Risk and the Efficacy of Antiinflammatory Agents

Retrospective and Confirmatory Studies of Sepsis

Peter Q. Eichacker, Chantal Parent, Andre Kalil, Claire Esposito, Xizhong Cui, Steven M. Banks,
Eric P. Gerstenberger, Yvonne Fitz, Robert L. Danner, and Charles Natanson
Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland

We investigated whether a relationship between risk of death and

treatment effect could explain the disparate results between the
preclinical and clinical sepsis trials of antiinflammatory agents over
the last decade. A metaregression analysis of cited preclinical studies
showed that the treatment effects of these agents were highly
dependent on risk of death (p 0.0001) and that animals were
studied at significantly higher control mortality rates than humans
(median [25th75th quartile], 88% [7996%] versus 39% [3242%],
p 0.0001). An analysis of the clinical trials showed that antiinflammatory agents were also significantly more efficacious in septic
patients with higher risk of death (p 0.002) and were harmful
in those with low risk. To test this relationship prospectively, we
studied antiinflammatory agents in models employing differing
doses of bacterial challenge to produce the full range of risk of
death. We found that the efficacy of these agents, although very
beneficial at high control mortality rates, was much reduced (p
0.0001) and similar to those in human trials at moderate control
mortality rates (i.e., 30 to 40%). The efficacy of antiinflammatory
agents during sepsis is dependent on the risk of death, an observation that explains the apparent contradiction between preclinical
and clinical trial results. Accounting for this relationship may be
necessary for the safe and effective development of antiinflammatory therapies for sepsis.
Keywords: septic shock; preclinical and clinical trials; metaregression
analysis; antiinflammatory therapies

Despite promising preclinical testing (138) and the expenditure of several billion dollars, antiinflammatory agents designed to inhibit specific host mediators during sepsis failed
to show benefit in 22 clinical trials involving over 10,000
patients (Table 1) (3960). This failure for the global pharmaceutical industry and academic community has been much
discussed but never adequately explained. The underlying
hypothesis of this therapeutic approachthat the intense
host inflammatory response becomes pathogenic in severe
sepsis and septic shockhas been questioned but not refuted
(6165). Even if this hypothesis is incorrect or its successful
application requires the blockade of different or multiple targets in the host response to infection, it would not explain
the marked disparity in the efficacy of these mediator-specific
antiinflammatory agents comparing animal models of sepsis to
infected patients. Identifying factors underlying this difference
between clinical and preclinical trials would likely strengthen

(Received in original form April 9, 2002; accepted in final form July 16, 2002)
Correspondence and requests for reprints should be addressed to Peter Q. Eichacker, M.D., Critical Care Medicine Department, National Institutes of Health,
Building 10, Room 7D43, 10 Center Drive, MSC 1662, Bethesda, MD 208921662.
E-mail: peichacker@nih.gov
This article has an online data supplement, which is accessible from this issues
table of contents online at www.atsjournals.org
Am J Respir Crit Care Med Vol 166. pp 11971205, 2002
Originally Published in Press as DOI: 10.1164/rccm.200204-302OC on July 19, 2002
Internet address: www.atsjournals.org

