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ORIGINAL ARTICLE

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Relationship between timing of endoscopy and mortality inpatients with peptic ulcer bleeding: a nationwide cohort study

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Stig B. Laursen, MD, PhD,1 Grigorios I. Leontiadis, MD, PhD,2 Adrian J. Stanley, MD, FRCP,3

Morten H. Møller, MD, PhD,4 Jane M. Hansen, MD, PhD,1 Ove B. Schaffalitzky de Muckadell, MD, DMSc1

Odense, Copenhagen, Denmark; Hamilton, Ontario, Canada; Glasgow, Scotland, United Kingdom

Background and Aims: The optimal timing of endoscopy in patients with peptic ulcer bleeding (PUB) remains
unclear. The aim of this study was to examine the association between timing of endoscopy and mortality in PUB.
Methods: In a nationwide cohort study based on a database of consecutive patients admitted to the hospital withPUB in Denmark, patients were stratified according to the presence of hemodynamic instability at presentationand American Society of Anesthesiologists (ASA) score. Using descriptive statistics and logistic regression analyses,we identified optimal time frames for endoscopy and analyzed the association between timing of endoscopy andin-hospital mortality after adjusting for confounding factors.

Results: In total, 12,601 patients were included. We did not find any universal association between timing ofendoscopy and mortality in hemodynamically stable patients with an ASA score of 1 to 2. In hemodynamicallystable patients with an ASA score of 3 to 5, endoscopy 12 to 36 hours after admission to the hospital was asso-ciated with lower in-hospital mortality (OR, .48; 95% CI, .34-.67) compared with endoscopy outside this timeframe. In patients with hemodynamic instability, endoscopy 6 to 24 hours after admission to the hospital was asso-ciated with lower in-hospital mortality (OR, .73; 95% CI, .54-.98) compared with endoscopy outside this timeframe.

Conclusions: Timing of endoscopy is associated with mortality in patients with PUB and an ASA score of 3 to 5 orhemodynamic instability. Our findings suggest that in these patients, a period of time to optimize resuscitationand manage comorbidities before endoscopy may improve outcome. (Gastrointest Endosc 2016;-:1-9.)

Endoscopy is essential for the diagnosis and manage-ment of peptic ulcer bleeding (PUB). In patients withhigh-risk ulcers, performance of endoscopic therapy iseffective in achieving hemostasis and reducing the risk ofrebleeding, need for surgery, and possibly mortality.1

Despite this, the optimal timing of endoscopy remainsunclear. Because endoscopic therapy is associated withimproved outcome, it seems logical that the timing ofendoscopy may also affect outcome.

ns: ASA, American Society of Anesthesiologists; DCRES,nical Register of Emergency Surgery; PUB, peptic ulcer

E: The following author received research support for thisOdense University Hospital and Region of Southern

S. B. Laursen. All other authors disclosed no financials relevant to this publication.

2016 by the American Society for Gastrointestinal Endoscopy36.00i.org/10.1016/j.gie.2016.08.049

ne 6, 2016. Accepted August 27, 2016.

urnal.org

Late performance of endoscopy and endoscopic therapymay increase the risk of ongoing or recurrent bleeding,thereby reducing the positive effect of the intervention.On the other hand, early endoscopy may be associatedwith suboptimal resuscitation and destabilization of comor-bidities. Therefore, it is possible that optimal timing ofendoscopy is within a “window” that allows sufficient timefor pre-endoscopic optimization of thepatient’s clinical statebut does not significantly delay performance of endoscopy.

Current affiliations: Department of Medical Gastroenterology, OdenseUniversity Hospital, Odense, Denmark (1), Department of Medicine,Division of Gastroenterology, McMaster University, Hamilton, Ontario,Canada (2), Department of Gastroenterology, Glasgow Royal Infirmary,Glasgow, Scotland, United Kingdom (3), Department of Intensive Care,Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark (4).

Reprint requests: Stig B. Laursen MD, PhD, Department of MedicalGastroenterology, Odense University Hospital, Søndre Boulevard 29,5000 Odense C, Denmark.

If you would like to chat with an author of this article, you may contactDr Laursen at [email protected].

Volume -, No. - : 2016 GASTROINTESTINAL ENDOSCOPY 1

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http://dx.doi.org/10.1016/j.gie.2016.08.049

mailto:[email protected]

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Timing of endoscopy and mortality in patients with PUB Laursen et al

Randomized controlled trials2-4 and observationalstudies5-7 have compared the outcome of endoscopy per-formed within 2 to 24 hours with a later endoscopy, withoutfinding any difference in mortality. Limitations of existingrandomized controlled trials include insufficient inclusionof high-risk patients resulting in low mortality rates (0%-3.7%),2-4 small sample sizes (nZ 93-325),2-4 exclusion of pa-tients with hemodynamic instability,2 lack of proton pumpinhibitor use,4 and lack of power calculation.4 Publisheddata suggest that performance of endoscopy within 8hours is associated with a higher frequency of ulcers withhigh-risk stigmata of bleeding and a higher need for endo-scopic therapy when compared with later endoscopy.3,5-7

Nevertheless, these studies did not find that early endos-copywas associatedwith any reduction in rate of rebleeding,need for surgery, or mortality. An observational study foundthat among high-risk patients with a need for endoscopictherapy, performance of therapeutic endoscopy within 24hours was associated with a lower risk of rebleeding and sur-gery.8 In another nonrandomized study, performance ofendoscopy within 13 hours was found to be associatedwith lower mortality in high-risk patients defined as thosewith a Glasgow Blatchford score above 12.9 This study wascriticized because of a low number of high-risk patients.10

Based on a large dataset from a national audit performedin the United Kingdom, Jairath et al11 found thatendoscopy performed within 12 hours was not associatedwith lower mortality or need for surgery compared withendoscopy performed after 24 hours. It is important tonote that most research within this field is characterizedby low-quality observational studies, including high risk ofselection bias, considerable risk of residual confoundingby severity, and low sample size. Further data are neededto identify the optimal timing of endoscopy in patientswith PUB.

