Content uploaded by Daniel Talmor
Author content
All content in this area was uploaded by Daniel Talmor on Aug 17, 2018
Content may be subject to copyright.
Copyright 2016 American Medical Association. All rights reserved.
Effect of Aspirin on Development of ARDS in At-Risk Patients
Presenting to the Emergency Department
The LIPS-A Randomized Clinical Trial
Daryl J. Kor, MD, MSc; Rickey E. Carter, PhD; PaulineK. Park, MD; Emir Festic, MD, MSc; Valerie M. Banner-Goodspeed, ALB, MPH;
Richard Hinds, MS, RRT; Daniel Talmor, MD, MPH; Ognjen Gajic, MD, MSc; Lorraine B. Ware, MD; Michelle Ng Gong, MD, MS;
for the US Critical Illness and Injury Trials Group: Lung Injury Prevention with Aspirin Study Group (USCIITG:LIP S-A)
IMPORTANCE Management of acute respiratory distress syndrome (ARDS) remains largely
supportive. Whether early intervention can prevent development of ARDS remains unclear.
OBJECTIVE To evaluate the efficacy and safety of early aspirin administration for the
prevention of ARDS.
DESIGN, SETTING, AND PARTICIPANTS A multicenter, double-blind, placebo-controlled,
randomized clinical trial conducted at 16 US academic hospitals. Between January 2, 2012,
and November 17, 2014, 7673 patients at risk for ARDS (Lung Injury Prediction Score ⱖ4) in
the emergency department were screened and 400 were randomized. Ten patients were
excluded, leaving 390 in the final modified intention-to-treat analysis cohort.
INTERVENTIONS Administration of aspirin, 325-mg loading dose followed by 81 mg/d
(n = 195) or placebo (n = 195) within 24 hours of emergency department presentation and
continued to hospital day 7, discharge, or death.
MAIN OUTCOMES AND MEASURES The primary outcome was the development of ARDS by
study day 7. Secondary measures included ventilator-free days, hospital and intensive care
unit length of stay, 28-day and 1-year survival, and change in serum biomarkers associated
with ARDS. A final α level of .0737 (α = .10 overall) was required for statistical significance of
the primary outcome.
RESULTS Among 390 analyzed patients (median age, 57 years; 187 [48%] women), median
(IQR) hospital length of stay was 6 (3-10) days. Administration of aspirin, compared with
placebo, did not significantly reduce the incidence of ARDS at 7 days (OR, 1.24; 92.6% CI,
0.67-2.31). No significant differences were seen in secondary outcomes or adverse events.
Aspirin
(n = 195)
Placebo
(n = 195) Mean Difference (90% CI)
P
Value
Primary outcome
ARDS within 7 d, No. (%) 20 (10.3) 17 (8.7) 1.5 (−3.8 to 6.8) .53
Secondary outcomes
Ventilator-free days to day 28,
mean (SD)
24.9 (7.4) 25.2 (7.0) −0.26 (−1.46 to 0.94) .72
ICU length of stay, mean (SD), d 5.2 (7.0) 5.4 (7.0) −0.16 (−1.75 to 1.43) .87
Hospital length of stay, mean (SD), d 8.8 (10.3) 9.0 (9.9) −0.27 (−1.96 to 1.42) .79
28-Day survival, %(90% CI) 90 (86 to 93) 90 (86 to 93) HR, 1.03 (90% CI, 0.60 to 1.79) .92
1-Yearestimated sur vival,
% (90% CI)
73 (67 to 78) 75 (69 to 80) HR, 1.06 (90% CI, 0.75 to 1.50) .79
Bleeding-related adverse events,
No. (%)
11 (5.6) 5 (2.6) OR, 2.27 (90% CI, 0.92 to 5.61) .13
CONCLUSIONS AND RELEVANCE Among at-risk patients presenting to the ED, the use of
aspirin compared with placebo did not reduce the risk of ARDS at 7 days. The findings of this
phase 2b trial do not support continuation to a larger phase 3 trial.
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01504867
JAMA. 2016;315(22):2406-2414. doi:10.1001/jama.2016.6330
Published online May 15, 2016. Corrected on September 13, 2016.
Editorial page 2403
Supplemental content at
jama.com
CME Quiz at
jamanetworkcme.com
Author Affiliations: Author
affiliations are listed at the end of this
article.
Group Information: The US Critical
Illness and Injury Trials Group: Lung
Injury Prevention with Aspirin Study
Group (USCIITG: LIPS-A) members
are listed at the end of this article.
Corresponding Author: DarylJ.Kor,
MD, Mayo Clinic College of Medicine,
Mayo Clinic, 200 First St SW,
Rochester,MN 55905
(kor.daryl@mayo.edu).
Section Editor: Derek C. Angus, MD,
MPH, Associate Editor,JAMA
(angusdc@upmc.edu).
Research
Original Investigation |CARING FOR THE CRITICALLY ILL PATIENT
2406 (Reprinted) jama.com
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: on 08/17/2018
Copyright 2016 American Medical Association. All rights reserved.
Acute respiratory distress syndrome (ARDS) remains a
life-threatening critical care syndrome
1-3
character-
ized by alveolar-capillary membrane injury and hy-
poxemic respiratory failure. The median time to onset of ARDS
is 2 days after hospital presentation.
4
The period between hos-
pital presentation and development of ARDS presents a brief
window of opportunity for ARDS prevention. Therefore, a ma-
jor inherent challenge for ARDS prevention trials is early and
accurate identification and treatment of patients at risk.
Mechanistically, ARDS has been viewed as an inflamma-
tory condition. Recently, additional pathways have been de-
scribed with accumulating evidence suggesting an important
role for platelets in both the onset
5-7
and resolution
8-10
of lung
injury. Observational studies have suggested a potential pre-
ventive role for antiplatelet therapy in patients at high risk for
ARDS.
11-14
To further understand the role of aspirin for the pre-
vention of ARDS, a randomized clinical trial was performed
aiming to test the efficacy and safety of aspirin for the preven-
tion of ARDS among at-risk patients: the Lung Injury Preven-
tion Study with Aspirin (LIPS-A).
Methods
Study Design
This was a multicenter, double-blind, placebo-controlled, par-
allel-group, phase 2b, randomized clinical trial. The full study
design and study procedures are published elsewhere
15
and are
included in Supplement 1. The study was approved by the in-
stitutional review boards of all participating locations prior to
the initiation of study-relatedac tivities. Written informed con-
sent was obtained from the patient, next of kin, or the legal
representative of the patient for those unable to provide con-
sent due to their medical condition(s). The patient or surro-
gate was informed about the right to withdraw from the study
at any point. Patients who wereunable to provide consent prior
to randomization due to their medical condition(s) were in-
formed accordingly if they regained consciousness.
