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Supplementary Data
TECHNICAL APPENDIX: SUMMARY OF SCIENTIFIC EVIDENCE
PRE-ENDOSCOPIC INDICATORS
QI 1: If patients present with suspected non-variceal upper gastrointestinal hemorrhage (NVUGIH), then they
should receive the following tests: complete blood count, levels of electrolytes, blood type, and cross-match at
the time of initial evaluation. (Grade Ic)
Routine blood tests allow estimation of severity of bleeding and presence of existing comorbidities as
well as preparation for blood transfusion, if needed. Although recommended by guidelines, 1,2 there are no
direct data to support that obtaining these tests impact patient outcomes. Despite this, the Delphi panel believed
that the benefit associated with obtaining routine blood tests outweighs the risk by a wide margin and that the
lack of data reflect the obviousness of this practice and should not be used as a compelling argument against
routine measurement of these tests in a patient with NVUGIH. (Class I, Level C).
QI 2: If patients present with suspected NVUGIH, then they should have a documentation of risk stratification
using one of the previously validated measures or the individual components of these measures (e.g., Blatchford
or pre-endoscopic Rockall score) at the time of initial evaluation. (Grade Ib)
The Blatchford score and pre-endoscopic Rockall score use clinical and laboratory data to identify
patients who require intervention,3,4 whereas the complete Rockall score also uses endoscopic variables to
predict rebleeding and mortality.4 Published guidelines and authoritative reviews recommend use of these
prognostic scales for early stratification of patients into low- and high-risk categories for early intervention,
rebleeding, and mortality.1,2, 5 The data supporting the validity of these prognostic scores has been recently
published elsewhere.5
Emerging data show that application of these prognostic scores in routine clinical care can accurately
identify patients with a low need for early intervention.6,7 These selected patients can be safely managed as
outpatients, thus shortening the duration of hospitalization. For example, Stanley et al prospectively assessed
the impact of introducing Blatchford scoring system at two hospitals in the UK.6 Introduction of the Blatchford
scoring system classified 15% patients with upper GI hemorrhage as low risk; these were managed as
outpatients without adverse events. The proportion of individuals with low risk GI bleeding admitted to hospital
also fell from 96% in the pre- to 71% in the post-Blatchford era (p<0.00001).6 Similarly, Soncini et al reported
their experience before and after introduction of Rockall score in routine practice.7 The mean hospital stay
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became shorter (7.1+/-5.0 vs. 6.3+/-4.5 days), and significantly fewer causes of bleeding remained undefined
after the introduction of the Rockall score.7
Collectively, these data not only further support the validity of these prognostic scores, but also show
that routine use of these scores can indeed change clinical practice and impact outcomes in NVUGIH. Based on
these data, the panel believed that the benefit associated with documentation of risk stratification outweighs the
risks by a wide margin. (Class I, Level B).
QI 3: If patients with suspected NVUGIH have normal resting vital signs (e.g., pulse < 100; systolic blood
pressure > 100 mmHg), then they should have orthostatic vital signs documented in the records at the time of
initial evaluation (Grade Ic)
It is essential to categorize patients with suspected NVUGIH based on the severity of bleeding. One
risk factor for severe bleeding is the presence of shock (defined as a pulse rate of more than 100 beats/min and
systolic blood pressure less than 100 mm Hg).1 Although we did not find any data that prospectively examined
the impact of documenting orthostatic vital signs on clinical outcomes in patients with NVUGIH, an exploratory
analysis of RUGBE (Registry on Non-variceal Upper Gastrointestinal Bleeding and Endoscopy) Canadian
cohort study found that presence of orthostatic changes in vital signs correlated highly with the severity of
bleeding (unpublished data), while a recent systematic review suggested this initial finding predicts subsequent
rebleeding post endoscopic hemostasis.10 Finally a recent review of studies that identified criteria for early
discharge from hospital also suggested the importance of initial hemodynamic instability not quickly resolved
with adequate fluid resuscitation.2 Thus, the panelists believed that in patients without clinical signs of shock, it
may be important to check for orthostatic changes in vital signs to ascertain the severity. (Class I, Level C).