The aim of the present study was to examine the associa-tion between timing of endoscopy and mortality inan unselected nationwide cohort of PUB patients. Wehypothesized that (1) optimal timing of endoscopy may bewithin a window, which leaves time for pre-endoscopic opti-mization of the patient without significantly delayingendoscopy, and (2) optimal timing of endoscopy maydepend on severity of bleeding and presence of severecomorbidity.

METHODS

Study design and populationThe study was conducted as a nationwide cohort study

based on data from the Danish Clinical Register ofEmergency Surgery (DCRES). The DCRES is a nationwidedatabase that includes prospectively collected data onconsecutive patients admitted to Danish hospitals withverified PUB since 2005. PUB was defined as presentationwith hematemesis and/or melena, with subsequent upper

2 GASTROINTESTINAL ENDOSCOPY Volume -, No. - : 2016

endoscopy confirming the source to be peptic ulceration.Danish hospitals are required by law to report all PUBpatients to the DCRES. The reported data are comparedwith the National Patient Registry to ensure data accuracyand completeness. The DCRES has previously beendescribed in further detail.12

Using the DCRES, we identified patients admitted to thehospital with PUB in Denmark from January 2005 toSeptember 2013. We included the following data from thedatabase: date and time of admission to hospital, develop-ment of PUB while already inpatients for another reason,date and time of development of symptoms of bleedingfor in-hospital patients, date and time of primary endoscopy,patient characteristics (age, sex, American Society of Anes-thesiologists [ASA] score,13 alcohol consumption, smokingstatus), medication use (low-dose aspirin � 150 mg/day,nonsteroidal anti-inflammatory drugs, anticoagulants oradenosine diphosphate receptor inhibitors, steroids), bloodtests (hemoglobin, creatinine) at time of presentation to thehospital, presence of hemodynamic instability at time of pre-sentation, findings at endoscopy (location of ulcer, stigmataof bleeding), interventions performed at primary bleedingepisode (endoscopic therapy, surgery, transarterial emboli-zation), development of rebleeding, severity of rebleeding(need of endoscopic therapy, surgery, or transarterial embo-lization), and in-hospital mortality.

The Patient Administrative System of Funen County in-cludes information on time of death in deceased patientswho at any time from 1985 to 2014 had been in contactwith hospitals in the Region of Southern Denmark (1.2million inhabitants corresponding to 21% of the Danishpopulation).14 Using the Patient Administrative System ofFunen County, we retrieved data on 30-day mortality inconsecutive patients admitted to the hospital with PUBin the Region of Southern Denmark and patients withPUB from other Danish regions who for any reason hadbeen in contact with a public hospital in the Region ofSouthern Denmark from 1985 to 2014.

According to Danish law, review by an ethics board is notrequired for noninterventional observational studies.15 Thestudy was approved by the Danish Data Protection Agency(2013-41-2501). Our report follows the STrengthening theReporting of OBservational studies in Epidemiology(STROBE) guidelines.16

DefinitionsTiming of endoscopy was defined as the period of time

from hospital admission (arrival at the emergency depart-ment) to performance of endoscopy. In patients within-hospital bleeding, the timing of endoscopy was definedas the period of time from development of symptoms ofPUB to performance of endoscopy. High-risk stigmata ofbleeding was defined as ulcers with active bleeding, a non-bleeding visible vessel, or an adherent clot. Hemodynamicinstability was defined as presentation with a combinationof systolic blood pressure below 100 mm Hg and heart rate

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Laursen et al Timing of endoscopy and mortality in patients with PUB

above 100 beats/min. Endoscopy-refractory bleeding wasdefined as bleeding that could not be controlled by endo-scopic therapy. Significant comorbidity was defined as anASA score of 3 to 5. High alcohol consumption was definedas a weekly intake of alcohol above 168 g for women and252 g for men. Out-of-hours admission was defined asadmission to the hospital from 4 PM to 7 AM. Weekendadmission was defined as admission to the hospital be-tween midnight on Friday and midnight on Sunday.

Outcome measuresThe primary outcome measure was in-hospital mortality.

Thirty-day mortality was selected as a secondary outcomemeasure because we did not have data on this endpointin all patients.

Statistical methodsBased on clinical knowledge, we hypothesized that the

association between timing of endoscopy and outcomemay depend on severity of bleeding and presence ofcomorbidity. Therefore, patients were stratified accordingto presence of hemodynamic instability and significantcomorbidity.

We performed scatterplots of the association betweentiming of endoscopy and in-hospital mortality in eachgroup of patients. Based on this, we identified time inter-vals that seemed to be associated with lowest in-hospitalmortality. Using logistic regression models with backwardelimination, we analyzed the association between endos-copy within these intervals and in-hospital mortalitywhen adjusting for predefined confounders. Candidate var-iables with P � .15 were evaluated and excluded from themodel 1 by 1 if a comparison of the full and reducedmodels using likelihood ratio tests was statistically insignif-icant. The order of elimination was determined by a com-bination of level of P-value and clinical importance.

