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Timing of colonoscopy in acute lower GI bleeding: a multicenter retrospective cohort study

Open AccessPublished:August 02, 2022DOI:https://doi.org/10.1016/j.gie.2022.07.025

      Background and Aims

      We aimed to determine the optimal timing of colonoscopy and factors that benefit patients who undergo early colonoscopy for acute lower GI bleeding.

      Methods

      We identified 10,342 patients with acute hematochezia (CODE BLUE-J study) admitted to 49 hospitals in Japan. Of these, 6270 patients who underwent a colonoscopy within 120 hours were included in this study. The inverse probability of treatment weighting method was used to adjust for baseline characteristics among early (≤24 hours, n = 4133), elective (24-48 hours, n = 1137), and late (48-120 hours, n = 1000) colonoscopy. The average treatment effect was evaluated for outcomes. The primary outcome was 30-day rebleeding rate.

      Results

      The early group had a significantly higher rate of stigmata of recent hemorrhage (SRH) identification and a shorter length of stay than the elective and late groups. However, the 30-day rebleeding rate was significantly higher in the early group than in the elective and late groups. Interventional radiology (IVR) or surgery requirement and 30-day mortality did not significantly differ among groups. The interaction with heterogeneity of effects was observed between early and late colonoscopy and shock index (shock index <1, odds ratio [OR], 2.097; shock index ≥1, OR, 1.095; P for interaction = .038) and performance status (0-2, OR, 2.481; ≥3, OR, .458; P for interaction = .022) for 30-day rebleeding. Early colonoscopy had a significantly lower IVR or surgery requirement in the shock index ≥1 cohort (OR, .267; 95% confidence interval, .099-.721) compared with late colonoscopy.

      Conclusions

      Early colonoscopy increased the rate of SRH identification and shortened the length of stay but involved an increased risk of rebleeding and did not improve mortality and IVR or surgery requirement. Early colonoscopy particularly benefited patients with a shock index ≥1 or performance status ≥3 at presentation.

      Graphical abstract

      Abbreviations:

      ALGIB (acute lower GI bleeding), CI (confidence interval), IPTW (inverse probability of treatment weighting), IVR (interventional radiology), OR (odds ratio), PRBC (packed red blood cell), PS (performance status), RCT (randomized controlled trial), SRH (stigmata of recent hemorrhage)
      Colonoscopy plays both diagnostic and therapeutic roles in patients with acute lower GI bleeding (ALGIB). Although guidelines for the treatment of ALGIB have been published in the United States,
      • Strate L.L.
      • Gralnek I.M.
      ACG clinical guideline: management of patients with acute lower gastrointestinal bleeding.
      ,
      • Pasha S.F.
      • Shergill A.
      • Acosta R.D.
      • et al.
      The role of endoscopy in the patient with lower GI bleeding.
      Europe,
      • Oakland K.
      • Chadwick G.
      • East J.E.
      • et al.
      Diagnosis and management of acute lower gastrointestinal bleeding: guidelines from the British Society of Gastroenterology.
      ,
      • Triantafyllou K.
      • Gkolfakis P.
      • Gralnek I.M.
      • et al.
      Diagnosis and management of acute lower gastrointestinal bleeding: European Society of Gastrointestinal Endoscopy (ESGE) guideline.
      and Asia,
      • Nagata N.
      • Ishii N.
      • Manabe N.
      • et al.
      Guidelines for colonic diverticular bleeding and colonic diverticulitis: Japan Gastroenterological Association.
      consensus on the ideal time to perform colonoscopy is lacking. The American College of Gastroenterology,
      • Strate L.L.
      • Gralnek I.M.
      ACG clinical guideline: management of patients with acute lower gastrointestinal bleeding.
      the American Society for Gastrointestinal Endoscopy guidelines,
      • Pasha S.F.
      • Shergill A.
      • Acosta R.D.
      • et al.
      The role of endoscopy in the patient with lower GI bleeding.
      and the Japan Gastroenterological Association
      • Nagata N.
      • Ishii N.
      • Manabe N.
      • et al.
      Guidelines for colonic diverticular bleeding and colonic diverticulitis: Japan Gastroenterological Association.
      recommend performing colonoscopy within 24 hours of presentation. Contrarily, the British Society of Gastroenterology
      • Oakland K.
      • Chadwick G.
      • East J.E.
      • et al.
      Diagnosis and management of acute lower gastrointestinal bleeding: guidelines from the British Society of Gastroenterology.
      and the European Society of Gastrointestinal Endoscopy
      • Triantafyllou K.
      • Gkolfakis P.
      • Gralnek I.M.
      • et al.
      Diagnosis and management of acute lower gastrointestinal bleeding: European Society of Gastrointestinal Endoscopy (ESGE) guideline.
      do not recommend early colonoscopy for patients with ALGIB as part of the usual clinical practice.
      Several randomized controlled trials (RCTs) revealed that early (≤24 hours) colonoscopy neither improves stigmata of recent hemorrhage (SRH) identification nor reduces rebleeding or mortality.
      • van Rongen I.
      • Thomassen B.J.W.
      • Perk L.E.
      Early versus standard colonoscopy: a randomized controlled trial in patients with acute lower gastrointestinal bleeding: results of the BLEED Study.
      • Niikura R.
      • Nagata N.
      • Yamada A.
      • et al.
      Efficacy and safety of early vs elective colonoscopy for acute lower gastrointestinal bleeding.
      • Laine L.
      • Shah A.
      Randomized trial of urgent vs. elective colonoscopy in patients hospitalized with lower GI bleeding.
      Systematic reviews of studies on ALGIB have concluded that although early colonoscopy is associated with higher rates of endoscopic intervention, there is no improvement in rebleeding or mortality.
      • Sengupta N.
      • Tapper E.B.
      • Feuerstein J.D.
      Early versus delayed colonoscopy in hospitalized patients with lower gastrointestinal bleeding: a meta-analysis.
      • Kherad O.
      • Restellini S.
      • Almadi M.
      • et al.
      Systematic review with meta-analysis: limited benefits from early colonoscopy in acute lower gastrointestinal bleeding.
      • Tsay C.
      • Shung D.
      • Stemmer Frumento K.
      • et al.
      Early colonoscopy does not improve outcomes of patients with lower gastrointestinal bleeding: systematic review of randomized trials.
      One such review reported a difference in the effectiveness of early colonoscopy reported by RCTs and observational studies.
      • Kherad O.
      • Restellini S.
      • Almadi M.
      • et al.
      Systematic review with meta-analysis: limited benefits from early colonoscopy in acute lower gastrointestinal bleeding.
      One possible reason for the discrepancy could be that background characteristics were balanced in the design phase and selection bias by indication was eliminated in RCTs. In contrast, this may be related to the restriction of patients enrolled in RCTs (eg, exclusion because of age, comorbidities, and severity of clinical status), which has contributed to the lower proportion of hemodynamically unstable patients in RCTs compared with that in observational studies. Considering the limited number of ALGIB patients recruited and the low incidences of rebleeding and mortality, it was considered difficult to observe significant differences for clinical outcomes in RCTs.
      • Kherad O.
      • Restellini S.
      • Almadi M.
      • et al.
      Systematic review with meta-analysis: limited benefits from early colonoscopy in acute lower gastrointestinal bleeding.
      Although observational studies using insurance databases have included a large number of patients, detailed patient-level data were lacking, and it was not ideal in assessing emergency interventions such as colonoscopy and interventional radiology (IVR).
      • Kherad O.
      • Restellini S.
      • Almadi M.
      • et al.
      Systematic review with meta-analysis: limited benefits from early colonoscopy in acute lower gastrointestinal bleeding.
      Additionally, no comparative studies have been performed on the nonearly (>24 hours) colonoscopy group. In an RCT from Japan,
      • Niikura R.
      • Nagata N.
      • Yamada A.
      • et al.
      Efficacy and safety of early vs elective colonoscopy for acute lower gastrointestinal bleeding.
      most of the elective group underwent colonoscopy within 24 to 48 hours. Outcomes may differ if the timing of colonoscopy is classified into 24 to 48 hours and 48 to 120 hours, and it may be valuable to determine whether to perform colonoscopy on weekends or holidays.
      We hypothesized that we could elucidate the optimal timing of colonoscopy for ALGIB and specify the patients who benefited from early colonoscopy after presentation by using a large database of detailed patient data.
      • Nagata N.
      • Kobayashi K.
      • Yamauchi A.
      • et al.
      Identifying bleeding etiologies by endoscopy affected outcomes in 10,342 cases with hematochezia: CODE BLUE-J Study.
      In this multicenter cohort study, we evaluated the effects of colonoscopy timing on the clinical outcomes of patients with ALGIB. Further, we investigated the interaction between colonoscopy timing and baseline characteristics for the primary outcome and aimed to identify which patients with ALGIB benefited from early colonoscopy.