QI 4: If patients with suspected NVUGIH receive a nasogastric tube, then they should have documentation of
the findings in the chart, that include the possibilities of fresh red blood, coffee grounds, bilious, or non bilious
aspirate. (Grade Ib)
Nasogastric aspirate is useful in predicting high-risk lesions in patients with NVUGIH. An analysis of
the Canadian RUGBE showed a high specificity of a bloody nasogastric aspirate for high-risk lesions on a
subsequent EGD with a negative predictive value of 78% (95% CI 73%-82%).8 A clear nasogastric aspirate
reduced the likelihood to having a high-risk lesion to 15%.8 Although use of a nasogastric tube may identify
patients who would benefit from earlier endoscopy, the panel disagreed on whether a nasogastric tube is
warranted for routine use in all patients who present with suspected NVUGIH. However, based on the RUGBE
data, they agreed that in patients who undergo nasogastric aspiration, the nasogastric aspirate findings (bloody,
"coffee ground," clear/bile) should be documented. (Class I, Level B)
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QI 5-8: Early resuscitation QI (Grade Ic)
If patients present with suspected NVUGIH, then they receive large bore IV lines at the time of initial
evaluation.
If patients with suspected NVUGIH exhibit signs of hypovolemia (e.g., pulse >100, systolic blood pressure
<100mmHg; or orthostatic changes), then they should receive crystalloids for fluid resuscitation at the time
of initial evaluation.
If patients with suspected NVUGIH have hypoxemia (arterial blood test or an oximeter reading <90%) then
they should receive supplemental oxygen at the time of initial evaluation
If patients with suspected NVUGIH have hypovolemia (pulse >100, systolic blood pressure <100 mmHg)
that is not responsive to initial fluid resuscitation, then they should be admitted to the intensive care or a
monitored unit
Despite advances in medical and endoscopic management, mortality in patients with NVUGIH remains
high. Inadequate early resuscitation is likely an important contributor to persistently high morality rates in
NVUGIH. In a prospective study including 2 cohorts of patients with clinically significant upper GI
hemorrhage (defined as hemodynamic instability; ~90% with NVUGIH), early intensive resuscitation decreased
morbidity and mortality and this was likely related to the decreased time interval between admission to
achievement of hemodynamic stability.9 Although these data provide direct support to the importance of early
resuscitation in improving clinical outcomes in upper GI hemorrhage, the study did not provide results stratified
by the common clinical circumstances specified in the resuscitation QIs above.
The importance of early resuscitation is recognized by published clinical guidelines in upper GI
hemorrhage.1,5,11,12 The guidelines recommend that intravenous access must be achieved in all patients. The
guidelines also specify that for patients who are hemodynamically compromised (pulse >100, systolic blood
pressure <100 mmHg)1 appropriate crystalloids should be infused to achieve a fall in pulse rate and rise in blood
pressure, 1,11,12 followed by admission for close monitoring.1,11 Patients with evidence of severe hypovolemia
should be admitted to an intensive care setting.11 (Class I, Level C)
QI 9: If patients with suspected NVUGIH have active hemetemesis with mental status changes, then they should
receive airway protection (i.e., intubation) before upper endoscopy. (Grade Ic)
In a retrospective study, outcomes were compared for intensive care unit patients with upper
gastrointestinal hemorrhage (UGIH) for 1 year during which prophylactic endotracheal intubation was not
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performed before endoscopy, with outcomes during a subsequent year in which endotracheal intubation was
routine for airway protection before or during EGD when there was hematemesis, altered mentation, unstable
cardiopulmonary status, or large amounts of blood in the proximal GI tract.13 Although, there was no difference
in the length of stay and mortality, patients in the latter year had no episodes of aspiration during EGD (2.0%
vs. 0% in the pre vs. post year; p = 0.21), did not require emergent post-EGD endotracheal intubation (6.0% vs.
