Download Efficacy and Safety of Tifacogin (Recombinant Tissue Factor

CARING FOR THE
CRITICALLY ILL PATIENT
Efficacy and Safety of Tifacogin
(Recombinant Tissue Factor
Pathway Inhibitor) in Severe Sepsis
A Randomized Controlled Trial
Edward Abraham, MD; Konrad
Reinhart, MD; Steven Opal, MD;
Ignace Demeyer, MD; Christopher
Doig, MD, MSc; Angel López
Rodriguez, MD; Richard Beale, MD;
Petr Svoboda, MD, PhD; Pierre
Francois Laterre, MD; Stuart Simon,
MD; Bruce Light, MD; Herbert
Spapen, MD; Judy Stone, MD; Allan
Seibert, MD; Claus Peckelsen, MD;
Cathy De Deyne, MD; Russell
Postier, MD; Ville Pettilä, MD;
Charles L. Sprung, MD; Antonio
Artigas, MD; Sandra R. Percell, PhD;
Vincent Shu, PhD; Christian
Zwingelstein, PharmD; Jeffrey
Tobias, MD; Lona Poole, MD;
James C. Stolzenbach, PhD;
Abla A. Creasey, PhD;
for the OPTIMIST Trial Study Group
S
YSTEMIC ACTIVATION OF COAGU-
lation and thrombus formation in the microvasculature accompanies organ dysfunction
and excess mortality in severe sepsis.1
Tissue factor (thromboplastin) is a major initiator of the blood coagulation
process.2 Tissue factor is a transmembrane cell surface receptor for plasma
clotting factor VII and exhibits homolFor editorial comment see p 256.
238
Context The expression and release of tissue factor is a major trigger for the activation of coagulation in patients with sepsis. Tissue factor pathway inhibitor (TFPI)
forms a complex with tissue factor and blood protease factors leading to inhibition of
thrombin generation and fibrin formation.
Objectives To determine if administration of tifacogin (recombinant TFPI) provides mortality benefit in patients with severe sepsis and elevated international normalized ratio (INR) and to assess tifacogin safety in severe sepsis, including patients
with low INR.
Design and Setting A randomized, double-blind, placebo-controlled, multicenter,
phase 3 clinical trial conducted from March 21, 2000, through September 27, 2001,
in 245 hospitals in 17 countries in North America, Europe, and Israel.
Patients The primary efficacy population consisted of 1754 patients (ⱖ18 years) with
severe sepsis and a high INR (ⱖ1.2) randomly assigned to intravenous infusion of either tifacogin (0.025 mg/kg per hour for 96 hours, n=880) or placebo (arginine citrate buffer, n=874), and 201 patients with a low INR (⬍1.2) randomly assigned to
receive the same dose of either tifacogin or placebo.
Main Outcome Measure All-cause 28-day mortality.
Results Overall mortality at 28 days in the tifacogin-treated group (n=880) vs the
placebo group (n=874) for high INR was 34.2% vs 33.9%, respectively (P=.88, Pearson ␹2 test; P=.75, logistic regression model). None of the protocol-specified secondary end points differed between the tifacogin vs placebo groups. An analysis on the
first 722 patients demonstrated a mortality rate of 38.9% for placebo vs 29.1% for
tifacogin (P=.006, Pearson ␹2 test). Tifacogin significantly attenuated prothrombin fragment 1.2 and thrombin:antithrombin complex levels (P⬍.001, 2-sample t test) in patients with high and low INR. Overall mortality was lower in the tifacogin response in
patients with low INR (12%; n=83) vs placebo (22.9%; n=118) (P=.051, Pearson ␹2
test; P=.03, logistic regression model). There was an increase in serious adverse events
with bleeding in the tifacogin group in both cohorts (6.5% tifacogin and 4.8% placebo for high INR; 6.0% tifacogin and 3.3% placebo for low INR).
Conclusions Treatment with tifacogin had no effect on all-cause mortality in patients with severe sepsis and high INR. Tifacogin administration was associated with
an increase in risk of bleeding, irrespective of baseline INR.
www.jama.com
JAMA. 2003;290:238-247
Author Affiliations, Financial Disclosure, and the
OPTIMIST Study Group are listed at the end of this
article.
Corresponding Author and Reprints: Edward Abraham, MD, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, 4200 E Ninth Ave, Campus Box C-272,
JAMA, July 9, 2003—Vol 290, No. 2 (Reprinted)
Denver, CO 80262 (e-mail: edward.abraham@uchsc
.edu).
Caring for the Critically Ill Patient Section Editor: Deborah J. Cook, MD, Consulting Editor, JAMA.
Advisory Board: David Bihari, MD; Christian BrunBuisson, MD; Timothy Evans, MD; John Heffner, MD;
Norman Paradis, MD; Adrienne Randolph, MD.
©2003 American Medical Association. All rights reserved.
EFFICACY AND SAFETY OF TIFACOGIN IN SEVERE SEPSIS
ogy with the cytokine-receptor family.3 Tissue factor pathway inhibitor
(TFPI) is an endogenous serine protease inhibitor, synthesized and secreted by endothelial cells, which inhibits factor Xa directly and the factor
VIIa/tissue factor catalytic complex in
a Xa dependent fashion.4,5 A significant portion of endogenous TFPI is
bound to the microvasculature through
low-affinity binding to glycosaminoglycans. This pool of TFPI is releasable into
the circulation by exposure to heparin. A small pool of TFPI is stored in
platelets and secreted on activation and
degranulation. The majority of circulating TFPI is bound to lipoproteins.5
The circulating concentrations of TFPI
vary widely in healthy volunteers and
in patients with sepsis.6 A study by
Shimura et al 7 suggested that fulllength TFPI was consumed in predisseminated intravascular coagulation
conditions and that the truncated form
of TFPI-antigen increased in patients
with disseminated intravascular coagulation. The functional properties of circulating TFPI are not well delineated.
Endothelial damage is common in severe sepsis, as shown by elevations in
endothelial derived factors, such as von
Willebrand factor, and by the presence of coagulation abnormalities, including prolongation of prothrombin
time, in more than 90% of patients who
are severely ill and infected.8 It is hypothesized that in patients with severe sepsis, TFPI may protect the microvasculature endothelium from
coagulation and sepsis-induced injury. This hypothesis is supported by
several preclinical studies in which exogenous TFPI expressed in mammalian cells and/or Escherichia coli improved outcome in septic animals.9-11
The safety and bioactivity of tifacogin (recombinant TFPI) has been previously evaluated in healthy volunteers and in patients with sepsis.
Tifacogin was found to be well tolerated with no clinically significant bleeding in healthy volunteers when administered as an infusion in doses of 0.5 to
1.8 mg/kg per hour for 72 hours.6 Phase
2 studies indicated that patients with
severe sepsis were more sensitive to the
anticoagulant action of TFPI than
healthy volunteers.12 Tifacogin has been
tested in 3 phase 2 studies.12,13 The most
recent phase 2 study was a randomized, multicentered, placebocontrolled, single-blind trial with dose
escalation in which 210 patients received a continuous infusion of either
placebo or tifacogin at 0.025 mg/kg per
hour or 0.05 mg/kg per hour for 96
hours.13 The findings of that study established the safety, tolerability, and
bioactivity of tifacogin in patients with
severe sepsis and suggested a possible
interaction between treatment and international normalized ratio (INR) by
logistic regression modeling. The objectives of the current phase 3 study was
to evaluate the safety and efficacy of tifacogin in patients with severe sepsis
with high INR (ⱖ1.2), and to evaluate
the safety of tifacogin in patients with
severe sepsis with low INR (⬍1.2).