Study Population
Patients aged 18 years or older admitted to the hospital
through the emergency department with elevated risk for
developing ARDS based on a calculated lung injury predic-
tion score (LIPS ≥4)
4
were considered for inclusion in the
trial. The LIPS threshold of 4 was previously identified as the
cut point that optimized both sensitivity and specificity of
the predictive model. The aim of this trial was to better
define the role of aspirin as a potential ARDS prevention
intervention (as opposed to a therapy for established ARDS).
Therefore, patients with prevalent ARDS at the time of
screening were excluded. Patients presenting to the emer-
gency department who were already receiving antiplatelet
therapies were also excluded. Considerations related to this
exclusion included the ethical implications of discontinuing
antiplatelet therapies in patients for whom they had previ-
ously been prescribed as well as the potential confounding
effects of preadmission antiplatelet therapies (and their
potential for extended impact on platelet function even after
discontinuation) with the primary outcome of interest. Addi-
tional exclusion criteria are described in Supplement 1.
Shortly after trial onset, the data and safety monitoring
board removed prevalent chronic kidney disease or acute
kidney injury as exclusion criteria. Randomization was
required to be completed within 12 hours of presentation to
the participating hospital. Information on race, stipulated by
the study funding agency, was collected from participants
via self-report.
Randomization and Blinding
Eligible participants were centrally randomized in a 1:1 ratio
to the aspirin or placebo treatment group using Medidata
Balance. Dynamic minimization with a second guess probabil-
ity of 0.2 was used to randomly allocate treatment assign-
ments while stratifying by center.
16
The study participant, clini-
cal team, and all members of the study team were blinded to
treatment allocation.
Interventions
Study Drug
The first dose of study drug was administered within 24 hours
after presentation to the hospital. For patients randomized to
the intervention group, a 325-mg loading dose of aspirin was
administered on day 1, followed by 81 mgof aspirin once daily
up to day 7, hospital discharge, or death, whichever occurred
first. The placebo group received an identical-appearing cap-
sule filled with lactose powder. The dose of aspirin selected
for this trial was influenced by existing literature noting low-
dose aspirin at 81 mg/d was effective in elevating plasma lev-
els of anti-inflammatory lipoxins and inhibitingplatelet throm-
boxane activity with only a slight increase in effect at higher
doses.
17,18
A larger loading dose of aspirin (325 mg) was se-
lected in an effort to mitigate potential risks related to insuf-
ficient dosing of study medication.
Co-Interventions
Important co-interventions, including mechanical ventila-
tion, aspiration precautions, infection control, and fluid and
transfusion management, were standardized across sites using
the web-based tool Checklist for Lung Injury Prevention
(CLIP)
19
(see full protocol in Supplement 1).
Outcomes
The primary outcome was the development of ARDS, as de-
fined by Berlin criteria (modified to require invasive mechani-
cal ventilation),
20
within 7 days of hospital admission. The in-
clusion of invasive mechanical ventilation as a requirementfor
adjudicating ARDS was pursued to mitigate concerns related
to the more subjective nature of implementing noninvasive
ventilator support. In addition, restriction of mechanical ven-
tilator support to include only invasive mechanical ventila-
tion provided a greater degree of consistency with prior ARDS
clinical trials. To assess for the primary outcome, study par-
ticipants were screened daily for receipt of mechanical venti-
lation and determination of the partial pressure of arterial oxy-
gen (PaO
2
) or oxygen saturation to fraction of inspired oxygen
ratio (SpO
2
:FIO
2
). If the study participant’s SpO
2
:FIO
2
ratio was
Aspirin for Prevention of ARDS in the Emergency Department Original Investigation Research
jama.com (Reprinted) JAMA June 14, 2016 Volume 315, Number 22 2407
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: on 08/17/2018
Copyright 2016 American Medical Association. All rights reserved.
consistently below 315,
21
hypoxemia was confirmed with mea-
surement of arterial blood gas. Chest radiographs for all intu-
bated patients with a PaO
2
:FIO
2
ratio of 300 or less were inde-
pendently reviewed by both site investigator and a member
of the trial’s executive committee (D.T.) for bilateral infil-
trates consistent with ARDS. Disagreements were resolved by
3 additional investigators blinded to the initial ARDS adjudi-
cation (D.J.K., O.G., M.N.G.). Study participants who died or
were discharged from the hospital before day 7 without meet-
ing criteria for ARDS were adjudicated as not having ARDS. Sec-
ondary outcome assessments included ventilator-free days to
hospital day 28, intensivec are unit (ICU) and hospital lengths
of stay, and 28-day and 1-year mortality.
Biomarker Analysis
Plasma samples were obtained at baseline (after randomiza-
tion, before administration of study drug), on study day 1
(approximately 24 hours after the first dose), and on study
day 4 for enzyme-linked immunosorbent assays (in dupli-
cate) of 9 plasma biomarkers previously found to be associ-
ated with the development of ARDS. These include surfac-
tant protein D (SP-D), a marker of lung epithelial injury
(BioVendor Inc); angiopoietin 2 (Ang-2), a marker and
mediator of endothelial injury (R&D Systems); interleukins
IL-1β, IL-2, IL-4, IL-6, IL-8, and IL-10; and tumor necrosis
factor α (TNF-α), markers of inflammation (Meso Scale
Diagnostics).
Statistical Methods
This study was designed as a phase 2b clinical trial using an a
priori α= .10 and planned interim analysis, which was con-
ducted with an information fraction of 62.5% (n = 250 par-
ticipants). This shifted the final α level from a planned .0889
to .0737 using the prespecified O’Brien-Fleming–like α spend-
ing function.
22,23
Therefore, for the primary end point to be
statistically significant, the 2-sided Pvalue would need to
be <.0737.For secondary end points, P<.10 was considered sta-
tistically significant. No adjustment for multiple testing was
applied to reported Pvalues, and these analyses should be in-
terpreted as exploratory.
We estimated the sample size of 197 per group based on
the following assumptions: (1) an ARDS development rate of
18%, (2) a minimum clinically relevant effect of 10 percent-
age points, and (3) a final 2-sided α of .0889, adjusted for a
planned interim analysis at 50% information fraction. The ef-
fect size of 10% was chosen by the study’s executive team at
the time of protocol creation based on the impression that this
represents a clinically relevant between-group difference in
ARDS event rates. Conservative sample size estimates were
based on ARDS event rates of 25% and 15%to dec rease the rela-
tive risk and increase the binomial proportion variance. Tar-
get randomization was set at 200 participants per group (400
total) to allow for attrition.