      Methods

      Patients and study design

      This multicenter, retrospective, cohort study was conducted in Japan using real-world data collected by gastroenterologists who were directly involved in the treatment of hematochezia between January 2010 and December 2019. The CODE-BLUE-J study has been described previously (Supplementary Table 1, available online at www.giejournal.org).
      • Nagata N.
      • Kobayashi K.
      • Yamauchi A.
      • et al.
      Identifying bleeding etiologies by endoscopy affected outcomes in 10,342 cases with hematochezia: CODE BLUE-J Study.
      We identified 10,342 patients hospitalized for acute hematochezia and excluded those who did not undergo colonoscopy (4 patients died within 24 hours after admission, before they underwent colonoscopy, because of multiple organ failure caused by liver cirrhosis, hepatoma, or sepsis), underwent colonoscopy >120 hours after presentation, experienced postprocedural bleeding, or were diagnosed with upper GI bleeding and colorectal tumors. A few studies have noted that tumor bleeding is associated with substantially higher mortality
      • Cho S.H.
      • Lee Y.S.
      • Kim Y.J.
      • et al.
      Outcomes and role of urgent endoscopy in high-risk patients with acute nonvariceal gastrointestinal bleeding.
      ,
      • Hearnshaw S.A.
      • Logan R.F.
      • Lowe D.
      • et al.
      Acute upper gastrointestinal bleeding in the UK: patient characteristics, diagnoses and outcomes in the 2007 UK audit.
      ; hence, we excluded patients with tumor bleeding in the present study. Additionally, because we intended to compare the outcomes using the propensity score, we excluded patients with second or subsequent episodes of acute hematochezia. Ultimately, a cohort of 6270 patients with ALGIB was included and divided into the early (≤24 hours), elective (24-48 hours), and late (48-120 hours) colonoscopy groups (Fig. 1). Considering the insufficient evidence of colonoscopy after 24 hours and the management of patients with ALGIB on weekends or holidays, we set the elective and late groups.
      Certain terms have been defined for this study. SRH was defined as the presence of active bleeding or detection of a nonbleeding visible vessel or an adherent clot on colonoscopy.
      • Jensen D.M.
      • Machicado G.A.
      • Jutabha R.
      • et al.
      Urgent colonoscopy for the diagnosis and treatment of severe diverticular hemorrhage.
      Rebleeding was defined as a significant quantity of fresh blood loss or passage of wine-colored stools after colonoscopy, associated with any of the following: systolic blood pressure <100 mm Hg, pulse rate ≥100 beats/min, or >2 g/dL decrease in hemoglobin levels.
      • Niikura R.
      • Nagata N.
      • Yamada A.
      • et al.
      Efficacy and safety of early vs elective colonoscopy for acute lower gastrointestinal bleeding.
      Furthermore, the requirement for IVR or surgery after colonoscopy during admission was evaluated. Blood transfusion was measured by the amount of packed red blood cells (PRBCs) received during admission, and the length of stay was measured in days.
      The study protocol was approved by the Institutional Ethics Committee of Tokyo Medical University (T2019- 0244). A single institutional review board review was applied to this study, and approval from the ethical committees and institutional review boards of all 49 participating hospitals was obtained through the opt-out method (Supplementary Table 1). The requirement for acquiring informed consent from patients was waived because of the retrospective nature of this study.

      Outcomes

      The primary outcome was 30-day rebleeding rate. Secondary outcomes were the rate of SRH identification, the requirement for corrective IVR or surgery, 30-day mortality, amount of PRBCs, and length of stay. In the subgroup analyses, we aimed to clarify the characteristics of patients who benefited from early colonoscopy for 30-day rebleeding. The requirements of IVR or surgery, mortality, blood transfusion, and length of stay were considered to be located downstream of rebleeding.
      • Kherad O.
      • Restellini S.
      • Almadi M.
      • et al.
      Systematic review with meta-analysis: limited benefits from early colonoscopy in acute lower gastrointestinal bleeding.

      Statistical analyses

      The characteristics of 6270 patients with ALGIB are shown in Supplementary Table 2 (available online at www.giejournal.org). Three data sets were derived from the 6270 cases: early versus elective, elective versus late, and early versus late.
      Missing data were observed in this study; a missing-data analysis was performed using Little’s test of missing completely at random test in each data set.
      • Little R.J.A.
      A test of missing completely at random for multivariate data with missing values.
      The probability that the data were missing completely at random was <.0001 in the 3 data sets. Because complete-case analysis is valid only under missing completely at random,
      • Little R.J.A.
      A test of missing completely at random for multivariate data with missing values.
      ,
      • Li C.
      Little’s test of missing completely at random.
      multiple imputation was performed in each data set by chained equations,
      • Azur M.J.
      • Stuart E.A.
      • Frangakis C.
      • et al.
      Multiple imputation by chained equations: What is it and how does it work?.
      fully conditional specification, or sequential generalized regression. No missing data were noted in colonoscopy timing and clinical outcomes including 30-day rebleeding, the requirement of IVR or surgery, and mortality. The outcome of 30-day rebleeding and patient characteristics were included in the imputation models, and 20 imputed sheets were created for each set.
      A propensity score was constructed in each sheet of imputed data using age ≥75 years; sex
      • Oakland K.
      • Jairath V.
      • Uberoi R.
      • et al.
      Derivation and validation of a novel risk score for safe discharge after acute lower gastrointestinal bleeding: a modelling study.
      ; body mass index ≥25 kg/m2; current habits of smoking and drinking; performance status (PS); histories of ALGIB
      • Oakland K.
      • Jairath V.
      • Uberoi R.
      • et al.
      Derivation and validation of a novel risk score for safe discharge after acute lower gastrointestinal bleeding: a modelling study.
      and colorectal surgery, hypertension, diabetes mellitus, dyslipidemia, and cerebral and cardiovascular diseases; malignancy; Charlson comorbidity index score ≥3
      • Charlson M.E.
      • Pompei P.
      • Ales K.L.
      • et al.
      A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
      ; use of antiplatelets,
      • Aoki T.
      • Nagata N.
      • Shimbo T.
      • et al.
      Development and validation of a risk scoring system for severe acute lower gastrointestinal bleeding.
      ,
      • Strate L.L.
      • Saltzman J.R.
      • Ookubo R.
      • et al.
      Validation of a clinical prediction rule for severe acute lower intestinal bleeding.
      anticoagulants, and nonsteroidal anti-inflammatory drugs
      • Oakland K.
      • Jairath V.
      • Uberoi R.
      • et al.
      Derivation and validation of a novel risk score for safe discharge after acute lower gastrointestinal bleeding: a modelling study.
      ; shock index ≥1
      • Oakland K.
      • Jairath V.
      • Uberoi R.
      • et al.
      Derivation and validation of a novel risk score for safe discharge after acute lower gastrointestinal bleeding: a modelling study.
      ; syncope
      • Aoki T.
      • Nagata N.
      • Shimbo T.
      • et al.
      Development and validation of a risk scoring system for severe acute lower gastrointestinal bleeding.
      ,
      • Strate L.L.
      • Saltzman J.R.
      • Ookubo R.
      • et al.
      Validation of a clinical prediction rule for severe acute lower intestinal bleeding.
      ; abdominal pain
      • Aoki T.
      • Nagata N.
      • Shimbo T.
      • et al.
      Development and validation of a risk scoring system for severe acute lower gastrointestinal bleeding.
      ; diarrhea
      • Charlson M.E.
      • Pompei P.
      • Ales K.L.
      • et al.
      A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
      ; hemoglobin level; albumin level
      • Oakland K.
      • Jairath V.
      • Uberoi R.
      • et al.
      Derivation and validation of a novel risk score for safe discharge after acute lower gastrointestinal bleeding: a modelling study.
      ,
      • Charlson M.E.
      • Pompei P.
      • Ales K.L.
      • et al.
      A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
      ; creatinine level; C-reactive protein level; prothrombin time-international normalized ratio; platelet count; and bleeding causes for colonoscopy timing. The inverse probability of treatment weighting (IPTW) method was used to adjust for the baseline characteristics among groups, and the average treatment effect of colonoscopy timing was evaluated for outcomes on the multiply imputed data in each comparison group. The average treatment effect is an average effect on all subjects in the population. The average treatment effect of colonoscopy timing is considered the effect of the experimental arm of colonoscopy timing on all subjects in the population if patients were forced to receive the experimental arm of colonoscopy timing. A robust sandwich variance estimator was used to correctly estimate the variance and confidence interval (CI) for the pseudo-population.
      Sensitivity analyses were performed by IPTW for the complete-case data (n = 4148) and multivariate logistic and linear regression for the multiply imputed data (n = 6270). SRH identification, 30-day rebleeding, corrective IVR or surgery requirement, 30-day mortality, amount of PRBCs, and length of stay were compared depending on the timing of colonoscopy.
      The interaction between the timing of colonoscopy (early vs elective vs late) and baseline characteristics was investigated for 30-day rebleeding using multivariate logistic regression on multiply imputed data. If an interaction was observed, 3 data sets (early vs elective, elective vs late, and early vs late) were divided depending on the characteristics on which the interaction was observed. Multiple imputation was performed by chained equations in each divided data set. A propensity score was constructed in each sheet of the multiply imputed data, and the average treatment effect of colonoscopy timing was investigated for outcomes using the IPTW method.
      A 2-tailed P < .05 was considered statistically significant. Multiple subgroup analyses can lead to false-positive results.
      • Lagakos S.W.
      The challenge of subgroup analyses—reporting without distorting.
      A P value was not demonstrated, and the magnitude and direction of treatment differences and a corresponding 95% CI were described in the subgroup analyses. Statistical analyses were performed using the Stata software, version 16 (Stata Corp LP, College Station, Tex, USA).

      Results

      Patient characteristics

      Detailed characteristics of patient with acute hematochezia were published previously in the CODE BLUE-J study report.
      • Nagata N.
      • Kobayashi K.
      • Yamauchi A.
      • et al.
      Identifying bleeding etiologies by endoscopy affected outcomes in 10,342 cases with hematochezia: CODE BLUE-J Study.
      We studied 6270 patients with hematochezia who met the inclusion criteria. The characteristics of the study population are shown in Supplementary Table 2. More than 10% of the information on current smoking, current drinking, and prothrombin time-international normalized ratio was missing. However, the data of colonoscopy timing were all included in the present study. The predominant causes of ALGIB were colonic diverticular bleeding, ischemic colitis, rectal ulcer, inflammatory bowel disease, hemorrhoids, and small-bowel bleeding.