Patient Characteristics
METHODS
The optimized phase 3 tifacogin in multicenter international sepsis trial
(OPTIMIST) study was a randomized,
double-blind, placebo-controlled trial,
with 245 contributing centers in 17 countries in North America, Europe, and
Israel. The institutional review boards at
each center approved the study. Randomization to the active study drug (tifacogin) and to a placebo group occurred
in a 1:1 fashion. The trial was performed in 2 stages: stage 1 recruited
patients with high INR only with severe
sepsis from March 21, 2000, through September 27, 2001, and stage 2 continued
to enroll patients with high INR and initiated the recruitment of patients with low
INR, which began January 19, 2001, and
ended September 27, 2001.
An independent, unblinded data
management committee evaluated the
safety, futility, and efficacy of tifacogin during 4 formal prospectively defined interim analyses. The main safety
assessment was the comparison of the
incidence and severity of bleeding
events as identified by the investigator
and mortality between the tifacogin and
placebo groups.
Study Entry Criteria
©2003 American Medical Association. All rights reserved.
Adult hospitalized men and women
aged at least 18 years who met the entry criteria were enrolled in the study
if they gave informed consent, had at
least 2 signs of systemic inflammatory
response syndrome, and at least 2 signs
of organ dysfunction and/or hypoperfusion within 24 hours before the start
of drug infusion. In addition, the baseline INR was determined within 24
hours before the start of drug infusion. The initial signs of systemic inflammatory response syndrome were
allowed to have started or been intermittently present for more than 24
hours before drug infusion. The initial sign of organ dysfunction or hypoperfusion also was allowed to be present for more than 24 hours before the
start of drug infusion. The onset of the
second organ failure could not be present for more than 24 hours before the
initiation of drug administration.
Stage 1 entry criteria included patients with a baseline INR of at least 1.2
not attributable to medications or conditions other than severe sepsis. Infection status was determined by using
clinical signs of infection and documented by culture, gram stain, antigenic or nucleic acid assay of a body
fluid, or a chest radiograph consistent
with a diagnosis of pneumonia. These
criteria were used to support the rationale for systemic therapy with antiinfectives (antimicrobial agents) and to
provide a clear verifiable focus of infection. The patients also had to have
at least 2 signs of organ dysfunction
and/or hypoperfusion.
Study Medication
Tifacogin is produced in E coli and is
distinguished from endogenous TFPI
by an alanine at the N terminus and lack
of glycosylation.14 Patients were randomly assigned to receive 0.025 mg/kg
per hour of tifacogin (Chiron Corporation, Emeryville, Calif) as a continuous intravenous infusion for 96 hours
or an equivalent volume of placebo (arginine citrate buffer). Patients were pro-
(Reprinted) JAMA, July 9, 2003—Vol 290, No. 2 239
EFFICACY AND SAFETY OF TIFACOGIN IN SEVERE SEPSIS
Figure 1. Tissue Factor Pathway Inhibitor Trial Flow
19 514 Patients Assessed for Eligibility
17 527 Excluded
Did Not Meet Protocol Eligibility Criteria
1987 Patients Eligible
1987 Randomized
1781 Had INR ≥1.2
206 Had INR <1.2
889 Assigned to Receive
Placebo
866 Received
Placebo as
Assigned
1 Refused
Consent to
Use Data
9 Infused With ≥1
Vial Tifacogin
14 Not Infused
892 Assigned to Receive
Tifacogin
875 Received
Tifacogin as
Assigned
1 Refused
Consent to
Use Data
6 Infused With ≥1
Vial Placebo
11 Not Infused
121 Assigned to Receive
Placebo
117 Received
Placebo as
Assigned
1 Infused With ≥1
Vial Tifacogin
3 Not Infused
85 Assigned to Receive
Tifacogin
82 Received
Tifacogin as
Assigned
1 Infused With ≥1
Vial Placebo
2 Not Infused
1 Withdrew Consent∗
0 Lost to Follow-up
2 Withdrew Consent∗
0 Lost to Follow-up
0 Withdrew Consent∗
1 Lost to Follow-up
0 Withdrew Consent∗
0 Lost to Follow-up
579 Completed Study
579 Completed Study
90 Completed Study
73 Completed Study
874 Included in Primary
Efficacy Analysis
880 Included in Primary
Efficacy Analysis
118 Included in Secondary
Efficacy Analysis
83 Included in Secondary
Efficacy Analysis
INR indicates international normalized ratio. Per protocol, all infused patients were analyzed as randomized.
*Withdrew consent for study participation only; data were used in all analyses.
spectively randomized by using random block sizes of 2, 4, or 6 within each
center and INR cohort. The placebo and
tifacogin vials were packaged identically to maintain blinding.
plasma because rabbit plasma does not
contain TFPI, which cross reacts with
the monoclonal antibody. The lower
limit of quantitation was 5 ng/mL.
TFPI Levels
End Points, Monitoring,
and Enrollment
Blood samples for obtaining TFPI plasma
concentrations were collected preinfusion (–2 hours to time 0) on days 1 (4
and 8 hours), 2, and 3, as well as at termination of dosing. Pharmacokinetic
samples were measured with a validated electrochemiluminescent immunoassay by using monoclonal and polyclonal antibodies to TFPI. The
monoclonal antibody was specific for the
first Kunitz domain of TFPI. As a result, the assay measured endogenous
TFPI as well as the recombinant form
(tifacogin). The assay standards and
quality controls were diluted in rabbit
The primary efficacy end point was
death from any cause occurring within
the 28 days following the initiation of
drug infusion in patients with high INR
at the time of randomization. Patients
who received any amount of study drug
were included in the safety and efficacy analyses and were analyzed according to the treatment group to which
they were randomized.
An external data management committee assessed the safety, futility, and
efficacy of the trial at 4 prospectively
defined interim analyses. The data management committee recommended in-
240
JAMA, July 9, 2003—Vol 290, No. 2 (Reprinted)
cluding up to an additional 400 patients having a baseline INR of at least
1.2 to maintain the power of the trial
at 90% to detect a relative decrease in
mortality of 25%.
The planned enrollment for the trial
was 1550 patients: 1350 patients with
high INR and 200 patients with low INR
at the time of randomization. An additional 400 patients were enrolled to
maintain trial power, per the protocol. Consequently, 1987 patients were
enrolled into the trial (FIGURE 1). Of
these, 30 patients were randomized but
not subsequently infused with study
drug and 2 patients withdrew consent. A total of 1955 patients were therefore included in the primary and secondary efficacy and safety analyses:
1754 patients with high INR and 201
patients with low INR at the time of randomization.
Statistical Methods
The difference between the tifacogin
and placebo groups in 28-day allcause mortality was assessed by using
a prespecified logistic regression model
having factors for treatment group,
baseline Acute Physiology and Chronic
Health Evaluation (APACHE) II score,
and baseline log10 IL-6 (both covariates treated as continuous variables).
P values were computed for the Wald
␹2 statistic with respect to a ␹2 distribution with 1 degree of freedom. The
presence of treatment by covariate interaction effects was assessed separately. To explore the robustness of the
primary analysis, a simple Pearson ␹2
test comparing tifacogin with placebo
was also performed. Additionally,
Kaplan-Meier method curves illustrating the unadjusted difference between
the tifacogin and placebo groups in time
to death were produced.
Exploratory analyses to investigate the
association between baseline covariates
and 28-day all-cause mortality and to
identify treatment by covariate interactions were performed by using forwardstepwise logistic regression. Because
treatment groups were well balanced
with respect to prognostic baseline covariates, P values presented for these ex-
©2003 American Medical Association. All rights reserved.
EFFICACY AND SAFETY OF TIFACOGIN IN SEVERE SEPSIS
ploratory subgroup analyses were unadjusted and based on the simple Pearson
␹2 test. Likewise, unadjusted 28-day allcause mortality relative risks and the associated 95% confidence intervals were
calculated. All reported P values are
2-sided. SAS version 8.2 statistical software (SAS Institute, Cary, NC) was used
for all analyses, and Pⱕ.05 was considered significant.