Conditional logistic regression was used to test the pri-
mary hypothesis that early aspirin administration would
decrease the rate of ARDS. Clinical site was included in the
model as a stratification variable. This analysis was supple-
mented by Cochran-Mantel-Haenszel stratified analysis
with odds ratios computed for each site. We used the
Breslow-Day test to test for differences in aspirin effect by
site. Secondary binary end points were tested using uncon-
ditional tests and time-to-event analyses were conducted
using Kaplan-Meier estimator. Continuous measures were
tested between groups using Wilcoxon rank sum and
2-sample ttests. Numerical summaries of these variables
are presented as median (quartile 1-quartile 3) and mean
(SD) unless otherwise specified. The protocol-specified full
intention-to-treat (ITT) analysis set was modified to account
for withdrawal of consent or ineligibility based on inclusion
or exclusion criteria. We conducted analyses on the resul-
tant full analysis set (ie, a modified ITT analysis set). Plasma
biomarkers were analyzed separately using mixed models to
test for the fixed effects of day of treatment, treatment
assignment, and the treatment by time. Participants were
modeled with a random intercept. Biomarker concentra-
tions were log transformed prior to analysis, and for concen-
trations below the assay lower limit of detection (LLD), a
numeric value was imputed as 0.5 × assay LLD.
In addition to statistical criteria for significance, the
study included a priori “go-no-go” definitions for recom-
mending continuation to phase 3 study (see section 10.3.5 in
the protocol in Supplement 1). Briefly, continuation to phase
3 would occur with a positive primary outcome finding
along with an acceptable safety profile. An acceptable safety
profile was defined as a serious adverse event profile for
aspirin that was not statistically worse than placebo (95% CI
for the relative risk of any serious adverse event covers the
null value of relative risk = 1.0). The “no-go decision” was
defined as early termination by the data and safety monitor-
ing board for safety or unfavorable risk/benefit ratio. An
indeterminate case in which there was a non–statistically
significant effect but this effect was in a clinically meaning-
ful direction was also defined. Final statistical analyses
were conducted using the base SAS System version 9.4 and
SAS/STAT version 14.1.
Results
Patient Characteristics
Between January 2, 2012, and November 17, 2014, 7673
patients were screened at 16 medical centers from across
the United States (Figure;eTable1inSupplement 2). The
most common reasons for exclusion included antiplatelet
therapy at the time of presentation (n = 3052), inability to
obtain informed consent within the prespecified 12-hour
window (n = 1299), and suspicion for active bleeding at time
of initial evaluation (n = 999). After excluding 7273 screen
failures, 400 patients were randomized. Ten randomized
patients were excluded from subsequent analyses (aspirin,
n = 7; placebo, n = 3; 6 for withdrawal of consent and 4 for
ineligibility discovered after randomization), leaving 195
patients in each group of the modified ITT analysis set.
Baseline demographics and clinical characteristics,
according to treatment allocation, are presented in Table 1.
Randomization procedures were effective at equalizing
Research Original Investigation Aspirin for Prevention of ARDS in the Emergency Department
2408 JAMA June 14, 2016 Volume315, Number 22 (Reprinted) jama.com
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: on 08/17/2018
Copyright 2016 American Medical Association. All rights reserved.
distributions of baseline variables. The median (interquartile
range [IQR]) time from hospital presentation to randomiza-
tion was 7.3 (5.1-10.2) hours. The median age was 57 (45-68)
years and 52% (203/390) were male. Baseline lung injury
prediction scores (LIPS) were not significantly different
between groups, with a median (IQR) LIPS of 6.0 (5.0-7.5) in
the aspirin group and 5.5 (4.5-7.0) in the placebo group.
Major risk factors for ARDS were similarly distributed in both
treatment groups.
Study Drug Administration
Of 2049 potential study drug administration episodes, 1742(85%)
were provided as per protocol. Of the 195 patients randomized
to receive aspirin, 185 (95%)received at least 1 dose of study medi-
cation. In the placebo group, 189 (96.9%) receivedat least 1 dose
of study drug. The median (IQR) number of doses was not sta-
tistically different (4 [2-7] for aspirin and 5 [3-7] for placebo;
P= .19).The median time from randomization to first study drug
administration was 12.7 (7.9-21.2) hours in the aspirin group and
12.4 (8.8-19.3) hours in the placebo group (P= .86). Reasons for
study participants not receiving at least 1 of their assigned study
medications are provided in the Figure.
Primary Outcomes
In the modified ITT analysis set, 37 patients (9.5%) developed
ARDS within 7 days of randomization: 20 patients (10.3%)in the
aspirin group compared with 17 patients in the placebo group
(8.7%), for a site-adjusted odds ratio (92.6% CI) of 1.24 (0.67-
2.31); P= .53. The distribution of ARDS by enrolling site is shown
in the online data supplement (eFigure 1 in Supplement 2). The
Breslow-Daytest for homogeneity did not suggest there was sig-
nificant variation in the odds ratio by site (P= .19).
Secondary Outcomes
There was no signal for a beneficial effect of aspirin across sec-
ondary efficacy outcome measures (Table 2). A total of 18 pa-
tients (9.2%) in the aspirin group and 18 patients (9.2%) in the
placebo group died by 28 days (28-day survival, 90% vs 90%,
hazard ratio [90% CI], 1.03 [0.60-1.79]; log-rank P= .92).
Longer-term mortality over the year of follow-up showed the
same pattern as shorter-duration mortality analyses (1-year sur-
vival, 73% vs 75%; hazard ratio [90% CI], 1.06 [0.75-1.50]; log-
rank P= .79; eFigure 2 in Supplement 2). No statistically sig-
nificant differences were noted in the additional secondary
clinical outcomes including need for mechanical ventilation,
Figure. Flowchart of Enrolled Participants and Progress Through the LIPS-A Trial
7673 Patients assessed for eligibility
400 Randomized
7273 Excluded
3052 Receiving antiplatelet therapy at presentation
to emergency department
644 Not committed to full life support
1299 Unable to consent within 12 h
999 Suspected active bleeding
279 Allergy to NSAIDS or aspirin
209 Chronic bilateral pulmonary infiltrates
180 Bleeding disorder
172 Hospital stay expected <48 h
161 Not anticipated to survive >48 h
105 Severe chronic liver disease
92 Admitted for hospice or comfort care
57 Admitted for elective/emergency surgery
24 Prevalent ARDS
dose of study drug
202 Randomized to receive aspirin
7Withdrawn after randomization but prior
to first scheduled dose of study drug
2Inclusion criteria not met
5Consent revoked
195 Included in primary efficacy analysis
7Randomized patients excluded from analysis
2Inclusion criteria not met
5Consent revoked
195 Included in primary efficacy analysis
3Randomized patients excluded from analysis
2Inclusion criteria not met
1Consent revoked
198 Randomized to receive placebo
3Withdrawn after randomization but prior
to first scheduled dose of study drug
2Inclusion criteria not met
1Consent revoked
195 Eligible to receive study drug
185 Received ≥1 dose
10 Did not receive study drug
5Care plan included antiplatelet therapy
2Bleeding concern
2Undisclosed daily antiplatelet therapy
at randomization
1Left treatment facility
195 Eligible to receive study drug
189 Received ≥1 dose
6Did not receive study drug
4Care plan included antiplatelet therapy
1Bleeding concern
1Undisclosed daily antiplatelet therapy
at randomization
Reasons for exclusion were not
mutually exclusive and exhaustive
because participants could have
more than 1 reason for exclusion.
