867687

research-article2019
HPXXXX10.1177/0018578719867687Hospital PharmacyBarletta et al

Critical Care Series

Hospital Pharmacy

The SUP-ICU Trial: Does It Confirm

1­–6
© The Author(s) 2019
Article reuse guidelines:
or Condemn the Practice of Stress sagepub.com/journals-permissions
DOI: 10.1177/0018578719867687
https://doi.org/10.1177/0018578719867687

Ulcer Prophylaxis? journals.sagepub.com/home/hpx

Jeffrey F. Barletta1 , Mitchell S. Buckley2 ,

and Robert MacLaren3

Abstract

Purpose: Stress ulcer prophylaxis (SUP) is routinely administered to critically ill patients for the prevention of stress
ulcer–induced, clinically important bleeding (CIB). Recently, the value of SUP has been questioned due to the perceived
decline in CIB and the potential for infectious complications secondary to acid suppressive therapy. The SUP-ICU trial is a
large, randomized controlled trial comparing intravenous pantoprazole with placebo for the indication of SUP. It is hoped
that this trial would answer many of the questions pertaining to the overall value of SUP. This article will provide an in-depth
assessment of the SUP-ICU trial in the context of the overall body of literature in this area. Furthermore, applications for
clinical practice and recommendations on the provision of SUP are provided. Summary: The SUP-ICU trial revealed no
difference in the primary outcome of 90-day mortality with pantoprazole but lower rates of CIB were noted (which was a
secondary outcome). Overall, these data provide important insight into the value of SUP along with other questions related
to the provision of SUP such as the relationship between CIB and mortality, infectious complications, and enteral nutrition.
Conclusions: The SUP-ICU trial is a landmark trial describing the value of SUP in a modern-day setting of intensive care
unit (ICU) practice. The provision of SUP should be continued in high-risk patients. Future studies are ongoing that will add
further insight to this routine practice.

Keywords
stress ulcer prophylaxis, pantoprazole, gastrointestinal hemorrhage, critical care