      Outcomes compared among the 3 groups on weighting multiply imputed data

      Of 6270 patients, 4133 (66%), 1137 (18%), and 1000 (16%) patients were categorized into the early (≤24 hours), elective (24-48 hours), and late (48-96 hours) groups, respectively (Table 1). The baseline characteristics were not balanced in observed and multiply imputed data. Therefore, weighting multiply imputed data was conducted, and most absolute standardized differences became <.1. Outcomes among the groups using observed data (Supplementary Table 3, available online at www.giejournal.org) and the IPTW method are demonstrated (Table 2). The rate of SRH identification was significantly higher in the early group: early versus elective (ref) (odds ratio [OR], 1.785; 95% CI, 1.521-2.094), elective versus late (ref) (OR, 1.505; 95% CI, 1.188-1.906), and early versus late (ref) (OR, 2.562; 95% CI, 2.089-3.143). More endoscopic therapies were performed in the early group (Supplementary Table 4, available online at www.giejournal.org). However, the results of 30-day rebleeding were diametrically opposite (Table 2). Early colonoscopy was associated with higher 30-day rebleeding: early versus elective (ref) (OR, 1.347; 95% CI, 1.119-1.622), elective versus late (ref) (OR, 1.712; 95% CI, 1.287-2.277), and early versus late (ref) (OR, 2.259; 95% CI, 1.752-2.914). No significant differences were noted in the requirement for IVR or surgery, mortality, and transfused PRBCs among the groups. Length of stay was significantly shorter in the early group than in the elective and late groups.
      Table 1Patient characteristics of observed, multiply imputed, and weighting multiply imputed data between colonoscopy timing (n = 6270)
      Demographic characteristicsObserved data (n = 6270)Multiply imputed data (n = 6270)Weighting multiply imputed data (n = 6270)
      Early (n = 4133)Elective (n = 1137)Late (n = 1000)Absolute standardized differenceAbsolute standardized differenceAbsolute standardized difference
      Early vs electiveElective vs lateEarly vs lateEarly vs electiveElective vs lateEarly vs lateEarly vs electiveElective vs lateEarly vs late
      Age ≥75 y1899 (45.9)562 (49.4)465 (46.5).034.019.015.155.145.010.083.089.014
      Sex, male2653 (64.2)726 (63.9)540 (54.0).015.217.232.002.166.164.025.021.020
      Body mass index ≥25 kg/m21013 (26.3)264 (24.7)212 (22.6).015.100.115.091.070.002.038.124.093
      Current smoker660 (18.2)191 (18.8)182 (20.7).022.024.046.014.083.055.018.046.010
      Current alcohol user1669 (47.3)469 (47.8)387 (46.0).012.041.030.022.022.043.002.038.038
      Performance status ≥3258 (6.3)57 (5.1)54 (5.4).077.054.023.005.049.054.053.059.010
      History of lower GI bleeding921 (22.3)229 (20.1)207 (20.7).084.037.047.011.036.026.064.063.031
      History of colorectal surgery292 (7.1)79 (7.0)65 (6.5).004.026.022.019.002.022.016.006.051
      Hypertension2341 (56.6)638 (56.1)526 (52.6).025.082.107.010.045.035.027.020.092
      Diabetes mellitus741 (17.9)227 (20.0)191 (19.1).048.028.021.052.008.044.022.005.015
      Dyslipidemia1062 (25.7)316 (27.8)268 (26.8).044.072.028.037.090.128.024.114.122
      Cerebral and cardiovascular disease588 (14.2)194 (17.1)149 (14.9).053.057.004.126.064.062.054.007.078
      Malignancy
      Malignancy included solid tumors and malignant lymphomas.
      506 (12.2)149 (13.1)130 (13.0).020.0200.025.037.063.005.036.044
      Charlson comorbidity index ≥31006 (24.3)300 (26.4)248 (24.8).008.001.008.156.115.041.126.092.042
      Medications
       Antiplatelet1231 (29.8)327 (28.8)281 (28.1).071.007.078.075.031.044.086.001.132
       Anticoagulant564 (13.6)156 (13.7)100 (10.0).039.066.104.084.229.146.086.129.033
       Nonsteroidal anti-inflammatory drugs403 (9.8)102 (9.0)99 (9.9).036.017.054.011.133.122.010.101.149
      Initial measurements
       Shock index ≥1362 (9.0)72 (6.4)83 (8.4).136.133.0030.058.073.081.115.054
       Syncope357 (8.7)81 (7.1)47 (4.7).100.056.156.029.201.173.082.105.013
       Abdominal pain423 (10.3)161 (14.2)254 (25.4).129.290.418.097.276.370.025.003.031
       Diarrhea303 (7.4)115 (10.1)160 (16.0).101.163.262.089.206.289.017.024.022
       Hemoglobin ≤11 g/dL1919 (46.4)556 (48.9)453 (45.3).046.032.014.063.166.102.029.083.103
       Albumin ≤3.0 g/dL468 (11.8)114 (10.4)122 (12.6).028.067.039.066.040.025.005.015.049
       Creatinine ≤1.5 mg/dL503 (12.2)136 (12.0)130 (13.1).047.118.071.074.167.096.076.181.123
       C-reactive protein ≥5 mg/dL155 (3.8)60 (5.3)64 (6.5).079.037.116.059.072.131.003.036.016
       Prothrombin time-international normalized ratio ≥1.5343 (9.5)88 (8.7)72 (7.9).076.036.040.098.171.072.123.135.014
       Platelets ≤15 104/μL608 (14.7)170 (15.0)147 (14.7).003.011.008.030.049.021.052.018.006
      Bleeding causes
       Colonic diverticular bleeding
      Colonic diverticular bleeding included definitive and presumptive. Enterocolitis included infectious colitis, inflammatory bowel disease, drug-induced colitis, nonspecific ulcer, and nonspecific colitis. Anal bleeding included hemorrhoids and anal lesions such as anal laceration. Small-bowel bleeding included definitive small-bowel bleeding, presumptive small-bowel bleeding, and Meckel's diverticulum. Other diseases included miscellaneous and unknown lesions.
      3154 (76.3)756 (66.5)588 (58.8).218.202.424.231.067.299.008.083.067
       Ischemic colitis152 (3.7)78 (6.9)135 (13.5).175.222.387.079.218.294.055.014.043
       Enterocolitis
      Colonic diverticular bleeding included definitive and presumptive. Enterocolitis included infectious colitis, inflammatory bowel disease, drug-induced colitis, nonspecific ulcer, and nonspecific colitis. Anal bleeding included hemorrhoids and anal lesions such as anal laceration. Small-bowel bleeding included definitive small-bowel bleeding, presumptive small-bowel bleeding, and Meckel's diverticulum. Other diseases included miscellaneous and unknown lesions.
      155 (3.8)64 (5.6)91 (9.1).092.130.219.083.140.221.009.005.008
       Rectal ulcer163 (3.9)36 (3.2)30 (3.0).039.004.035.038.036.074.013.021.034
       Anal bleeding
      Colonic diverticular bleeding included definitive and presumptive. Enterocolitis included infectious colitis, inflammatory bowel disease, drug-induced colitis, nonspecific ulcer, and nonspecific colitis. Anal bleeding included hemorrhoids and anal lesions such as anal laceration. Small-bowel bleeding included definitive small-bowel bleeding, presumptive small-bowel bleeding, and Meckel's diverticulum. Other diseases included miscellaneous and unknown lesions.
      106 (2.6)36 (3.2)29 (2.9).059.018.0410.009.009.028.002.027
       Small-bowel bleeding
      Colonic diverticular bleeding included definitive and presumptive. Enterocolitis included infectious colitis, inflammatory bowel disease, drug-induced colitis, nonspecific ulcer, and nonspecific colitis. Anal bleeding included hemorrhoids and anal lesions such as anal laceration. Small-bowel bleeding included definitive small-bowel bleeding, presumptive small-bowel bleeding, and Meckel's diverticulum. Other diseases included miscellaneous and unknown lesions.
      111 (2.7)33 (2.9)27 (2.7).006.003.002.051.043.008.037.037.005
       Vascular ectasia65 (1.6)25 (2.2)15 (1.5).036.066.031.065.023.043.028.030.062
       Radiation colitis39 (.9)9 (.8)4 (.4).012.079.067.072.010.062.066.061.007
       Varices12 (.3)1 (.1)3 (.3).043.058.016.064.064.053.064
       Dieulafoy's ulcer5 (.1)3 (.3)1 (.1).006.005.001.088.106.037.041.073.039
       Other diseases
      Colonic diverticular bleeding included definitive and presumptive. Enterocolitis included infectious colitis, inflammatory bowel disease, drug-induced colitis, nonspecific ulcer, and nonspecific colitis. Anal bleeding included hemorrhoids and anal lesions such as anal laceration. Small-bowel bleeding included definitive small-bowel bleeding, presumptive small-bowel bleeding, and Meckel's diverticulum. Other diseases included miscellaneous and unknown lesions.
      171 (4.1)96 (8.4)77 (7.7).138.032.170.256.157.103.062.145.043
      Values are n (%). The covariates used for the construction of the propensity score were well balanced in the weighting multiply imputed data.
      Malignancy included solid tumors and malignant lymphomas.
      Colonic diverticular bleeding included definitive and presumptive. Enterocolitis included infectious colitis, inflammatory bowel disease, drug-induced colitis, nonspecific ulcer, and nonspecific colitis. Anal bleeding included hemorrhoids and anal lesions such as anal laceration. Small-bowel bleeding included definitive small-bowel bleeding, presumptive small-bowel bleeding, and Meckel's diverticulum. Other diseases included miscellaneous and unknown lesions.
      Table 2Outcomes between colonoscopy timing using inverse probability of treatment weighting on the multiply imputed data
      Identification of stigmata of recent hemorrhage30-day rebleedingInterventional radiology or surgery30-day mortalityBlood transfusion (packs)Length of stay (days)
      OR, 95% CIP valueOR, 95% CIP valueOR, 95% CIP valueOR, 95% CIP valueCoefficient, 95% CIP valueCoefficient, 95% CIP value
      ElectiveReferenceReferenceReferenceReferenceReferenceReference
      Early1.785, 1.521-2.094<.0011.347, 1.119-1.622.0021.021, .676-1.541.9211.052, .438-2.527.909–.302, –.659 to .055.097–.820, –1.504 to –.136.019
      LateReferenceReferenceReferenceReferenceReferenceReference
      Elective1.505, 1.188-1.906.0011.712, 1.287-2.277<.001.979, .579-1.655.9381.362, .425-4.366.603.433, –.003 to .868.051–.649, –1.752 to .454.249
      LateReferenceReferenceReferenceReferenceReferenceReference
      Early2.562, 2.089-3.143<.0012.259, 1.752-2.914<.001.958, .619-1.483.8461.631, .580-4.586.353.056, –.275 to .387.740–1.296, –.041 to –.552.001
      P < .05 was considered to indicate statistical significance.
      CI, Confidence interval; OR, odds ratio.
      Our analyses did not use the Oakland score as a covariate because we created a propensity score using the covariates used to estimate the Oakland score.
      • Oakland K.
      • Chadwick G.
      • East J.E.
      • et al.
      Diagnosis and management of acute lower gastrointestinal bleeding: guidelines from the British Society of Gastroenterology.
      For reference, we also included the Oakland score in our analyses, but the results were similar.