Exclusion after randomization
(n = 10) resulted in a change from an
intention-to-treat analysis to a
modified intention-to-treat analysis
denoted as the full analysis set in
International Conference on
Harmonization statistical guidelines
(E9 guidelines). The full analysis set
was used for all analyses. The
ineligibility reasons for the 4
participants withdrawn from the
intention-to-treat sample were
allergy to aspirin confirmed before
first dose but after randomization;
non-English speaking and removed
per institutional review board
determination; participant enrolled
into study twice (second enrollment
excluded); and patient was
determined to have acute kidney
injury after consent but prior to first
dose. The 6 participants who
withdrew consent indicated that
previously collected data could not
be used in the study.
Aspirin for Prevention of ARDS in the Emergency Department Original Investigation Research
jama.com (Reprinted) JAMA June 14, 2016 Volume 315, Number 22 2409
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: on 08/17/2018
Copyright 2016 American Medical Association. All rights reserved.
ventilator-free days at day 28, ICU length of stay, or hospital
length of stay. Patients in the aspirin group were more likely
to be admitted to the ICU (59.0% vs 50.3%; odds ratio [90%
CI], 1.42 [1.02-1.99]; P= .08). In the biomarker analysis, IL-2
was higher in the aspirin group vs placebo on day 1 (P= .08)
with a time × treatment interaction effect (P= .08) that met
the prespecified level of significance (P< .10). However, there
were no other between-group differences or time × treat-
ment interaction effects for any of the other biomarker levels
analyzed at baseline, day 1, or day 4 (P> .10) (eFigure 3 in
Supplement 2).
Adverse Events
No statistically significant differences were found in mea-
sures of safety (Table 3;eTable2inSupplement 2). Study-
reported adverse events were observed in 7.7% (30/390) of
the participants. Of these, bleeding-related adverse events
were reported in 11 of 195 patients (5.6%) assigned to the
aspirin group and 5 of 195 patients (2.6%) assigned to the
placebo group (odds ratio [90% CI], 2.27 [0.92-5.61];
P= .13). Moderate or severe bleeding-related adverse events
were infrequent in both groups [aspirin (n = 8) vs placebo
(n = 4), 4.1% vs 2.1%, odds ratio [90% CI], 2.04 [0.74-5.67];
P= .24). Development of worsening renal function as esti-
mated by the modified RIFLE criteria (Risk, Injury, Failure,
Loss, End-stage Renal Disease
24
) did not differ statistically
by treatment assignment. Detailed numerical summaries of
changes in renal function are included in Table 3.
Discussion
We report the results of a multicenter, randomized, double-
blind, placebo-controlled phase 2b trial evaluating early aspi-
rin administration for prevention of ARDS. In at-risk patients,
initiating aspirin therapy within 24 hours of presentation to
the emergency department was safe when compared with pla-
cebo. However, early aspirin therapy did not decrease the pri-
mary outcome of ARDS development or improve anyof the sec-
ondary outcomes. As such, the results of this phase 2b trial did
not meet the prespecified criteria to recommend pursuing a
larger, phase 3 study.
Despite substantial improvements over the past 2
decades,
1,25
mortality in severe ARDS remains as high as 40%
to 50%.
3,20
The search for further reductions in mortality has
shifted attention from targeted therapeutics administered af-
ter the development of critical illness to earlier interventions
designed to ameliorate or even prevent organf ailure.
26,27
The
majority of patients and clinicians are willing to consider an
acceptably safe, early intervention before the development of
disease in order to prevent later, more severe consequences.
In this paradigm, timely risk stratification is essential to maxi-
mize administration to patients who have the highest prob-
ability of benefit and to mini-mize the risk to patients who will
never go on to develop the disease.
The time course of ARDS development following presen-
tation to the emergency department is rapid, with most cases
developing within 1 to 2 days of initial hospitalization.
4,28
To
effectively test a true prevention strategy, we based patient
identification and risk stratification on early determination of
LIPS of 4 or higher in the emergency department or ICU coupled
with a 12-hour trial eligibility window, well in advance of the
usual time frame for enrolling participants in ARDS treat-
ment trials.
Early aspirin administration for ARDS prevention was
tested based on the body of existing experimental data
Table 1. Demographics and Baseline Characteristicsof the 390
Participants Included in the Modified Intention-to-Treat Analysis Set
No. (%)
Aspirin
(n = 195)
Placebo
(n = 195)
Age, median (IQR), y 57.0
(44.0-67.0)
57.0
(47.0-68.0)
Male sex 107 (54.9) 96 (49.2)
White race 142 (72.8) 137 (70.3)
Hispanic or Latino ethnicity 21 (10.8) 20 (10.3)
BMI, median (IQR)
a
28.5 (23.3-33.9) 26.2 (21.7-32.4)
Diabetes 37 (19.0) 35 (17.9)
History of alcohol abuse 31 (15.9) 29 (14.9)
Tobacco use
Never 64 (32.8) 60 (30.8)
Current 38 (19.5) 43 (22.1)
Former 67 (34.4) 64 (32.8)
Unknown 26 (13.3) 28 (14.4)
Creatinine, median (IQR),
mg/dL
b
1.0 (0.7-1.4) 1.0 (0.8-1.5)
Estimated glomerular
filtration rate, median (IQR),
mL/min/BSA
b
80.1
(51.6-112.2)
74.2
(44.8-104.5)
ARDS risk factor
Suspected sepsis 150 (76.9) 153 (78.5)
Noncardiogenic shock 41 (21.0) 40 (20.5)
Suspected or witnessed
aspiration
28 (14.4) 22 (11.3)
Possible pneumonia 120 (61.5) 116 (59.5)
Pancreatitis 1 (0.5) 0
Trauma (lung contusion,
multiple fractures, near
drowning, smoke
inhalation)
9 (4.6) 15 (7.7)
High risk or emergent
surgery
0 1 (0.5)
Ventilated on day
of randomization
39 (20.0) 29 (14.9)
Ventilated prior to first dose
of study drug
c
39 (20.5) 31 (16.5)
Lung Injury Prediction score,
median (IQR)
d
6.0
(5.0-7.5)
5.5
(4.5-7.0)
Abbreviations: ARDS, acute respiratory distress syndrome; BMI, body mass
index (calculated as weight in kilograms divided by height in meters squared);
BSA, body surface area; IQR, interquartile range.
SI conversion factor: Toconvert creatinine to μmol/L, multiply values by 88.4.
a
Sample size is 192 vs 193 for aspirin and placebo, respectively.
b
Sample size is 184 vs 185 for aspirin and placebo, respectively.
c
Sample sizes is 190 vs 188 for aspirin and placebo, respectively.
d
The Lung Injury Prediction Score (theoretical range: −1 to 30.5)combines
predisposing conditions and risk modifiers to predict the probability of ARDS,
with higher scores indicating greater probability for ARDS. The protocol
contains the scoring algorithm (see Appendix F in Supplement 1).