the development and application not only of antiinflammatory

agents but also of other new therapies for sepsis.
Clinical investigators have suggested that the severity of
the underlying septic process and its associated risk of death
may be linked to the treatment effect of antiinflammatory
agents in sepsis (66). If preclinical and clinical testing was
performed at very different control group mortality rates,
then a strong relationship between risk of death and efficacy
could explain why animal studies and patient trials of antiinflammatory agents produced such divergent results. For example, a drug with this profile might be effective only at high
and not at low risks of death. The results of preclinical testing
would be misleading unless clinical studies were conducted
at a risk of death similar to those found in clinical trials.
Also, at some levels of risk, agents might become harmful,
leading to excess deaths in clinical trials. Such a relationship
between the treatment effect of an agent and risk of death
has been previously proposed for several other potentially
fatal conditions (67) such as antiarrhythmics for sudden death
(68), magnesium for myocardial infarction (69), cholesterollowering drugs for atherosclerosis (70), and tocolytic agents
(71) for premature birth.
To test the potential relationship between risk of death
and the efficacy of antiinflammatory agents in sepsis, we first
examined the published preclinical trials used to support
testing mediator-specific antiinflammatory agents in septic
patients. None of these individual animal studies examined
this relationship. We then analyzed the treatment effect across
published studies in a metaregression analysis to see whether
it changed as risk of death varied. This led us to perform
a similar analysis of the clinical trials themselves, looking
separately at those trials that stratified patients treatment
effect based on their predicted risk of death and then those
that did not. Finally, we prospectively tested in our own
laboratories the influence of risk of death on antiinflammatory agents by altering the dose of bacterial-challenge animals
received and thereby mortality rates. This allowed us to examine animal studies at lower risks of death more similar to
human sepsis studies. In addition, the route and type of
challenge and type of antiinflammatory agent studied were
varied because these factors had also been proposed as a
basis for the differing effects of antiinflammatory agents (61
65). As a control, we tested the influence of risk of death on
fluid therapy, a conventional treatment for sepsis not known
to have antiinflammatory effects.
Our metaregression analyses of published preclinical and
clinical sepsis trials and confirmatory prospective animal sepsis studies each showed similarly that the risk of death influences the effects of antiinflammatory agents in sepsis. This
relationship explains the contradictory results noted in prior
preclinical and clinical trials. More importantly, accounting
for this relationship may be necessary for the safe and effective development of new agents for the treatment of sepsis
and septic shock.

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TABLE 1. RESULTS OF CLINICAL TRIALS OF MEDIATOR-SPECIFIC ANTIINFLAMMATORY AGENTS
TESTED IN SEPTIC PATIENTS

Antiinflammatory Agent (Company) (Reference)

Anti-TNF antibodies
MAK 195F (Knoll) (39)
CDP571 (Celltech) (40)
CA2 (Centacor) (45)
CB006 (Celltech) (41)
MAK 195F (Knoll) (42)
MAK 195F (Knoll) (46)
BAYx1351 (Bayer/Miles) (43)
BAYx1351 (Bayer/Miles) (44)
BAYx1351 (Bayer/Miles) (47)
TNF-soluble receptors
P80 (Immunex) (48)
P55 (Hoffman) (49)
P55 (Hoffman) (50)
IL-1ra
Antril (Synergen) (51)
Antril (Synergen) (52)
Antril (Synergen) (53)
PAFra
BN 52021 (Ipsen) (54)
BN 52021 (Ipsen) (55)
Antiprostaglandin
Ibuprofen (Upjohn) (56)
Ibuprofen (Upjohn) (57)
Ibuprofen (Upjohn) (58)
Antibradykinin
CPO127 (Cortech) (59)
CPO127 (Cortech) (60)

Odds Ratio
(95% Confidence Interval
for Survival )*

Number of
Patients Enrolled

Control
Mortality Rate

39
42
56
80
122
446
553
971
1,878

50%
60%
39%
32%
41%
57%
40%
33%
43%

2.86
0.90
1.16
0.58
0.79
1.12
1.10
1.13
1.11

141
498
1,362

30%
39%
28%

0.52 (0.23, 1.20)

1.02 (0.69, 1.53)
1.12 (0.88, 1.43)

99
893
906

44%
34%
36%

2.44 (0.94, 6.33)

1.19 (0.89, 1.60)
1.10 (0.84, 1.45)

262
608

51%
49%

1.44 (0.89, 2.35)

1.11 (0.81, 1.53)

29
30
455

31%
43%
40%

0.35 (0.07, 1.61)

3.25 (0.63, 16.79)
1.12 (0.77, 1.64)

251
504

29%
41%

0.68 (0.38, 1.20)

1.07 (0.71, 1.61)

(0.69,
(0.21,
(0.39,
(0.20,
(0.34,
(0.77,
(0.76,
(0.85,
(0.92,

11.84)
3.85)
3.44)
1.73)
1.83)
1.63)
1.59)
1.51)
1.33)

Definition of abbreviations: IL-1ra interleukin one receptor antagonist; PAFra platelet-activating factor receptor antagonist;
TNF tumor necrosis factor.
* We averaged over dose of drug in each trial to increase our ability to find significant effects because there were no significant
effects of dose on survival rates with the exception that the high and middle dose of P-80 TNF-soluble receptor significantly
increased mortality rates compared with low dose and controls (48) (modified and updated from Zeni and colleagues [72]).

