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Endoscopy for Acute Nonvariceal Upper Gastrointestinal Tract Hemorrhage: Is Sooner Better?
A Systematic Review
Brennan M. R. Spiegel, MD;
Nimish B. Vakil, MD;
Joshua J. Ofman, MD, MSHS
Arch Intern Med. 2001;161:1393-1404.
ABSTRACT
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Background While the effectiveness of upper endoscopy has been established for
acute nonvariceal upper gastrointestinal tract hemorrhage, its optimal timing
has not been clearly defined. Early endoscopy has been advocated for its ability
to achieve prompt diagnosis, risk stratification, and therapeutic hemostasis.
Objective To determine whether early vs delayed endoscopy improves patient and
economic outcomes for all risk groups with nonvariceal upper gastrointestinal
tract hemorrhage.
Methods A systematic review of 3 computerized databases (MEDLINE, HEALTHSTAR,
and Cochrane Database of Systematic Reviews) was performed along with hand
searching of published abstracts to identify English-language citations from
1980 to 2000.
Results Twenty-three studies met explicit inclusion criteria. The highest-quality
study examining outcomes in low-risk patients found no significant complications
at 1-month follow-up for any outpatients managed with early endoscopy. The
largest randomized trial of high-risk patients showed no mortality benefit
but a significant decrease in transfusion requirements with early endoscopy.
Seven of the 8 studies examining the effect of early endoscopy on length of
stay as a measure of resource utilization demonstrated a significant reduction
compared with that of delayed endoscopy. However, most included studies were
found to suffer from 1 or more potentially significant methodologic shortcomings.
Conclusions The overwhelming majority of existing data suggest that early endoscopy
is safe and effective for all risk groups. The clinical and economic outcomes
of early endoscopy should be confirmed in additional well-designed randomized
controlled trials. Given the strength of the evidence, efforts to develop
a more standardized and time-sensitive approach to acute nonvariceal upper
gastrointestinal tract hemorrhage should be undertaken.
INTRODUCTION
UPPER gastrointestinal tract hemorrhage (UGIH) occurs in 150 per 100 000
people annually, results in up to 300 000 hospitalizations, and costs
more than $2.5 billion per year.1-2
Despite earlier studies to the contrary,3-4
endoscopy has been established as being effective for acute nonvariceal UGIH5-6 and is now the standard of care for
patients presenting with this frequent and costly condition.7-8
Once a medical intervention is deemed effective, its optimal timing of use
in clinical practice must be clearly defined. In many instances, effectiveness
and timing are inseparable, as timing alone often dictates clinical success.
For example, it is not adequate to simply provide coronary angioplasty for
patients with myocardial infarction, but to perform it within 1 hour of presentation.9 Similarly, while tissue plasminogen activator has
proved effective in acute ischemic stroke, it must be initiated within 3 hours
of onset to maximize outcomes.10
The optimal timing of endoscopy in UGIH, however, has not been clearly
established. Well-designed prospective studies, including a trial demonstrating
the safety of early refeeding after therapeutic endoscopy11
and a sequential endoscopic confirmation of the low rebleeding risk of clean-based
ulcers,12 bolster the argument that early endoscopy
may provide clinical benefit by promoting safe patient disposition for both
high- and low-risk groups. Moreover, it has been suggested that delayed endoscopy
provides no additional benefit over standard medical management.13-14
Nonetheless, mortality rate has remained unchanged despite therapeutic endoscopy,15 and an increased rate of complications with early
vs delayed endoscopy has been reported.16-17
The controversy is further confounded by the paucity of literature specifically
addressing the timing of endoscopy and by the lack of clear guidelines on
the timing of endoscopy in major consensus statements.7-8
In the absence of clear guidelines, early endoscopy is presently an
inconsistent practice. For example, the decision to perform early vs delayed
endoscopy has been independently associated with sex,18
insurance status,19 and day of the week.19 The definition of "early" endoscopy varies as well,
ranging from 120 to 2419
hours after initial presentation. Current evidence suggests that upper gastrointestinal
tract endoscopy is performed within 24 hours of admission in 40% to 70% of
cases.19, 21
How might the effectiveness of early endoscopy be measured? The end
point of a successful management strategy may be to ensure patient safety
while stemming costs by minimizing unnecessary hospitalizations and reducing
length of stay. With the advent of therapeutic potential, the use of early
endoscopy may achieve these objectives by allowing prompt diagnosis, risk
stratification, and therapeutic hemostasis.22
To prove a benefit from early endoscopy, a link must be established between
this practice and significant clinical and economic outcomes. Our objective
was to perform a systematic review of the medical literature23-24
to address the following questions: (1) Does early endoscopy allow for safe
and prompt discharge of low-risk patients with acute nonvariceal UGIH? (2)
Does early endoscopy improve patient outcomes vs delayed endoscopy in high-risk
patients with acute nonvariceal UGIH? (3) Does early endoscopy reduce resource
utilization vs delayed endoscopy for all comers with acute nonvariceal UGIH?