The following covariates were included as candidatevariables in the regression models: high alcohol consump-tion (yes or no; see Definitions, above), smoking status(categorical variable: never-smoker, previous smoker, dailysmoker), use of low-dose aspirin � 150 mg/day (yes or no),use of anticoagulants or adenosine diphosphate receptorinhibitors (yes or no), use of nonsteroidal anti-inflammatory drugs (yes or no), use of steroids (yes orno), creatinine measured at time of hospital presentation(continuous variable; measured in mmol/L), ulcer location(gastric or duodenal), out-of-hours admission to hospital(yes or no; see Definitions, above), weekend admissionto hospital (yes or no; see Definitions, above), and yearof admission to hospital (continuous variable). Timing ofendoscopy (categorical variable; values used are presentedin Results, below), age (continuous variable; measured inyears), sex (male or female), ASA score (categorical vari-able), hemoglobin measured at time of hospital presenta-tion (continuous variable; measured in g/dL), high-riskstigmata of bleeding (yes or no; see Definitions, above),

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endoscopy-refractory bleeding during hospitalization (yesor no; see Definitions, above), and in-hospital bleeding(binary variable; development of PUB while already inpa-tients for another reason: yes or no) were included asmandatory variables in all models. Similar regressionmodels were used to analyze the association betweentiming of endoscopy and 30-day mortality in observationswith data on this outcome.

Results are presented as odds ratios (ORs) with 95%confidence intervals (CIs). The appropriateness of the un-derlying assumptions (collinearity and linearity of indepen-dent variables and log odds) was examined graphically andstatistically. Potential multiplicative interactions betweentiming of endoscopy and stigmata of bleeding found atendoscopy; timing of endoscopy and severity of bleeding;timing of endoscopy and weekend admission to hospital;timing of endoscopy and year, age, and ASA score; ageand in-hospital bleeding; and ASA score and in-hospitalbleeding were analyzed using interaction terms. Goodnessof fit was evaluated using the Hosmer-Lemeshow test.

The prevalence and pattern of missing data wereevaluated and found not to be missing completely atrandom (Little’s test: P < .001). Missing data were handledusing multiple imputation.17 All outcomes and baselinevariables were included in the imputation model, and 20imputations were used.

We undertook the following 2 sensitivity analyses and 1subgroup analysis. The first sensitivity analysis was timingof endoscopy. The ORs of mortality associated with endos-copy within the time intervals identified by scatterplotswere compared with ORs of mortality associated withendoscopy in the periods: <12 hours, between 12 and 24hours, and <24 hours. The second sensitivity analysis wasout-of-hours admission to hospital. The impact of thedefinition of out-of-hours was evaluated using differentdefinitions (5 PM-7 AM; 6 PM-7 AM), including splittingthe out-of-hours period into 2 periods (4 PM to midnightand midnight to 7 AM). The subgroup analysis wasin-hospital status; we performed subgroup analyses onpatients with in-hospital bleeding and patients presentingwith PUB outside the hospital, respectively.

The required sample size was estimated based on thework of Peduzzi et al.18 Based on an average in-hospitalmortality of 5.9% and inclusion of 18 covariates in theregression models, a minimum of 3050 patients wereneeded in each model.

Two-sided P < .05 were considered to be statistically sig-nificant. Data were analyzed using STATA 13.0 (StataCorp,College Station, Tex).

RESULTS

PopulationBased on the search in DCRES 13,569 cases were

identified. We excluded cases without an exact/correct



TABLE 1. Characteristics of patients

Hemodynamically stable patients(n [ 9668)

Patients with hemodynamic instability(n [ 2933)

Total(n [ 12,601)

General characteristics

Median age, y (95% CI) 75 (48-91) 73 (50-90) 74 (48-91)

Sex; male 5223 (54) 1661 (57) 6884 (55)

ASA score 3-5 4232 (44) 1658 (57) 5890 (47)

High alcohol consumption 1388 (15) 608 (22) 1996 (16)

Daily smoking status 2897 (32) 1084 (40) 3981 (34)

Medication

Aspirin 4383 (45) 1236 (42) 5619 (45)

NSAIDs 2247 (23) 751 (26) 2998 (24)

AC/ADP-RI 1837 (19) 593 (20) 2430 (19)

Steroids 698 (7) 281 (10) 979 (8)

In-hospital bleeding 2628 (27) 978 (33) 3606 (29)

Time of admission to hospital

Out-of-hours 4478 (46) 1465 (50) 5943 (47)

Weekend 2208 (23) 763 (26) 2971 (24)

Blood tests

Median hemoglobin level, g/dL (95% CI) 8.9 (5.3-13.7) 8.1 (4.5-12.3) 8.7 (5.0-13.4)

Median creatinine level, mmol/L (95% CI) 83 (47-211) 90 (47-246) 84 (47-220)

Ulcer characteristics

Duodenal location 4668 (50) 1707 (60) 6375 (53)

High-risk stigmata 4369 (45) 2006 (69) 6375 (51)

Endoscopy-refractory bleeding 263 (2.7) 255 (8.7) 518 (4.1)

Rebleeding 1135 (12) 646 (22) 1781 (14)

In-hospital mortality 372 (3.8) 369 (13) 741 (5.9)

30-Day mortality* 335 (6.5) 258 (17) 593 (8.9)

Values are number of patients with percents in parentheses, unless otherwise stated. Values are missing for alcohol consumption (n Z 386), ASA score (n Z 110), smokingstatus (n Z 765), medication use (n Z 139), hemoglobin (n Z 13), creatinine (n Z 117), ulcer location (n Z 464), bleeding stigmata (n Z 32), and rebleeding (n Z 34).NSAIDs, Nonsteroidal anti-inflammatory drugs; AC/ADP-RI, anticoagulants or adenosine diphosphate receptor inhibitors.*Data on 30-day mortality were available in 6643 patients. Please see text for details.


registered time of admission to the hospital (or time ofclinical suspicion of upper GI bleeding in in-hospitalbleeders; n Z 85), known time of endoscopy (n Z 211),missing values regarding hemodynamic instability(n Z 18), and cases where the endoscopy was performedlater than 1 week from time of hospital admission (or timeof clinical suspicion of upper GI bleeding for patients within-hospital bleeds; n Z 79). In patients who were readmit-ted during the period of inclusion, we only used data fromthe first admission to hospital. This led to exclusion of 575observations. Thus, a total of 12,601 patients were includedin the study. Patient characteristics are shown in Table 1.