Treatment differences in geometric
mean of prothrombin fragment 1.2 and
thrombin:antithrombin complex at baseline and in the geometric mean ratio of
prothrombin fragment 1.2 and thrombin:antithrombin complex at 6, 24, and
96 hours after baseline were compared
by using a simple 2-sample t test. The
mean log10 transformed prothrombin
fragment 1.2 and thrombin:antithrombin complex baseline values between the
tifacogin and the placebo groups were
compared by using a 2-sample t test as
well as the mean change from baseline
in log10 transformed prothrombin fragment 1.2 and thrombin:antithrombin
complex values between the tifacogin
and placebo groups.
RESULTS
Characteristics of
the Study Population
Details of study conduct, randomization, and resulting patient population
are shown in Figure 1. The study population consisted of 1955 adult patients
aged at least 18 years randomly distributed between 2 patient cohorts: patients with severe sepsis with high INR
or low INR. Within each cohort, patients were randomly assigned to the
placebo group or tifacogin group. All
patients were analyzed as randomized. The primary efficacy population
consisted of 1754 patients with high
INR randomly assigned to the placebo
group (n = 874) or tifacogin group
(n=880).
Patients were well matched at study
entry for age, sex, APACHE II score,
body weight, and race (T ABLE 1).
The most common sites of infection
were respiratory, followed by intraabdominal, genitourinary, skin and soft
tissue, and infections due to intravas-
Table 1. Patient Characteristics of Primary Efficacy Population (INR ⱖ1.2)*
Characteristics
Age, mean (SD), y
Placebo (n = 874)
62.3 (15.1)
Tifacogin (n = 880)
62.4 (15.2)
495 (57)
25.0 (7.2)
77.8 (19.9)
521 (59)
25.0 (7.1)
77.0 (19.0)
743 (85)
72 (8)
59 (7)
747 (85)
73 (8)
60 (7)
432 (49)
249 (28)
114 (13)
62 (7)
35 (4)
22 (3)
465 (53)
244 (28)
108 (12)
66 (8)
29 (3)
12 (1)
196 (22)
224 (26)
224 (26)
230 (26)
257 (29)
310 (35)
666 (76)
202 (23)
207 (24)
239 (27)
232 (26)
279 (32)
300 (34)
635 (72)
Sex, male
APACHE II score, mean (SD)
Body weight, mean (SD), kg
Race
White
Black
Other
Underlying site of infection†
Respiratory system
Intra-abdominal infection
Genitourinary infection
Skin and soft tissue
Intravascular device
Unknown
Culture results
Gram-negative
Gram-positive
Other/mixed
Negative/not done
Positive blood culture
Surgical‡
Shock at baseline
Abbreviations: APACHE, Acute Physiology and Chronic Health Evaluation; INR, international normalized ratio.
*Data are No. (%) unless otherwise specified.
†Patients may have more than 1 site of infection.
‡Defined in the analysis as having had a major surgical procedure requiring spinal or general anesthesia within 5 days
before drug infusion.
cular devices. The patients were similar at study entry with respect to culture results, surgical status (having had
a major surgical procedure requiring
spinal or general anesthesia within 5
days before drug infusion), and shock
at baseline.
TFPI Levels in Treatment Groups
The mean (SE) baseline TFPI level concentration in patients with high INR was
71 (1.5) ng/mL in the placebo group. Patients randomized to the tifacogin group
rapidly achieved mean circulating TFPI
levels that were approximately twice the
mean endogenous circulating levels observed in the placebo group (147 [16]
ng/mL). The increase in mean TFPI levels in the tifacogin group with high INR
was observed throughout the conduct
of the trial. A similar increase in mean
TFPI levels was also observed in patients with low INR. Mean baseline TFPI
levels in patients with low INR were
comparable with patients with high INR
(data not shown).
©2003 American Medical Association. All rights reserved.
Efficacy of Tifacogin in Patients
With High INR
The observed 28-day all-cause mortality for patients receiving tifacogin did
not significantly differ from the placebo group in the primary study population (34.2% for the tifacogin group vs
33.9% for the placebo group; P = .88,
Pearson ␹2 test; P=.75, logistic regression model). The Kaplan-Meier method
survival curves are shown in FIGURE 2A.
There was no difference in the mortality rate between the tifacogin and the
placebo groups in any of the prospectively defined study subpopulations
(TABLE 2).
A trend in favor of tifacogin was present for the first 9 months of enrollment into the trial, but was then reversed in favor of placebo in the last 7
months of enrollment. This finding is
demonstrated in the 3-month moving
average (FIGURE 3). The second interim analysis was performed on the
first 722 patients enrolled in the study.
At the time of that analysis, which was
(Reprinted) JAMA, July 9, 2003—Vol 290, No. 2 241
EFFICACY AND SAFETY OF TIFACOGIN IN SEVERE SEPSIS
and clinical studies5,10,11 have previously demonstrated that TFPI is a potent thrombin-generation inhibitor.
Therefore, differences in plasma levels
of prothrombin fragment 1.2 and thrombin:antithrombin complex in the placebo and tifacogin groups were assessed. The geometric mean (SE) ratio
of prothrombin fragment 1.2 and thrombin:antithrombin complex plasma levels during treatment (24 and 96 hours)
for the placebo group as a percentage of
baseline were 120 (5) at 24 hours and
157 (8) at 96 hours, and 87 (7) at 24
hours and 84 (8) at 96 hours, respectively. The geometric mean (SE) ratio of
prothrombin fragment 1.2 and thrombin:antithrombin complex plasma levels for the tifacogin group were 101 (5)
performed by the data management
committee, the mortality rate was 38.9%
in the placebo group and 29.1% in the
tifacogin group (P = .006, Pearson ␹2
test). However, a decrease in placebo
mortality and an increase in tifacogin
mortality were observed in the later part
of the study, leading to a complete reversal of the initial favorable results and
final neutral trial outcome.
Bioactivity of Tifacogin
Because there was no apparent survival
benefit in the primary efficacy population (patients with INR ⱖ1.2) and in the
prespecified subgroups, we investigated whether or not tifacogin exhibited in vivo bioactivity in the patients
who were treated. In vitro, preclinical,
Analysis of Tifacogin Response
in Patients With Low INR
Figure 2. Cumulative Proportion of 28-Day All-Cause Mortality of TFPI and Placebo for
Patients With High and Low INR
A INR ≥1.2
B INR <1.2
Cumulative Proportion
0.4
0.3
0.2
0.1
TFPI
Placebo
0
0
5
10
15
20
25
30
0
5
10
Days
15
20
25
Days
No. at Risk
TFPI 880
754
688
641
603
582
83
81
78
76
73
73
Placebo 874
764
701
646
612
588
118
111
103
97
93
91
TFPI indicates tissue factor pathway inhibitor; INR, international normalized ratio.
at 24 hours and 126 (7) at 96 hours, and
65 (5) at 24 hours and 60 (6) at 96
hours, respectively. Tifacogin treatment was associated with lower prothrombin fragment 1.2 and thrombin:
antithrombin complex levels at 24 and
96 hours postinitiation of treatment
(P⬍.001, 2-sample t test vs placebo).
This finding demonstrates that tifacogin exhibited biological activity in patients with severe sepsis. Similar decreases in thrombin:antithrombin
complex levels had been previously observed in the phase 2 clinical trial.13 Tifacogin administration also resulted in
decreased thrombin:antithrombin complex and prothrombin fragment 1.2 levels in patients with low INR (data not
shown).