METHODS
A structured search of 3 computerized bibliographic databases (MEDLINE,
HEALTHSTAR, and the Cochrane Database of Systematic Reviews), along with a
CD-ROM–assisted (DDW [Digestive Disease Week] Abstracts-on-Disc; American
Gastroenterological Association, Bethesda, Md) review of published abstracts
from 3 major subspecialty journals, was performed to identify English-language
publications from January 1980 to January 2000. The search strategy, including
selection of subject headings and key words, was performed with an expert
librarian to maximize search sensitivity for targeted information. Generated
titles were assessed for relevancy and were rejected only if they fulfilled
explicit exclusion criteria, including (1) not written in English; (2) not
concerned with human subjects; (3) not related to UGIH or lesions that can
cause UGIH; (4) solely related to variceal bleeding or other complications
of portal hypertension; (5) solely related to nonendoscopic interventions
or complications thereof; and (6) solely related to occult, subacute, or chronic
UGIH. Selected abstracts were reviewed and were rejected if they (1) made
no reference to outcome or process measurement, (2) referred only to bleeding
severity, but not to the effectiveness of endoscopy, or (3) made no reference
to time factors. Disagreements were resolved by consensus. In addition, bibliographies
of included studies and key review articles were reviewed for references not
captured by the search strategy.
Remaining studies were independently reviewed and included if they had
information regarding the effectiveness of early endoscopy, as determined
by impact on patient outcomes (mortality, rebleeding, transfusion requirements,
need for emergency surgery, endoscopic complications, and readmission) and
economic outcomes (length of stay and direct costs). Where methodology was
unclear, authors were contacted for additional information. Each included
study was independently abstracted for data, and randomized clinical trials
were assessed for methodologic quality by means of a standardized instrument
focusing on features related to internal validity. Quasi-experimental designs,
including interrupted time series and controlled before-and-after trials,
were assessed for methodologic quality by means of criteria established by
the Cochrane Collaboration on Effective Professional Practice.25
RESULTS
The search strategy identified 933 titles (Figure 1). Of these, 327 were selected for abstract review, of which
97 studies were retained for consideration. Independent review of these remaining
studies yielded 23 that met our explicit inclusion criteria. Interrater agreement
was high ( = 0.70).
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Figure 1. Results of literature search.
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DOES EARLY ENDOSCOPY ALLOW FOR SAFE AND PROMPT DISCHARGE OF LOW-RISK
PATIENTS WITH ACUTE NONVARICEAL UGIH?
Risk stratification of patients with nonvariceal UGIH involves a combination
of both clinical and endoscopic criteria. Therefore, early endoscopy may potentially
assist in the selection of low-risk patients eligible for prompt discharge
by rapidly confirming clinical suspicion. Twenty studies were identified that
examined the relationship between the timing of endoscopy and outcomes for
low-risk patients with nonvariceal UGIH. These reports may be categorized
both by study design and by whether early endoscopy was the principal focus
of the study intervention (Figure 2).
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Figure 2. Studies that relate to timing
of endoscopy for low-risk patients with nonvariceal upper gastrointestinal
tract bleeding. Arrow indicates direction of strongest evidence by study strategy
and design. Values indicate number of studies in each subcategory.
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The most direct evidence comes from experimental studies with discharge
protocols that explicitly include early endoscopy. Of these, strategies that
compare the protocol with a control population undergoing standard medical
management provide the strongest evidence. Other study designs examine discharge
protocols that do not explicitly involve early endoscopy, but that nonetheless
perform post hoc analysis relating the timing of endoscopy to outcomes for
low-risk patients.
Table 1 summarizes the controlled
trials that compare early endoscopy with "usual care" for low-risk patients.
