Risk (%)
See important safety information in this presentation.
Data on file, Eli Lilly and Company
54
Serious Bleeding Events in PROWESS by
Site of Hemorrhage: Study Drug Infusion Period
Drotrecogin alfa
(activated) n=850
Placebo n=840
Total Events
Total Events
Gastrointestinal
5
4
Intra-abdominal
2
3
Intra-thoracic
4
0
Retroperitoneal
3
0
Cerebral hemorrhage
2
0
Genitourinary
2
0
Skin/soft tissue
1
0
Other source*
1
1
20 (2.4%)
8 (1.0%)
Site of Hemorrhage
Total
*Event requiring 3 U packed RBCs/d for 2 consecutive days, but a site of bleeding could not be identified
See important safety information in this presentation.
55
Procedure-Related Bleeding Events in
PROWESS: 28-Day Study Period
Drotrecogin alfa (activated)
(n=850)
Site of Hemorrhage
Placebo
(n=840)
Total Events
Procedure-Related
Total Events
Procedure-Related
Gastrointestinal
9
1
9
0
Intra-abdominal
3
3
4
0
Intra-thoracic
6
3
1
1
Retroperitoneal
4
4
0
0
Cerebral hemorrhage
2
0
1
0
Genitourinary
2
1
0
0
Skin/soft tissue
2
1
0
0
Other source*
2
2
2
2
30
15
17
3
Total
*Event requiring 3 U packed RBCs/d for 2 consecutive days, but a site of bleeding could not be identified
See important safety information in this presentation.
Data on File, Eli Lilly and Company
56
Safety Evaluations in PROWESS
• Incidence of serious bleeding events defined as:
— Any intracranial hemorrhage
— Any life-threatening bleed
— Bleeds that required 3 units of PRBC per day for
2 consecutive days
— Any bleeding event classified as serious by the investigator
•
•
•
•
Incidence of thrombotic events
Incidence of new infections
Immunogenicity: Anti-APC antibody formation
Other: Serious adverse events, organ function,
hematology and chemistry data, vital signs
See important safety information in this presentation.
Bernard GR, et al. N Engl J Med 2001;344:699-709.
57
Serious Bleeding Events in PROWESS
• Bleeding is the most common adverse reaction associated with drotrecogin
•
•
•
alfa (activated) therapy
In the Phase 3 study, serious bleeding events were observed during the
28-day study period in 3.5% of drotrecogin alfa (activated)-treated and 2.0%
of placebo-treated patients (P=.06)
The difference in serious bleeding occurred primarily during infusion
Serious bleeding events were primarily related to1:
— Trauma or instrumentation of blood vessel or a highly vascular organ
— Ulceration of gastrointestinal tract
• Non–procedure-related serious bleeding events were similar in both the
•
placebo and drotrecogin alfa (activated) groups1
The incidence of intracranial hemorrhage (ICH) was .2% for
drotrecogin alfa (activated)-treated and .1% for placebo-treated patients
See important safety information in this presentation.
1Data
on file, Eli Lilly and Company
58
Safety Results in PROWESS
• Similar incidence of thrombotic events
— Placebo 3.0%
— Drotrecogin alfa (activated) 2.0%
— (P=.20)
• Similar incidence of new infections
— Placebo 25.1%
— Drotrecogin alfa (activated) 25.5%
— (P=.85)
• No other safety concerns identified based on
— Serious adverse events
— Organ function
— Hematology and chemistry data
See important safety information in this presentation.
Bernard GR, et al. N Engl J Med 2001;344:699-709.
59
Drotrecogin Alfa (Activated):
Potential Mechanisms of Action in PROWESS*
• Antiinflammatory
— Decrease IL-6 levels
• Antithrombotic
— Decrease D-dimers
• Profibrinolytic
— Decrease PAI-1 activity
* The specific mechanisms by which drotrecogin alfa (activated)
exerts its effect on survival in patients with severe sepsis are not
completely understood.
See important safety information in this presentation.
60
Drotrecogin Alfa (Activated) is
Antiinflammatory: Effects on IL-6 in PROWESS
Median IL-6, pg/mL
600
Drotrecogin alfa (activated)
Placebo
500
400
300
200
100
0
PRE
1
2
3
4
5
6
7
Infusion Period
The specific mechanisms by which drotrecogin alfa (activated) exerts its effect
on survival in patients with severe sepsis are not completely understood.
See important safety information in this presentation.
Data on file, Eli Lilly and Company
61
Drotrecogin Alfa (Activated) is
Antiinflammatory: Effects on IL-6 in PROWESS (cont)
Drotrecogin alfa (activated)
Placebo
Change from Baseline
0
-100
*
*P<.05
-200
*
-300
*
*
*
6
7
-400
-500
PRE
1
2
3
4
5
Infusion Period
The specific mechanisms by which drotrecogin alfa (activated) exerts its effect
on survival in patients with severe sepsis are not completely understood.