30
Two hundred and one patients with low
INR were randomized and treated, of
which 118 received placebo and 83 received tifacogin. The Kaplan-Meier
method plot of survival during the 28day period is shown for both tifacogin
and placebo groups (Figure 2B). Overall, 28-day all-cause placebo mortality
was 22.9% compared with 12.0% for patients receiving tifacogin (P=.051, Pearson ␹2 test). A prespecified logistic
regression analysis was also performed, adjusting for treatment, baseline APACHE II score, and log10 IL-6
varia bles. The adjusted analysis dem-
Table 2. 28-Day Mortality Overall and in Prespecified Subpopulations
No. of Patients
28-Day Mortality Rate,
No. (%)
Placebo
874
Tifacogin
880
Placebo
296 (33.9)
Tifacogin
301 (34.2)
Relative Risk
(95% Confidence Interval)
1.01 (0.89-1.15)
Baseline INR ⱖ1.5 and coagulation
organ dysfunction score ⬍4
149
125
68 (45.6)
52 (41.6)
0.91 (0.69-1.20)
Baseline INR ⬍1.5 or coagulation
organ dysfunction score ⱖ4
Shock at baseline
No
Yes
Baseline APACHE II score
⬍20
ⱖ20
Baseline PaO2/FiO2 ratio ⬍300
Baseline PaO2/FiO2 ratio ⱖ300
724
753
228 (31.5)
248 (32.9)
1.05 (0.90-1.21)
208
666
245
635
62 (29.8)
234 (35.1)
70 (28.6)
231 (36.4)
0.96 (0.72-1.28)
1.04 (0.90-1.20)
207
665
767
107
188
689
752
127
45 (21.7)
249 (37.4)
264 (34.4)
32 (29.9)
33 (17.6)
267 (38.8)
263 (35.0)
38 (29.9)
0.81 (0.54-1.21)
1.03 (0.90-1.19)
1.02 (0.89-1.17)
1.00 (0.67-1.48)
Population
Primary efficacy (baseline INR ⱖ1.2)
Abbreviations: APACHE, Acute Physiology and Chronic Health Evaluation; INR, international normalized ratio.
242
JAMA, July 9, 2003—Vol 290, No. 2 (Reprinted)
©2003 American Medical Association. All rights reserved.
EFFICACY AND SAFETY OF TIFACOGIN IN SEVERE SEPSIS
Post-hoc Analyses of Factors
Contributing to the Primary Patient
Population Outcome
Because of the changes in the 28-day
mortality observed during the course
of the trial (Figure 3) and the observation that the findings from the tifacoginattenuated coagulation were abnormal in the patient populations with both
high and low INR (but only provided
a mortality benefit in patients with low
INR), post hoc analyses were conducted to identify confounding factors that could have contributed to the
final outcome of the study in the primary population with high INR.
Tifacogin Interaction With Heparin
in Patients With High and Low INR
In vitro and preclinical studies indicate that the third Kunitz domain and
C terminus of TFPI bind heparin with
low affinity.6,15 Similarly, heparin displaces TFPI from binding to glycosaminoglycans on the surface of endothelial cells.
Patients who received at least 1 dose
of unfractionated heparin or low molecular-weight heparin during the period beginning 24 hours before dosing
through the end of the dosing period
(heparin) were compared with patients who did not receive heparin during that time (no heparin). Mortality was
examined in patients with high INR and
low INR, stratified by heparin use. The
mortality of patients receiving tifacogin who did not receive heparin before
or during dosing was 34.6% compared
with 42.7% in the placebo group (P=.05)
(TABLE 3). In contrast, the mortality of
patients receiving tifacogin with high
INR who received heparin under similar conditions was 34.0%, although the
mortality rate was 29.8% for the placebo group. There was no increase in
bleeding or other nonsepsis-related serious adverse events in patients receiving tifacogin and heparin. Despite the
small numbers, improved survival was
observed in patients receiving tifacogin with low INR both with and with-
out concomitant heparin use, although
the improvement in outcome was more
apparent in patients receiving no heparin. Mortality was lower in patients receiving placebo and heparin compared
with those who did not. However, the
patients who received heparin were not
as severely ill as determined by APACHE
II scores, INR value, and mean organ
dysfunction score compared with patients who did not receive heparin (data
not shown).
Safety Findings in Patients
With High and Low INR
The incidence of investigatoridentified adverse events and serious
adverse events (those that were lifethreatening or prolonged hospitalization) in patients with high and low INR
was similar in both the tifacogin and
placebo groups (TABLE 4). The majority of patients experienced at least 1 adverse event during the 28-day trial period (INR ⱖ1.2: tifacogin group, 91%
and placebo group, 92%; INR ⬍1.2: tifacogin group, 94% and placebo group,
92%). Approximately half of the patients had at least 1 serious adverse
event (tifacogin group, 51%; placebo
group, 51%) in the high INR group.
Slightly fewer patients experienced at
least 1 serious adverse event in the low
INR group (tifacogin group, 36%; placebo group, 43%).
There was an increase in the incidence of adverse events with bleeding
in the tifacogin group compared with
the placebo group (INR ⱖ1.2: tifacogin group, 24% and placebo group,
19%; INR ⬍1.2: tifacogin group, 24%
and placebo group, 21%). The most
common events with bleeding were
from the gastrointestinal and respiratory tracts (data not shown).
There was an increase in the overall
incidence of serious adverse events with
bleeding in the tifacogin group (6.5%)
compared with the placebo group
(4.8%) for high INR. In patients with
low INR, serious adverse events with
bleeding occurred in 5 (6.0%) of 83 patients in the tifacogin group and 4
(3.3%) of 118 patients in the placebo
group. In the patients with high INR,
there were more events with bleeding
in the central nervous system (CNS) in
the tifacogin group (9 events) compared with the placebo group (3
events). In the patients with low INR,
there were 2 events with CNS bleedFigure 3. 3-Month Moving Average for
Mortality, TFPI vs Placebo
45
40
35
Mortality, %
onstrated significant benefit for the low
INR group (P=.03).
30
25
20
15
TFPI
10
Placebo
5
0
Jun
Aug
Oct
2000
Dec
Feb
Apr
Jun
2001
The mortality rate by 3-month moving average during the 14 months ( June 2000 to July 2001) of data
from the 17 months of trial enrollment for patients with
an international normalized ratio of at least 1.2. TFPI
indicates tissue factor pathway inhibitor.
Table 3. Mortality Rate by Heparin Use*
Heparin
No Heparin
Placebo
P
Tifacogin
Value†
Baseline INR ⱖ1.2
Placebo
Tifacogin
P
Value†
No. of patients
Mortality rate, No. (%)
600
179 (29.8)
600
204 (34.0)
274
117 (42.7)
280
97 (34.6)
.05
No. of patients
Mortality rate, No. (%)
81
16 (19.8)
37
11 (29.7)
18
2 (11.1)
.18
.12
Baseline INR ⬍1.2
65
8 (12.3)
.23
Abbreviation: INR, international normalized ratio.
*Patients receiving any heparin during the period beginning 24 hours before dosing through the end of the dosing
period (heparin); those patients who did not receive heparin during that time (no heparin).
†Comparing tifacogin with placebo from Pearson ␹ 21 test.
©2003 American Medical Association. All rights reserved.
(Reprinted) JAMA, July 9, 2003—Vol 290, No. 2 243
EFFICACY AND SAFETY OF TIFACOGIN IN SEVERE SEPSIS
ing in the tifacogin group and none in
the placebo group.
The ␤ half-life of tifacogin in the blood
is relatively short (8 hours); therefore,
tifacogin safety was best evaluated during dosing and up to 2 days after stopping the infusion. More than half of the
serious adverse events with bleeding in
patients with high INR occurred during dosing or within 2 days of stopping
the infusion in both the tifacogin and
placebo groups (tifacogin group, 34
[60%] of 57 events; placebo group, 22
[52%] of 42 events). During this period, 5 of the 9 events with CNS bleeding occurred in the tifacogin group and
no events occurred in the placebo group.
Six patients experienced a serious adverse event with bleeding during dosing or in the 2 days following the
completion of dosing in the group with
low INR (tifacogin group, 3.6% [3 of
83 patients]; placebo group, 2.5% [3 of
118 patients]). One patient receiving tifacogin experienced an event with CNS
bleeding within 2 days of dosing.