There were 3 randomized studies. In the largest, Lee et al20
compared a strategy of prompt endoscopy within 2 hours of presentation vs
direct hospital admission for clinically "stable" subjects. The study group
was retained in the emergency department until endoscopy could be performed,
at which point clinically stable patients without stigmas of recent hemorrhage
were discharged. The control group was hospitalized and underwent endoscopy
within 24 to 48 hours. With this strategy, 46% of the study group avoided
hospitalization and had no complications or readmissions at 30 days' follow-up
despite the initial impression by the emergency department staff that these
patients would require admission. The study is notable for a careful delineation
of inclusion and exclusion criteria, a randomized design with concealed allocation
(in the form of opaque envelopes), and thorough patient follow-up with a full
description of patient dropouts. A potential shortcoming of this study is
that patients with suspected variceal bleeding by clinical criteria were excluded
before endoscopy. Because patients with clinical signs of portal hypertension
frequently bleed from a nonvariceal source, this study may underestimate the
true prevalence of nonvariceal hemorrhage.
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Table 1. Controlled Trials Relating to Timing of Endoscopy for Low-Risk
Patients With Nonvariceal Upper Gastrointestinal Tract Hemorrhage*
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Campo et al26 compared a strategy of
inpatient vs outpatient care of low-risk subjects undergoing endoscopy within
12 hours of admission. Clinically stable patients without stigmas of recent
hemorrhage and with adequate home support were randomly assigned to either
discharge on a proton pump inhibitor regimen with daily telephone follow-up
for a week or admission for standard inpatient management. In those allocated
to outpatient care, there were no deaths and only 1 episode of successfully
treated "minor" rebleeding within 1 week. Although the study design was randomized,
there was no indication of concealed allocation and no description of withdrawals
and dropouts. In addition, the follow-up period of 1 week may have been inadequate
to fully account for all postdischarge complications.
Brullet et al27 randomized clinically
stable patients to outpatient vs inpatient management after undergoing emergent
epinephrine and polidocanol injection of nonbleeding visible vessels within
12 hours of presentation. There were no deaths or episodes of rebleeding in
the outpatient group. However, this study suffers from a small sample of only
8 subjects in the outpatient arm, no description of concealed allocation or
patient withdrawals, and a potentially inadequate 1-week follow-up. Moreover,
the method used (epinephrine alone) is no longer considered adequate for effective
hemostasis. Nonetheless, the study is notable for demonstrating safe outpatient
management for a group that might normally be deemed high risk by endoscopic
criteria.
Almela et al28 compared outpatient vs
inpatient care of all comers with UGIH undergoing immediate endoscopy in the
emergency department. Clinically stable patients without stigmas of recent
hemorrhage were either admitted for inpatient care or discharged with follow-up
at 1 month. Those with active bleeding, stigmas of recent hemorrhage, or hemodynamic
instability were admitted for inpatient care. Of 201 outpatients, there were
3 deaths (1.5%) and 1 episode of successfully treated gastrointestinal tract
bleeding from an aortoenteric fistula vs 20 deaths (2.6%) and 56 episodes
of rebleeding (7.3%) in 767 inpatients. The authors conclude that outpatient
care of selected patients is a safe alternative to admission. This study is
limited by a lack of randomization and by an apparent incompatibility between
the control and study groups, because low-risk subjects managed as inpatients
were grouped with hospitalized high-risk patients.
The methodologic quality of the 4 trials with concurrent control groups
is summarized in Table 2. With
the use of a validated scoring scale,31 only
the study by Lee et al20 is considered high
quality. All of the trials describe explicit inclusion and exclusion criteria,
and 3 of the 4 describe the study design as randomized. However, only the
study by Lee et al described a concealed randomization process (this refers
to measures taken to prevent investigators from influencing the allocation
process, such as using serially numbered, opaque, sealed envelopes, or central
randomization). None of the studies was blinded. However, in settings where
blinding is not possible, outcome can be assessed by individuals blinded to
the original treatment allocation. This was not described in any of the studies.
Concealment of allocation and blinding are study quality indicators and, when
not satisfied, may result in an overestimation of the intervention effect.