The biological response to “stress” was first introduced by
Seyle1 in a classic Letter to the Editor published in Nature in
1936 where he described a 3-phase syndrome (later referred
to as the “stress syndrome”) resulting from the exposure to
acute nonspecific nocuous agents. Part of this stress syn-
drome, occurring 6 to 48 hours after the initial injury, is the
formation of acute erosions in the digestive tract, particularly
in the stomach, small intestine, and appendix that occur due to
tissue ischemia and reperfusion injury. More than 30 years
later, the occurrence of these stress erosions were linked to
surgical or traumatic stress and specifically found in patients
with respiratory failure, hypotension, sepsis, or jaundice.2,3 In
1978, the provision of antacid therapy titrated to maintain
gastric pH of 3.5 in high-risk critically ill patients led to a
reduction in gastrointestinal bleeding events (3.9% vs 24%,
P < .005).4 The potential role of acid suppressive therapy for
the prevention of gastrointestinal bleeding was recognized,
and the concept of stress ulcer prophylaxis (SUP) was born.
Over the next 40 years, there have been numerous random-
ized controlled trials, observational studies, systematic
reviews, and practice guidelines addressing various aspects of
SUP therapy. Nevertheless, despite the overwhelming body
of evidence, there are still questions regarding this widely
used and, for the most part, universally accepted practice.
The proton pump inhibitors (PPI) are the most widely used
pharmacologic agents for the provision of SUP.5-7 Over the
last decade, though, there has been great concern with their
widespread use. Acutely, PPIs have been associated with
infectious complications such as nosocomial pneumonia and
Clostridium difficile infection.8,9 Long-term use of PPIs has
been linked to kidney disease, dementia, and fractures.10
While these adverse drug reactions have primarily been
reported through observational research, inadvertent continu-
ation upon discharge occurs at rates approaching 25%.11 It
remains speculative if the risk of adverse reactions associated
1
Midwestern University, Glendale, AZ, USA
2
Banner—University Medical Center Phoenix, Phoenix, AZ, USA
3
University of Colorado, Aurora, CO, USA
Corresponding Author:
Jeffrey F. Barletta, Department of Pharmacy Practice, College of
Pharmacy-Glendale, Midwestern University, 19555 N 59th Avenue,
Glendale, AZ 85308, USA.
Email: jbarle@midwestern.edu
2 Hospital Pharmacy 00(0)
with PPIs increases with long-term use, thus emphasizing
prudent utilization during transitions of care. In addition to
the potential harms with these agents, there is the perception
that stress-related gastrointestinal mucosal clinically impor-
tant bleeding (CIB) is rare due to the advancements with
modern day intensive care unit (ICU) care. Some systematic
reviews suggest that acid suppression offers no benefit over
placebo.12 Therefore, the potential for clinical equipoise
exists due to concerns that the benefits observed with PPI
therapy may be overshadowed by their complications.
The SUP-ICU study is the first large, multi-center, inter-
national, outcome-based, randomized controlled trial con-
ducted in the modern era comparing PPI therapy with
placebo.13 Study aims were to assess both the benefits and
harms of SUP and provide a clearer picture of the value of
PPI therapy for this indication. The remainder of this article
will focus on the SUP-ICU trial and provide insight on how
clinicians can interpret this trial (while appreciating the com-
plete body of evidence) and optimize SUP use at their respec-
tive institutions.
The SUP-ICU trial included adult patients who were
admitted to an ICU for an acute condition with at least one
risk factor for CIB. Risk factors for CIB were shock, renal
replacement therapy, invasive mechanical ventilation, receipt
of therapeutic anticoagulants, ongoing or history of coagu-
lopathy (defined as platelets <50 000, international normal-
ized ratio >1.5, or prothrombin time >20 seconds within the
past 24 hours or 6 months prior to admission, respectively),
and history of chronic liver disease. Enrolled patients were
randomized to receive either intravenous pantoprazole 40
mg once daily or matching placebo. Study drug was admin-
istered until ICU discharge, death, or a maximum of 90 days.
The primary outcome was 90-day mortality while secondary
outcomes were rates of at least one clinically important event
(defined as CIB, new-onset pneumonia, C. difficile infection,
or acute myocardial ischemia), CIB, infectious adverse
events, serious adverse reactions, and the percentage of days
alive without the use of life support. It was estimated that
3350 patients would be required to have 90% power to detect
a mortality difference of 5% assuming a baseline 90-day
mortality of 25%. There were 3298 patients enrolled. No dif-