Research Original Investigation Aspirin for Prevention of ARDS in the Emergency Department
2410 JAMA June 14, 2016 Volume 315, Number 22 (Reprinted) jama.com
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: on 08/17/2018
Copyright 2016 American Medical Association. All rights reserved.
demonstrating alterations in platelet function during the
development of ARDS.
29
Platelet activation, aggregation,
and sequestration, as well as modulation of anti-
inflammatory lipid mediators, including leukotrienes,
thromboxane, and prostaglandins, have all been implicated
as important mediators of ARDS progression and
severity.
5,6,8,9,29
Aspirin directly modifies these mechanistic
pathways, making it a plausible preventive and therapeutic
measure in this setting.
5,30,31
To date, clinical studies have
suggested conflicting benefits of aspirin or other nonsteroi-
dal anti-inflammatory drugs in the setting of both sepsis
and lung injury.
11-14,32
In this first randomized clinical trial
evaluating aspirin for the prevention of ARDS, no effects on
the primary or secondary clinical outcomes were noted.
Increased IL-2 concentrations after treatment with aspirin
were present on day 1, consistent with prior work suggest-
ing increased IL-2 production following aspirin
administration.
33
These results may signify a biological
effect of aspirin. However, type I error cannot be excluded
and any potential biological effect of aspirin was not associ-
ated with a difference in clinical outcomes nor alterations in
the other 8 plasma biomarkers of inflammation, endothelial
injury, and lung epithelial injury.
In trials of early aspirin administration for acute coro-
nary syndrome and stroke, the excess risk of major extracra-
nial bleeding has been estimated as a proportional increase
of approximately half of the baseline absolute risk of bleed-
ing, a risk offset by the much greater absolute benefits of
treatment.
34
We observed similar risks for moderate or
severe bleeding events; however, the results of the investi-
gation failed to associate aspirin administration with any
benefits of reduced rate of ARDS, intensity of hospital use,
or mortality.
In addition to testing the specific hypotheses of this trial,
we gleaned potentially useful additional information during
this investigation. The study demonstrated that the conduct
of a large multicenter ARDS prevention trial, though chal-
lenging, was feasible. Unlike most ARDS treatment trials in
which the primary screening and enrollment activity occurs
in the ICU, the primary screening environment for this inves-
tigation was the emergency department. Furthermore, the
window for randomization was limited (12 hours from pre-
Table 2. Primary and Secondary Outcome Measures by Treatment Assignment
Aspirin
(n = 195)
Placebo
(n = 195) Difference (90% CI)
a
Odds Ratio (90% CI)
a
PValue
b
Primary outcome, No. (%)
ARDS within 7 d 20 (10.3) 17 (8.7) 1.5 (−3.8 to 6.8) 1.24 (0.67 to 2.31) .53
Secondary outcomes, No. (%)
Hospital mortality 14 (7.2) 14 (7.2) 0.0 (−4.3 to 4.3) 1.00 (0.53 to 1.91) >.99
ARDS or mortality within 7 d 27 (13.9) 21 (10.8) 3.1 (−2.4 to 8.5) 1.33 (0.80 to 2.22) .36
Mechanical ventilation at any time
during hospitalization
51 (26.2) 41 (21.0) 5.1 (−1.9 to 12.2) 1.33 (0.90 to 1.97) .23
Ventilator-free to day 28 (ventilated
patients)
Median (Q1-Q3), d 23.0 (17.0 to 26.0) 23.0 (9.0 to 26.0) .67
Mean (SD), d 24.9 (7.4) 25.2 (7.0) −0.26 (−1.46 to 0.94) .72
Admission to ICU, No. (%) 115 (59.0) 98 (50.3) 8.7 (0.5 to 17.0) 1.42 (1.02 to 1.99) .08
ICU length of stay (ICU admitted
patients)
Median (Q1-Q3), d 3.2 (1.8 to 6.0) 2.4 (1.6 to 5.2) .39
Mean (SD), d 5.2 (7.0) 5.4 (7.0) −0.16 (−1.75 to 1.43) .87
Hospital length of stay
Median (Q1-Q3), d 5.0 (3.0 to 10.0) 6.0 (4.0 to 10.0) .38
Mean (SD), d 8.8 (10.3) 9.0 (9.9) −0.27 (−1.96 to 1.42) .79
28-d survival
No. of deaths 18 18
Estimated survival probability
(90% CI)
c
0.90 (0.86 to 0.93) 0.90 (0.86 to 0.93) HR, 1.03 (0.60 to 1.79) .92
1-Year survival
c
No. of deaths 45 44
Estimated survival probability
(90 CI%)
c
0.73 (0.67 to 0.78) 0.75 (0.69 to 0.80) HR, 1.06 (0.75 to 1.50) .79
Abbreviations: ARDS, acute respiratory distress syndrome; HR, hazard ratio;
ICU, intensive care unit; Q1 and Q3, first and third quartile of the distributions.
a
Confidence intervals are 90% CI for all outcomes except for the primary
outcome. The primary outcome significance level was adjusted for multiple
testing associated with the interim analysis. Its significance level is 92.6%.
Categorical data are presented as risk difference percentage (CI) and
continuous variables are presented as mean difference (90% CI).
b
Pvalues are from Pearson χ
2
(categorical variables) or Wilcoxon rank sum
(continuous variables) tests with 2 exceptions: (1) the primary outcome
measure, which was a large sample (Wald) test estimated using a conditional
logistic regression model with site as a stratification variable and (2) the
survival estimates, which were from log-rank tests.
c
Values estimated from a Kaplan-Meier product limit estimator.
Aspirin for Prevention of ARDS in the Emergency Department Original Investigation Research
jama.com (Reprinted) JAMA June 14, 2016 Volume 315, Number 22 2411
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: on 08/17/2018
Copyright 2016 American Medical Association. All rights reserved.
sentation). These constraints required meaningful modifica-
tions to the traditional screening and recruitment strategies
used in prior ARDS treatment trials. Computer-assisted high-
throughput screening algorithms greatly facilitated study
activities at participating centers where they could be imple-
mented. Modifications in study coordinator screening times
(extending screening activities through the evenings to bet-
ter capture the presentation times of the target population)
also facilitated the identification of study participants.
Strengths of this investigation include the robust study
design, secondary review of ARDS outcomes by an indepen-
dent review panel, implementation of the LIPS risk predic-
tion score to enrich the study population, and use of the CLIP
19
to assist with standardizing important co-interventions that
may have otherwise confounded the interactions of interest.