0%; p < 0.05), and had fewer in-hospital cardiopulmonary arrests (12.9% vs. 5.0%; p < 0.05). Another recent
retrospective analysis included 53 patients who underwent elective prophylactic intubation before EGD and
similar number of propensity-matched controls (patients without intubation but with similar probability of
receiving intubation).14 There were fewer cardiac arrests within 12 hours of EGD in patients who received
prophylactic intubation (4 patients in controls vs 1 in cases), but a small sample size precluded finding a
statistically significant difference. Overall, there was no difference in the incidence of cardiopulmonary
complications, ICU length of stay, hospital length of stay, or hospital mortality between patients who received
intubation and propensity-matched controls. The small sample size limited any sub-group analyses (i.e.,
patients with or without altered mental status).
Given the scarcity of data and based on clinical experience, the panel believed that airway intubation is
important for patients with active hemetemesis and altered mentation, but not for the more commonly
encountered circumstances, such as hemetemesis without altered mental status or blood in the nasogastric
lavage. (Class I, Level C)
ENDOSCOPIC INDICATORS
QI 1: If patients suspected present with NVUGIH and do not have contraindications to EGD, then they should
receive an EGD within 24 hours of presentation (Grade Ib)
The performance of an early EGD (within 24 hours of presentation) allows for safe and prompt
discharge of patients classified as low risk, improves patient outcomes for patients classified as high risk, and
reduces resource utilization for patients classified as either low or high risk.
Several observational studies15-20 and a systematic review21 support the use of early endoscopic
stratification for all risk groups, as defined within the first 24 hours following presentation. RCT data have
shown resultant decreases in transfusion requirements and length of hospital stay in high-risk patients with a
bloody nasogastric tube aspirate but not in those with clear or “coffee grounds” aspirates.22 Studies in all
patient-risk groups have demonstrated statistically significant reductions in length of hospital stay17,21-26, as well
as significant cost reductions in low risk patients.25,26 Importantly, studies in low-risk patients have shown no
major complications in those triaged to outpatient care with early endoscopy.15,16,18,19,21,25-27
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Administrative data have found that early endoscopy is associated with a decreased need for surgery in
elderly patients without an improvement in mortality.28 Moreover, NVUGIH patients admitted on weekends had
higher rates of adjusted in-hospital mortality,29,30 surgical interventions,30 while they had a longer mean time to
endoscopy and were less likely to undergo early endoscopy within 1 day of hospitalization,29 suggesting a
relationship between early endoscopy and mortality. However, in one study, weekend admission remained an
independent predictor of increased mortality even after adjusting for the timing of endoscopy.30 Early EGD is
associated with significantly shorter hospital stays29,30 and lower hospitalization charges.30 Although not fully
reported as of yet, a recent small retrospective analysis of 395 patients treated at a US Veteran’s Administration
hospital suggested that the performance of early endoscopy may be associated with a significant 85% reduction
in mortality.31
The panelists recognized that there may be justifiable reasons for not undergoing early EGD. For
example, EGD may need to be delayed or deferred in selected high-risk patients, such as those with active acute
coronary syndrome, suspected perforation, or those in terminal malignancy. The QI explicitly accounted for
this and excluded patients who may be too sick to undergo endoscopy. (Class I, Level B).
QI 2: If patients have an ulcer related bleeding on EGD, then the stigmata of bleeding should be documented in
the procedure note for the index endoscopy using a standardized taxonomy (e.g., Forrest classification, NIH
Consensus Conference taxonomy) (Grade Ia)
Endoscopic predictors of increased risk of rebleeding and mortality include active bleeding, nonbleeding visible vessel, or adherent clot. In a meta-analysis of 30 randomized controlled trials evaluating
hemostatic endoscopic treatment in patients with acute NVUGIH, endoscopic treatment decreased rates of
further bleeding, surgery, and mortality in patients with high-risk endoscopic features, such as active bleeding
or non-bleeding visible vessels.32 These findings were corroborated by a second meta-analysis of 25 trials.33
These data show that the identification of the bleeding stigmata directly impacts the selection of treatment
modality, risk stratification, and subsequent management in patients with NVUGIH.
(Class I, Level A).
QI 3: If patients with NVUGIH undergo an EGD, then a large (single or double) channel endoscope should be
used. (Grade IIc)
Experts recommend use of large-channel therapeutic endoscopes in patients undergoing EGD for upper
GI bleeding.34 A double channel endoscope (therapeutic endoscope) is particularly useful in patients with more
severe bleeding mainly for the purpose of lavage, better visualization, and ability to use the 10-Fr heater probe,
although there are no clear data on its advantages. Thus, although the benefit of using large-channel endoscope
may be greater than the risk, additional data are needed to confirm this advantage. (Class II, Level C).