In-hospital mortality was available for all patients. Dataon 30-day mortality were available in 6643 patients(53%), of which 1510 had hemodynamic instability. Therewere no clinically relevant differences in mean age (72years [95% CI, 48-90] versus 73 years [95% CI, 49-91]),mean ASA score (2.4 [95% CI, 1-4] versus 2.4 [95% CI, 1-4]), or in-hospital mortality (5.3% [95% CI, .048-.059]


versus 6.5% [95% CI, .059-.071]) between observationswith versus observations without data on 30-day mortality.

Hemodynamically stable patientsA total of 9668 patients were hemodynamically stable at

time of admission to hospital or at time of development ofsymptoms of PUB for patients with in-hospital bleeds.

Hemodynamically stable patients with an ASAscore of 1 to 2. In-hospital mortality appeared to be con-stant when endoscopy was performed within the first24 hours in the subgroup of patients with an ASA scoreof 1 to 2 (Fig. 1). Based on Figure 1, we proposed thatthe optimal timing of endoscopy in hemodynamicallystable patients with an ASA score of 1 to 2 was between0 and 24 hours from time of hospital admission or timeof development of symptoms for patients with in-hospitalbleeding. Using logistic regression analysis, we found thatperformance of endoscopy within this time frame wasnot associated with lower in-hospital mortality (OR, .59;

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10 20Timing / hours

ASA 1-2 Fitted valuesFitted valuesASA 3-5

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Figure 1. Association between timing of endoscopy and in-hospital mor-tality in hemodynamically stable patients.


95% CI, .33-1.05; P Z .075) (Table 2) or 30-day mortality(OR, 1.02; 95% CI, .50-2.09; P Z .96) compared with laterendoscopy.

The Hosmer-Lemeshow goodness-of-fit test showed noindication of lack of fit. A comparison of patient character-istics between patients undergoing endoscopy in eachperiod is available in Supplementary Table 1, availableonline at www.giejournal.org.

Hemodynamically stable patients with an ASAscore of 3 to 5. We found a U-shaped associationbetween timing of endoscopy and in-hospital mortalityin patients with an ASA score of 3 to 5 (Fig. 1). Based onFigure 1, we proposed that the optimal timing ofendoscopy in hemodynamically stable patients with anASA of 3 to 5 was between 12 and 36 hours from time ofhospital admission or time of development of symptomsin in-hospital bleeders. Using logistic regression analysis,we found that performance of endoscopy within thistime frame was associated with lower in-hospital mortality(OR, .48; 95% CI, .34-.67; P < .001) (Table 3) and a trendtoward lower 30-day mortality (OR, .73; 95% CI, .53-1.01;P Z .059) compared with endoscopy outside this timeinterval.

The Hosmer-Lemeshow goodness-of-fit test showed noindication of lack of fit. A comparison of patient character-istics between patients undergoing endoscopy in the afore-mentioned periods is available in Supplementary Table 2,available online at www.giejournal.org.

Patients with hemodynamic instabilityA total of 2933 patients had hemodynamic instability at

time of admission to the hospital or at time of develop-ment of symptoms of PUB in in-hospital bleeders.Scatter plots did not indicate a clear association betweentiming of endoscopy and in-hospital mortality for patientswith hemodynamic instability irrespective of ASA score(Fig. 2). Based on Figure 2 we hypothesized that

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performance of endoscopy between 6 and 24 hours afterhospital admission could be associated with optimaloutcome. Using logistic regression analysis, we foundthat performance of endoscopy within this time framewas associated with lower in-hospital mortality (OR, .73;95% CI, .54-.98; P Z .035) (Table 4) and lower 30-day mor-tality (OR, .66; 95% CI, .46-.95; P Z .025) compared withendoscopy outside this time interval.

The Hosmer-Lemeshow goodness-of-fit test showed noindication of lack of fit. A comparison of patient character-istics between patients undergoing endoscopy in the afore-mentioned periods is available in Supplementary Table 3available online at www.giejournal.org.

Sensitivity and subgroup analysesHemodynamically stable patients with an ASA

score of 1 to 2. Sensitivity analyses indicated that perfor-mance of endoscopy between 0 and 12 hours was not asso-ciated with lower in-hospital mortality (OR, .97; 95% CI,.59-1.59) compared with later endoscopy. Likewise, endos-copy in the period from 12 to 24 hours (OR, .65; 95% CI,.35-1.19) was not associated with lower in-hospital mortal-ity than endoscopy outside this time frame.

A subgroup analysis in patients presenting with PUBoutside the hospital showed that performance of endos-copy between 0 and 24 hours from hospital admissionwas associated with lower in-hospital mortality comparedwith later endoscopy (OR, .48; 95% CI, .24-097; P Z.042; n Z 4249). In patients with in-hospital bleedingwe found no association between endoscopy from 0 to24 hours and in-hospital mortality (OR, .71; 95% CI,.24-2.09; P Z .54; n Z 1166). Sensitivity analyses on defi-nition of out-of-hours admission to the hospital showedthe same association between timing of endoscopy andmortality as in the main analysis.