ference was reported in the primary outcome of 90-day mor-
tality (pantoprazole, 31.1% vs placebo, 30.4%; P = .76). For
secondary outcomes, 21.9% of patients receiving pantopra-
zole had a clinically important event compared with 22.6%
in the placebo group—unadjusted relative risk (RR) (95%
confidence interval [CI]) = 0.96 (0.83-1.11). The incidence
of CIB was 2.5% versus 4.2% (unadjusted RR [95% CI] =
0.58 [0.4-0.86]); infectious complications were 16.8% ver-
sus 16.9% (unadjusted RR [95% CI] = 0.99 [0.84-1.16]);
serious adverse reactions were 0% and 0%, and percentage
of days alive without the use of life support (median, inter-
quartile range [IQR]) was 92 (60-97) and 92 (65-97) days for
the pantoprazole and placebo groups, respectively. P values
were not reported for secondary outcomes because of the
lack of adjustment for multiple comparisons.
This study represents the largest single randomized con-
trolled trial in the realm of SUP and the first robust study to
evaluate clinical outcomes in the era of modern day critical
care practice. Thirty-three ICUs from 6 countries contributed
to the patient sample representing a vast array of clinical
practice patterns. The protocol was pragmatic allowing for
routine ICU practice with the exception of SUP medications.
The patient population was diverse representing both medi-
cal and surgical ICUs and consisted of high-risk patients
(approximately 78% were mechanically ventilated, 67%
required vasopressors, 20% were coagulopathic) resulting in
a high degree of generalizability. Although there was no dif-
ference in the primary outcome, there are several noteworthy
points to consider when integrating the results of this trial
into bedside practice.
1. We should not abandon SUP even though it did not
influence mortality. Historically, SUP has not been
shown to affect mortality likely because death as a
direct result of CIB is infrequent. In fact, a recent
meta-analysis evaluating acid suppression therapy
for SUP versus no therapy utilized trial-sequential
analysis and demonstrated statistical futility for the
outcome of mortality.14 This suggests an extremely
low probability of any clinical trial being capable of
demonstrating a significant difference in mortality. A
second systematic review identified trials published
before March 2013 and the odds ratio (OR) (95% CI)
for mortality was 1.00 (0.84-1.2).12 This is consistent
with that reported in the SUP-ICU trial (90-day mor-
tality, OR [95% CI] = 1.02 [0.91-1.13]). Death is an
unequivocal endpoint and provides a complete
assessment of benefits versus harms, but lack of mor-
tality benefit should not be interpreted as a lack of
value. There are many interventions that are routinely
used and considered standard-of-care in the ICU
despite lacking survival data (eg, invasive mechani-
cal ventilation for respiratory failure, antimicrobials
for surgical prophylaxis, hyperosmolar therapy for
intracranial hypertension, etc). The provision of SUP
to reduce CIB, irrespective of the relationship with
mortality, does have benefit. Gastrointestinal bleed-
ing can lead to increased blood transfusions, addi-
tional invasive procedures, high-dose PPI therapy,
increased monitoring, resource utilization, and cost.
2. The relationship between CIB and mortality is not
clear. Early research has described the association
between gastrointestinal bleeding and mortality.3
Later, a large analysis of 2 multicenter databases,
which included 1666 patients, evaluated the attribut-
able mortality from CIB using multiple analytic
methods.15 Two of the 3 methods identified a signifi-
cant increase in mortality (RR increase = 1-4). Most
recently, a large international study evaluated the
prevalence of risk factors and prognostic implica-
tions of gastrointestinal bleeding for mortality.6 There
Barletta et al 3
were 1034 patients included and the incidence of CIB
was 2.6%. The 90-day mortality was 55.6% in
patients with CIB compared with 25.4% in those
without (crude OR [95% CI] = 3.72 [1.72-8.04]).
After adjusting for numerous confounders, however,
no association was noted (OR [95% CI] = 1.7
[0.68-4.28]).
3. The perception that CIB due to stress ulceration no
longer exists in high-risk patients has not been vali-
dated. Recent advances in critical care practice have
led to the perception that the incidence CIB due to
stress ulceration is negligible. This belief, however, is
not necessarily supported by the bleeding rates
reported in clinical studies. In 1994, a landmark study
evaluating risk factors for CIB reported bleeding
rates of 3.7% (95% CI, 2.5%-5.2%) for high-risk
patients (ie, those with respiratory failure and/or
coagulopathy) and 0.1% (95% CI, 0.02%-0.5%) for
low-risk patients.16 In 1998, a large, randomized con-
trolled trial conducted in high-risk patients compar-
ing ranitidine with sucralfate reported an overall rate
of CIB of 2.8%.17 Seventeen years later, a large