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QI 4: If patients have an ulcer related bleeding on EGD, then whether hemostasis was achieved or not should
be documented in the procedure note for the index EGD (Grade Ic)
Documentation of hemostasis (or failure thereof) results in a change in subsequent management
strategy (use of high dose proton pump inhibitor [PPI], length of hospital stay, interventional radiology/surgery
consultation).5,12 Therefore, the panel believed that documentation of hemostasis should be a recommended
component of care in the patients undergoing endoscopic hemostasis. (Class I, Level C)
QI 5: If patients with ulcer related bleeding have active spurting, oozing, or visible vessel and normal INR
(<1.5), then they should receive endoscopic hemostasis using any of the following modalities: hemoclip,
thermal devices, combination epinephrine and contact thermal therapy, or combination epinephrine and
hemoclip. (Grade Ia)
Several recent meta-analyses have better quantified the efficacy of endoscopic therapies in patients with
NVUGIH.35-41 Although monotherapy with epinephrine injection is more effective than medical therapy in
patients with high-risk stigmata, it is inferior to other monotherapies or to combination therapy that uses 2 or
more methods. 35-41 Numerous meta-analyses indicate that adding a second procedure, such as a second injectate
(for example, alcohol, thrombin, or fibrin glue), thermal contact, or clips, is superior to epinephrine injection
alone.35-37,39,41
Epinephrine plus a second method for treating high-risk stigmata significantly reduced rebleeding (OR,
0.51 [CI, 0.39 to 0.66]), surgery (OR, 0.63 [CI, 0.45 to 0.89]), and mortality compared with epinephrine
monotherapy (OR, 0.50 [CI, 0.30 to 0.82]).40 Monotherapy with thermal devices, sclerosants, clips, thrombin, or
fibrin glue provides more effective endoscopic hemostasis than epinephrine alone35 or pharmacotherapy alone.39
Clips were superior to injection monotherapy in 4 35,37,38,41 of 5 meta-analyses.35,37-39,41 Clips with injection were
superior to injection alone but not to clips alone.38,41 Combination therapy (injection plus second injectate,
thermal, or clips) was superior to injection therapy alone, but not to clips or thermal therapy alone.37,41 Although
the data are insufficient to show superiority or equivalence of the recommended treatments, they are strongest
for the use of thermal devices, clips, or combination treatments. (Class I, Level A)
QI 6: If patients with ulcer related bleeding have active spurting, oozing, or visible vessel and INR 1.5 to 2.0,
then they should receive endoscopic hemostasis using any of the following modalities: hemoclip or combination
epinephrine and hemoclip. (Grade Ic)
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There is a paucity of prospective data on the effect of different endoscopic hemostasis modalities in
patients with coagulopathy. A cohort study in patients who underwent endoscopic treatment found no
differences in rebleeding, surgery, mortality, or complication rates between patients receiving warfarin whose
INRs were corrected to 1.5 to 2.5 by using fresh frozen plasma, and a control group who did not receive
anticoagulants.42 This study suggests that endoscopic treatment with injection or heater probe may be safely
performed in patients with an INR less than 2.5.42 In a recently reported large study, endoscopic therapy
achieved initial success in 94.7% of patients with INRs between 1.3 and 2.7 by using a variety of hemostatic
techniques including injection therapy, heater probe, and hemoclips. However, the rebleeding rate in this series
was 23%, and the results were not stratified by the therapeutic modality used for hemostasis.43 Mechanical
hemostasis (e.g., hemoclips) may provide therapeutic advantages in patients who must resume anticoagulation
after endoscopy, although this has not been rigorously studied.
Although the data are insufficient to confirm superiority or equivalence of different endoscopic
treatments in patients with INR 1.5-2.0, the panel members believed that mechanical devices have important
advantages and are thus preferable compared to other techniques in these vulnerable patients. Of note, the
median rating for the use combination treatment (thermal therapy and epinephrine) was > 7 (Appendix Table).