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Table 2. Quality Assessment of Controlled Trials Relating to Endoscopy
for Low-Risk Patients With Nonvariceal Upper Gastrointestinal Tract Bleeding
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Two controlled studies compared early endoscopy for low-risk patients
with historical or retrospective controls. Rockall et al30
compared outcomes of all comers with UGIH before and after implementation
of a national early discharge protocol that encouraged endoscopy within 24
hours. The authors found that, compared with a preintervention control group,
patients underwent endoscopy more frequently and earlier after the guidelines
were in place, without any impact on severity-adjusted mortality rates. It
is unclear whether the study had sufficient power to detect a mortality reduction,
or whether this is the most relevant outcome in low-risk patients. Additional
relevant outcomes, including rebleeding and readmission, were not reported,
nor was there follow-up of outpatients on discharge. Finally, this study included
variceal and nonvariceal causes of UGIH, thereby further confounding conclusions
specifically regarding nonvariceal hemorrhage.
Hussain et al29 compared outcomes for
patients with peptic ulcer bleeding before and after implementation of an
early discharge protocol requiring endoscopy within 12 hours of admission.
Clinically stable patients with a clean-based ulcer were discharged from the
hospital on a histamine2-blocker regimen and contacted for follow-up
at 5 to 7 days, while those with active bleeding underwent immediate hemostasis
and were hospitalized. Compared with a retrospective control group, fewer
patients required surgical intervention in the postguideline period. Although
the authors conclude that low-risk patients with clean-based ulcers can be
safely managed as outpatients, it is unclear whether the study findings substantiate
this conclusion. In particular, the authors did not report any outcomes for
the patients discharged, nor did they describe the completeness of outpatient
follow-up. While need for emergent surgery is an important patient outcome,
it relates more directly to high-risk groups and may not contribute meaningfully
to conclusions regarding outpatient management of low-risk subjects.
Six uncontrolled trials examined early endoscopy for low-risk patients
(Table 3). Cebollero-Santamaria
et al32 evaluated a protocol in which clinically
low-risk elderly (age  65 years) patients were discharged after immediate
endoscopic confirmation in the emergency department. Those with a low risk
for rebleeding, as determined by explicit endoscopic and clinical criteria,
were discharged and followed up intermittently for 1 month. The authors reported
no deaths, rebleeding, or readmissions among 24 outpatients. Although limited
by the lack of a control group, this study is notable for focusing on the
elderly population, a group that tends to be at higher risk and is often treated
more conservatively.
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Table 3. Uncontrolled Trials Relating to Timing of Endoscopy for Low-Risk
Patients With Nonvariceal Upper Gastrointestinal Tract Hemorrhage*
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Of the remaining 6 uncontrolled trials,33-38
all showed low complication rates of outpatients triaged by early endoscopy.
In particular, there were no deaths and rebleeding occurred in 0%33 to 2.9%36 of patients.
All incidents of rebleeding were successfully treated with readmission. The
follow-up period ranged from 1 week33, 37
to 16 months.34 Five studies focused exclusively
on nonvariceal hemorrhage,33-37
while the study by Chang et al38 included variceal
hemorrhage as well. The trial by Hsu et al33
specifically evaluated peptic ulcer hemorrhage, while Lai et al34
focused only on patients with duodenal ulcer hemorrhage. Patients were selected
for outpatient care by a combination of both clinical and endoscopic criteria
in all studies. Two studies32, 36
excluded potential variceal hemorrhage before endoscopic confirmation by selecting
out subjects with evidence of alcoholic liver disease. One study excluded
from enrollment patients taking noncorticosteroidal anti-inflammatory drugs.33
There were 2 experimental studies in which early endoscopy was not the
primary focus of the intervention, but the authors nonetheless drew corollary
findings relating timing of endoscopy to patient outcomes. Hay et al,21 in a prospective controlled time-series study with
an alternate-month design, evaluated the safety of a clinical guideline that
recommended early discharge for patients with acute UGIH considered to be
at low risk for subsequent complications. Recommendations for length of stay
were dependent on a combination of validated clinical and endoscopic criteria.
The authors found that there were 3 deaths and only 1 episode of rebleeding
at 1 month of follow-up among 209 patients deemed low risk by the guideline.