METHODS
Analysis of Published Preclinical Studies
Twenty-two clinical trials (3960) were conducted between January
1986 and January 2000 that tested the effects of seven different nonsteroidal mediator-specific antiinflammatory agents (i.e., anti-TNF [tumor
necrosis factor] antibodies, P-55 and P-80 TNF-soluble receptors [sometimes referred to as the P-75 TNF-soluble receptor], interleukin-1 receptor antagonist, platelet-activating factor receptor antagonist, antibradykinin, and antiprostaglandin) (see online data supplement) (72). To
investigate the basis for the differing effects that these agents were
reported to have in animal models versus human trials, all preclinical
studies cited to support their use in clinical trials were reviewed for
this metaregression analysis (138). All reported experiments in these
studies were included provided that survival rates of the treatment
agent were directly compared with a survival rate of a placebo or lower
dose treatment group. In addition, in all experiments, the type and
route of septic challenge, the regimen of treatment employed, including
both timing and dose, the species studied, and the duration of observation were recorded for analysis.
For each experiment, treatment mortality rate was plotted on the
y axis and the corresponding control mortality rate on the x axis, yielding
a graph on the unit square in which each axis represents fully independent measures. To avoid constraining data at the extremes of the mortality rate ranges, we reparameterized the unit square to occupy the whole
plane (73). The y axis was transformed to become the log of the odds
of treatment mortality and the x axis to become the log of the odds of
control mortality. A weighted linear regression based on the number
of animals in each study was performed. Although the analysis was
always done with the y axis expressed as the log of the odds of treatment
mortality, for ease of presentation, the results are presented with the

y axis expressed as the log odds ratio of survival. The odds ratio of
survival is the odds of survival in the treatment group divided by the
odds of survival in the control group. The odds ratio of survival is
mathematically equivalent and is a commonly used measure of efficacy
in clinical trial literature. No other factor examined (i.e., type or route
of septic challenge, regimen of treatment, including timing and dose,
duration of observation, or species studied) significantly changed (all
p 0.20) the relationship between treatment effect and control mortality rate (74).

Analysis of Published Clinical Trials

We assessed the consistency of the clinical trials by determining whether
the odds ratios of the 22 human sepsis trials fell within the 95% confidence interval for the mean regression line calculated with the preclinical animal studies. In addition, two trials stratified patients based on
the predicted risk of death, and these trials, along with the remaining
20 studies, were analyzed in a manner similar to the published preclinical
studies.

Prospective Preclinical Studies

To examine prospectively the relationship between risk of death and
treatment effect with antiinflammatory agents in sepsis, Sprague-Dawley rats (n 1,296) were randomized to be challenged intravenously
or intrabronchially with varying doses of Escherichia coli 0111:B4,
Staphylococcus aureus (0.25 to 100 109 CFU kg1 body weight), or
E. coli 0111:B4 endotoxin (0.75 to 2 g kg1; Sigma, St. Louis, MO).
These differing bacterial doses, types, and routes of challenge were
studied to attempt to simulate the diverse types of infection that would
be present in a population of septic patients producing a wide range
of mortality rates. We studied antiinflammatory agents with different

Eichacker, Parent, Kalil, et al.: Risk Alters Antiinflammatory Therapies

1199

mechanisms of action to examine prospectively whether the effect of

risk of death is dependent on one type of immunomodulator. After
challenge, one group of animals (n 653) was treated with high molecular weight TNF-soluble receptor (P-80 TNF-soluble receptor; 100 g
kg1 intravenously; Immunex, Seattle, WA) or placebo. This agent was
significantly harmful in a clinical sepsis trial (48) after animal studies
had shown it to be beneficial in a highly lethal gram-negative bacterial
or bacterial toxin model (23). Another group of animals (n 638)
received a tyrosine kinase inhibitor (7581) (tyrphostin AG556, 2.5 g
kg1, intraperitoneally) or placebo given immediately and 6 hours after
challenge to examine an antiinflammatory agent that blocks the release
of multiple inflammatory mediators simultaneously (7581) rather than
directly neutralizing circulating TNF. To investigate whether risk of
death affected the efficacy of a conventional sepsis treatment, an additional group of rats (n 192) was challenged with varying doses of E.
coli and then treated with or without normal saline (20 ml kg1h1
intravenously for 24 hours) (82). All animals received daily antibiotics
for 3 days, and after 7 days, animals were considered survivors as
previously described (83).
The relationship between risk of death and treatment efficacy was
examined in a manner similar to the published animal studies, and
these relationships were not significantly changed (p 0.20) by any of
the other variables studied. The consistency of this data with published
preclinical and clinical trials was assessed as previously described.
All animal protocols used in these studies were approved by the
Animal Care and Use Committee of the Clinical Center of the National
Institutes of Health. Every effort was made to minimize animal suffering
during these protocols. The research protocols required the veterinarian
staff or principle investigators to euthanize any animal that experienced
unexpected severe pain or distress.