observational study noted an incidence of CIB of
2.6% (95% CI, 1.6%-3.6%).6 Seventy-three percent
of patients received acid suppressants for at least 1
day. Two feasibility studies comparing pantoprazole
with placebo were recently published whereby the
reported CIB rates in the placebo group were 0%18
and 4.8%,19 respectively. Finally, 2 large observa-
tional studies compared SUP with PPI versus H2RAs
(histamine-2-receptor antagonists).20,21 The first
included high-risk patients who were admitted to an
ICU between 2003 and 2008.21 The incidence of gas-
trointestinal hemorrhage (identified via International
Classification of Diseases, Ninth Revision [ICD-9])
was 4.4%. The second included patients admitted
between 2008 and 2012 and reported CIB rates of
0.6%.20 Differences could be due to the definitions
used for bleeding (any vs clinically important), the
reliance on ICD-9 coding, or the exclusion of patients
with an ICU length of stay <72 hours in the latter
study. One report found roughly half of CIB events
were observed within the first 72 hours of ICU admis-
sion which correlates to when mucosal ischemia and
reperfusion injury are heightened.6
4. Proton pump inhibitors may provide benefit with
reducing CIB. The primary outcome in the SUP-ICU
trial was 90-day mortality but CIB was assessed as a
secondary outcome. The incidence of CIB was 2.5%
and 4.2% for the pantoprazole and placebo groups,
respectively (RR [95% CI] = 0.58 [0.4-0.86]). P val-
ues were not reported for this outcome because of the
lack of adjustment for multiple comparisons. These
results are similar to a network meta-analysis evalu-
ating the efficacy and safety of various modalities
used for SUP (eg, PPIs, H2RAs, sucralfate).22
Network meta-analyses allow for indirect compari-
sons of interventions and provide estimates that are
more reliable when the number of studies reporting a
particular outcome is small. In this analysis, PPIs
were significantly associated with a reduction in CIB
versus no prophylaxis (OR [95% CI] = 0.24 [0.1-
0.6]). This translates to a number needed to treat (to
prevent a CIB) of 6. Whether this benefit outweighs
the risk of infectious complications is unknown.
5. The relationship between PPI therapy and infectious
complications is complicated. The SUP-ICU trial did
not report any differences in infectious adverse events
(RR [95% CI] = 0.99 [0.84-1.16]). Specifically, the
incidence of pneumonia was 16.2% and 16.2% for the
pantoprazole and placebo groups, respectively (RR
[95% CI] = 1.00 [0.84-1.19]). Similarly, there was no
difference in C. difficile infection (1.2% vs 1.5%; RR
[95% CI] = 0.76 [0.42-1.39]). Evidence linking acid
suppressive therapy with adverse infectious outcomes
has been widely noted.8 In the aforementioned net-
work meta-analysis, PPIs increased the risk for pneu-
monia compared to sucralfate (OR [95% CI] = 1.65
[1.2-2.27]) and placebo (OR [95% CI] = 1.52 [0.95-
2.42]).22 The number needed to harm was 3. Similarly,
PPIs have been associated with increased risk for
pneumonia in observational trials.21,23,24 The absence
of this association in the SUP-ICU trial may relate to
the relatively short duration of therapy of a median of
4 days relative to most other studies reporting average
durations exceeding a week. Risk of infectious com-
plications typically increases over the first 7 to 14
days likely because the microbial distribution requires
some time to change composition in response to gas-
tric acid suppression.9
6. Stress ulcer prophylaxis may be of benefit even in
patients receiving enteral nutrition. The need for SUP
in patients who are receiving enteral nutrition has
been debated. Enteral nutrition has been shown to
reduce mucosal ischemia through its effect on
splanchnic blood flow. Furthermore, enteral nutrition
formulations are usually alkaline and can increase
gastric pH. In contrast, some studies have shown
enteral nutrition may reduce gastric mucosal pH sug-
gesting gastric ischemia is heightened possibly due to
blood flow being redirected away from the mucosa.25
The majority of information pertaining to enteral
nutrition and CIB originates from subgroup analyses
from previously published data. It is not surprising
that systematic reviews have produced dichotomous
results as to whether the addition of acid suppression
infers protection from CIB in the presence of enteral
nutrition.14,26 These polarizing results are likely due
to few studies directly comparing enteral nutrition
with acid-suppressive therapy.27 The most rigorous
4 Hospital Pharmacy 00(0)
systematic review and meta-analysis evaluated ran-
domized controlled trials comparing pharmacologic
SUP with placebo where at least 50% of enrolled
patients received enteral nutrition.28 Clinically impor-
tant bleeding was reported in 4 trials which included
725 patients and no difference was noted with SUP
(RR [95% CI] = 0.63 [0.29-1.37]). One randomized