      Sensitivity analyses

      We evaluated the robustness of our results by using the IPTW method of complete-case data and multivariate regression (Table 3). Baseline characteristics of weighting complete data are demonstrated in Supplementary Table 5 (available online at www.giejournal.org). The baseline characteristics were well balanced among the 3 groups in the weighting complete data. The higher rates of SRH identification and 30-day rebleeding were observed in the early group, similar to the results on weighting multiply imputed data. There were no significant differences in the requirement for IVR or surgery and transfused PRBCs among the groups. Mortality was significantly higher in the early group than in the late group (OR, 4.584; 95% CI, 1.027-20.466). Length of stay was significantly shorter in the early group than in the late group (Table 3).
      Table 3Outcomes between colonoscopy timing using inverse probability of treatment weighting on the complete data and multivariate logistic regression on the multiply imputed data
      Identification of stigmata of recent hemorrhage30-day rebleedingInterventional radiology or surgery30-day mortalityBlood transfusion (packs)Length of stay (days)
      OR, 95% CIP valueOR, 95% CIP valueOR, 95% CIP valueOR, 95% CIP valueCoefficient, 95% CIP valueCoefficient, 95% CIP value
      inverse probability of treatment weighting on complete data
      ElectiveReferenceReferenceReferenceReferenceReferenceReference
      Early1.914, 1.566-2.337<.0011.340, 1.070-1.677.0111.127, .683-1.860.6381.252, .408-3.842.694–.246, –.733 to .240.321–.844, –1.765 to .077.073
      LateReferenceReferenceReferenceReferenceReferenceReference
      Elective1.285, .963-1.713.0881.652, 1.174-2.324.0041.006, .541-1.868.9862.297, .412-12.825.343.563, –.070 to 1.196.081–.215, –1.689 to 1.260.776
      LateReferenceReferenceReferenceReferenceReferenceReference
      Early2.361, 1.848-3.015<.0012.047, 1.506-2.783<.001.960, .575-1.603.8764.584, 1.027-20.466.046.132, –.265 to .529.515–1.044, –1.200 to –.088.032
      Multivariate logistic and linear regression on multiply imputed data
      LateReferenceReferenceReferenceReferenceReferenceReference
      Elective1.595, 1.252-2.031<.0011.755, 1.320-2.333<.001.966, .569-1.639.8971.336, .378-4.721.653.405, .046-.765.027–.640, –1.450 to .170.121
      Early2.934, 2.396-3.593<.0012.409, 1.889-3.072<.001.968, .628-1.493.8831.148, .392-3.360.801.041, –.256 to .338.787–1.578, –2.248 to –.908<.001
      ElectiveReferenceReferenceReferenceReferenceReferenceReference
      Early1.840, 1.562-2.166<.0011.372, 1.140-1.652.0011.003, .666-1.510.990.860, .331-2.232.756–.364, –.642 to –.087.010–.937, –1.563 to –.312.003
      P < .05 was considered to indicate statistical significance. CI, Confidence interval; OR, odds ratio.
      Multivariate logistic regression using the multiply imputed data revealed that the rates of SRH identification and 30-day rebleeding were significantly higher in the early group (Table 3). No significant differences were observed in the requirement for IVR or surgery and mortality among the groups. Length of stay was shorter in the early group than in the elective and late groups.

      Subgroup analyses based on shock index and PS

      The interaction between the timing of colonoscopy (early vs elective vs late) and baseline patient characteristics was investigated for 30-day rebleeding. Interactions were observed between early and late colonoscopy and shock indices of <1 and ≥1 (P for interaction = .038) and PS 0 to 2 and PS ≥3 (P for interaction = .022) regarding 30-day rebleeding (Table 4). Although there was a higher OR of early and late colonoscopy to 30-day rebleeding for both a shock indices of <1 and ≥1 (OR, 2.097; 95% CI, 1.553-2.832 and OR, 1.095; 95% CI, .541-2.218, respectively), the direction of OR of early and late colonoscopy to 30-day rebleeding was opposite in the PS 0 to 2 and PS ≥3 cohorts (OR, 2.481; 95% CI, 1.898-3.244 and OR, .458; 95% CI, .164-1.278, respectively). In addition, the early group had a significantly decreased IVR or surgery requirement in the shock index ≥1 cohort compared with the late group (OR, .267; 95% CI, .099-.721).
      Table 4Subgroup analyses depending on shock index and performance status on the weighting multiply imputed data


      Shock index <1Shock index ≥1Performance status 0-2Performance status ≥3
      OR, 95% CIOR, 95% CIOR, 95% CIOR, 95% CI
      Early vs elective (reference)
      30 day-rebleeding1.317, 1.084-1.5991.784, .824-3.8631.384, 1.143-1.6761.116, .465-2.677
      IVR or surgery1.015, .657-1.568.659, .172-2.5271.030, .673-1.5771.000, .208-4.801
      30 day-mortality.850, .328-2.2046.475, .768-54.5911.981, .547-7.176.433, .123-1.517
      Coefficient, 95% CICoefficient, 95% CICoefficient, 95% CICoefficient, 95% CI
      Blood transfusion–.324, –.690 to .042.344, –1.374 to 2.061–.301, –.675 to .073–.219, –1.532 to 1.094
      Length of stay–.831, –1.527 to –.135–.934, –4.460 to 2.592–.787, –1.451 to –.123–.356, –4.677 to 3.965
      Elective vs late (reference)
      OR, 95% CIOR, 95% CIOR, 95% CIOR, 95% CI
      30-day rebleeding1.853, 1.358-2.528.553, .221-1.3851.783, 1.322-2.4061.116, .366-3.402
      IVR or surgery1.262, .695-2.2922.135, .331-13.7561.039, .600-1.800.688, .105-4.499
      30-day mortality1.166, .350-3.8831.881, .194-4.0054.493, .412-48.993
      Coefficient, 95% CICoefficient, 95% CICoefficient, 95% CICoefficient, 95% CI
      Blood transfusion.473, .021-.9262.031, –2.184 to 6.245.487, .031-.943.579, –1.077 to 2.236
      Length of stay.032, –.937 to 1.000–2.769, –14.701 to 9.164–.532, –1.657 to .593–1.609, –7.308 to 4.091
      Early vs late (reference)
      OR, 95% CIOR, 95% CIOR, 95% CIOR, 95% CI
      30-day rebleeding2.097, 1.553-2.8321.095, .541-2.2182.481, 1.898-3.244.458, .164-1.278
      IVR or surgery1.337, .778-2.297.267, .099-.7211.026, .648-1.625.341, .056-2.091
      30-day mortality1.121, .418-3.00811.667, .526-5.2781.098, .132-9.119
      Coefficient, 95% CICoefficient, 95% CICoefficient, 95% CICoefficient, 95% CI
      Blood transfusion.108, –.228 to .444–1.044, –2.935 to .847.093, –.225 to .411–1.002, –4.519 to 2.515
      Length of stay–.887, –1.527 to –.247-4.402, –9.321 to .518–1.244, –1.963 to –.524–1.866, –6.817 to 3.087
      CI, Confidence interval; IVR, interventional radiology; OR, odds ratio.