Hemodynamically stable patients with an ASAscore of 3 to 5. Sensitivity analyses indicated that endos-copy between 12 and 36 hours after hospital admissionwas associated with lower in-hospital mortality than per-formance of endoscopy between 0 and 24 hours (OR,1.13; 95% CI, .76-1.66) or between 0 and 12 hours (OR,1.65; 95% CI, 1.22-2.22) and similar in-hospital mortalitycompared with endoscopy between 12 and 24 hours(OR, .55; 95% CI, .38-.79). Subgroup analyses in patientswith in-hospital bleeding and patients presenting withPUB outside the hospital confirmed the primary finding.Sensitivity analyses on definition of out-of-hours admis-sion to the hospital showed the same associationbetween timing of endoscopy and mortality as in themain analysis.

Patients with hemodynamic instability. Sensitivityanalyses indicated that performance of endoscopybetween 12 and 24 hours was associated with a similarreduction (OR, .58; 95% CI, .37-.90) in in-hospital mortalityas performance of endoscopy between 6 and 24 hours.However, endoscopy between 12 and 24 hours was not






TABLE 2. Association between endoscopy within 24 hours and in-hospital mortality in hemodynamically stable patients with an ASA scoreof 1-2 (n [ 5415)

Variable Univariate OR (95% CI) Multivariate, adjusted OR (95% CI) P value

Timing (0-24 hours) .74 (.44-1.26) 0.59 (0.33-1.05) NS


Age 1.07 (1.05-1.10) 1.07 (1.04-1.09) <.001

Male sex .46 (.29-.73) .67 (.41-1.10) NS

ASA score 1.41 (.76-2.61) .77 (.40-1.49) NS

High alcohol consumption .51 (.22-1.18) d

Smoking status .88 (.67-1.14) d

Hemoglobin .86 (.78-.94) .92 (.83-1.02) NS

Creatinine 1.00 (1.00-1.01) d

Medication

Aspirin 1.08 (.69-1.69) d

AC/ADP-RI .55 (.24-1.27) d

NSAIDs .95 (.56-1.59) d

Steroids 2.60 (1.23-5.45) d

Bleeding characteristics

Duodenal ulcer location 2.09 (1.31-3.33) d

High-risk stigmata of bleeding 2.84 (1.78-4.54) 1.96 (1.18-3.27) .009

Endoscopy-refractory bleeding 14.6 (8.91-23.8) 10.5 (6.00-18.3) <.001


Out-of-hours 1.38 (.88-2.14) 1.47 (.91-2.36) NS

Weekend 1.93 (1.21-3.06) 1.75 (1.06-2.89) .030

Year .84 (.75-.93) .83 (.74-.93) .002

In-hospital bleeding 2.34 (1.49-3.69) 2.02 (1.23-3.30) .005

Variables presented as “d” were removed from the model during backward elimination (P � .15). For details on how variables were handled in the model, please refer toStatistical methods.NS, Nonsignificant; AC/ADP-RI, anticoagulants or adenosine diphosphate receptor inhibitors; ASA, American Society of Anesthesiologists; NSAIDs, nonsteroidal anti-inflammatorydrugs.


associated with a reduced 30-day mortality (OR, .72; 95%CI, .45-1.17). Endoscopy performed between 0 and12 hours (OR, 1.53; 95% CI, 1.07-2.19) or between 0 and24 hours (OR, 1.13; 95% CI, .67-1.90) was not associatedwith reduced in-hospital mortality compared with laterendoscopy. Subgroup analyses in patients with in-hospital bleeding and patients presenting with PUB outsidethe hospital confirmed the primary finding. Sensitivityanalyses on definition of out-of-hours admission to thehospital showed the same association between timing ofendoscopy and mortality as in the main analysis.

DISCUSSION

The present study finds a U-shaped association betweentiming of endoscopy and mortality in hemodynamicallystable patients with an ASA score of 3 to 5. Mortality seemsto be lowest when endoscopy is performed between 12and 36 hours from the time of admission to the hospitalor from the time of development of symptoms of PUB


in patients with in-hospital bleeding. According to ourdata, performance of endoscopy within this time intervalis associated with a clinically significant reduction inin-hospital mortality and a clear trend toward lower30-day mortality.

In patients with hemodynamic instability, the associa-tion between timing of endoscopy and mortality seemsless clear than in hemodynamically stable patients. In thepresent study, endoscopy between 6 and 24 hours wasassociated with lower in-hospital mortality and lower30-day mortality compared with endoscopy outside thistime frame.

For hemodynamically stable patients with an ASA scoreof 1 to 2, we did not find any association between timingof endoscopy and mortality when including the completedataset. However, a subgroup analysis showed thatendoscopy within 24 hours was associated with reducedin-hospital mortality in patients presenting with PUBoutside the hospital. We did not find any associationbetween endoscopy within 24 hours and mortality inpatients with in-hospital bleeding, but this may be

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TABLE 3. Association between endoscopy within 12-36 hours and in-hospital mortality in hemodynamically stable patients with an ASA scoreof 3-5 (n [ 3941)


Timing (12-36 hours) .39 (.29-.54) .48 (.34-.67) <.001


Age 1.03 (1.02-1.04) 1.05 (1.03-1.06) <.001

Male sex 1.02 (.80-1.30) 1.07 (.81-1.41) NS

ASA-score 4.90 (3.80-6.31) 4.03 (3.03-5.36) <.001

High alcohol consumption 1.00 (.71-1.40) 1.52 (1.00-2.32) .048

Smoking status 1.00 (.86-1.16) d

Hemoglobin .96 (.91-1.01) 1.03 (.97-1.09) NS

Creatinine 1.00 (1.00-1.00) 1.00 (1.00-1.00) .019

Medication

Aspirin .70 (.55-.89) .67 (.51-.87) .003

AC/ADP-RI .67 (.50-.90) .72 (.52-.99) .041

NSAIDs .92 (.68-1.24) d

Steroids 1.84 (1.34-2.52) 1.70 (1.20-2.40) .003


Duodenal ulcer location 2.01 (1.55-2.60) 1.52 (1.14-2.01) .004

High-risk stigmata of bleeding 2.11 (1.63-2.73) 1.55 (1.16-2.06) .003



Out-of-hours 1.04 (.82-1.33) d

Weekend .73 (.54-.99) .69 (.50-.95) .024

Year .99 (.94-1.05) d

In-hospital bleeding 1.65 (1.30-2.10) 1.19 (.91-1.56) NS


0 10 20Timing / hours

0.0

5M

orta

lity

ASA 1-2 Fitted valuesFitted valuesASA 3-5

.1.1

5.2

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Figure 2. Association between timing of endoscopy and in-hospitalmortality in patients with hemodynamic instability.