The deaths were related to chronic medical conditions and not to complications
of UGIH. While early endoscopy was not an explicit component of the intervention
guidelines, it was found to be an independent predictor of decreased length
of stay for low-risk patients. These data were confirmed by Moreno et al39 in a study using the same discharge guidelines. In
contrast to the Hay et al study, this trial covered a continuous period and
compared data with retrospective controls. Moreover, during the study period,
guidelines were implemented by 1 team in consecutive patients. There were
1 death and 7 episodes of rebleeding among 488 low-risk patients at 1 week
of follow-up. The authors conclude that "most" low-risk patients can be safely
discharged.
Our review identified 5 observational studies,19, 40-43
of which 242-43 directly examined
the effect of early endoscopy on patient outcomes. In a large retrospective
cohort study, Lindenauer et al42 failed to
detect a mortality benefit for all comers undergoing early (<24 hours)
vs delayed (24 hours) endoscopy and extended these conclusions to low-risk
patients through multivariate analysis stratifying patients by clinical severity.
However, mortality was the only outcome assessed. In a retrospective application
of a discharge protocol encouraging early endoscopy, Rockall et al43 projected that 25% of all comers with UGIH could
have been safely discharged immediately after prompt endoscopy.
Hay et al,41 in a retrospective validation
of the previously described discharge protocol by the same authors, found
a 0.6% complication rate for patients deemed low risk. Conversely, in a large
retrospective cohort study of consecutive patients with UGIH, Cooper et al19 established through multivariate analysis that early
endoscopy was associated with a slightly higher but not statistically significant
risk of in-hospital death for patients in the lowest risk group. In a second
retrospective study by the same authors,40
early endoscopy was found to be equivocal as a risk factor for poor patient
outcomes in low-risk subjects. Because of limitations of study design, it
is difficult to draw firm conclusions for low-risk patients from these observational
studies, as there was no postdischarge follow-up, no description of additional
important patient outcomes beyond mortality and need for surgery, and no distinction
between variceal and nonvariceal causes of bleeding.
It appears that the weight of the evidence supports early vs delayed
endoscopy for low-risk patients with acute nonvariceal UGIH (Figure 3). If only the highest-quality controlled study is considered,
Lee et al20 showed that early endoscopy and
prompt discharge of low-risk patients was safe and effective. Of the remaining
controlled trials, all showed low complication rates for low-risk subjects
managed as outpatients. Furthermore, there were no deaths and only 9 instances
of rebleeding of a combined 594 low-risk outpatients in 7 uncontrolled prospective
trials.33-38
Of the 20 described studies, 16 suggested that early endoscopy for low-risk
patients is safe and effective, 3 were equivocal, and only 1 detected a statistically
insignificant trend toward increased mortality.
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Figure 3. Literature synthesis. For each
clinical question, the conclusions either support or do not support the effectiveness
of early vs delayed endoscopy in the management of acute nonvariceal upper
gastrointestinal tract hemorrhage (UGIH).
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DOES EARLY ENDOSCOPY IMPROVE PATIENT OUTCOMES VS DELAYED ENDOSCOPY
FOR HIGH-RISK PATIENTS WITH ACUTE NONVARICEAL UGIH?
Although many prospective studies have carefully documented the timing
of emergent endoscopy for high-risk patients with nonvariceal UGIH,44-47 few
have used a control group of patients undergoing delayed endoscopy to compare
patient outcomes on the basis of timing alone. Moreover, of the studies that
have made this comparison, few have examined the role of early endoscopy as
both a diagnostic and a therapeutic tool. These trials are summarized in Table 4.
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Table 4. Controlled Trials Comparing Early vs Delayed Endoscopy for
High-Risk Patients With Nonvariceal Upper Gastrointestinal Tract Hemorrhage*
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In the only randomized trial, Lin et al48
compared early vs delayed endoscopy for diagnostic and therapeutic efficacy
in patients with bleeding peptic ulcer presenting with clear, "coffee ground,"
or bloody nasogastric aspirates. Patient were first randomized to either early
(<12 hours) or late (12-24 hours) endoscopy on the basis of the time of
arrival at the emergency department. Early endoscopy resulted in a reduction
in transfusion requirements in those with bloody aspirates but had no improvement
in outcomes measured in those with coffee ground aspirates. Of note, it is
unclear whether an intention-to-treat analysis was performed, since patients
who were unable to cooperate with endoscopy or who had "massive bleeding"
but refused endoscopy were excluded from the trial after randomization. This
could overestimate the usefulness of the intervention by excluding a potentially
confounding group from one arm of the study but not the other. While the authors
note that the randomization envelopes of excluded patients were sealed and
returned to the pool, this does not negate the potential effect of narrowing
the study arm to a select group at the expense of the comparison group. Nonetheless,
this study is notable for its strict delineation of exclusion criteria and
for its use of concealed allocation in the form of opaque sealed envelopes.