There were also several limitations that deserve discus-
sion. First and foremost was the lower than expected rate of
ARDS development (9.5% vs 18%expected). Although the rea-
sons for this unexpectedly low rate of ARDS remain unclear,
considerations include suboptimal performance of the LIP
score, biased enrollment as a result of the informed consent
process (less severely ill patients being more likely to provide
consent), effectiveness of adherence with CLIP elements in re-
ducing the risk of hospital-acquired ARDS, or temporal reduc-
tions in the rate of ARDS from the time of study planning to
actual study conduct. In addition to the lower than expected
rate of ARDS, low rates of mechanical ventilation, acute kid-
ney injury,and mortality suggest that the enrolled study popu-
lation may have had a more modest overall severity of illness
than what was anticipated at study onset. As a result, the ex-
ternal validity of our findings in a cohort of critically ill pa-
tients with greater severity of illness remains unclear. Still, the
results of this trial appear robust and consistent between the
clinical and biomarker outcome measures.
Second, despite the intention of early identification of
patients at risk for ARDS to facilitate the testing of aspirin as
a prevention intervention, a large number of potential study
participants (n = 1152) had bilateral infiltrates consistent
with ARDS at the time of screening. This limitation high-
lights the challenge of pursuing ARDS prevention strategies
even when targeting screening efforts to environments such
as the emergency department. Also noted is the larger than
expected number of patients who were excluded for preva-
lent antiplatelet therapy or who were thought to be at high
risk for bleeding. In addition to potentially biasing the study
population toward a less severely ill cohort, thereby contrib-
uting to the lower than expected rate of ARDS, these exclu-
sions may further limit the generalizability of the study
findings.
Third, the time from randomization to first drug admin-
istration was longer than anticipated at study onset. The
goal was to encourage informed consent, randomization,
Table 3. SafetyOutcome s byTreatment Assignment
Aspirin
(n = 195)
Placebo
(n = 195) Difference (90% CI)
b
Odds Ratio (90% CI) PValue
Adverse event summary, No. (%)
a
Any adverse event 17 (8.7) 13 (6.7) 2.1 (−2.4 to 6.5) 1.34 (0.71 to 2.51) .45
Bleeding-related adverse event
Any severity 11 (5.6) 5 (2.6) 3.1 (−0.2 to 6.4) 2.27 (0.92 to 5.61) .13
Moderate or severe 8 (4.1) 4 (2.1) 2.1 (−0.8 to 4.9) 2.04 (0.74 to 5.67) .24
Renal function
c
RIFLE classification, No. (%)
Risk 28 (17.0) 20 (11.2) 5.8 (−0.4 to 12.0) 1.61 (0.96 to 2.71) .13
Injury 5 (3.0) 6 (3.4) −0.3 (−3.5 to 2.8) 1.12 (0.41 to 3.07) .86
Failure 0 0 >.99
Change in creatinine, median
(Q1-Q3), mg/dL
0.0 (−0.2 to 0.1) −0.1 (−0.2 to 0.1) .29
Mean (SD), mg/dL 0.04 (0.76) −0.19 (1.08) 0.2 (0.1 to 0.4)
d
.03
% Change in creatinine 0.0 (−20.0 to 15.4) −5.2 (−18.8 to 8.6) .36
Mean (SD), % 5.7 (59.4) 1.1 (51.8) 4.6 (−5.3 to 14.5) .44
Change GFR, median (Q1-Q3),
mL/min/BSA
0.0 (−20.5 to 7.2) −0.7 (−15.4 to 4.1) .70
Mean (SD) 0.2 (63.8) −5.1 (42.8) 5.3 (−4.3 to 14.9) .37
% Change in GFR, median (Q1-Q3) 0.0 (−29.4 to 15.2) −6.3 (−27.1 to 9.1) .36
Mean (SD), % −10.1 (41.0) −32.9 (186.2) 4.3 (−3.7 to 12.4)
e
.13
Abbreviations: ARDS, acute respiratory distress syndrome; BSA, body surface
area; GFR, glomerular filtration rate; ICU, intensive care unit; Q1 and Q3, first
and third quartile of the distributions; RIFLE, Risk, Injury, Failure, Loss of
Function, End-Stage Renal Disease.
SI conversion factor: Toconvert creatinine to μmol/L, multiply values by 88.4.
a
Given the acuity of the patients enrolled, many common adverse events were
not captured per protocol. Please see online appendix for scope of adverse
event surveillance. The number reported is the number of participants that
experienced an event.
b
Categorical data are presented as risk difference percentage (90% CI) and
continuous variables are presented as mean difference (90% CI).
c
Change in renal function and assessment of RIFLE staging were calculable for
165 aspirin and 178 placebo participants.
d
Two individuals in the placebo group had a >5-mg/dl decrease. This resulted in
a statistically significance difference for the parametric analysis.
e
The two individuals with large decrease in creatinine were removed due to
>1000% change in GFR prior to estimating the mean difference. The mean (SD)
for the placebo group after the removal of the 2 participants was -14.5(48.4).
Research Original Investigation Aspirin for Prevention of ARDS in the Emergency Department
2412 JAMA June 14, 2016 Volume 315, Number 22 (Reprinted) jama.com
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: on 08/17/2018
Copyright 2016 American Medical Association. All rights reserved.
and first study medication administration to be as acceler-
ated as ethically possible. Delays were occasionally experi-
enced due to the need for legally authorized representative
consent as well as the lack of a 24-hour research pharmacy
at many of the participating institutions.
Fourth, it is also possible the aspirin dose chosen for this
study was too low. Although prior studies informed the dosing
regimen used in this trial,
17,18
larger doses of aspirin or extended
duration of administration may have resulted in different out-
comes. Additional mechanistic studies on the effect of aspirin
on thromboxane and platelet-neutrophil function are in prog-
ress to better address this question.
Conclusions
Among at-risk patients presenting to the emergency depart-
ment, the use of aspirin compared with placebo did not re-
duce the risk of ARDS at 7 days. The findings of this phase 2b
trial do not support continuation to a larger phase 3 trial.
ARTICLE INFORMATION
Correction: This article was corrected on
September 13, 2016, to clarify exclusion criteria in
the flow diagram and the Results section.
Published Online: May 15, 2016.
doi:10.1001/jama.2016.6330.
Author Affiliations: Department of
Anesthesiology, MayoClinic College of Medicine,
Rochester,Minne sota (Kor, Hinds); Department of
Health Sciences Research, Division of Biomedical
Statistics and Informatics, Mayo Clinic College of
Medicine, Rochester,Minnesota (Car ter);
Department of Surgery, University of Michigan
School of Medicine, Ann Arbor (Park); Department
of Medicine, Mayo Clinic College of Medicine,
Jacksonville, Florida (Festic); Beth Israel Deaconess
Medical Center, Boston, Massachusetts
(Banner-Goodspeed); Department of Anaesthesia,
Beth Israel Deaconess Medical Center, Harvard
Medical School, Boston, Massachusetts (Talmor);
Department of Medicine, Mayo Clinic College of
Medicine, Rochester,Minnesota (Gajic);
Department of Medicine and Pathology, Vanderbilt
University School of Medicine, Nashville, Tennessee
(Ware); Department of Microbiology and
Immunology, Vanderbilt University School of
Medicine, Nashville, Tennessee(Ware);
Department of Medicine, Albert Einstein College of
Medicine, Bronx, New York (Gong).