The administration of heparin at
baseline and/or during dosing did not
appear to increase the overall risk of
events with investigator-identified
bleeding or serious events with bleeding for either the tifacogin or the placebo groups (TABLE 5). The risk of
events with CNS bleeding in the high
INR group was not increased in patients receiving both tifacogin and heparin (6 [1%] of 600 patients) compared with those receiving tifacogin
alone (3 [1%] of 280 patients). The risk
of events with CNS bleeding in the low
Table 4. Summary of Patients With Adverse Events*
Baseline INR ⱖ1.2
Any adverse event
Any serious adverse event
Adverse event with bleeding
Serious adverse event
with bleeding
Bleeding in central
nervous system
Placebo
(n = 874)
802 (92)
443 (51)
168 (19)
42 (4.8)
3 (0.3)
Baseline INR ⬍1.2
Tifacogin
(n = 880)
801 (91)
447 (51)
215 (24)
57 (6.5)
P
Value†
.58
.96
.008
.13
9 (1)
.08
Placebo
(n = 118)
108 (92)
51 (43)
25 (21)
4 (3.3)
0
Tifacogin
(n = 83)
78 (94)
30 (36)
20 (24)
5 (6.0)
P
Value†
.52
.31
.63
.37
2 (2)
.09
Abbreviation: INR, international normalized ratio.
*Data are presented as No. (%).
†Comparing tifacogin with placebo from Pearson ␹ 21 test.
Table 5. Summary of Patients Experiencing Adverse Events With Bleeding and Serious
Adverse Events With Bleeding by Concomitant Heparin Use*
Heparin
No Heparin
P
Tifacogin
Value†
Baseline INR ⱖ1.2
600
600
114 (19)
138 (23)
.09
Placebo
No. of patients
Adverse event with
bleeding, No. (%)
Serious adverse event
with bleeding, No. (%)
No. of patients
Adverse event with
bleeding, No. (%)
Serious adverse event
with bleeding, No. (%)
29 (5)
81
16 (20)
2 (2)
39 (7)
.21
Baseline INR ⬍1.2
65
16 (25)
.48
5 (8)
.14
Placebo
Tifacogin
P
Value†
274
54 (20)
280
77 (28)
.03
13 (5)
18 (6)
.39
37
9 (24)
18
4 (22)
.86
2 (5)
0
.32
Abbreviation: INR, international normalized ratio.
*Patients receiving any heparin during the period beginning 24 hours before dosing through the end of the dosing
period (heparin); those patients who did not receive heparin during that time (no heparin).
†Comparing tifacogin with placebo from Pearson ␹21 test.
244
JAMA, July 9, 2003—Vol 290, No. 2 (Reprinted)
INR group also did not appear to increase in patients receiving heparin.
COMMENT
In this study, there was no survival benefit provided by tifacogin in the primary study population of patients with
severe sepsis with high INR. The change
in trial outcome after the enrollment of
more than 700 patients with high INR
is unusual and distinct from that observed in previous severe sepsis studies, including those examining 2 other
endogenous coagulation inhibitors.8,16 For example, a decrease in mortality rates among patients treated with
activated protein C was observed after
720 patients were enrolled during the
later stages of the recombinant human
activated protein C worldwide evaluation in severe sepsis (PROWESS)
trial.17 However, unlike this study, the
mortality rate in the placebo group of
the PROWESS trial was relatively constant throughout the duration of the
study. Large changes in mortality rates
over time were not observed in the Kybersept trial for either patients treated
with antithrombin III or the placebo
group (S. Opal, MD, written communication, March 5, 2003).
Several hypotheses were evaluated to
determine possible variables that could
account for the time-dependent changes
observed in the outcome of the current trial. Among the hypotheses evaluated were changes in study operational variables, changes in the enrolled
patient population, changes in standard of care, and changes in tifacogin
activity or toxicity. Although the recruitment at new sites and the simultaneous enrollment of patients with
high and low INR in the second stage
of the trial occurred at the same time
as the change in mortality rates in the
tifacogin and placebo groups, these operational issues did not explain the reversal in study outcome. An extensive
audit of clinical trial procedures excluded a process error (eg, randomization error) and confirmed that patients were correctly analyzed according
to the treatment received. The population pharmacokinetic data support the
©2003 American Medical Association. All rights reserved.
EFFICACY AND SAFETY OF TIFACOGIN IN SEVERE SEPSIS
randomization code. The TFPI levels
were consistent over time in the tifacogin group.
The possibility that the patient population enrolled in the current study
changed over time was also examined.
There were no detectable temporal
changes in the degree of disease severity. The mean APACHE II scores of the
patients receiving placebo enrolled in the
first stage of the study were 25.0 for the
tifacogin group and 25.1 for the placebo group, and those for the second
stage of the study were 25.0 and 24.8,
respectively. An increase in tifacogin levels was not observed in the placebo
group. Additionally, patient characteristics in this trial were examined by using the APACHE III database. Baseline
mortality risk by day 28 was well balanced between treatment groups and did
not change over time (W. A. Knaus, MD,
written communication, April 15, 2002).
Possible changes in the standard of
care and the adoption of emerging treatment modalities were also evaluated by
polling the clinical sites involved in the
study and by the review of the hospital records of the patients enrolled in
the study. There were no apparent
changes in patient management that
correlated with patient outcome. Although heparin appeared to be a confounding factor, changes in heparin use
did not explain the reversal in study
outcome.
The increase in mortality with tifacogin could have been the result of a decrease in tifacogin in vivo activity or an
increase in toxicity. This hypothesis was
not substantiated by the in vivo anticoagulant measures of tifacogin bioactivity, such as extent of decrease in thrombin:antithrombin complex, prothrombin
fragment 1.2, prolongation of INR, and
activated partial thromboplastin time.
There also was no evidence of decreased drug activity by in vitro parameters to match the increase in mortality
in the tifacogin group in the second stage
of the study. The tifacogin safety profile, measured by frequency of adverse
events and serious adverse events, was
similar in the first and second stage of
the trial. A change in tifacogin potency
or toxicity, if such an event occurred,
would only explain alterations in mortality for 1 group of the trial (ie, the tifacogin group) and would not address
the simultaneous decline in placebo
mortality observed in the second half of
the study.
Post hoc analyses suggested that
there was an interaction between heparin and tifacogin in which patients who
did not receive concomitant heparin appeared to benefit from treatment with
tifacogin. Interactions with heparin
were also observed in clinical trials with
2 other endogenous anticoagulants, activated protein C and antithrombin III.
Specifically, both the PROWESS and
Kybersept trials noted an apparent attenuation of activated protein C and antithrombin III efficacy in patients who
received heparin.16,18 The biological basis for this interaction is more evident
for antithrombin III, which is a cofactor of heparin, and for TFPI, which has
heparin-binding domains and is reported to be displaced by heparin from
the endothelium.15,19 The nature of the
activated protein C and heparin interaction is not well understood. Optimal use of low-dose heparin and activated protein C is being investigated.20
In addition to the observation of an interaction between heparin and the endogenous anticoagulants, the PROWESS,
Kybersept, and OPTIMIST studies also
showed that 28-day all-cause mortality
was lower in patients receiving placebo
who also received low-dose prophylactic heparin. Patients who received prophylactic heparin were found to be less
severely ill in the OPTIMIST study than
the corresponding group of patients who
did not receive heparin (evaluated by
APACHE II score, INR value, and mean
organ dysfunction score). The patients
were not randomized to receive heparin in all 3 endogenous anticoagulant severe sepsis trials. Hence, it is difficult to
assess the true effect of heparin on mortality of patients with severe sepsis from
these trials.