Yen et al16 examined the effects of emergent
(<2 hours) vs delayed (2-24 hours) endoscopy on oxygen saturation for patients
presenting to the emergency department with UGIH. The authors found both a
significantly higher rate of oxygen desaturation and a decreased recovery
of preendoscopic saturation with early endoscopy, and therefore concluded
that early endoscopy is associated with more complications than delayed endoscopy.
However, the increased complications associated with early endoscopy were
more likely a function of increased patient risk in the study arm, as patients
with active hematemesis received early endoscopy, while those without it received
delayed endoscopy.
There were 4 observational studies that evaluated the role of early
vs delayed endoscopy for high-risk patients.19, 40, 42, 49
Cooper et al, in a pair of retrospective multicenter cohort studies,19, 40 examined the impact of early ( 24
hours of admission) vs delayed (>24 hours after admission) endoscopy on in-hospital
mortality, surgical intervention, and rebleeding for all comers with UGIH.
The authors found that early therapeutic endoscopy for high-risk patients
resulted in a significant reduction in rebleeding and surgery and a statistically
insignificant trend toward reduced mortality. Lindenauer et al,42
in a large retrospective study of Medicare beneficiaries, detected no mortality
advantage of early (24 hours) vs delayed (>24 hours) endoscopy for high-risk
elderly patients. Finally, in a retrospective evaluation of high-risk subjects
with peptic ulcer bleeding, Choudari and Palmer49
found no difference in patient outcomes for groups undergoing early (<6
hours), intermediate (>6-12 hours), and delayed (>12-24 hours) endoscopy.
However, these were all uncontrolled retrospective studies, had no description
of postdischarge complications, and, with the exception of the Choudari and
Palmer study, included variceal and nonvariceal causes of hemorrhage.
In summary, the weight of the evidence supports early vs delayed endoscopy
for high-risk patients with acute nonvariceal UGIH (Figure 3). If only the highest-quality clinical trial is considered,
the study by Lin et al48 showed no mortality
benefit but a significant decrease in transfusion requirements for high-risk
patients. Of the remaining studies, 2 showed a significant improvement of
patient outcomes with early vs delayed endoscopy for high-risk patients, and
2 were equivocal. One study suggested the potential for more complications
with emergent nonsedated endoscopy, and no studies detected any significant
impact on mortality for high-risk patients.
DOES EARLY ENDOSCOPY IMPROVE UTILIZATION OUTCOMES VS DELAYED ENDOSCOPY
FOR ALL COMERS WITH ACUTE NONVARICEAL UGIH?
Early endoscopy may potentially reduce costs both by reducing hospital
length of stay50 and by avoiding admission
when compared with delayed endoscopy. Table
5 summarizes the studies investigating the impact of early vs delayed
endoscopy on costs and utilization.
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Table 5. Studies Comparing Resource Utilization for Patients Undergoing
Early vs Delayed Endoscopy*
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Two randomized trials met our inclusion criteria. Lee et al20 evaluated the effect of early endoscopy on length
of stay and total costs for low-risk patients with nonvariceal UGIH. The authors
found a decrease in mean hospital stay of 1 day (1 vs 2 days) with the use
of early endoscopy. Moreover, they calculated a cost reduction of $1594 per
patient ($2068 vs $3662) associated with the use of early endoscopy. This
savings reflected both a decreased length of stay and a difference in admission
location, as significantly fewer patients in the study group were managed
in the intensive care unit but were instead admitted to the less costly medical
ward. To investigate the potential of cost shifting to the outpatient arena,
the authors monitored postdischarge unplanned physician visits. They found
significantly fewer visits in the early endoscopy group, thereby contributing
to the overall cost reduction associated with early endoscopy.
Lin et al48 investigated the effect of
early endoscopy on length of stay for high-risk patients with nonvariceal
UGIH. For the subgroup of patients with a bloody nasogastric aspirate, early
endoscopy saved 10.5 days per patient compared with delayed endoscopy (4.0
± 3.5 vs 14.5 ± 10.8 days). While this represents a dramatic
reduction, the small sample size and potential outlier effect may have skewed
the results.