Author Contributions: Drs Kor and Carter had full
access to all of 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: All authors.
Acquisition, analysis, or interpretation of data: Kor,
Carter, Park, Festic,Banner-Goodspeed, Hinds,
Talmor, Ware, Gong.
Drafting of the manuscript: Kor, Carter, Park, Festic,
Banner-Goodspeed, Hinds, Talmor, Gong.
Critical revision of the manuscript for important
intellectual content: Kor, Carter, Park, Festic,
Banner-Goodspeed, Talmor, Gajic, Ware, Gong.
Statistical analysis: Kor, Carter, Talmor.
Obtained funding: Kor,Hinds, Talmor, Gong.
Administrative, technical, or material support: Kor,
Banner-Goodspeed, Hinds, Talmor,
Study supervision: Kor, Banner-Goodspeed,Hinds,
Talmor, Gajic, Gong.
Conflict of Interest Disclosures: All authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest. Dr Kor
reports grants from the National Heart, Lung, and
Blood Institute (NHLBI) during the conduct of the
study as well as grants from NHLBI, personal fees
from NHLBI, and personal fees from UptoDate
outside the submitted work. Dr Park reports grants
from NHLBI and nonfinancial support from the
National Center for Advancing Translational
Sciences during the conduct of the study. Mr Hinds
reports grants from NHLBI during the conduct of
the study.Dr Talmor reports grants from NHLBI
during the conduct of the study.Dr Gajic repor ts
grants from NHLBI during the conduct of the study.
Dr Ware reports grants from the National Institutes
of Health during the conduct of the study as well as
consulting fees from Abbott, GlaxoSmithKline, and
Hemocue, and grants from Boehringer Ingleheim
and Global Blood Therapeutics. Dr Gong reports
grants from NHLBI during the conduct of the study
as well as grants from the Centers for Medicare &
Medicaid Services, the Food and Drug
Administration, and the National Institute on Aging
with nonfinancial support from La Jolla
Pharmaceutical outside the submitted work.
NIH NHLBI Lung Injury Prevention Study with
Aspirin Network of Investigators: Beth Israel Dea-
coness Medical Center (D. Talmor*, V.M. Banner-
Goodspeed, T.L. Henson, A.L. Mueller, V.A. Nielsen,
L.V. Off icer, H. Yuan), Bridgeport Hospital (D.A.
Kaufman*), Brigham and Women’s Hospital
(P.C. Hou*, R.E. Abdulnour, I.P. Aisiku, R.C. Dwyer,
G. Frendl, R.E. Gish, E. Goralnick, T.M. Kuczmarski,
B.D. Levy, S. Parmar, J.S. Rempell, R.R. Seethala,
M.Q. Wilson), Duke University Medical Center
(I.J. Welsby*, W.G. Drake, J. Davies), Massachusetts
General Hospital (E. Bajwa*, K. Briat, K. Cosgrove,
C. Holland), Mayo Clinic (E. Festic*, O. Gajic*, D.J.
Kor*, R. Hinds, V. Bansal, R.K. Lingenini, T.M.
Gunderson), Montefiore Medical Center (M.N.
Gong*, G. Soto, S.J. Hsieh, A. Hope, M. Martinez,
J. Salcedo, J. Lora), Stanford University (J.E. Levitt*,
A. Asuni, R. Vojnik), Temple University(N. Mar-
chetti*, N.T. Gentile*, K. Dehnkamp, V. Kalugdan),
University of Florida (M.C. Elie-Turenne*,
H. Alnuaiman, M. Plourde), University of Illinois
College of Medicine at Chicago (R. Sadikot*),
University of Louisville Medical Center (O. Akca*,
R. Cavallazzi, M. Platt), University of Michigan
(P. Park*, K.J. Brierley, J. Cherry-Bukowiec,
L.M. Napolitano, K. Raghavendran, J. Younger),
University of Washington- Harborview Medical
Center (T.R. Watkins *, C.L. Hough*, S.A. Gundel,
L. Hogl, A. Minhas, E. Tran), Wake Forest University
School of Medicine (J.J. Hoth*, C. Wells, B.K. Yoza).
Clinical Coordinating Center: D.S. Talmor*,
V.M. Banner-Goodspeed. Data Coordinating
Center: O. Gajic, D.J. Kor, R.E. Carter, R. Hinds,
R.K. Lingenini, T.M. Gunderson. Biospecimen and
Knowledge Translation Coordinating Center:
M.N. Gong*, G. Soto. Data and Safety Monitoring
Board: G. Martin (Chair), Y. Arabi, S. Carson,
N. Ferguson, J. Mandrekar. Independent Medical
Monitors: P.F. Clardy, M.D. Howell. National Heart,
Lung, and Blood Institute: A. Harabin, P. Ghofrani.
* denotes Principal Investigator.
Funding/Support: This study is supported by NIH
grants U01-HL108712-01, KL2 RR024151,
K23HL112855, UL1TR000433 and the Mayo Clinic
Critical Care Research Committee.
Role of the Funder/Sponsor:Neither the National
Heart, Lung, and Blood Institute nor the Mayo Clinic
Critical Care Research Committee had any role in
the design and conduct of the study; collection,
management, analysis, and interpretation of the
data; preparation, review,or approval of the
manuscript; and decision to submit the manuscript
for publication.
REFERENCES
1. Erickson SE, Martin GS, Davis JL, Matthay MA,
Eisner MD; NIH NHLBI ARDS Network. Recent
trends in acute lung injury mortality: 1996-2005.
Crit Care Med. 2009;37(5):1574-1579.
2. Rubenfeld GD, Caldwell E, Peabody E, et al.
Incidence and outcomes of acute lung injury. N Engl
J Med. 2005;353(16):1685-1693.
3. Bellani G, Laffey JG, Pham T, et al; LUNG SAFE
Investigators; ESICM TrialsGroup. Epidemiology,
Patterns of Care, and Mortality for Patients With
Acute Respiratory Distress Syndrome in Intensive
Care Units in 50 Countries. JAMA. 2016;315(8):788-
800.
4. Gajic O, Dabbagh O, Park PK, et al; U.S. Critical
Illness and Injury Trials Group: Lung Injury
Prevention Study Investigators (USCIITG-LIPS).
Early identification of patients at risk of acute lung
injury: evaluation of lung injury prediction score in a
multicenter cohort study. Am J RespirCrit Care Med.
2011;183(4):462-470.
5. Looney MR, Nguyen JX, Hu Y, Van Ziffle JA,
Lowell CA, Matthay MA. Platelet depletion and
aspirin treatment protect mice in a two-event
model of transfusion-related acute lung injury.J Clin
Invest. 2009;119(11):3450-3461.
6. Zarbock A, Ley K. The role of platelets in acute
lung injury (ALI). Front Biosci (Landmark Ed). 2009;
14:150-158.