The differing control mortality rates reported for these subgroups allowed us to examine the relationship between risk of
death and treatment effect over a wider range. In a phase III
trial of interleukin-1 receptor antagonist (53, 66) and a phase
III trial of P-55 TNF-soluble receptor (50), patients were categorized into groups with increasing risks of death as determined
by physiology-based scoring systems (modified Acute Physiology
and Chronic Health Evaluation III score and Stratified Acute
Physiology score, respectively) (Figures 3A and 3C). Stratifying
by the risk of death score, we found that the treatment effect of
these two antiinflammatory agents was significantly (p 0.0002)
related to the risk of death (Figures 3A and 3C). The effect of
these antiinflammatory agents in septic humans at higher risks
of death was very similar to the effects seen with these agents
in published animal studies with the same high risks (Figure 1A).
The 20 remaining clinical trials studied control mortality rates
over a significantly narrower range of overall control mortality
rates than the two trials categorizing patients by risk of death
(29 to 60% versus 10 to 78%, p 0.0001) (Figures 3A and 3B).
Despite this, the relationship between risk of death and the
treatment effect for these 20 remaining clinical trials had an
identical slope and intercept to the one based on patients segregated by risk of death in the other two trials (both p 0.85
comparing the two groups of trials) (Figures 3A and 3B). Moreover, even within the narrower range of control mortality rates
studied in these other 20 trials, the slope for this relationship
between risk of death and treatment effect approached being
significant (p 0.07).

RESULTS

Prospective Preclinical Studies with Antiinflammatory

Therapies or Fluids

Published Preclinical Studies of Antiinflammatory Agents

In 22 human sepsis trials of antiinflammatory agents (Table 1)

(3960), a total of 38 animal sepsis studies were cited (95 individual experiments; Figures 1A1C) (138). Animals were studied
at much higher control mortality rates than humans (median
[25th75th quartile] 88% [7996%] versus 39% [3243%], p
0.0001) (Figures 1B and 1C). Regardless of the type of challenge,
timing or dose of treatment, species studied, or duration of
observation, the odds ratio of survival with all mediator-specific
antiinflammatory agents diminished as the risk of death (control
mortality rate studied) decreased (p 0.0001) (Figure 1). Notably, anti-TNF antibodies were found to be significantly harmful
in two animal studies cited with very low (less than 15%) control
mortality rates that were below those studied in most clinical
and preclinical sepsis trials (17, 18). Each of these two studies
significantly increased the slope of the relationship between risk
of death and treatment. Although shown with other data, because these two studies were overly influential, they were excluded from analysis; however, inclusion would make this relationship even stronger. Among all factors examined, risk of death
explained the majority of the variability (70%) in the treatment
effects of antiinflammatory agents comparing these 95 experiments.
Published Clinical Trials of Mediator-Specific
Antiinflammatory Therapies

Control mortality rates in clinical trials were lower and studied

over a narrower range than in preclinical trials (Figures 1B and
1C). At comparable control mortality rates, the effects of mediator-specific antiinflammatory therapies in 19 (3941, 4346, 48
54, 5660) of the 22 (3960) clinical trials fit within the 95%
confidence interval for the odds ratio for survival predicted from
the 95 published preclinical experiments (Figure 2A). However,
two clinical trials provided data that categorized patients at study
entry into subgroups based on predicted risk of death (50, 53).