There were 2 studies with quasi-experimental designs that addressed
costs and utilization. Hay et al,21 in an interrupted
time series with alternate-month design, investigated the impact of a management
guideline on length of stay for all comers with nonvariceal UGIH. Although
the authors did not perform analysis for individual risk groups, they demonstrated
an independent association between early endoscopy and shorter length of stay
for all patients, and projected a 63% decrease in total inpatient costs with
the early discharge guidelines vs usual care. There was no evidence of cost
shifting, as an equal number of patients in both groups sought postdischarge
physician visits. Hussain et al29 compared
length of stay for both low- and high-risk patients before and after instituting
a management protocol for peptic ulcer bleeding. They found a reduction of
1.24 days per patient for low-risk and 1.01 days per patient for high-risk
patients with the use of early endoscopy.
There were 4 observational studies,19, 40, 42-43
all of which demonstrated a significant reduction in length of stay with early
endoscopy for low-risk patients (range of 1-2 days per patient). Of the 2
studies that specifically examined high-risk patient subgroups, 1 showed a
decreased length of stay (2 days saved per patient)40
while 1 demonstrated an insignificant increase in length of stay with early
endoscopy.43
Figure 4 displays the composite
data on length of stay for the 8 studies as a function of risk group. Of the
4 studies that examined low-risk patients, all demonstrated a decrease in
length of stay associated with early vs delayed endoscopy. Of the 4 studies
that examined high-risk subgroups, all but 1 detected a shorter length of
stay. Finally, each of the 3 studies that performed no risk stratification
portrayed an advantage for all comers undergoing early endoscopy. All data
in support of early vs delayed endoscopy were statistically significant, although
the one instance of increased length of stay failed to achieve statistical
significance.
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Figure 4. Studies comparing length of stay
for early vs delayed endoscopy by risk group. For studies with more than 2
risk groups, data are presented for highest and lowest risk group. Studies
without subgroup data are presented as "all comers."
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COMMENT
Since no consensus exists regarding the costs and benefits of early
endoscopy in UGIH, we sought to identify and critically appraise the evidence
in the medical literature regarding the effectiveness of early vs delayed
endoscopy on patient and economic outcomes. For all 3 clinical questions,
the weight of the evidence favors early endoscopy (Figure 3). For low-risk patients, the evidence clearly supports
the claim that early endoscopy promotes safe patient disposition. However,
of the studies that directly investigated early vs delayed endoscopy, only
the trial by Lee et al20 was deemed high quality
by means of a validated scoring scale. While the study by Hay et al21 was also of high quality, it only indirectly examined
the association of early vs delayed endoscopy for low-risk patients. The remaining
studies were found to suffer from 1 or more potentially significant methodologic
shortcomings, including lack of an appropriate comparison group, inadequate
patient follow-up, lack of sufficient statistical power, or lack of prospective
experimental design.
For high-risk patients, our review suggests that there is a benefit
from early vs delayed endoscopy in many patient outcomes, including transfusion
requirements, rebleeding, and need for emergency surgery. Furthermore, while
there was no evidence that early endoscopy decreases mortality, there was
also no evidence that the practice results in patient harm. The data were
limited by several methodologic shortcomings, and the only identified randomized
control trial did not perform an intention-to-treat analysis.
Regarding resource utilization, the evidence suggests that early endoscopy
significantly reduces length of stay compared with delayed endoscopy for all
risk groups with nonvariceal UGIH without evidence of cost shifting to the
outpatient setting. Of the 2 studies that conducted an absolute cost analysis,20-21 both found a significant savings
from early endoscopy. There were no formal cost-effectiveness analyses reporting
incremental cost-effectiveness ratios.