explained by low power because of the low number ofpatients in the analysis (n Z 1166) and low number ofevents (n Z 111).

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Performance of early endoscopy in patients with sus-pected PUB seems logical to ensure rapid diagnosis andto apply endoscopic therapy if indicated. Nevertheless, itis important to be aware that the causes of death within30 days after PUB are nonbleeding-related in almost 80%of patients.19 Most deaths are related to comorbidities, inparticular cardiopulmonary diseases, terminal malignancy,and multiorgan failure.19 This may explain why we founda U-shaped association between endoscopic timing andmortality in hemodynamically stable patients with an ASAscore of 3 to 5 but not in hemodynamically stablepatients with an ASA score of 1 to 2. Our data maysuggest that in patients with major comorbidities, thefirst few hours of hospital admission might be best usedfor optimizing treatment of comorbidities, which mayinclude correction of severe anemia, reversal ofanticoagulants, and investigation for possible infectionthat requires rapid treatment with antibiotics. Likewise,in patients with hemodynamic instability, endoscopybetween 6 and 24 hours from time of admission to thehospital allows time for optimal resuscitation and



TABLE 4. Association between endoscopy within 6-24 hours and in-hospital mortality in patients with hemodynamic instability (n [ 2803)


Timing (6-24 hours) .63 (.49-.82) .73 (.54-.98) .035


Age 1.03 (1.02-1.04) 1.05 (1.03-1.06) <.001

Male sex 1.28 (1.02-1.60) 1.41 (1.08-1.84) .011

ASA score 3.27 (2.78-3.85) 3.17 (2.65-3.80) <.001

High alcohol consumption 1.17 (.90-1.51) 1.66 (1.18-2.35) .004

Smoking status 1.04 (.92-1.19) d

Hemoglobin .91 (.86-.95) .96 (.90-1.01) NS

Creatinine 1.00 (1.00-1.00) d

Medication

Aspirin 1.01 (.81-1.26) .82 (.63-1.06) NS

AC/ADP-RI .93 (.71-1.23) d

NSAIDs 1.08 (.84-1.38) d

Steroids 1.41 (1.00-1.97) d


Duodenal ulcer location 2.34 (1.81-3.02) 1.57 (1.17-2.10) .003

High-risk stigmata of bleeding 1.99 (1.52-2.60) 1.27 (.93-1.74) NS



Out-of-hours .88 (.71-1.09) d

Weekend .88 (.68-1.13) .79 (.59-1.07) NS

Year .98 (.93-1.03) .94 (.88-1.00) NS

In-hospital bleeding 1.45 (1.16-1.82) 1.01 (.78-1.32) NS



initiating treatment of comorbid diseases beforeendoscopy. However, these data should not lead todelayed endoscopy in patients with severe hemodynamicinstability not responding to intensive resuscitation.

Several previous studies have examined the associationbetween timing of endoscopy and outcome in upper GIbleeding, without finding any differences in mortality.Most of these trials are characterized by inclusion of a rela-tively small number of patients (81-325),2-7 resulting in lowpower. In a retrospective study of 3801 patients with upperGI bleeding, Cooper et al8 found that endoscopy within 24hours was associated with a nonsignificant trend towardlower in-hospital mortality. Based on data from a prospec-tive national audit on 4478 patients with upper GIbleeding, Jairath et al11 found that performance ofendoscopy within 12 hours was not associated with lowermortality compared with endoscopy after 24 hours. Incontrast to the aforementioned studies, we believed thatthe optimal timing of endoscopy might be within awindow that allows enough time for pre-endoscopic opti-mization of the patient’s clinical state. Our data seem to


confirm this theory for patients with significant comorbid-ity or hemodynamic instability.

There are several limitations in this study. Confoundingby indication and residual confounding will have an impacton all nonrandomized controlled trials assessing the associ-ation between timing of endoscopy and mortality in upperGI bleeding. In general, patients with suspected severebleeding and poor prognosis will undergo early endoscopy,and in many of these cases mortality will be related to thedisease severity rather than to the timing of endoscopy.However, in some cases with coexisting life-threatening dis-eases, performance of endoscopy may be delayed if endos-copy was initially deemed futile. Consistent with this, ourdata (see Supplementary Material, available online at www.giejournal.org) show differences in patient characteristicsand bleeding severity according to time of endoscopy.These factors may confound our results. Therefore,logistic regression modeling was used to control for this.An alternative strategy would have been the use ofpropensity scores. Propensity score analysis offersadvantages in situations with very few outcomes and

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therefore risk of overfitting or small-sample bias,20 but thiswas not a problem in the present study. Despite ourefforts to control for confounding there will remainunmeasurable and unknown confounders that may affectour findings. To what degree and in which direction thesefactors affect our results and conclusions are unknown.Although a well-powered randomized controlled trial repre-sents the best way to account for these problems, random-izing patients with PUB to early versus late endoscopy isvery difficult, including from an ethical and methodologicpoint of view.