In prospective experiments testing P-80 TNF-soluble receptor

and tyrphostin AG556 in rats, increasing the dose of each type
of challenge (E. coli, S. aureus, or endotoxin) caused mortality
rates to increase (combined; r 0.83; p 0.0001) (data not
shown). Regardless of the type or route of challenge or the type
of antiinflammatory agent used, as the control mortality rates
increased, the odds ratio of survival with antiinflammatory therapy increased (combined, p 0.0002) (Figures 4A and 4C).
For our prospective and previously unpublished studies
(Figure 4A) and the published preclinical studies from other
laboratories (Figure 1A) of antiinflammatory therapies, the
slopes of this regression relationship comparing risk of death
and treatment effect were similar (0.40 versus 0.48, respectively,
p NS). However, the y intercept was greater in the published
compared with the prospective preclinical studies (2.95 versus
1.17, respectively, p 0.0001) (Figures 1A and 4A). The greater
beneficial effects and increases in y intercept in published versus
prospective studies can be partially explained as positive results
are more likely to be published, causing an overestimation of
treatment effects (84). All 22 clinical trials fit within the 95%
confidence interval for the odds of survival in these prospective
preclinical trials of antiinflammatory agents (Figure 2B).
In this preclinical model, fluid therapy had a significantly
different relationship (i.e., slope and intercept) between risk of
death and treatment effect (Figure 4B) compared with antiinflammatory agents in prospective studies (p 0.008 for both
slope and intercept) (Figure 4A). After E. coli challenges, fluids
produced significant beneficial effects that were similar regardless of control mortality rate. At comparable control mortality
rates, only 4 (39, 45, 51, 57) of the 22 (3960) clinical trials fit
within the 95% confidence interval for the effects of fluid therapy
in animals (Figure 2C). Notably, more of the 22 clinical trials
fit within the 95% confidence intervals for survival with antiinflammatory therapies than with fluid therapy in animals (22 of
22 versus 4 of 22, respectively; p 0.0001) (Figures 2B and 2C).

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Figure 1. (AC) The weighted regression

line in A shows the relationship between
control odds and the odds ratio of survival
with treatment for 95 experiments (open circles) in 38 published animal studies cited
(138) in 22 clinical sepsis trials of mediatorspecific antiinflammatory agents (Table 1)
(3960). B is the same as A but also shows
the control odds and odds ratio for survival
for the 22 clinical trials (open diamonds) (39
60) testing mediator-specific antiinflammatory agents. C divides the data in B by type
of antiinflammatory agent. The circle size in
each panel is adjusted for the number of
animals in each experiment, but not the diamond size in B and C because the number
of patients in each trial was not used to calculate the weighted regression line.

Comparison of Time of Observation Used to Calculate Survival

Rates in Animals and Human Sepsis Studies

In this meta-analysis, we analyzed survival rates and not survival

times because this was the only outcome measure universally
reported. Differences in follow-up times within species or differing life spans across species could potentially produce differences in control mortality rates and thereby alter the relationship
between control mortality rate and treatment effect. The median
(range) duration of follow-up for determining survival rates in
published animal studies was 168 hours (24 to 288 hours) in rats,
75 hours (24 to 360 hours) in mice, 72 hours (24 to 336 hours)
in primates, and 24 hours (5 to 168 hours) in rabbits. For these
previously published animal studies, there was no significant
correlation between control mortality rate and the length of
follow-up time within or across these species (r values, 0.30 to
0.14; p values, 0.40 to 0.98). Therefore, in the published animal
studies, differences in follow-up times cannot explain the significant relationship found between increasing control mortality
rate and the treatment effects of antiinflammatory agents. All
of our prospective animal studies were based on 7-day survival
rates, and all of the human clinical sepsis trials were based on
28- to 30-day survival rates. Therefore, differences in follow-

up times also cannot explain the significant relationship found

between control mortality rate and treatment effects of antiinflammatory agents in either our animal studies or the human
sepsis trials. Finally, because the time of observation after treatment was actually much longer in human sepsis trials than all
of the preclinical sepsis studies examined, it is unlikely that this
variable caused the significantly higher control mortality rates
found in animal compared with human sepsis studies.