However, panelists disagreed on the appropriateness of this practice, with 3 of the 9 rating this QI as
“uncertain” (4-6 range). (Class I, Level C)
QI 7: If patients with ulcer related bleeding have clots, then targeted irrigation of the clot should be performed
and this should be documented in the procedure note (Grade IC)
Rigorous washing of a clot in an ulcer bed has successfully exposed the underlying stigmata in 26% to
43% of cases,44,45 and the revealed stigmata were high risk in 70% of those cases.45 The endoscopic findings
present after clot removal should be appropriately managed.
The risk for rebleeding with clots that remain adherent after washing without endoscopic therapy (with
or without PPI therapy) has been reported to be as low as 0% to 8%,45,46 (94, 95) but also as high as 25% to
35%44,47-49 in clinically high-risk patients. The disparity of these data led to a disagreement among the panelists
as to the optimal management of clots that remain adherent after washing. (Class I, Level C)
QI 8: If patients with ulcer related bleeding have a clean-based ulcer or a flat pigmented spot in the ulcer bed,
then they should not receive endoscopic hemostasis. (Grade Ia)
Based on the favorable natural history of clean-based ulcer or a non-protuberant pigmented spot in ulcer
bed, experts do not recommend any endoscopic treatment for patients with these low risk stigmata.
Furthermore, the 2 meta-analysis discussed under endoscopic QI 2 that have demonstrated the benefits of
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endoscopic treatment mainly examined patients with high-risk rather than low-risk stigmata.32,33 (Class I, Level
A).
QI 9: If patients have thermal contact therapy during hemostasis, then a large size (e.g., 10 French) probe
should be used. (Grade Ib)
A randomized control trial compared the efficacy of bipolar electrocoagulation (gold probe) with 10French versus 7-French catheter after epinephrine injection in the treatment of bleeding peptic ulcers.50 Use of
large-size gold probe was significantly associated with a smaller number and duration of electrocoagulations.
Overall, there was no difference in the initial hemostasis rate, rebleeding rate, and duration of hospital stay
between the 10-F and 7-F groups, likely related to the small number of patients enrolled in the study. Although
this topic has been subjected to a randomized trial, given the limitations of the study, the evidence was
decreased from Level A to Level B. (Class I, Level B).
QI 10: If patients with NVUGIH have clinical evidence of recurrent hemorrhage after index EGD, then they
should receive repeat endoscopy within 24 hours of the recurrent episode. (Grade Ib)
In the only randomized comparison, immediate endoscopic retreatment in patients with rebleeding after
endoscopic hemostasis reduced the need for surgery without increasing the risk for death and was associated
with fewer complications than surgery.51 However, these surgical procedures performed in Hong Kong were
somewhat more complex and had greater attendant morbidity than those usually performed in North America,
and this limits the generalizability of the results. (Class I, Level B).
QI 11: If patients with ulcer related bleeding fail initial endoscopic hemostasis for high risk stigmata, then they
should receive a surgical or interventional radiology consultation. (Grade Ic)
Percutaneous or transcatheter arterial embolization has been investigated as an alternative to surgery in
patients for whom endoscopic therapy has failed, especially those who are high-risk candidates for surgery. In
uncontrolled trials, primary rates of technical success range from 52% to 98%, with recurrent bleeding
occurring in about 10% to 20% of patients.52-56 A retrospective, single-center study57 showed no significant
differences between embolization therapy and surgery for rates of rebleeding, surgery, or mortality, despite
patients in the embolization group being older and having a higher prevalence of heart disease.