Activation of the coagulation cascade has been postulated to contribute to organ system dysfunction and
mortality in patients with sepsis. Three
©2003 American Medical Association. All rights reserved.
known endogenous anticoagulants (antithrombin III, activated protein C, and
TFPI) have been evaluated for the treatment of severe sepsis. Only treatment
with recombinant activated protein C
demonstrated benefit in the more severely ill patients with sepsis. The lack
of benefit with antithrombin III and tifacogin may have been due to differences in biological activities unrelated
to coagulation6,21 or insufficient dosing to overcome the procoagulant environment. Other potential factors that
may have influenced the outcome of
these studies include differences in trial
design and the confounding effect of
concomitant heparin. Additional studies with all 3 agents in the absence of
heparin may be warranted.
Author Affiliations: Division of Pulmonary Sciences
and Critical Care Medicine, University of Colorado
Health Sciences Center, Denver (Dr Abraham); Anaesthesia Intensivtherapie, Friedrich-SchillerUniversity Jena, Jena, Germany (Dr Reinhart); Infectious Disease Division, Brown Medical School,
Providence, RI (Dr Opal); Intensive Care Department, Onze-Lieve-Vrouw Ziekenhuis, Aalst, Belgium
(Dr Demeyer); Department of Critical Care, University of Calgary, Calgary, Alberta (Dr Doig); Intensive
Care Unit, Hospital Regional Universitario Infanta Cristina, Badajoz, Spain (Dr Rodriguez); Intensive Care Research Office, St Thomas Hospital, London, England
(Dr Beale); Research Centre for Traumatology and Surgery of Ministry of Health, Brno, Czech Republic (Dr
Svoboda); Intensive Care Service, University Hospital
St Luc, Brussels, Belgium (Dr Laterre); South East Research Associates at Wellstar Cobb Medical Center,
Austell, Ga (Dr Simon); St Boniface Hospital, Winnipeg, Manitoba (Dr Light); Intensive Care Unit, University Hospital, Brussels, Belgium (Dr Spapen); Memorial Hospital, Cumberland, Md (Dr Stone); Mobile
Diagnostic Center at Providence Park, Mobile, Ala (Dr
Seibert); City Hospital Munich-Harlaching, Munich,
Germany (Dr Peckelsen); Oost Limburg Hospital, Genk,
Belgium (Dr De Deyne); Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City (Dr Postier); Helsinki University Central Hospital, Helsinki, Finland (Dr Pettilä); Hadassah Hebrew
University Medical Center, Jerusalem, Israel (Dr
Sprung); Corporació Sanitaria Parc Tauli, Sabadell, Spain
(Dr Artigas); Chiron Corporation, Emeryville, Calif (Drs
Percell, Zwingelstein, Tobias, Poole, and Creasey); and
Pharmacia Corporation, Skokie, Ill (Drs Shu and
Stolzenbach).
Financial Disclosures: Dr Reinhart has served as an
advisor and consultant for Chiron and Pharmacia. Dr
Opal has received grant support from Chiron. Drs Percell and Zwingelstein are employees of Chiron. Drs Shu
and Stolzenbach are employees of Pharmacia. Dr Tobias is a consultant for Chiron.
Author Contributions: As principal investigator, Dr
Abraham had full access to all the data in the study and
takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Abraham, Reinhart, Opal,
Svoboda, Artigas, Shu, Zwingelstein, Poole,
Stolzenbach, Creasey.
Acquisition of data: Abraham, Reinhart, Demeyer,
Doig, López Rodriguez, Beale, Svoboda, Laterre, Simon,
(Reprinted) JAMA, July 9, 2003—Vol 290, No. 2 245
EFFICACY AND SAFETY OF TIFACOGIN IN SEVERE SEPSIS
Light, Spapen, Stone, Seibert, Peckelsen, De Deyne,
Postier, Pettilä, Artigas, Percell, Tobias, Poole.
Analysis and interpretation of data: Abraham, Reinhart, Opal, Doig, Postier, Pettilä, Sprung, Percell, Shu,
Tobias, Stolzenbach, Creasey.
Drafting of the manuscript: Abraham, Postier, Percell,
Creasey.
Critical revision of the manuscript for important intellectual content: Abraham, Reinhart, Opal, Demeyer,
Doig, López Rodriguez, Beale, Svoboda, Laterre, Simon,
Light, Spapen, Stone, Seibert, Peckelsen, De Deyne,
Postier, Pettilä, Sprung, Artigas, Percell, Shu,
Zwingelstein, Tobias, Poole, Stolzenbach, Creasey.
Statistical expertise: Pettilä, Percell, Shu.
Obtained funding: Abraham, Creasey.
Administrative, technical, or material support: Abraham, Reinhart, Demeyer, Doig, Simon, Light, Postier,
Sprung, Percell, Zwingelstein, Poole, Creasey.
Study supervision: Abraham, Reinhart, Opal, Svoboda,
Seibert, Postier, Poole, Stolzenbach, Creasey.
Steering Committee: E. Abraham (chair), University
of Colorado Health Science Center, Denver; K. Reinhart, Clinic for Anaethesiology and Intensive Care, University of Jena, Germany; S. M. Opal, Infectious Disease Division, Brown Medical School, Pawtucket, RI;
C. Sprung, Hadassah University Hospital, Jerusalem,
Israel; L.J. Thijs, Free University of Amsterdam, Amsterdam, the Netherlands.
Data and Safety Monitoring Board: Tom Fleming,
PhD, Washington University, Seattle; M. P. Fink, University of Pittsburgh, Pa; T. van der Poll, Academic
Medical Center, Amsterdam, the Netherlands; E. P.
Dellinger (chair), University of Washington, Seattle;
J. Cohen, Imperial College School of Medicine, London, England.
OPTIMIST Study Group: Austria: Wien: W. Hackl, Kaiser-Franz-Josef Spital; W. Ilias, Krankenhaus der Barmherzigen Brüder; H. Steltzer, Allgemeines Krankenhaus.
Belgium: Bouge: P. Van Der Rest, St Luc. Brainel’Alleud: H. Lignian, Hôpital de Braine-l’Alleud–
Waterloo asbl. Brugge: M. Bourgeois, AZ St. Jan. Brussels: J. L. Vincent, Universite Libre de Bruxelles Hôpital
Erasme; P.H. Weyers, Hôpital St Jean. Gent: F. Colardyn, Universitair Ziekenhuis Gent. Liege: P. Damas,
Centre Hospitalier Universitaire Liège. Mons: F. Forêt,
CHR Clinique St. Joseph. Ottignies: P. Honoré, Clinique Saint-Pierre. Seraing: M. Quinonez, Centre Hospitalier du Bois de l’Abbaye. Yvoir: E. Installe, Cliniques Universitaires du Mont-Godinne.
Canada: Brampton: B. Kashin, William Osler Health
Center. Calgary: D. Zuege, Peter Lougheed Centre.
Edmonton: R. Johnston, Royal Alexandra Hospital; I.
Mayers, University of Alberta Hospital. Halifax: R. Hall,
Queen Elizabeth II Health Sciences Centre. Hamilton: L. Mandell and C. Rotstein, Hamilton Health Sciences Corporation. Kingston: D. Heyland, Kingston
General Hospital. London: C. Martin, London Health
Sciences Centre–Victoria Campus. Montreal: R. Bouali,
Hopital Dieu de Montreal; N. Christou, McGill University Health Center–Royal Victoria Hospital Site. Ottawa: P. Hebert, University of Ottawa, Ottawa Hospital General Campus; R. Hodder, Ottawa Hospital–
Civic Campus. Saskatoon: A. Wong, Royal University
Hospital. St. Johns: S. Peters, Health Sciences Center.
Toronto: J. Marshall, Toronto General Hospital; G.
Mehta, Mt. Sinai Hospital; T. Rogovein, St. Joseph’s
Health Center; T. Smith, Sunnybrook & Women’s College Health Science Center. Vancouver: J. Fenwick,
Vancouver General Hospital; J. Russell and K. Walley,
St. Paul’s Hospital. Windsor: J. Muscedere, Respirology and Critical Care Associates.