See important safety information in this presentation.
Data on file, Eli Lilly and Company
62
Drotrecogin Alfa (Activated) is Antithrombotic:
Effects on D-dimer in PROWESS
Median D-dimer µg/mL
5
Drotrecogin alfa (activated)
Placebo
*P<.05
4
*
*
3
*
*
*
3
4
*
*
2
PRE
1
2
5
6
7
Infusion Period
The specific mechanisms by which drotrecogin alfa (activated) exerts its effect
on survival in patients with severe sepsis are not completely understood.
Data on file, Eli Lilly and Company
See important safety information in this presentation.
63
PROWESS Conclusions
• The study groups at baseline were well matched and
representative of a diverse severe sepsis population
• Drotrecogin alfa (activated) produced a highly significant
reduction in mortality vs placebo (25% vs 31%, P=.006)
• No substantial differences in drotrecogin alfa (activated)
treatment effect were observed in sub-groups defined by
gender, ethnic origin, infectious agent or Protein C level
• Adverse events associated with drotrecogin alfa (activated)
treatment were limited to bleeding and the majority of them
were manageable
See important safety information in this presentation.
Bernard GR, et al. N Engl J Med 2001;344:699-709.
64
Drotrecogin Alfa (Activated)
Administration Guidelines
and Safety
65
Drotrecogin Alfa (Activated):
Administration
• Supplied as a sterile, lyophilized powder in 5 mg and 20 mg vials
• Administer intravenously at the infusion rate of 24 µg/kg of actual
body weight/hr for a total duration of 96 hours
• Administer through a dedicated line or a single lumen of a
multilumen catheter
• The ONLY other solutions that can be administered through the
same line are 0.9% Sodium Chlorine Injection, Lactated Ringer’s
Injection, Dextrose, or Dextrose and Saline mixtures
• Dose escalation or bolus doses are not recommended
66
Drotrecogin Alfa (Activated):
Contraindications
• Drotrecogin alfa (activated) increases the risk of bleeding. Drotrecogin
alfa (activated) is contraindicated in patients with the following clinical
situations in which bleeding could be associated with a high risk of
death or significant morbidity:
—
—
—
—
—
—
Active internal bleeding
Recent (within 3 months) hemorrhagic stroke
Recent (within 2 months) intracranial or intraspinal surgery, or severe head trauma
Trauma with increased risk of life-threatening bleeding
Presence of an epidural catheter
Intracranial neoplasm or mass lesion or evidence of cerebral herniation
• Drotrecogin alfa (activated) is contraindicated in patients with known
hypersensitivity to drotrecogin alfa (activated) or any component of
this product
Please refer to complete prescribing information available at presentation.
67
Drotrecogin Alfa (Activated):
Warnings
• Bleeding is the most common serious adverse effect associated with
drotrecogin alfa (activated) therapy. Each patient being considered
for therapy with drotrecogin alfa (activated) should be carefully
evaluated and anticipated benefits weighed against potential risks
associated with therapy
• Certain conditions, many of which led to exclusion from the Phase 3
trial, are likely to increase the risk of bleeding with drotrecogin alfa
(activated) therapy
Please refer to complete prescribing information available at presentation.
68
Drotrecogin Alfa (Activated):
Warnings (cont)
• For patients with severe sepsis who have one or more of the
following conditions, the increased risk of bleeding should be
carefully considered when deciding whether to use drotrecogin
alfa (activated) therapy:
— Concurrent therapeutic heparin (15 units/kg/hr)
— Platelet count 30,000 x 106/L, even if the platelet count is
increased after transfusions
— Prothrombin time-INR 3.0
— Recent (within 6 weeks) gastrointestinal bleeding
— Recent administration (within 3 days) of thrombolytic therapy
— Recent administration (within 7 days) of oral anticoagulants or
glycoprotein IIb/IIIa inhibitors
Please refer to complete prescribing information available at presentation.
69
Drotrecogin Alfa (Activated):
Warnings (cont)
— Recent administration (within 7 days) of aspirin >650 mg/d or
other platelet inhibitors
— Recent (within 3 months) ischemic stroke
— Intracranial arteriovenous malformation or aneurysm
— Known bleeding diathesis
— Chronic severe hepatic disease
— Any other condition in which bleeding constitutes a significant
hazard or would be particularly difficult to manage because of
its location
Please refer to complete prescribing information available at presentation.
70
Drotrecogin Alfa (Activated):
Warnings (cont)
• Bleeding is the most common adverse event associated
with drotrecogin alfa (activated) therapy
• During the 28-day Phase 3 study
— Serious bleeding events were observed during the study
period in 3.5% of drotrecogin alfa (activated)-treated patients
and 2.0% of placebo-treated patients
— The difference in serious bleeding occurred primarily during
infusion
— The incidence of intracranial hemorrhage (ICH) was .2% for
drotrecogin alfa (activated)-treated and .1% for placebotreated patients
Please refer to complete prescribing information available at presentation.