There is controversy regarding the ideal time to perform endoscopy in
patients presenting with UGIH. Early endoscopy may provide prompt diagnosis,
rapidly confirm clinical suspicion, and serve as an aid to decision making
regarding triage and subsequent management. For high-risk patients, early
endoscopy may result in rapid hemostasis, while low-risk patients may benefit
by safely avoiding hospitalization. A policy of early endoscopy may reduce
resource use by minimizing potentially unnecessary admissions, by reducing
the length of stay for those who are admitted, and by downgrading the admission
location to less costly venues. Moreover, data suggest that delaying endoscopy
is of little benefit to patients with nonvariceal UGIH.13-14
Conversely, opponents of early endoscopy contend that there is scant
evidence to support the claim that endoscopy provides a mortality benefit,
regardless of timing.3-4,15
Moreover, some indirect evidence suggests that early endoscopy may be associated
with more complications than delayed endoscopy.16-17
Only 1 study16 directly assessed the safety
of early endoscopy, suggesting that it may result in an increased risk of
oxygen desaturation. However, this study used early endoscopy disproportionately
in a high-risk group, and all other studies identified suggest that early
endoscopy is safe. Therefore, while some argue that emergently subjecting
low-risk patients to a potentially unhelpful and invasive procedure is not
worth the risk of subsequent or preventable complications, supportive evidence
is lacking.
Moreover, a policy of early endoscopy may be difficult and expensive
to implement in the real world. The associated costs of operating a 24-hour
endoscopy service may be substantial, as this not only requires support of
additional physicians, nurses, and equipment technicians, but also requires
extensive facility investments, particularly for those institutions not well
equipped to perform endoscopy in the emergency department. Early endoscopy
could further escalate costs by detecting stigmas of recent hemorrhage that
might otherwise have resolved by the time of delayed endoscopy, thereby leading
to potentially unnecessary interventions.
There are some limitations to this analysis. As with any systematic
review, there is a potential for publication bias, which refers to the common
practice of publishing only trials with positive outcomes. However, we believe
there may be incentive to publish studies that demonstrate negative outcomes
for an otherwise time-consuming and potentially costly intervention if it
existed. Additionally, there is a paucity of randomized trials, and many of
our conclusions are based on uncontrolled and observational studies. The heterogeneity
of the study designs, inclusion criteria, timing of endoscopy, and reported
end points precluded formal meta-analysis. Nonetheless, where possible, we
attempted to weigh the evidence by methodologic rigor and to base our conclusions
on the findings from prospective randomized controlled clinical trials.
Although our review identified a substantial number of studies examining
the impact of early vs delayed endoscopy, there were few experimental trials
and even fewer of high methodologic quality. Additional well-designed, randomized
clinical trials comparing early vs delayed endoscopy for all risk groups must
be performed before firm conclusions can be reached regarding the impact on
long-term patient outcomes. To clarify issues of utilization, there is a need
for studies comparing the costs of 24-hour endoscopy services with "usual
care." In addition, the definition of early must
be elucidated and confirmed in comparative trials. For example, is 4 hours
better than 12 hours?
These findings suggest that a more streamlined and standardized approach
to acute nonvariceal UGIH—akin to the time-sensitive paradigm of acute
myocardial infarction management—may improve patient outcomes. A 24-hour
gastrointestinal rapid response team, similar to the "code blue" revascularization
service omnipresent in major medical centers, would ensure that patients with
UGIH receive prompt and high-quality care. For low-risk patients, an emergency
department UGIH observation unit,38, 51
similar to recently proposed "chest pain observation units,"52
could serve as a way station for patient triage decisions. The evidence suggests
that hesitancy to discharge low-risk patients may be unfounded, and that it
should no longer be obligatory to admit all patients with acute nonvariceal
UGIH to the hospital. Likewise, high-risk patients may benefit from a more
coordinated and timely delivery of endoscopic hemostasis than the often inconsistent
and time-insensitive approach currently practiced. Until additional well-designed
trials are conducted, it is difficult to draw definitive conclusions. Until
then, existing data suggest that early endoscopy may be safe and effective
for all risk groups.
AUTHOR INFORMATION
Accepted for publication January 11, 2001.
Presented in part in abstract form at Digestive Disease Week 2000, San
Diego, Calif, May 22, 2000.
Corresponding author and reprints: Joshua J. Ofman, MD, MSHS, 9100
Wilshire Blvd, Suite 655, Beverly Hills, CA 90212 (e-mail:
ofmanj{at}zynx.com).
From the Department of Medicine and Health Services Research, Cedars-Sinai
Medical Center, Los Angeles, Calif (Drs Spiegel and Ofman); Department of
Gastroenterology, University of Wisconsin Medical School, Milwaukee (Dr Vakil);
and Zynx Health Incorporated, a Subsidiary of Cedars-Sinai Health System,
Los Angeles (Dr Ofman).
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