Because all Danish hospitals treating patients with PUBhad access to 24-hour endoscopy, we do not believe thatour results are significantly biased by the availability ofendoscopy services. We only had access to 30-day mortalityin 53% of patients. There were no clinical relevant differ-ences in patient characteristics or in-hospital mortalitybetween patients with data on 30-day mortality andpatients with data on in-hospital mortality only. This sug-gests that patients with data on 30-day mortality wererepresentative for the whole group of patients.

The present study is based on patients with PUB. Aprevious study found that the most frequent endoscopicfindings in patients admitted to the hospital with symp-toms of upper GI bleeding were PUB (31%), esophagitis,gastritis or duodenitis (29%), normal findings (13%), vari-ceal bleeding (7%), and Mallory Weiss tears (4%).21 Wedo not expect that timing of endoscopy is significantlyassociated with mortality in patients with esophagitis,gastritis, duodenitis, or normal findings at endoscopywhen comorbidity is taken into account. We are unawareof data indicating that patients with Mallory Weiss tears,Dieulafoy lesions, or arteriovenous malformationsshould undergo endoscopy within a different time framethan patients with PUB. Therefore, we believe thatthe endoscopic time frames we have identified can beused to guide optimal management for patients withnonvariceal upper GI bleeding.

In conclusion, we have shown that timing of endoscopyis associated with mortality in patients with PUB. Ourresults indicate that optimal timing may depend on theclinical situation. Although caution should be appliedwhen interpreting these data, the current recommendationof endoscopy within 0 to 24 hours may not be optimal forall patients. An initial period of time to optimize resuscita-tion and management before endoscopy appears to beadvantageous in patients with significant comorbidity orhemodynamic instability.

ACKNOWLEDGMENT

The present study was based on data from the DCRES.The authors are grateful to all who contributed data to theDCRES.

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REFERENCES

1. Cook DJ, Guyatt GH, Salena BJ, et al. Endoscopic therapy for acute non-variceal upper gastrointestinal hemorrhage: a meta-analysis. Gastroen-terology 1992;102:139-48.

2. Lee JG, Turnipseed S, Romano PS, et al. Endoscopy-based triage signif-icantly reduces hospitalization rates and costs of treating upper GIbleeding: a randomized controlled trial. Gastrointest Endosc 1999;50:755-61.

3. Bjorkman DJ, Zaman A, Fennerty MB, et al. Urgent vs. elective endos-copy for acute non-variceal upper-GI bleeding: an effectiveness study.Gastrointest Endosc 2004;60:1-8.

4. Lin HJ, Wang K, Perng CL, et al. Early or delayed endoscopy for patientswith peptic ulcer bleeding: a prospective randomized study. J Clin Gas-troenterol 1996;22:267-71.

5. Schacher GM, Lesbros-Pantoflickova D, Ortner MA, et al. Is early endos-copy in the emergency room beneficial in patients with bleedingpeptic ulcer? Endoscopy 2005;37:324-8.

6. Targownik LE, Murthy S, Keyvani L, et al. The role of rapid endoscopyfor high risk patients with acute nonvariceal upper gastrointestinalbleeding. Can J Gastroenterol 2007;21:425-9.

7. Tai CM, Huang SP, Wang HP, et al. High-risk ED patients with nonvar-iceal upper gastrointestinal hemorrhage undergoing emergency or ur-gent endoscopy: a retrospective analysis. Am J Emerg Med 2007;25:273-8.

8. Cooper GS, Chak A, Way LE, et al. Early endoscopy in upper gastroin-testinal hemorrhage: associations with recurrent bleeding, surgery,and length of hospital stay. Gastrointest Endosc 1999;49:145-52.

9. Lim LG, Ho KY, Chan YH, et al. Urgent endoscopy is associated withlower mortality in high-risk but not low-risk nonvariceal upper gastro-intestinal bleeding. Endoscopy 2011;43:300-6.

10. Corbett GD, Cameron EA. Timing of endoscopy in high-risk patientswith nonvariceal upper gastrointestinal bleeding. Endoscopy2011;43:925.

11. Jairath V, Kahan BC, Logan RF, et al. Outcomes following acute nonvar-iceal upper gastrointestinal bleeding in relation to time to endoscopy:results from a nationwide study. Endoscopy 2012;44:723-30.

12. Rosenstock SJ, Møller MH, Larsson H, et al. Improving quality of care inpeptic ulcer bleeding: nationwide cohort study of 13,498 consecutivepatients in the Danish Clinical Register of Emergency Surgery. Am JGastroenterol 2013;108:1449-57.

13. Dripps RD, Lamont A, Eckenhoff JE. The role of anesthesia in surgicalmortality. JAMA 1961;178:261-6.

14. Available at: http://www.noegletal.dk/. Accessed March 1, 2016.15. Thygesen LC, Daasnes C, Thaulow I, et al. Introduction to Danish

(nationwide) registers on health and social issues: structure, access,legislation, and archiving. Scand J Public Health 2011;39:12-6.

16. von Elm E, Altman DG, Egger M, et al. STROBE Initiative. The Strength-ening the Reporting of Observational Studies in Epidemiology(STROBE) statement: guidelines for reporting observational studies.J Clin Epidemiol 2008;61:344-9.

17. Royston P. Multiple imputation of missing values: further update of ice,with an emphasis on interval censor monitoring. Stata J 2007;7:445-64.

18. Peduzzi P, Concato J, Kemper E, et al. A simulation study of the num-ber of events per variable in logistic regression analysis. J Clin Epide-miol 1996;49:1373-9.