POST-ENDOSCOPIC INDICATORS
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QI 1: If patients have NVUGIH from a >1 cm gastric ulcer that is not biopsied in the setting of bleeding, then
they should receive repeat endoscopy within 2-3 months of index endoscopy. (Grade Ic)
Approximately 5% of endoscopically benign-appearing gastric ulcers can be malignant, and this risk
increases with the size of the ulcer. As a result, the ASGE and ACG recommend routinely performing biopsies
of all gastric ulcers to exclude malignancy.58 Despite these recommendations, panel members believed that
many patients undergoing EGD for upper GI bleeding may not receive biopsy of a bleeding ulcer and that these
patients (without biopsies during index EGD) should undergo a repeat examination for ulcer biopsy and/or
documentation of healing. (Class I, Level C)
QI 2: If patients with ulcer related bleeding have low risk stigmata of bleeding on endoscopy, then they should
receive PPI after index endoscopy. (Grade Ic)
Because rebleeding episodes may occur more than 3 days after endoscopy,59-61 most RCTs that assess
the role of post-endoscopic PPI therapy have also included a prescription for once-daily PPI therapy that starts
72 hours after endoscopic hemostasis.59-63 In the non-acute setting, once-daily PPI therapy has demonstrated
effective ulcer healing for patients with peptic ulcer disease.64 However, there are no direct comparisons
between oral PPI vs. no PPIs therapy or histamine-2 receptor agonist in patients who meet the criteria to be
included in this QI. (Class I, Level C)
QI 3: If patients receive successful hemostasis for high risk stigmata of ulcer bleeding, then they should receive
an IV bolus of PPI followed by continuous IV infusion for a minimum of 48 hours. (Grade Ia)
Strong evidence demonstrates the efficacy of high-dose intravenous PPI therapy after successful
endoscopy. The evidence base for this QI is extensively reviewed elsewhere.5 Briefly, 2 recent meta-analyses
found that PPI therapy with or without endoscopic therapy reduced rebleeding and surgery compared with
placebo or histamine-2 receptor agonist.65,66 Proton-pump inhibitor therapy also reduced mortality among
patients with active bleeding or non-bleeding visible vessel.65 The meta-analysis by Laine et al found
significant benefit mortality (RR, 0.41 [CI, 0.20 to 0.84]) with high-dose intravenous PPI therapy after
endoscopic therapy, whereas lower doses were associated with significant benefits in rebleeding but not surgery
or mortality compared with placebo or no treatment.66 (Class I, Level A)
QI 4: If patients have bleeding peptic ulcers, then they should be tested for Helicobacter pylori using one of the
following tests within 3 months of the index bleeding: CLO, histology, breath test, or antigen test.
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QI 5: If patients have bleeding peptic ulcers and documented Helicobacter pylori infection, then they should be
treated with a recommended antibiotic combination within 1 month of the positive result (Grade Ia)
H. pylori infection status has been shown to be an independent predictor of rebleeding.67 Eradication of
H. pylori has been demonstrated,68-73 to reduce the rate of ulcer recurrence and rebleeding in complicated ulcer
disease. Although the optimal diagnostic approach remains unclear, it may include acute testing for H. pylori
infection, followed, if results are negative, by a confirmatory test outside the acute context of bleeding. There is
no rationale for urgent intravenous eradication therapy; oral therapy can be initiated either immediately or
during follow-up in patients found to have H. pylori infection. (Class I, Level A)
6. If patients with peptic ulcer bleeding are prescribed aspirin, NSAIDs, or COX-2 inhibitors, then they should
also receive a PPI. (Grade Ia)
Two small RCTs conducted in Asia found no significant difference in the rate of recurrent bleeding or
ulcer complications (about 4% to 6%) at 6 months with COX-2 inhibitor therapy alone versus therapy with a
traditional NSAID plus PPI.74-76 Population-based studies also support adding a PPI to traditional NSAID
therapy or administering a COX-2 inhibitor to reduce the risk for upper gastrointestinal complications; however,
the combination of a COX-2 inhibitor with a PPI was associated with the greatest risk reduction.77,78 One RCT
demonstrated a significantly lower rate of recurrent NVUGIB with a COX-2 inhibitor plus a PPI (0%)
compared with a COX-2 inhibitor alone (8.9%) over 1 year (difference, 8.9 percentage points [CI, 4.1 to 13.7
percentage points).79 A subgroup analysis of pooled data from 3 RCTs with similar study designs, comprising
34 701 patients, suggested a lower incidence of clinical gastrointestinal events with a COX-2 inhibitor plus a
PPI compared with a COX-2 inhibitor alone; however, no statistical analysis was performed.80 Several studies
(198, 199) have also shown lower risks for endoscopic ulcers in patients who receive a COX-2 inhibitor plus a
PPI compared with those who receive a COX-2 inhibitor alone.81,82
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