Czech Republic: Brno: P. Chalupa, Faculty Hospital
Brno.
Denmark: Herlev: J. Bonde, Amtssygehuset i Herlev.
Finland: Jyvaskyla: R. Laru-Sompa, Keski-Suomen
keskussairaala/teho-osasto. Lahti: A. Haavisto, PäijätHämeen Keskussairaala. Oulu: J. Laurila, Oulu Uni246
versity Central Hospital. Turku: J. Perttila, Turun Yliopistollinen Keskussairaala/Aikuisten teho. Vassa: P.
Kairi, Vaasan Keskussairaala/teho-osasto.
France: Aix En Provence Cedex: B. Garrigues, Centre
Hospitalier du Pays d’Aix. Amiens Cedex: M. Slama,
C.H.U. Hopital Sud. Argenteuil: J. P. Sollet, Centre Hospitalier Victor Dupouy. Besancon Cedex: G. Capellier, CHU de Besancon–Hopital Jean Minjoz. Bordeaux: Y. Castaing, Centre Hospitalier PellegrinTripode. Bourg en Bresse Cedex: L. Holzapfel, Centre
Hospitalier Fleyriat. Brest Cedex: A. Renault, CHU Hopital de la Cavale Blanche. Clamart Cedex: F. Brivet,
Hopital Antoine Beclere. Evry Cedex: A. Tenaillon, Hopital Louise Michel. Lille Cedex: D. Mathieu, Hopital
Albert Calmette. Nimes Cedex: J. E. De la Coussaye,
CHU Gaston Doumergue. Paris: J. Carlet, Fondation
Hopital Saint-Joseph; J. Chastre, Hopital Bichat; J-Y
Fagon, Hopital Europeen Georges Pompidou; J. P. Mira,
Hopital Cochin; G. Offenstadt, Hopital SaintAntoine. Pierre Benite Cedex: A. Lepape, CHU Lyon
Sud. Reims: A. Leon, Hopital Robert Debre. Rennes
Cedex: Y. Malledant, CHU Pontchaillou. Saint Etienne Cedex: C. Auboyer, CHU Hopital Nord; F. Zeni,
Hopital Bellevue. Vandoeuvre les Nancy: A. Gerard,
CHU Hopital Brabois.
Germany: Berlin: S. Danzmann, HELIOS Klinikum Berlin-Buch; S. Kljucar, DRK Kliniken Westend; C. Spies,
Universitätsklinikum Charite, Campus Mitte. Bonn: P.
Walger, Medizinische Universitäts-Poliklinik. Bremen:
C. Manhold, Zentralkrankenhaus “Links d. Weser.”
Dresden: K. F. Rothe, Krankenhaus DresdenFriedrichstadt. Giessen: G. Hempelmann, Klinikum der
Justus-Liebig-Universität. Greifswald: M. Gründling,
Klinikum der Ernst-Moritz-Arndt-Universität. Halle: R.
E. Silber, Klinikum der Ernst-Moritz-ArndtUniversität. Hamburg: K-H Kuck, AK St. Georg. Heidelberg: J. Motsch, Universitätsklinikum RuprechtKarls. Leipzig: D. Olthoff, Universitätsklinik Leipzig.
Lübeck: H. Djonlagic, Med Universität zu Lübeck.
Mainz: S. Weilemann, Universitätsklinikum Mainz. Oldenberg: A. Weyland, Städtische Kliniken Station 113.
Regensburg: K-W Jauch, Chirurgische Universitätsklinik. Rostock: G. Nöldge-Schomburg, Universitätsklinik Rostock. Wuppertal: H. Zirngibl, Klinikum
Wuppertal GmbH.
Israel: Haifa: S. Bursztein, Lady Davis Carmel Medical Center. Petach Tikva: P. Singer, Rabin Medical Centre. Rehovot: S. Konichezky, Kaplan Medical Center.
Tel Aviv: P. Sorkine, Tel Aviv Sourasky Medical Center. Tel Hashomer: E. Segal, Sheba Medical Center.
Italy: Bologna: G. Martinelli, Policlinico Sant’OrsolaMalpighi. Firenze: G. Tulli, Nuovo Ospedale San Giovanni di Dio. Parma: P. Zuccoli, Azienda Ospedaliera
di Parma. Rome: R. Proietti, Policlinico Agostino Gemelli–Universita Cattolica
the Netherlands: Apeldoorn: J. Bakker, Gelre Ziekenhuizen. Blaricum: C. Boerma, Ziekenhuis GooiNoord. Bosch: H. van der Hoeven, Bosch Medicentrum, Locatie Groot Ziekengasthuis. Groningen: J. E.
Tulleken, Academisch Ziekenhuis Groninger. Rotterdam: H. A. Bruining, Academic Hospital Rotterdam.
Tilburg: B. Speelberg, Saint Elisabeth Ziekenhuis.
Poland: Sosnowiec: L. Krawczyk, Wojewodzki Szpital. Wroclaw: A. Kubler, Medical Academy. Warsaw:
J. Jastrzebski, Center of Postgraduate Studies.
Spain: Alicante: P. Marco Vera, Hospital G.U. de Alicante. Badalona: P. Torrabadella de Reynoso, Hospital Germans Trias i Pujol. Barcelona: J. Mancebo, Hospital Sant. Pau; F. Solsona, Hospital Nuestra Senora
del Mar. Madrid: B. Galvan Guijo, Hospital Universitario La Paz, J. A. Lorente Balanza, Hospital Universitario Getafe; J. Tellado, Hospital Universitario Gregorio Maranon; A. Valverde Conde, Hospital San
Carlos. Palma de Mallorca: J. Ibañez, Hospital de Son
Dureta. Seville: C. León Gil, Hospital Nuestra Senora
de Valme; C. Ortiz Leyba, Hospital Virgen del Rocio.
Tarragona: J. Rello, Hospital Universitario Joan XXIII.
Terrassa: J. Nava, Hospital Mútua de Terressa.
JAMA, July 9, 2003—Vol 290, No. 2 (Reprinted)
Sweden: Gävle: J. Mälstam, Sjukhuset GävleSandviken. Karlstad: L-A Johansson, Centralsjukhuset Karlstad. Ö rebro: L. Berggren, Regionssjukhuset Örebro. Norrköping: C. Lennmarken,
Vrinnevisjukhuset in Norrköping.
Switzerland: Geneva: D. Lew, Hôpital Cantonal Universitaire de Genève.
United Kingdom: Berkshire: A. Kapila, Royal Berkshire
Hospital. Broomfield: A. Short, Broomfield Hospital.
Leeds: M. Bellamy, St. James’ University Hospital. Leicester: M. Pepperman, the Leicester Royal Infirmary. London: P. S. Withington, Royal London Hospital. Manchester: J. Eddleston, Manchester Royal Infirmary.
Portsmouth: P. McQuillan, Queen Alexandra Hospital. Sussex: M. Street, Royal Sussex County Hospital.
Wales: G. Findlay, University Hospital of Wales.
United States: Alabama: Birmingham: J. Hasson, Princeton Baptist Medical Center; D. G. Warnock, University of Alabama. Jasper: J. H. Westerman, Pulmonary
& Sleep Associates of Jasper, PC, Walker Baptist Medical Center.
Alaska: Anchorage: G. Stewart, Alaska Clinical Research.
Arizona: Phoenix: R. W. Carlson, Maricopa Medical
Center; R. A. Kearl and J. Siever, Arizona Pulmonary
Specialists. Tucson: M. Dolich, University of Arizona
Health Science Center.
Arkansas: Little Rock: N. Salian, John L. McClellan Veterans Administration.