DISCUSSION
In a retrospective analysis of clinical and preclinical trials and
confirmatory animal studies, we found that risk of death altered
the efficacy of antiinflammatory agents during sepsis. This relationship provides an explanation for the contradictory results
noted with this therapeutic approach in preclinical (138) and
clinical sepsis trials (3960) over the past decade. Antiinflammatory agents had greater treatment effects in animal models compared with clinical trials because preclinical studies were done
at significantly higher risks of death (Figure 1). Furthermore,
human trials of antiinflammatory therapies failed because they
enrolled patients at a level of risk where these agents have
minimal effects (Figure 1 and Table 1). Animal studies we con-

Eichacker, Parent, Kalil, et al.: Risk Alters Antiinflammatory Therapies

Figure 2. A compares the
treatment effect of mediator-specific antiinflammatory agents in 22 clinical trials (3960) (open diamonds)
(Table 1) to the 95% confidence interval (gray bar)
for the regression line describing their effects in
cited animal studies (138)
from Figure 1A. B and C
compare these same 22
clinical trials to the 95%
confidence interval (gray
bars) for the regression line
describing their effects in
prospective animal studies
testing either antiinflammatory agents from Figure
4A or fluid support in animals from Figure 4B, respectively. Because preclinical trials included fewer
subjects than clinical ones,
for ease of presentation,
these confidence intervals
are adjusted for the median
number of patients in clinical trials. However, all comparisons in the
results section were based on actual numbers of animals or patients in
each trial.

ducted at low risks of death produced the same results seen in

septic patients (Figure 2B). A small number of published animal
studies conducted at low control mortality rates (Figure 1) (17,
18) demonstrated that antiinflammatory agents in sepsis have
the potential to be harmful in less severely ill subjects. This
effect is consistent with the adverse outcome seen after P-80
TNF-soluble receptor administration in a subgroup of patients
with gram-positive infection that had a low control mortality
rate (13%) (48) (Figure 4C).
Two clinical trials provided data that categorized patients
into groups based on their predicted risk of death (50, 53, 66).
These trials allowed us to evaluate the effects of two different
agents over a range of control mortality rates similar to the

1201

animal studies. Just as in animal studies, these agents were most

beneficial in those groups of patients with high risks of death
and were harmful in those with low risks (Figure 3A). The other
20 sepsis trials (3949, 51, 52, 5460), studied over a more limited
range of control mortality rates, showed a very similar relationship between risk of death and treatment effects (Figure 3B).
We believe that this consistency among preclinical studies from
different laboratories and clinical trials strongly supports our
hypothesis that risk of death alters the effects of antiinflammatory agents during sepsis.
Results of a phase III sepsis trial of activated protein C (APC),
an agent with antiinflammatory and antithrombotic properties,
could be an exception to our findings because of a highly significant (p 0.005) beneficial effect. Therefore, this agent deserves
comparison to these clinical trials even though published after
completion of this metaregression analysis (Figure 5A) (85, 86).
Although APC significantly improved survival rates compared
with standard sepsis therapies, its treatment effect was not significantly different compared with the combined effects of all
these previously studied mediator-specific antiinflammatory
agents (n 22) (p 0.10) (Figure 5A) or the phase III trials
of these agents (n 9) (odds ratio [95% confidence interval];
1.36 [1.10, 1.68] versus 1.13 [1.03, 1.24], respectively, p 0.20)
(Table 1) (3960). Furthermore, a prospective analysis divided
the 1,690 patients in the clinical APC trial into four equal groups
based on Acute Physiology and Chronic Health Evaluation II
scores (8587). Similar to clinical trials of the other antiinflammatory agents, APC was less beneficial (odds ratio of survival
1.56, 1.82, 1.19, and 0.77, respectively) as control mortality rates
(49, 36, 26, and 12%, respectively) and Acute Physiology and
Chronic Health Evaluation scores decreased (5230, 2925, 24
20, 193, respectively) (Figure 5B). Accordingly, APC was licensed for use by the Food and Drug Administration for only
patients with severe sepsis (sepsis associated with acute organ
dysfunction) and a high risk of death (e.g., as determined by
Acute Physiology and Chronic Health Evaluation II scores) (87).
Because of the consistency of the APC data to our findings
(Figure 5) examining other antiinflammatory agents, it must be
considered that in patients with a low risk of death, APC may
not only be ineffective but also harmful.
Even though all of these agents may work through different
biologic pathways, we found that the slopes for the relationship
between risk of death and treatment efficacy were similar (0.32
to 0.48). One possible explanation for this consistency is that