      Discussion

      This large retrospective study was conducted to determine the optimal timing of colonoscopy for patients with ALGIB. Although early colonoscopy was associated with higher SRH identification allowing more frequent endoscopic hemostasis and a shorter length of stay, the 30-day rebleeding rate was significantly higher than elective and late colonoscopy. Conversely, the rates of 30-day rebleeding and IVR or surgery requirement were lower in early colonoscopy for patients with shock index ≥1 or PS ≥3 than in late colonoscopy.
      Previous RCTs showed that early (≤24 hours) colonoscopy for ALGIB did not improve SRH identification
      • Niikura R.
      • Nagata N.
      • Yamada A.
      • et al.
      Efficacy and safety of early vs elective colonoscopy for acute lower gastrointestinal bleeding.
      and did not reduce rebleeding or mortality.
      • van Rongen I.
      • Thomassen B.J.W.
      • Perk L.E.
      Early versus standard colonoscopy: a randomized controlled trial in patients with acute lower gastrointestinal bleeding: results of the BLEED Study.
      ,
      • Niikura R.
      • Nagata N.
      • Yamada A.
      • et al.
      Efficacy and safety of early vs elective colonoscopy for acute lower gastrointestinal bleeding.
      Moreover, a single-center RCT revealed that urgent (≤12 hours) compared with nonurgent (>36 hours) colonoscopy for ALGIB did not improve further bleeding.
      • Laine L.
      • Shah A.
      Randomized trial of urgent vs. elective colonoscopy in patients hospitalized with lower GI bleeding.
      However, this RCT was discontinued during patient enrollment because of the difficulty in reaching the prespecified sample size, which was a significant limitation of the study. The findings were associated with a potential risk of Type II error and lack of generalizability. Contrarily, 5 retrospective studies
      • Nagata N.
      • Niikura R.
      • Sakurai T.
      • et al.
      Safety and effectiveness of early colonoscopy in management of acute lower gastrointestinal bleeding on the basis of propensity score matching analysis.
      • Navaneethan U.
      • Njei B.
      • Venkatesh P.G.
      • et al.
      Timing of colonoscopy and outcomes in patients with lower GI bleeding: a nationwide population-based study.
      • Nigam N.
      • Patel P.
      • Sengupta N.
      Outcomes of early versus delayed colonoscopy in lower gastrointestinal bleeding using a hospital administrative database.
      • Kim J.H.
      • Kim J.H.
      • Chun J.
      • et al.
      Early versus late bedside endoscopy for gastrointestinal bleeding in critically ill patients.
      • Nigam N.
      • Ham S.A.
      • Sengupta N.
      Early colonoscopy for diverticular bleeding does not reduce risk of postdischarge recurrent bleeding: a propensity score matching analysis.
      and 3 systematic reviews
      • Sengupta N.
      • Tapper E.B.
      • Feuerstein J.D.
      Early versus delayed colonoscopy in hospitalized patients with lower gastrointestinal bleeding: a meta-analysis.
      • Kherad O.
      • Restellini S.
      • Almadi M.
      • et al.
      Systematic review with meta-analysis: limited benefits from early colonoscopy in acute lower gastrointestinal bleeding.
      • Tsay C.
      • Shung D.
      • Stemmer Frumento K.
      • et al.
      Early colonoscopy does not improve outcomes of patients with lower gastrointestinal bleeding: systematic review of randomized trials.
      suggested that early (≤24 hours) colonoscopy may increase the yield of endoscopic intervention, decrease the length of stay, and reduce the requirement for blood transfusion. However, none has demonstrated benefits in reducing rebleeding rates or mortality, a finding corroborated by our study. This differences between RCTs and observational studies may be associated with the restriction of patients enrolled in RCTs (eg, exclusion because of high age, comorbidities, and unstable status) and selection bias by indication.
      Our study potentially helps estimate the optimal timing of colonoscopy by comparing outcomes among early, elective, and late colonoscopy groups. In addition to our large database with detailed patient data, no studies have been done on colonoscopy conducted after 24 hours of presentation. The early group experienced a higher rate of SRH identification, whereas a higher 30-day rebleeding rate was observed. This may be explained by the fact that bleeding stops spontaneously in most ALGIB patients,
      • Longstreth G.F.
      Epidemiology and outcome of patients hospitalized with acute lower gastrointestinal hemorrhage: a population-based study.
      and ALGIB patients may be triaged as those requiring interventions through subsequent colonoscopy. Although the requirements for IVR or surgery and mortality were not different based on the colonoscopy timing, early colonoscopy was significantly associated with a shorter length of stay in the present study. Because this design was a multicenter observational study and an indication for extending the length of stay was not prespecified, the length of stay may be dependent on the timing of colonoscopy and the preference of each gastroenterologist. Outcomes such as 30-day rebleeding, IVR or surgery requirement, and mortality did not differ between elective and late colonoscopy. These results may be valuable, especially in the areas in which there is no timely availability of staff and other support services after work hours on weekends and holidays.
      We observed interactions between early and late colonoscopy and patient characteristics (PS and shock index) for 30-day rebleeding, and a subgroup analyses based on PS 0 to 2 and PS ≥3 and shock indices of <1 or ≥1 were performed. The direction and the magnitude of ORs for 30-day rebleeding were different between patients with PS 0 to 2 and PS ≥3. Therefore, PS was determined to be a modifier of the qualitative effect of colonoscopy timing on 30-day rebleeding. Although the magnitude of ORs for rebleeding was different between patients with shock indices of <1 and ≥1, the direction of ORs was the same. The shock index was the quantitative effect modifier between early and late colonoscopy on 30-day rebleeding. However, the direction and magnitude of ORs were different between shock indices of <1 and ≥1 for IVR or surgery requirement. Early colonoscopy significantly decreased the risk of requiring IVR or surgery in patients with shock index ≥1 compared with late colonoscopy.
      To find the reason for the interaction, we compared the causes of bleeding by subgroups on shock index and PS. The results of the comparison of bleeding causes regarding shock index and PS subgroups are demonstrated in Supplementary Table 6 (available online at www.giejournal.org). The proportion of rectal ulcer was significantly higher in the PS ≥3 subgroup than in the PS 0 to 2 subgroup. Significant differences were observed in colonic diverticular bleeding, ischemic colitis, rectal ulcer, small-bowel bleeding, colorectal varices, and Dieulafoy’s ulcer between shock indices of <1 and ≥1. The different causes of bleeding may contribute to the effectiveness of colonoscopy timing through baseline characteristics of shock index and PS. Because the guideline of the British Society of Gastroenterology recommends the use of a shock index as a risk stratification tool for patients with ALGIB, and IVR and endoscopic therapy were considered the treatment options depending on the results of enhanced CT in patients with shock index ≥1,3 our results support the management algorithm of this guideline.
      The difference in analyses between our study and other studies may be explained by adjusting the bleeding causes. We used the IPTW method as previously conducted by Guo et al,
      • Guo C.L.T.
      • Wong S.H.
      • Lau L.H.S.
      • et al.
      Timing of endoscopy for acute upper gastrointestinal bleeding: a territory-wide cohort study.
      who performed an observational study of endoscopy timing for upper GI bleeding. Considering the onset of GI bleeding, the causes of bleeding may precede the allocation of endoscopy timing. Bleeding causes were included for the construction of the propensity score to eliminate the confounding effect of bleeding causes in our study (Fig. 2). In the previous observational study, the proportion of bleeding causes was significantly different among the timing of endoscopy.
      • Kherad O.
      • Restellini S.
      • Almadi M.
      • et al.
      Systematic review with meta-analysis: limited benefits from early colonoscopy in acute lower gastrointestinal bleeding.
      Certainly, in our study, when baseline characteristics except for causes of bleeding were balanced on our weighted data (Supplementary Table 7, available online at www.giejournal.org), the absolute standardized differences were >.2 regarding the cause of bleeding (Supplementary Table 8, available online at www.giejournal.org). When observational studies of endoscopy timing for GI bleeding are being planned as quasi-RCTs, it may be better to manage the causes of bleeding as covariates to be balanced.
      • Nigam N.
      • Ham S.A.
      • Sengupta N.
      Early colonoscopy for diverticular bleeding does not reduce risk of postdischarge recurrent bleeding: a propensity score matching analysis.
      Figure thumbnail gr2
      Figure 2Schema of colonoscopy timing for acute lower GI bleeding. Considering the onset of GI bleeding, causes of bleeding precede the allocation of endoscopy timing and are not changed by colonoscopy timing. The causes of bleeding were considered the confounders between colonoscopy timing and clinical outcomes from the viewpoint of causal inference. The causes of bleeding and confounders were not omitted in the analysis of the association between colonoscopy timing and clinical outcomes in the cohort study that matched patient characteristics.
      The notable strength of this study was the large population that was analyzed for the influence of pertinent confounding factors on colonoscopy timing such as clinical status, blood investigation findings, comorbidities, and concomitant medications.
      • Nagata N.
      • Kobayashi K.
      • Yamauchi A.
      • et al.
      Identifying bleeding etiologies by endoscopy affected outcomes in 10,342 cases with hematochezia: CODE BLUE-J Study.
      Essentially, the proportion of hemodynamically unstable patients is higher in observational studies, including the present study, than in RCTs (6.0%-47.2%
      • Nagata N.
      • Niikura R.
      • Sakurai T.
      • et al.
      Safety and effectiveness of early colonoscopy in management of acute lower gastrointestinal bleeding on the basis of propensity score matching analysis.
      ,
      • Nigam N.
      • Patel P.
      • Sengupta N.
      Outcomes of early versus delayed colonoscopy in lower gastrointestinal bleeding using a hospital administrative database.
      vs .02%-5.1%
      • van Rongen I.
      • Thomassen B.J.W.
      • Perk L.E.
      Early versus standard colonoscopy: a randomized controlled trial in patients with acute lower gastrointestinal bleeding: results of the BLEED Study.
      ,
      • Niikura R.
      • Nagata N.
      • Yamada A.
      • et al.
      Efficacy and safety of early vs elective colonoscopy for acute lower gastrointestinal bleeding.
      ). Furthermore, we investigated the characteristics of patients who benefit from early colonoscopy.
      The limitations of this study are its retrospective and observational design. However, we applied robust inclusion and exclusion criteria to eliminate selection bias as much as possible and maintained internal validity. Conversely, the generalizability of results from RCTs may sometimes be reduced because of the differences in patient characteristics between RCTs and observational studies. Second, unmeasured confounders may still exist in the IPTW method. Finally, our study only included patients who received colonoscopy. Patients who received colonoscopy had relatively greater ALGIB severity, and this may be a limitation of generalizability. Nonetheless, by using interaction analysis, we were able to identify the patient characteristics that were considered as indications for early colonoscopy.
      In summary, we have demonstrated that early colonoscopy improved SRH identification and shortened the length of stay. However, early colonoscopy was associated with a higher 30-day rebleeding rate and did not improve IVR or surgery requirement or mortality. Early colonoscopy was beneficial for those with a shock index ≥1 or PS ≥3. Therefore, most ALGIB patients do not need to receive colonoscopy immediately but rather vitals and PS can be an indication of the requirement for early colonoscopy. Further RCTs are warranted to clarify these findings.