71
Drotrecogin Alfa (Activated):
Warnings (cont)
• ICH has been reported in drotrecogin alfa (activated)treated patients in non–placebo-controlled trials with an
incidence of approximately 1% during infusion
• The risk of ICH may be increased in patients with risk
factors for bleeding such as severe coagulopathy and
severe thrombocytopenia
• Should clinically important bleeding occur, immediately stop
the drotrecogin alfa (activated) infusion
Please refer to complete prescribing information available at presentation.
72
Management of Bleeding Risks Associated with
Drotrecogin Alfa (Activated)
• In the event of clinically important bleeding:
— Immediately stop infusion of drotrecogin alfa (activated)
— Continued use of other agents affecting the coagulation system should
be carefully assessed
— Once adequate hemostasis has been achieved, continued use of
drotrecogin alfa (activated) may be reconsidered
• Discontinue drotrecogin alfa (activated) 2 hours prior to
undergoing an invasive surgical procedure or procedures
with an inherent risk of bleeding
• Once adequate hemostasis has been achieved, initiation
of drotrecogin alfa (activated) may be:
— Reconsidered 12 hours after major invasive procedures or surgery
— Restarted immediately after uncomplicated, less invasive procedures
Please refer to complete prescribing information available at presentation.
73
Reimbursement Issues in
the Patient with
Severe Sepsis
74
Septicemia:
Definition
• A systemic disease associated with the presence and
persistence of pathogenic microorganisms or their toxins
in the blood
• Includes symptoms such as increased or decreased
temperature, tachypnea, tachycardia and impaired
organ perfusion
Linde-Zwirble WT, et al. Value in Health 2001;4:2:61.
Jones MK. Illustrated ICD-9-CM Code Book.
75
Confusion Between Septicemia and
Severe Sepsis
Problem: Use of septicemia codes as identifiers of
severe sepsis
Number of Cases
Mortality
Cost
Septicemia without
severe sepsis
7927
14.4%
$ 18,381
Severe sepsis
without septicemia
21,655
23.1%
$ 24,396
9970
42.1%
$ 33,470
39,552
26.1%
$ 25,478
Severe sepsis
with septicemia
Overall
Linde-Zwirble WT, et al. Value in Health 2001;2:61.
76
Septicemia/Severe Sepsis Sensitivity Analysis
• Sensitivity of septicemia as a predictor of severe sepsis
— 29.6%
• Positive predictive value of septicemia as a predictor of
severe sepsis
— 30.0%
• Conclusion: Septicemia codes are not accurate for
identifying patients with severe sepsis
Linde-Zwirble WT, et al. Value in Health 2001;2:61.
77
Severe Sepsis Reimbursement
• DRG - Diagnosis Related Groups (DRGs) are used by
Medicare and some private insurers. Each DRG represents
clinically similar patients based on average resource
intensity during acute inpatient hospitalization
• ICD-9-CM - International Classification of Diseases, 9th
edition, includes codes for both diagnoses and certain
procedures
• Severe sepsis occurs in 392 of the possible 511 DRGs
Data on file, Eli Lilly and Company
78
Conclusions
79
Conclusions
• Sepsis + acute organ dysfunction = severe sepsis
• Severe sepsis is a common, deadly disorder that
consumes significant healthcare resources and is increasing
in incidence
• Severe sepsis is a complex syndrome with inflammatory,
prothrombotic and impaired fibrinolytic components
• Until recently, development of interventions to reduce mortality
in life-threatening severe sepsis has been an unmet need
• Endogenous Activated Protein C has multiple mechanisms of
action including:
— Modulation of the inflammatory response
— Antithrombosis
— Profibrinolysis
80
Conclusions (cont)
• Drotrecogin alfa (activated) = Xigris = recombinant human Activated
Protein C
• The results of a Phase 3 trial of drotrecogin alfa (activated)
(PROWESS) indicated the following:
— No substantial differences in drotrecogin alfa (activated) treatment effect
were observed in subgroups defined by gender, ethnic origin, infectious
agent or Protein C level
— Drotrecogin alfa (activated) significantly reduced mortality as compared to
placebo (25% vs 31%, P=.006)
— Adverse events associated with drotrecogin alfa activated therapy were
limited to bleeding and the majority of them were manageable
— Conditions and therapies associated with hemorrhagic complications
increase the risk of drotrecogin alfa (activated)-related bleeding
See important safety information in this presentation.
81
Xigris is a trademark of Eli Lilly and Company
DR. 22250 3000000500 01021
Copyright © 2002, Eli Lilly and Company. All rights reserved.