Figure 3. (AC) In one phase III trial of interleukin-1 receptor antagonist and one of P-55 TNF-soluble receptors, septic patients were
categorized at study entry into groups based on their predicted
risks of death, as determined by a modified Acute Physiology and
Chronic Health Evaluation II or Stratified Acute Physiology score,
respectively (open diamonds) (50, 53, 66). Using the same format
as Figure 1, A shows the observed control odds and odds ratio of
survival with antiinflammatory treatment for these risk categories
as well as the weighted regression line for the relationship. B shows
the relationship between the overall control odds and odds ratio
of survival for the remaining 20 trials of antiinflammatory agents
(3949, 51, 52, 5460) that did not provide segregated data like
that shown in A. C divides the data from A by type of antiinflammatory agent. The size of the diamonds in each panel is adjusted to
the number of patients in each subgroup (A and C ) or trial (B )
because a weighted regression analysis was done.

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Figure 4. (AC) This format is similar to Figure 1

except that here each circle represents an experiment in which we prospectively challenged animals
with a dose of bacterial challenge designed to produce a range of mortality rates and then treated
them with an antiinflammatory agent or placebo
(A ). In B, the format is similar to A except now
each circle represents an experiment in which we
prospectively challenged animals with a differing
dose of bacteria and then either did or did not treat
with fluids. C divides the data in A by type of antiinflammatory agent used as well as by the type and
route of bacterial challenge.

regardless of the type of immunomodulator, when the overwhelming majority of subjects are going to die from sepsis, inhibiting an excessive and lethal inflammatory response improves
outcome. Conversely, if the majority of subjects with sepsis are
likely to survive, disrupting an inflammatory response that is
working well is harmful. In this case, an immunosuppressive
effect may disrupt well-regulated inflammatory pathways and
weaken protective host defense mechanisms. When a mixture
of subjects either destined to survive or die from sepsis are
treated, harm caused by inhibiting inflammation in subjects that
would have otherwise survived may negate the potential benefit
of inhibiting inflammation in subjects that would have died. This
would explain the smaller treatment effects evident with all of

these agents in our analysis when control mortality rates were

in the mid-range.
Our model also has a term predicting the treatment efficacy
of an agent at a 50% control mortality rate. If this value had
actually been very high for the agents we analyzed, then the
slopes for the regression lines reported might have been of little
consequence. In this case, although the efficacy of antiinflammatory agents might decrease as risk of death decreased, it would
still be beneficial throughout the entire range of control mortality
rates. However, in most of our analyses, these terms were relatively small. With such small treatment effects at a 50% control
mortality rate (odds ratio, 1.17 to 1.48), any significant change in
efficacy as control mortality rate decreases becomes worrisome

Figure 5. (A and B ) This figure shows the results of the clinical

(85) and cited preclinical (86) sepsis trial of APC (open diamond
and circle in A ) as well as the effects of APC in patients categorized
based on their predicted risk of death (87) (open diamonds in
B ). For comparison, in A, data are included from Figure 1 (gray
diamonds and circles) and in B from Figure 3 (gray diamonds).

Eichacker, Parent, Kalil, et al.: Risk Alters Antiinflammatory Therapies

because at low risks of death (i.e., less than a 50% control

mortality rate) these agents become harmful. It would be ideal
to find an antiinflammatory agent for sepsis that functions as
fluids did, with a relatively large treatment effect at a 50% control
mortality and a relatively small slope. Such an agent would be
beneficial over the full range of control mortality rates.
For a highly lethal disease such as sepsis, use of preclinical
studies conducted over a wide range of risk may provide a transformative method for the preclinical testing of new agents. They
permit an estimation of an agents treatment effect at a 50%
mortality rate and can demonstrate the influence risk of death
may have on the agents efficacy. Together, these data suggest
whether there is a level of risk below which an agent may produce
harm. Ideally, drugs taken into clinical testing would be those
that have significant beneficial effects over a wide range of competing risks. However, a different approach must be considered
if preclinical or later clinical testing indicates that an agent is
beneficial above, but harmful below, a particular risk of death.
Subsequent clinical trials should then incorporate entry and exclusion criteria such as risk prediction scores to ensure that
patients likely to benefit are included and that those likely to
be harmed are excluded. Examining this relationship between
risk of death and treatment effect preclinically and then using
this information to optimally design the clinical trial are likely
to reduce the size and expense of human research in highly
lethal disease and may also help minimize the risk of drugrelated fatalities.

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