California: Berkeley: J. McFeely, Alta Bates Medical
Center. Escondido: J. Otoshi, Escondido Pulmonology. La Mesa: K. Bagheri, Saddleback Medical Research Services. Orange: M. Lekawa, University of California Irvine Medical Center. San Diego: J. S. Parrish,
Naval Medical Center. Sacramento: T. Albertson, University of California Davis Medical Center. San Francisco: C. R. Brown, California Pacific Medical Center;
M. A. Gropper, University of California. Stanford: R.
Pearl, Stanford Medical Center.
Colorado: Denver: P. Offner, Denver Health Medical
Center.
Delaware: Newark: G. Fulda, Christiana Care.
Florida: Bay Pines: C. L. Anderson, Bay Pines VA Medical Center. Tampa: M. Rumbak, University of South
Florida. Jacksonville: L. Laos, University of Florida Health
Science Center/Shands Hospital. Lakeland: B. Meyers,
the Watson Clinic/Lakeland Regional Medical Center.
Hawaii: Honolulu: S. Berman, St. Francis Medical
Center.
Illinois: Chicago: J. Dematte-D’Amico, Northwestern Memorial Hospital. Elk Grove: E. J. Diamond, Suburban Lung Associates. Oak Park: B. Margolis, West
Suburban Hospital. Peoria: W. Tillis, University of Illinois College of Medicine, St. Francis Medical Center.
Springfield: D. R. Graham, Springfield Clinic Research.
Indiana: Indianapolis: M. Farber, VA Medical Center;
G. Rubeiz, Community Hospital; K. P. Vohra, Indiana
Nephrology/Internal Medicine PC.
Kansas: Kansas City: S. Pingleton, University of Kansas Medical Center. Olathe: D. Lawlor, Consultants
in Pulmonary Medicine.
Kentucky: Lexington: P. Kearney, University of Kentucky Medical Center. Louisville: W. Cheadle, University of Louisville/VA Medical Center.
Maine: Portland: R. Riker, Maine Medical Center.
Maryland: Baltimore: H. Silverman, University of Maryland School of Medicine.
Massachusetts: Boston: H. Kesselman, Massachusetts General Hospital. Springfield: T. Higgins, Baystate Medical Center. Worcester: D. A. Kaufman, St.
Vincent’s Hospital/Worcester Medical Center.
Michigan: Barrien Springs: M. Harrison, Southwestern Medical Center PC; Detroit: J. Guzman, Detroit
Receiving Hospital.
Minnesota: Minneapolis: G. J. Beilman, University of
Minnesota. Rochester: M. Murray, Mayo Clinic and
Foundation.
Missouri: St. Louis: G.M. Matuschak, St. Louis Uni-
©2003 American Medical Association. All rights reserved.
EFFICACY AND SAFETY OF TIFACOGIN IN SEVERE SEPSIS
versity Health Science Center; DP Schuster, Washington University Medical Center; R. Taylor, St Johns
Mercy Medical Center.
Nebraska: Omaha: M. Rupp, University of Nebraska
Medical Center.
Nevada: Las Vegas: A. Barber, University of Nevada
School of Medicine.
New Jersey: East Orange: M. Park, VA New Jersey
Health Care System. New Brunswick: H. L. Paz, UMDNJ-Robert Wood Johnson Medical School.
New York: Buffalo: T. Ferrario, VA Western New York
Healthcare System; J. Hassett, Kaleida Health. Manhasset: D. Ost, North Shore University Hospital. New York:
M. Astiz, St. Vincent Hospital; E. Benjamin, Mount Sinai Medical Center; S. Pastores, Memoral Sloan Kettering Cancer Center. Rochester: D. C. Kaufman, University of Rochester Medical Center, Strong Memorial
Hospital.
North Carolina: Chapel Hill: S. Carson, University of
North Carolina Medical Center. Charlotte: M. Forshag, Carolinas Medical Center. Durham: J. A. Govert, Duke University Medical Center. Greenville: G.
Pape, East Carolina University School of Medicine. Winston-Salem: P. E. Morris, Wake Forest University School
of Medicine.
Ohio: Akron: D. Heiselman, Akron General Medical
Center; SM Traeger, Summa Health System. Cincinnati: S. Miller, University of Cincinnati Medical Center. Cleveland: M. Malangoni and J. Finley, MetroHealth Medical Center. Columbus: I. Baird, Remington
Davis Inc. Toledo: L. Jauregui, Saint Vincent Mercy
Medical Center; D.E. Olson, Medical College of Ohio.
Oregon: Portland: R. Maunder, the Oregon Clinic.
Pennsylvania: Allentown: M. Cipolle, Lehigh Valley
Hospital. Hershey: R. Cooney, the Milton S. Hershey
Medical Center. Philadelphia: S. Fiel, Medical College of Pennsylvania; H. Patrick, Hahnemann University Hospital. Pittsburgh: J. A. Kellum, University of Pittsburgh Medical Center Health System.
Rhode Island: Providence: M. Levy, Rhode Island Hospital.
South Carolina: Charleston: C. B. Strange, Medical University of South Carolina.
Tennessee: Jackson: P. Sioson, Jackson Madison County
General Hospital. Memphis: R. G. Wunderink, Methodist Healthcare.
Texas: Dallas: A. Dal Nogare, University of Texas Southwestern Medical Center. El Paso: H. Ho, Texas Tech University Health Science Center. Ft. Worth: D. W. Ziegler, John Peter Smith Hospital. Galveston: J. A. Daller,
University of Texas Medical Branch. Houston: V. Bandi,
Baylor College of Medicine, Ben Taub General Hospital; R. F. Lodato, University of Texas-Health Science Center. Lackland Air Force Base: D. Mueller, 59th MSGS/
MCSG, Wilford Hall Medical Center. Lubbock: T. Butler,
Texas Tech University Health Science Center. San Antonio: A. Anzueto, Audie L. Murphy VA Hospital.
Vermont: Burlington: W. K. Alston, Fletcher Allen
Health Care MCHV Campus.
Virginia: Alexandria: J. Pfundstein, Inova Alexandria
Hospital. Falls Church: J. Lamberti, Inova Fairfax Hospital. Norfolk: L. J. Weireter Jr, Eastern Virginia Medical School, Sentara Norfolk General Hospital. Richmond: T. Ferro, McGuire VA Medical Center.
Washington: Seattle: K. Steinberg, University of Washington, Harborview Medical Center. Tacoma: L. Kirkegaard, Franciscan Health System, St. Joseph Medical
Center.
Washington, DC: J. Kirkpatrick, Washington Hospital Center; M. Seneff, George Washington University Medical Center.
West Virginia: Morgantown: H. Dedhia, West Virginia University Health Science Center.
Wisconsin: Madison: D. Coursin, University of Wisconsin Hospitals and Clinics. Milwaukee: E. Y. Cheng,
Medical College of Wisconsin, Froedtert Memorial Lutheran Hospital–West.
Funding/Support: Chiron and Pharmacia provided
funding for this study.
Role of the Sponsor: Drs Abraham, Reinhart, and Opal
developed the study design in close cooperation with
the study sponsors. The study conduct and data collection were monitored by the sponsor and by the contract research organization (NCGS Laboratories Inc),
along with the study sponsors and the steering committee. All the primary data and statistical analyses were
reviewed by Dr Abraham, the corresponding author, and
Dr Opal on behalf of the coauthors and investigative
team. Data interpretation was conducted by the statistical group of the sponsor, Drs Jeff Tobias, Sandra Percell, and Abla Creasey in collaboration with steering committee members. The manuscript was prepared by Drs
Abraham and Creasey with input from Drs Percell and
Tobias and reviewed by each of the coauthors.
Acknowledgment: We thank the staff of NCGS Laboratories Inc (Charleston, NC), which is a contract research organization, for professional assistance with
monitoring and data collection; the staff of Clinserve
(Hamburg, Germany), which is research laboratory
evaluator, for the superior performance evaluation of
our research laboratories; and J. Chiu for his technical support.
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©2003 American Medical Association. All rights reserved.
(Reprinted) JAMA, July 9, 2003—Vol 290, No. 2 247