19. Sung JJ, Tsoi KK, Ma TK, et al. Causes of mortality in patients withpeptic ulcer bleeding: a prospective cohort study of 10,428 cases.Am J Gastroenterol 2010;105:84-9.

20. Glynn RJ, Schneeweiss S, Stürmer T. Indications for propensity scoresand review of their use in pharmacoepidemiology. Basic Clin Pharma-col Toxicol 2006;98:253-9.

21. Laursen SB, Dalton HR, Murray IA, et al. Performance of new thresholdsof the Glasgow Blatchford score in managing patients with uppergastrointestinal bleeding. Clin Gastroenterol Hepatol 2015;13:115-21.


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SUPPLEMENTARY TABLE 1. Characteristics of hemodynamically stablepatients with PUB and an ASA score of 1-2 in relation to timing ofendoscopy (n [ 5436)

Timing of endoscopy

0-24 Hours(n [ 4468)

>24 Hours(n [ 968)


Median age, y (95% CI) 71 (44-90) 74 (45-92)

Sex; male 2420 (54) 502 (52)

Mean ASA score (95% CI) 1.8 (1-2) 1.8 (1-2)

High alcohol consumption 678 (16) 104 (11)

Daily smoking status 1425 (34) 271 (29)

Medication

Aspirin 1711 (38) 362 (37)

NSAIDs 1118 (25) 255 (26)

AC/ADP-RI 557 (13) 133 (14)

Steroids 57 (1.3) 11 (1.1)

In-hospital bleeding 1024 (23) 146 (15)


Out-of-hours 2112 (47) 384 (40)

Weekend 968 (22) 230 (24)

Median hemoglobin level,g/dL (95% CI)

9.2 (5.5-13.9) 9.5 (5.5-14.3)


Duodenal location 2064 (48) 452 (48)

High-risk stigmata 1948 (44) 238 (25)

Endoscopy-refractory bleeding 103 (2.3) 14 (1.4)

Rebleeding 452 (10.1) 68 (7.1)

Mortality 62 (1.4) 18 (1.9)

Values are number of patients with percents in parentheses, unless otherwise stated.Values are missing for alcohol consumption (n Z 141), smoking status (n Z 293),medication use (n Z 49), hemoglobin (n Z 5), ulcer location (n Z 222), bleedingstigmata (n Z 14), and rebleeding (n Z 18).NSAIDs, Nonsteroidal anti-inflammatory drugs; AC/ADP-RI, anticoagulants oradenosine diphosphate receptor inhibitors.

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SUPPLEMENTARY TABLE 2. Characteristics of hemodynamically stable patients with PUB and an ASA score of 3-5 in relation to timing ofendoscopy (n [ 4232)

Timing of endoscopy

<12 Hours (n [ 2472) 12-36 Hours (n [ 1396) >36 Hours (n [ 364)


Median age, y (95% CI) 77 (54-92) 79 (56-92) 79 (53-91)

Sex; male 1361 (55) 745 (53) 195 (54)

Mean ASA score (95% CI) 3.1 (3-4) 3.1 (3-4) 3.1 (3-4)



Medication

Aspirin 1333 (54) 771 (55) 206 (57)

NSAIDs 540 (22) 274 (20) 60 (17)

AC/ADP-RI 635 (26) 416 (30) 96 (26)

Steroids 139 (6) 53 (4) 13 (4)



Out-of-hours 1105 (45) 703 (50) 174 (48)

Weekend 608 (25) 305 (22) 97 (27)






Rebleeding 422 (17) 159 (11) 34 (9.3)

Mortality 217 (8.8) 49 (3.5) 26 (7.1)

Values are number of patients with percents in parentheses, unless otherwise stated. Values are missing for alcohol consumption (nZ 135), ASA score (nZ 85), smoking status(n Z 243), medication use (n Z 56), hemoglobin (n Z 7), ulcer location (n Z 144), bleeding stigmata (n Z 102), and rebleeding (n Z 8).NSAIDs, Nonsteroidal anti-inflammatory drugs; AC/ADP-RI, anticoagulants or adenosine diphosphate receptor inhibitors; ASA, American Society of Anesthesiologists; mPUB,peptic ulcer bleeding.

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SUPPLEMENTARY TABLE 3. Characteristics of patients with hemodynamic instability and PUB in relation to timing of endoscopy (n [ 2933)

Timing of endoscopy

<6 Hours (n [ 1808) 6-24 Hours (n [ 908) >24 Hours (n [ 217)


Median age, y (95% CI) 72 (50-90) 74 (51-91) 76 (46-91)

Sex; male 1016 (56) 524 (58) 121 (56)

Mean ASA score (95% CI) 2.6 (1-4) 2.5 (1-4) 2.5 (1-4)



Medication

Aspirin 755 (42) 385 (42) 96 (44)

NSAIDs 476 (27) 218 (24) 57 (27)

AC/ADP-RI 342 (19) 200 (22) 51 (24)

Steroids 174 (9.7) 85 (9.4) 22 (10)



Out-of-hours 905 (50) 465 (51) 95 (44)

Weekend 473 (26) 231 (25) 59 (27)






Rebleeding 435 (24) 175 (19) 36 (17)

Mortality 261 (14) 85 (9.4) 23 (11)

Values are number of patients with percents in parentheses, unless otherwise stated. Values are missing for alcohol consumption (n Z 110), smoking status (n Z 229),medication use (n Z 139), hemoglobin (n Z 1), ulcer location (n Z 98), bleeding stigmata (n Z 8), and rebleeding (n Z 8).NSAIDs, Nonsteroidal anti-inflammatory drugs; AC/ADP-RI, anticoagulants or adenosine diphosphate receptor inhibitors; ASA, American Society of Anesthesiologists; mPUB,peptic ulcer bleeding.

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