controlled exploratory study evaluated 102 patients
who received enteral nutrition plus pantoprazole ver-
sus enteral nutrition plus placebo.27 No difference in
the incidence of CIB was noted (1.8% vs 2.1% for the
treatment and placebo groups, respectively). In the
SUP-ICU trial, a large majority of patients were
receiving enteral nutrition. In fact, the percentage of
patients receiving enteral nutrition on days 1, 2, and 3
postenrollment was 57%, 75%, and 81%, respec-
tively. Thus, the benefits observed were likely recog-
nized in addition to that provided by enteral nutrition.
Further research is required to delineate the role of
enteral nutrition in preventing CIB or if SUP can
safely be discontinued when patients are tolerating
enteral feeds as tolerance may signify the reversal of
gastrointestinal ischemia.
7. Risk factors for CIB are poorly defined. The 2 most
commonly quoted risk factors for CIB are mechanical
ventilation exceeding 48 hours and coagulopathy.
These parameters result from a landmark study of 2252
ICU patients that evaluated risk factors after physicians
were encouraged to withhold prophylaxis unless
patients had head injury, burns >30% BSA, transplant,
or recently a peptic ulcer or gastrointestinal bleed ulti-
mately resulting in 674 patients who received prophy-
laxis and 1578 who did not.16 The univariate analyses
showed that respiratory failure, coagulopathy, hypoten-
sion, sepsis, hepatic failure, renal failure, enteral nutri-
tion, glucocorticoid administration, organ
transplantation, and anticoagulant therapy were all
associated with CIB. Only mechanical ventilation and
coagulopathy were significantly associated with CIB
after multivariate regression analyses (although the
presence of hypotension resulted in a P value of .08).
The majority of patients enrolled had either the primary
diagnosis of cardiovascular disease or cardiovascular
surgery representing 54.8% of the study cohort. Few
patients had central nervous system injury (4%), sepsis
(1.6%), head injury (1.2%), or multiple trauma (0.8%).
Therefore, the results of this study must be taken into
context given the population evaluated and the exclu-
sion of patients with potential risk factors. Moreover,
this study was conducted 25 years ago when practices
were substantially different (eg, lack of noninvasive
ventilation, lack of revascularization procedures for
coronary emergencies, etc). It is not surprising that
additional risk assessments have shown some of the
same risk factors as this landmark trial but also a vari-
ety of additional parameters that include nutritional
failure, multiple trauma, spinal cord injury, head injury,
thermal injury, acute kidney injury, need for renal
replacement therapy, liver disease, use of anticoagu-
lants, and the number of comorbid disease states.6,29-32
When assessed as a whole, the risk factors that are fre-
quently quoted are generally delineated into parameters
that represent mucosal ischemia (respiratory failure,
need for mechanical ventilation, multiple trauma,
shock/hypotension, nutritional failure, solid organ
transplant), increased bleeding risk (acute or chronic
kidney injury, need for renal replacement therapy, acute
or chronic liver disease, use of anticoagulants), or
heightened gastric acid production or reduced produc-
tion of protective substances (spinal cord injury, head
injury or other intracranial processes, thermal injury,
history of gastrointestinal injury, use of corticoste-
roids). Unfortunately, all these parameters are common
across critically ill patients, so definitively delineating
risk factors to guide the selection of patients who
should receive SUP is challenging. Moreover, studies
often focus on medical or surgical patients, so applying
findings to a heterogeneous critically ill population is
problematic. A recent systematic review found acid
suppression provided significant reductions in CIB
over placebo in neurosurgical patients but not in sur-
gery/trauma or medical ICU patients with risk factors.14
This same systematic review, however, found no ben-
efit of SUP in studies conducted after the practice of
early goal directed therapy. This further reinforces the
concept that therapies have evolved over the past 25
years to the extent that information from the 1990s may
no longer apply. Ultimately, risk factors are numerous
and the lack of definition of risk means that most criti-
cally ill patients will receive SUP. Another concern
related to risk is the use of acid suppression prior to
admission to the ICU. These patients were excluded
from the SUP-ICU trial. Typical practice is to continue
outpatient acid suppression therapy during hospitaliza-
tion irrespective of risk for CIB.
Questions the SUP-ICU Trial Does Not
Address
Although the SUP-ICU trial provides insight on numerous
dilemmas surrounding SUP, it is important to address the