7. Zarbock A, Polanowska-Grabowska RK, Ley K.
Platelet-neutrophil-interactions: linking hemostasis
and inflammation. Blood Rev. 2007;21(2):99-111.
8. El Kebir D, József L, Pan W, et al. 15-epi-lipoxin
A4 inhibits myeloperoxidase signaling and
enhances resolution of acute lung injury. Am J
Respir Crit Care Med. 2009;180(4):311-319.
9. Fukunaga K, Kohli P, Bonnans C, Fredenburgh
LE, Levy BD. Cyclooxygenase2 plays a pivotal role
in the resolution of acute lung injury. J Immunol.
2005;174(8):5033-5039.
10. Maderna P, Godson C. Lipoxins: resolutionary
road. Br J Pharmacol. 2009;158(4):947-959.
Aspirin for Prevention of ARDS in the Emergency Department Original Investigation Research
jama.com (Reprinted) JAMA June 14, 2016 Volume 315, Number 22 2413
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: on 08/17/2018
Copyright 2016 American Medical Association. All rights reserved.
11. Boyle AJ, Di Gangi S, Hamid UI, et al. Aspirin
therapy in patients with acute respiratory distress
syndrome (ARDS) is associated with reduced
intensive care unit mortality: a prospective analysis.
Crit Care. 2015;19:109.
12. Chen W, Janz DR, Bastarache JA, et al.
Prehospital aspirin use is associated with reduced
risk of acute respiratory distress syndrome in
critically ill patients: a propensity-adjusted analysis.
Crit Care Med. 2015;43(4):801-807.
13. Erlich JM, Talmor DS, Cartin-Ceba R, Gajic O,
Kor DJ.Prehospitalization antiplatelet therapy is
associated with a reduced incidence of acute lung
injury: a population-based cohort study.Chest.
2011;139(2):289-295.
14. Kor DJ, Erlich J, GongMN, e t al; U.S. Critical
Illness and Injury Trials Group: Lung Injury
Prevention Study Investigators. Association of
prehospitalization aspirin therapy and acute lung
injury: results of a multicenter international
observational study of at-risk patients. Crit Care Med.
2011;39(11):2393-2400.
15. Kor DJ, Talmor DS, Banner-Goodspeed VM,
et al; US Critical Illness and Injury Trials Group: Lung
Injury Prevention with Aspirin Study Group
(USCIITG: LIPS-A). Lung Injury Prevention with
Aspirin (LIPS-A): a protocol for a multicentre
randomised clinical trial in medical patients at high
risk of acute lung injury. BMJ Open. 2012;2(5):
e001606.
16. Pocock SJ, Simon R. Sequential treatment
assignment with balancing for prognostic factors in
the controlled clinical trial. Biometrics. 1975;31(1):
103-115.
17. Patrono C, García Rodríguez LA, Landolfi R,
Baigent C. Low-dose aspirin for the prevention of
atherothrombosis. N Engl J Med. 2005;353(22):
2373-2383.
18. Chiang N, Bermudez EA, Ridker PM, Hurwitz S,
Serhan CN. Aspirin triggers antiinflammatory
15-epi-lipoxin A4 and inhibits thromboxane in a
randomized human trial. Proc Natl Acad SciUSA.
2004;101(42):15178-15183.
19. Litell JM, Gajic O, Sevransky J, et al. Multicenter
consensus development of a checklist for lung
injury prevention. Crit Care. 2012;(16)(suppl 1):504.
20. Ranieri VM, Rubenfeld GD, Thompson BT, et al;
ARDS Definition Task Force.Acute respiratory
distress syndrome: the Berlin Definition. JAMA.
2012;307(23):2526-2533.
21. Rice TW, Wheeler AP, Bernard GR, Hayden DL,
Schoenfeld DA, Ware LB. Comparison of the
SpO2/FiO2 ratio and the PaO2/FiO2 ratio in patients
with acute lung injury or ARDS. Chest. 2007;132(2):
410-417.
22. Gordon Lan KK, Demets DL. Discrete
sequential boundaries for clinical trials. Biometrika.
1983;70(3):659-663.
23. O’Brien PC, Fleming TR. A multiple testing
procedure for clinical trials. Biometrics. 1979;35(3):
549-556.
24. Bellomo R, Ronco C, Kellum JA, Mehta RL,
Palevsky P. Acute renal failure: definition, outcome
measures, animal models; International Consensus
Conference of the Acute Dialysis Quality Initiative
(ADQI) Group. Crit Care. 2004.
25. Phua J, Badia JR, Adhikari NK, et al. Has
mortality from acute respiratory distress syndrome
decreased over time?: A systematic review. Am J
Respir Crit Care Med. 2009;179(3):220-227.
26. Spragg RG, Bernard GR, Checkley W, et al.
Beyond mortality: future clinical research in acute
lung injury. Am J RespirCrit Care Med. 2010;181(10):
1121-1127.
27. Festic E, Kor DJ, Gajic O.Prevention of acute
respiratory distress syndrome. Curr Opin Crit Care.
2015;21(1):82-90.
28. Ferguson ND, Frutos-Vivar F, Esteban A, et al.
Clinical risk conditions for acute lung injury in the
intensive care unit and hospital ward: a prospective
observational study.Crit Care. 2007;11(5):R96.
29. Yadav H, Kor DJ. Platelets in the pathogenesis
of acute respiratory distress syndrome. Am J Physiol
Lung Cell Mol Physiol. 2015;309(9):L915-L923.
30. Bates JJ, Watson RWG, Glynn CM, O’Neill AJ,
Fitzpatrick JM, Buggy DJ. Aspirin preserves
neutrophil apoptosis after cardiopulmonary bypass.
Shock. 2004;21(6):495-499.
31. Jin SW, Zhang L, Lian QQ, et al. Posttreatment
with aspirin-triggered lipoxin A4 analog attenuates
lipopolysaccharide-induced acute lung injury in
mice: the role of heme oxygenase-1.Anesth Analg.
2007;104(2):369-377.
32. Bernard GR, Wheeler AP, Russell JA, et al;
The Ibuprofen in Sepsis Study Group. The effects of
ibuprofen on the physiology and survival of
patients with sepsis. N Engl J Med. 1997;336(13):
912-918.
33. Hsia J, Sarin N, Oliver JH, Goldstein AL.
Aspirin and thymosin increase interleukin-2 and
interferon-gamma production by human peripheral
blood lymphocytes. Immunopharmacology. 1989;17
(3):167-173.
34. Antithrombotic Trialists’ Collaboration.
Collaborative meta-analysis of randomised trials of
antiplatelet therapy for prevention of death,
myocardial infarction, and stroke in high risk
patients. [Erratum appears in BMJ 2002 Jan
19;324(7330):141].BMJ. 2002;324(7329):71-86.
Research Original Investigation Aspirin for Prevention of ARDS in the Emergency Department
2414 JAMA June 14, 2016 Volume 315, Number 22 (Reprinted) jama.com
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: on 08/17/2018