      Acknowledgments

      We thank Kazuyo Jo, Shiho Kamimura, Sanae Habu, Akiko Takamatsu, Minako Kajihara, and Kenko Yoshida for their help with data collection and analysis. Access to the data supporting the results of this study can be requested and will be reviewed with the principal investigator of this study through the corresponding author. The data are not available to the public because of privacy and ethical restrictions.

      Appendix

      Supplementary Table 1Affiliations of and ethics committee approval numbers from 49 participating hospitals
      InstitutionPrefectureDepartmentEthics committee approval no.Period of data collectionNo. of cases
      1Tokyo Medical UniversityTokyoDepartment of Gastroenterological EndoscopyT201902442013.01.02 to 2019.11.13134
      2National Center for Global Health and MedicineTokyoDepartment of Gastroenterology and Hepatology35392010.01.19 to 2019.06.181375
      3Tokyo Shinagawa HospitalTokyoDepartment of Gastroenterology20-A-042014.07.28 to 2019.12.30250
      4Nippon Medical School, Graduate School of MedicineTokyoDepartment of GastroenterologyB-2020-1472014.10.31 to 2019.12.23538
      5Chiba Hokusoh Hospital, Nippon Medical SchoolChibaDepartment of Gastroenterology8022011.08.28 to 2019.12.23188
      6Saga Medical Center KoseikanSagaDepartment of Gastroenterology20-01-01-032013.01.02 to 2019.12.30394
      7St Luke’s International UniversityTokyoDepartment of Gastroenterology20-R0122014.01.03 to 2019.12.29536
      8Kawasaki Medical SchoolOkayamaDivision of Endoscopy and Ultrasonography, and Department of Clinical Pathology and Laboratory Medicine38902014.03.27 to 2018.2.18156
      9Kawasaki Medical School General Medical CenterOkayamaDivision of Endoscopy and Ultrasonography, and Department of Clinical Pathology and Laboratory Medicine38902012.02.07 to 2017.12.2788
      10University of TsukubaIbarakiDepartment of Gastroenterology, and Division of Endoscopic CenterR02-0302013.01.02 to 2019.12.30134
      11Tokyo Metropolitan Bokutoh HospitalTokyoDepartment of Gastroenterology02-0242013.04.02 to 2019.12.31808
      12Saiseikai Yokohamashi Tobu HospitalKanagawaEmergency and Critical Care Center202000302011.01.22 to 2019.12.17131
      13The University of TokyoTokyoDepartment of Gastroenterology2020067NI2010.01.04 to 2018.08.10542
      14Toranomon HospitalTokyoDepartment of Gastroenterology20212011.04.02 to 2019.12.04134
      15Nagoya University HospitalAichiDepartment of Endoscopy2020-01522016.01.02 to 2019.12.27206
      16Hiroshima City Asa Citizens HospitalHiroshimaDepartment of Gastroenterology2002/1/242010.01.02 to 2019.12.27517
      17National Hospital Organization Fukuokahigashi Medical CenterFukuokaDepartment of Gastroenterology and Hepatology2020-臨-22017.04.02 to 20.9.12.3107
      18Nara City HospitalNaraDepartment of Gastroenterology and Hepatology, and Center for Digestive and Liver DiseasesNCH倫20-82013.05.02 to 2019.12.25264
      19Graduate School of Medical and Dental Sciences, Niigata UniversityNiigataDivision of Gastroenterology2020-00522010.8.28 to 2019.12.18142
      20St Marianna University School of MedicineKanagawaDivision of Gastroenterology and Hepatology, Department of Internal Medicine48022013.08.12 to 2019.12.13343
      21Oita UniversityOitaDepartment of Gastroenterology18452010.03.06 to 2019.12.03199
      22Tokyo Saiseikai Central HospitalTokyoDepartment of Internal Medicine2020-015-012017.01.09 to 2019.12.29120
      23Fukuoka University HospitalFukuokaDepartment of Gastroenterological EndoscopyU20-05-0162016.03.30 to 2019.12.1280
      24Fukuoka University Chikushi HospitalFukuokaDepartment of GastroenterologyC20-0522010.01.05 to 2017.03.04199
      25Kitano Hospital, Tazuke Kofukai Medical Research InstituteOsakaDepartment of Gastroenterology and HepatologyP2005004002010.1.24 to 2019.12.21586
      26Graduate School of Medical Sciences, Kyushu UniversityFukuokaDepartment of Medicine and Clinical Science2020-2892010.05.30 to 2019.12.25101
      27University of Miyazaki HospitalMiyazakiDepartment of Gastroenterology and Hepatology, and Center for Digestive Disease and Division of Endoscopy0-07342010.07.16 to 2019.10.20142
      28University of the Ryukyus HospitalOkinawaDepartment of Endoscopy16562016.01.04 to 2019.12.0886
      29Naha City HospitalOkinawaDepartment of Gastroenterology2004a42018.11.02 to 2019.12.26121
      30Kagoshima University Graduate School of Medical and Dental SciencesKagoshimaDigestive and Lifestyle Diseases200041疫2019.02.26 to 2019.10.077
      31Kagoshima City HospitalKagoshimaDepartment of Gastroenterology2020-252019.01.27 to 2019.12.2745
      32Kagoshima Kouseiren HospitalKagoshimaDepartment of Gastroenterology2152019.01.03 to 2019.12.2528
      33Kagoshima Medical CenterKagoshimaDepartment of Gastroenterology2020-222019.01.01 to 2019.12.2540
      34Izumi General Medical CenterKagoshimaDepartment of Gastroenterology602019.01.08 to 2019.12.2634
      35Kirishima City Medical Association Medical CenterKagoshimaDepartment of Gastroenterology2020052019.01.16 to 2019.10.1219
      36Kagoshima Prefectural Oshima HospitalKagoshimaDepartment of Gastroenterology972018.12.25 to 2019.12.2723
      37National Hospital Organization Kyoto Medical CenterKyotoDepartment of Gastroenterology20-0202011.05.31 to 2019.12.20205
      38Fukushima Medical UniversityFukushimaDepartment of Gastroenterology一般2020-1122013.12.07 to 2019.12.26100
      39Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome HospitalTokyoDepartment of Gastroenterology25032010.06.15 to 2019.12.16205
      40Kitasato University, School of MedicineKanagawaDepartment of GastroenterologyC20-1742010.10.07 to 2019.12.2676
      41Suita Municipal HospitalOsakaDepartment of Gastroenterology and Hepatology2020-研22011.03.04 to 2019.12.3088
      42Akita University Graduate School of MedicineAkitaDepartment of Gastroenterology and Neurology24912010.09.22 to 2019.05.1169
      43Japanese Red Cross Shizuoka HospitalShizuokaDepartment of GastroenterologyJun-202010.01.08 to 2019.12.30173
      44Hirosaki University HospitalAomoriDivision of Endoscopy2020-322010.04.16 to 2019.12.28112
      45Graduate School of Medical Sciences, Kumamoto UniversityKumamotoDepartment of Gastroenterology and Hepatology20402010.01.03 to 2019.12.22111
      46National Hospital Organization Kyushu Medical CenterFukuokaDepartment of Gastroenterology20C0652010.4.12 to 2019.12.2382
      47Iwate Medical UniversityIwateDepartment of Internal MedicineMH2020-0502015.01.07 to 2019.7.1998
      48Shuto General HospitalYamaguchiDepartment of GastroenterologyH31-242014.07.25 to 2019.08.19114
      49National Defense Medical CollegeSaitamaDepartment of Internal Medicine42172010.04.12 to 2019.12.0792
      Supplementary Table 2Characteristics of patients with acute lower GI bleeding (n = 6270)
      Study populationMissing data
      Demographic characteristics
       Mean age, y (SD)70.7 (14.3)0
       Age ≥75 y2926 (46.7)0
       Sex, male3919 (62.5)0
       Mean body mass index, kg/m2 (SD)22.8 (3.9)413
       Body mass index ≥25 kg/m21489 (25.4)413
       Current smoker1033 (18.7)757
       Current alcohol user2525 (47.2)922
       Performance status ≥3369 (6.0)78
       History of lower GI bleeding1357 (21.6)0
       History of colorectal surgery436 (7.0)2
       Hypertension3505 (55.9)0
       Diabetes mellitus1159 (18.5)0
       Dyslipidemia1646 (26.3)1
       Cerebral and cardiovascular disease931 (14.9)1
       Malignancy
      Malignancy included solid tumors and malignant lymphomas.
      785 (12.5)0
       Charlson comorbidity index ≥31554 (24.8)0
      Medications
       Antiplatelet1839 (29.3)0
      Low-dose aspirin1317 (21.0)0
      Thienopyridine647 (10.3)0
      Cilosotazol143 (2.3)0
      Other antiplatelet193 (3.1)0
       Anticoagulant820 (13.1)0
      Warfarin459 (7.3)0
      Direct oral anticoagulants361 (5.8)0
      Nonsteroidal anti-inflammatory drugs604 (9.6)0
      Initial measurements
       Shock index ≥1517 (8.4)125
       Systolic blood pressure ≤100 mm Hg867 (14.1)105
       Heart rate ≥100 beats/min1246 (20.3)122
       Syncope485 (7.7)9
       Abdominal pain838 (13.4)11
       Diarrhea578 (9.3)23
       Mean hemoglobin, g/dL (SD)11.0 (2.6)2
       Hemoglobin ≤11 g/dL2928 (46.7)2
       Mean albumin, g/dL (SD)3.63 (.59)253
       Albumin ≤3.0 g/dL704 (11.7)253
       Mean creatinine, mg/dL (SD)1.17 (1.31)27
       Creatinine ≤1.5 mg/dL769 (12.3)27
       Mean C-reactive protein, mg/dL (SD).90 (2.44)130
       C-reactive protein ≥5 mg/dL279 (4.5)130
       Mean prothrombin time-international normalized ratio (SD)1.14 (.59)723
       Prothrombin time-international normalized ratio ≥1.5503 (9.1)723
       Mean platelets, 104/μL (SD)21.7 (8.3)1
       Platelets ≤15 104/μL925 (14.8)1
       Mean time of colonoscopy, h (SD)24.2 (27.0)0
      Diagnoses
       Colonic diverticular bleeding4498 (71.7)0
       Definitive Colonic diverticular bleeding1726 (27.5)0
       Presumptive colonic diverticular bleeding2771 (44.2)0
       Colonic diverticulitis1 (.0)0
       Ischemic colitis365 (5.8)0
       Enterocolitis310 (4.9)0
       Infectious colitis75 (1.2)0
       Inflammatory bowel disease150 (2.4)0
       Drug-induced colitis9 (.1)0
       Nonspecific ulcer46 (.7)0
       Nonspecific colitis30 (.5)0
       Rectal ulcer229 (3.7)0
       Anal bleeding171 (2.7)0
       Hemorrhoids161 (2.6)0
       Anal lesions10 (.2)0
       Small-bowel bleeding171 (2.7)0
       Definitive small-bowel bleeding71 (1.1)0
       Presumptive small-bowel bleeding89 (1.4)0
       Meckel's diverticulum11 (.2)0
       Vascular ectasia105 (1.7)0
       Radiation colitis52 (.8)0
       Varices16 (.3)0
       Dieulafoy's ulcer9 (.1)0
       Other diseases344 (5.5)0
       Miscellaneous
      Miscellaneous (n = 26) included mucosal bleeding (n = 7), colorectal laceration (n = 4), mucosal prolapse syndrome (n = 4), pseudoaneurysm (n = 2), hematoma (n = 2), fistula or penetration into the colorectum (n = 2), mucosal lymphoid hyperplasia (n = 1), Kaposi's sarcoma (n = 1), stoma-related bleeding (n = 1), graft-versus-host disease (n = 1), and Cronkite-Canada syndrome (n = 1).
      26 (.4)0
       Unknown318 (5.1)0
      Outcomes
       Stigmata of recent hemorrhage identification1813 (28.9)0
       Endoscopic therapy1738 (27.7)0
       Clipping1029 (16.4)0
       Ligation548 (8.7)0
       Coagulation158 (2.5)0
       30-day rebleeding1103 (17.6)0
       Interventional radiology or surgery178 (2.8)0
       30-day mortality37 (.6)0
       Mean blood transfusion, packs (SD)1.99 (4.52)0
       Mean length of stay, days (SD)9.72 (10.26)0
      Values are n (%) unless otherwise defined. Colonic diverticular bleeding is the most common cause (71.7%). More than 10% of the information of current smoking, current drinking, and prothrombin time-international normalized ratio was missed.
      SD, Standard deviation.
      Malignancy included solid tumors and malignant lymphomas.
      Miscellaneous (n = 26) included mucosal bleeding (n = 7), colorectal laceration (n = 4), mucosal prolapse syndrome (n = 4), pseudoaneurysm (n = 2), hematoma (n = 2), fistula or penetration into the colorectum (n = 2), mucosal lymphoid hyperplasia (n = 1), Kaposi's sarcoma (n = 1), stoma-related bleeding (n = 1), graft-versus-host disease (n = 1), and Cronkite-Canada syndrome (n = 1).
      Supplementary Table 3Outcomes between colonoscopy timing on the observed data (n = 6270)
      Early (n = 4133)Elective (n = 1137)Late (n = 1000)P value
      Stigmata of recent hemorrhage identification1442 (34.9)240 (21.1)131 (13.1)<.001