issues that it does not address. First is whether these results
would also apply to H2RAs. As there was no H2RA arm in
the SUP-ICU trial, it remains unknown if their overall effect
(ie, the balance between bleeding and infectious complica-
tions) would be similar to that recognized with PPIs. H2RAs
inhibit the secretion of histamine-stimulated acid and limit
the extent of reperfusion injury by mediating inflammation
(perhaps more so than PPIs).9 Data examining CIB rates
between H2RAs and PPIs though are conflicting as a recent
network meta-analysis suggests CIB rates may be lower with
PPIs22 while observational studies report CIB rates that are
Barletta et al 5
higher.20,21 Nevertheless, a conclusion regarding the most
appropriate agent (ie, PPI or H2RA), solely based on the
SUP-ICU trial, cannot be made. Second pertains to the
cost-effectiveness of SUP. Cost-effectiveness accounts for
all related costs of a particular therapy including drug
acquisition costs, treatment benefits, and adverse effects.
Pharmacoeconomic analyses comparing PPI therapy with
H2RAs have demonstrated the incidence of pneumonia as
one of the primary drivers of incremental costs.33-35 The
fact that no difference in pneumonia rates was recognized in
the SUP-ICU trial could impact future pharmacoeconomic
analyses. Further studies are needed. Next, the SUP-ICU
trial was conducted in ICU patients who were at high risk for
stress-related mucosal bleeding. These data should not be
extrapolated to patients who are at low risk or those in a non-
ICU setting. The practice of providing routine SUP to these
patients should be discouraged. A pharmacist-led SUP man-
agement program has been shown to reduce inappropriate
use of acid suppressing agents.36 Finally, the most appropri-
ate duration for SUP administration remains a clinical con-
troversy. Future trials should evaluate the risk-benefit ratio
of SUP as it relates to duration of therapy.
Future Trials
The SUP-ICU trial provides tremendous insight on the provi-
sion of SUP. Building on the success of this trial, other ongo-
ing clinical trials will collectively redefine the landscape for
SUP. Re-evaluating the Inhibition of Stress Erosions
(REVISE) is a large multicenter randomized controlled trial
comparing pantoprazole with placebo in high-risk ICU
patients.37 The primary outcome measure is CIB. The PEPTIC
(Proton Pump Inhibitors versus Histamine-2 Receptor
Blockers for Ulcer Prophylaxis Therapy in the Intensive Care
Unit) study is a cluster randomized, crossover, registry-
embedded trial comparing PPIs with H2RAs in mechanically
ventilated patients.38 The primary endpoint will be in-hospital
mortality. Finally, SIREN (Sup-Icu RENal) is an observa-
tional study evaluating patients included in the SUP-ICU trial
that will address the benefits and harms of SUP specifically in
ICU patients in need of renal replacement therapy.39
Summary
The SUP-ICU trial is a landmark study describing the provi-
sion of SUP in a modern-day setting of ICU practice. It repre-
sents the first large-scale trial revisiting the overall value of
this widespread intervention. It is important for clinicians to
critically evaluate which patients should receive SUP recog-
nizing the benefits and risks associated with acid suppressive
therapy. The decision to administer SUP must be individual-
ized and only considered in patients who are at high risk for
stress ulcer–related CIB. Although risk cannot be determined
based on the presence or absence of a single factor, high-risk
patients generally consist of those patients who have a high
severity of illness (eg, shock, high organ-failure score), require
organ support therapy (eg, mechanical ventilation, renal
replacement therapy), and have multiple coexisting disease
states, disorders of coagulation (eg, coagulopathy, liver dis-
ease), or severe neurologic injury (eg, severe traumatic brain
injury). Stress ulcer prophylaxis should be administered for as
long as patients remain severely ill. There may be some bene-
fit with SUP even in patients who are receiving enteral feeds
particularly during the acute phase of critical illness. As criti-
cal illness subsides, it is anticipated that the risk of CIB may
also subside; thus, some patients may require only a few days
of therapy rather than a prolonged course. It may not be neces-
sary to administer SUP for the entire duration of mechanical
ventilation or the complete ICU length of stay. This may lead
to a more favorable balance between bleeding avoidance and
infectious risk. Future randomized controlled trials are ongo-
ing, and upcoming evidence-based guidelines will provide
further insight on the role of acid-suppressive therapy for SUP.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
ORCID iDs
Jeffrey F. Barletta https://orcid.org/0000-0002-9054-8218
Mitchell S. Buckley https://orcid.org/0000-0002-3385-8105
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