      Endoscopic therapy1352 (32.7)249 (21.9)137 (13.7)<.001
      Clipping809 (19.6)146 (12.8)74 (7.4)<.001
      Ligation426 (10.3)74 (6.5)48 (4.8)<.001
      Coagulation112 (2.7)30 (2.6)16 (1.6).13
      30-day rebleeding856 (20.7)165 (14.5)82 (8.2)<.001
      Interventional radiology or surgery119 (2.9)31 (2.7)28 (2.8).96
      30-day mortality25 (.6)7 (.6)5 (.5).92
      Mean blood transfusion, packs (SD)1.97 (4.21)2.25 (5.72)1.76 (4.22).043
      Mean length of stay, days (SD)9.19 (8.84)10.24 (11.62)11.33 (13.40)<.001
      Values are n (%) unless otherwise defined. P < .05 was considered to indicate statistical significance.
      SD, Standard deviation.
      Supplementary Table 4Endoscopic therapies between colonoscopy timing using inverse probability of treatment weighting on the multiply imputed data
      Endoscopic therapiesClippingLigationCoagulation
      OR, 95% CIP valueOR, 95% CIP valueOR, 95% CIP valueOR, 95% CIP value
      ElectiveReferenceReferenceReferenceReference
      Early1.524, 1.301-1.785<.0011.478, 1.218-1.794<.0011.448, 1.116-1.879.005.997, .655-1.516.987
      LateReferenceReferenceReferenceReference
      Elective1.488, 1.179-1.877.0011.575, 1.168-2.123.0031.228, .840-1.793.2891.302, .698-2.428.407
      LateReferenceReferenceReferenceReference
      Early2.227, 1.822-2.722<.0012.317, 1.791-2.998<.0011.674, 1.216-2.303.0021.294, .732-2.290.375
      P < .05 was considered to indicate statistical significance. CI, Confidence interval; OR, odds ratio.
      Supplementary Table 5Patient characteristics of weighting complete data between colonoscopy timing (n = 4148)
      Demographic characteristicsEarly (n = 2679)Elective (n = 781)Late (n = 688)Absolute standardized difference
      Early vs electiveElective vs lateEarly vs late
      Age ≥75 y1207 (45.1)365 (46.7)315 (45.8)0.005.005
      Sex, male1748 (65.2)504 (64.5)371 (53.9)0.003.021
      Body mass index ≥25 kg/m2704 (26.3)200 (25.6)147 (21.4).003.003.006
      Current smoker481 (18.0)147 (18.8)136 (19.8).003.006.001
      Current alcohol user1274 (47.6)376 (48.1)317 (46.1).001.002.008
      Performance status ≥3142 (5.3)29 (3.7)33 (4.8).010.001.002
      History of lower GI bleeding617 (23.0)153 (19.6)145 (21.1)0.001.001
      History of colorectal surgery186 (6.9)55 (7.0)44 (6.4).0030.011
      Hypertension1556 (58.1)444 (56.9)363 (52.8).001.007.014
      Diabetes mellitus504 (18.8)162 (20.7)135 (19.6).007.010.007
      Dyslipidemia746 (27.8)233 (29.8)183 (26.6).011.008.022
      Cerebral and cardiovascular disease401 (15.0)132 (16.9)102 (14.8).005.004.011
      Malignancy
      Malignancy included solid tumors and malignant lymphomas.
      362 (13.5)111 (14.2)93 (13.5).001.001.025
      Charlson comorbidity index ≥3695 (25.9)200 (25.6)176 (25.6).005.002.020
      Medications
       Antiplatelet831 (31.0)217 (27.8)189 (27.5).003.001.020
       Anticoagulant389 (14.5)103 (13.2)76 (11.0).0170.003
       Nonsteroidal anti-inflammatory drugs276 (10.3)72 (9.2)60 (8.7).019.001.003
      Initial measurements
       Shock index ≥1259 (9.7)47 (6.0)66 (9.6)0.005.010
       Syncope243 (9.1)50 (6.4)35 (5.1).010.004.008
       Abdominal pain277 (10.3)114 (14.6)180 (26.2).003.005.007
       Diarrhea198 (7.4)80 (10.2)108 (15.7).0140.015
       Hemoglobin ≤11 g/dL1235 (46.1)378 (48.4)322 (46.8).006.002.007
       Albumin ≤3.0 g/dL305 (11.4)82 (10.5)87 (12.6).007.001.016
       Creatinine ≤1.5 mg/dL332 (12.4)85 (10.9)102 (14.8).003.001.003
       C-reactive protein ≥5 mg/dL97 (3.6)41 (5.2)42 (6.1).008.005.003
       Prothrombin time-international normalized ratio ≥1.5244 (9.1)55 (7.0)55 (8.0).0090.010
       Platelets ≤15 104/μL397 (14.8)115 (14.7)104 (15.1).001.005.006
      Bleeding causes
       Colonic diverticular bleeding
      Colonic diverticular bleeding included definitive and presumptive. Enterocolitis included infectious colitis, inflammatory bowel disease, drug-induced colitis, nonspecific ulcer, and nonspecific colitis. Anal bleeding included hemorrhoids and anal lesions such as anal laceration. Small-bowel bleeding included definitive small-bowel bleeding, presumptive small-bowel bleeding, and Meckel's diverticulum. Other diseases included miscellaneous and unknown lesions.
      2080 (77.6)531 (68.0)401 (58.3).008.005.007
       Ischemic colitis88 (3.3)56 (7.2)96 (14.0)0.003.001
       Enterocolitis
      Colonic diverticular bleeding included definitive and presumptive. Enterocolitis included infectious colitis, inflammatory bowel disease, drug-induced colitis, nonspecific ulcer, and nonspecific colitis. Anal bleeding included hemorrhoids and anal lesions such as anal laceration. Small-bowel bleeding included definitive small-bowel bleeding, presumptive small-bowel bleeding, and Meckel's diverticulum. Other diseases included miscellaneous and unknown lesions.
      99 (3.7)44 (5.6)62 (9.0).003.004.007
       Rectal ulcer90 (3.4)21 (2.7)19 (2.8).008.004.005
       Anal bleeding
      Colonic diverticular bleeding included definitive and presumptive. Enterocolitis included infectious colitis, inflammatory bowel disease, drug-induced colitis, nonspecific ulcer, and nonspecific colitis. Anal bleeding included hemorrhoids and anal lesions such as anal laceration. Small-bowel bleeding included definitive small-bowel bleeding, presumptive small-bowel bleeding, and Meckel's diverticulum. Other diseases included miscellaneous and unknown lesions.
      57 (2.1)24 (3.1)19 (2.8).005.005.001
       Small-bowel bleeding
      Colonic diverticular bleeding included definitive and presumptive. Enterocolitis included infectious colitis, inflammatory bowel disease, drug-induced colitis, nonspecific ulcer, and nonspecific colitis. Anal bleeding included hemorrhoids and anal lesions such as anal laceration. Small-bowel bleeding included definitive small-bowel bleeding, presumptive small-bowel bleeding, and Meckel's diverticulum. Other diseases included miscellaneous and unknown lesions.
      71 (2.7)20 (2.6)18 (2.6)0.003.003
       Vascular ectasia45 (1.7)17 (2.2)9 (1.3).006.008.009
       Radiation colitis21 (.8)7 (.9)2 (.3).003.009.014
       Varices9 (.3)1 (.1)3 (.4).026.006.001
       Dieulafoy's ulcer4 (.1)1 (.1)1 (.1).00500
       Other diseases
      Colonic diverticular bleeding included definitive and presumptive. Enterocolitis included infectious colitis, inflammatory bowel disease, drug-induced colitis, nonspecific ulcer, and nonspecific colitis. Anal bleeding included hemorrhoids and anal lesions such as anal laceration. Small-bowel bleeding included definitive small-bowel bleeding, presumptive small-bowel bleeding, and Meckel's diverticulum. Other diseases included miscellaneous and unknown lesions.
      115 (4.3)59 (7.6)58 (8.4)0.0070
      Values are n (%). The covariates used for the construction of the propensity score were well balanced in the weighting complete data.
      Malignancy included solid tumors and malignant lymphomas.
      Colonic diverticular bleeding included definitive and presumptive. Enterocolitis included infectious colitis, inflammatory bowel disease, drug-induced colitis, nonspecific ulcer, and nonspecific colitis. Anal bleeding included hemorrhoids and anal lesions such as anal laceration. Small-bowel bleeding included definitive small-bowel bleeding, presumptive small-bowel bleeding, and Meckel's diverticulum. Other diseases included miscellaneous and unknown lesions.
      Supplementary Table 6Comparison of the causes of bleeding in shock indices of <1 and ≥1 and PS 0-2 and ≥3 subgroups
      Bleeding causesShock index <1 (n = 5628)Shock index ≥1 (n = 517)P valuePS 0-2 (n = 5823)PS ≥3 (n = 369)P value
      CDB
      CDB included definitive and presumptive. Enterocolitis included infectious colitis, inflammatory bowel disease, drug-induced colitis, nonspecific ulcer, and nonspecific colitis. Anal bleeding included hemorrhoids and anal lesions such as anal laceration. Small-bowel bleeding included definitive small-bowel bleeding, presumptive small-bowel bleeding, and Meckel's diverticulum. Other diseases included miscellaneous and unknown lesions.
      4074 (72.4)344 (66.5).0054262 (73.2)179 (48.5)<.001
      Ischemic colitis337 (6.0)20 (3.9).049341 (5.9)21 (5.7).90
      Enterocolitis
      CDB included definitive and presumptive. Enterocolitis included infectious colitis, inflammatory bowel disease, drug-induced colitis, nonspecific ulcer, and nonspecific colitis. Anal bleeding included hemorrhoids and anal lesions such as anal laceration. Small-bowel bleeding included definitive small-bowel bleeding, presumptive small-bowel bleeding, and Meckel's diverticulum. Other diseases included miscellaneous and unknown lesions.
      266 (4.7)33 (6.4).094294 (5.0)12 (3.3).12
      Rectal ulcer183 (3.3)43 (8.3)<.001126 (2.2)99 (26.8)<.001
      Anal bleeding
      CDB included definitive and presumptive. Enterocolitis included infectious colitis, inflammatory bowel disease, drug-induced colitis, nonspecific ulcer, and nonspecific colitis. Anal bleeding included hemorrhoids and anal lesions such as anal laceration. Small-bowel bleeding included definitive small-bowel bleeding, presumptive small-bowel bleeding, and Meckel's diverticulum. Other diseases included miscellaneous and unknown lesions.
      149 (2.6)15 (2.9).73155 (2.7)15 (4.1).11
      Small-bowel bleeding
      CDB included definitive and presumptive. Enterocolitis included infectious colitis, inflammatory bowel disease, drug-induced colitis, nonspecific ulcer, and nonspecific colitis. Anal bleeding included hemorrhoids and anal lesions such as anal laceration. Small-bowel bleeding included definitive small-bowel bleeding, presumptive small-bowel bleeding, and Meckel's diverticulum. Other diseases included miscellaneous and unknown lesions.
      142 (2.5)21 (4.1).037159 (2.7)8 (2.2).52
      Vascular ectasia91 (1.6)10 (1.9).5996 (1.6)7 (1.9).72
      Radiation colitis50 (.9)2 (.4).2352 (.9)0 (.0).068
      Varices12 (.2)4 (.8).01715 (.3)1 (.3).96
      Dieulafoy's ulcer6 (.1)3 (.6).0078 (.1)1 (.3).51
      Other diseases
      CDB included definitive and presumptive. Enterocolitis included infectious colitis, inflammatory bowel disease, drug-induced colitis, nonspecific ulcer, and nonspecific colitis. Anal bleeding included hemorrhoids and anal lesions such as anal laceration. Small-bowel bleeding included definitive small-bowel bleeding, presumptive small-bowel bleeding, and Meckel's diverticulum. Other diseases included miscellaneous and unknown lesions.
      318 (5.7)22 (4.3).18315 (5.4)26 (7.0).18
      Values are n (%). The proportions of CDB and rectal ulcer were significantly higher in the PS ≥3 subgroup. The significant differences were observed in CDB, ischemic colitis, rectal ulcer, small-bowel bleeding, colorectal varices, and Dieulafoy's ulcer between the shock index <1 and shock index ≥1 cohorts. The data of PS and shock index were missed in 78 and 125 patients. CDB, Colonic diverticular bleeding; PS, performance status.
      CDB included definitive and presumptive. Enterocolitis included infectious colitis, inflammatory bowel disease, drug-induced colitis, nonspecific ulcer, and nonspecific colitis. Anal bleeding included hemorrhoids and anal lesions such as anal laceration. Small-bowel bleeding included definitive small-bowel bleeding, presumptive small-bowel bleeding, and Meckel's diverticulum. Other diseases included miscellaneous and unknown lesions.
      Supplementary Table 7Balancing check between endoscopy timing in the complete data and weighting complete data


      Demographic characteristics
      Complete data (n = 4148)Weighting complete data (n = 4148)
      Absolute standardized differenceAbsolute standardized difference
      Early vs electiveElective vs lateEarly vs lateEarly vs electiveElective vs lateEarly vs late
      Age ≥75 y.034.019.015.008.004.017
      Sex, male.015.217.232.007.004.022
      Body mass index ≥25 kg/m2.015.100.115.008.002.006
      Current smoker.022.024.046.006.005.011
      Current alcohol user.012.041.030.002.001.005
      Performance status ≥3.077.054.023.002.003.007
      History of lower GI bleeding–.084.037.047.005.003.004
      History of colorectal surgery.004.026.022.004.002.010
      Hypertension.025.082.107.001.007.010
      Diabetes mellitus.048.028.021.007.008.002
      Dyslipidemia.044.072.028.012.005.031
      Cerebral and cardiovascular disease.053.057.004.004.006.005
      Malignancy
      Malignancy included solid tumors and malignant lymphomas.
      .020.020.000.002.001.018
      Charlson comorbidity index ≥3.008.001.008.004.002.016
      Medications
       Antiplatelet.071.007.0780.001.026
       Anticoagulant.039.066.104.013.003.001
       Nonsteroidal anti-inflammatory drugs.036.017.054.014.001.009
      Initial measurements
       Shock index ≥1.136.133.003.003.007.022
       Syncope.100.056.156.009.001.002
       Abdominal pain.129.290.418.001.003.002
       Diarrhea.101.163.262.005.001.014
       Hemoglobin ≤11 g/dL.046.032.014.004.0040
       Albumin ≤3.0 g/dL.028.067.039.004.001.005
       Creatinine ≤1.5 mg/dL.047.118.071.001.002.005
       C-reactive protein ≥5 mg/dL.079.037.116.004.009.003
       Prothrombin time-international normalized ratio ≥1.5.076.036.040.007.002.008
       Platelets ≤15 104/μL.003.011.008.002.004.003
      The propensity scores were constructed by demographic characteristics, medications, and initial measurements. The causes of bleeding were not used for the propensity score.
      Malignancy included solid tumors and malignant lymphomas.
      Supplementary Table 8Balancing check of the causes of bleeding between endoscopy timing in the complete data and weighting complete data


      Bleeding causes
      Complete data (n = 4148)Weighting complete data (n = 4148)
      Absolute standardized differenceAbsolute standardized difference
      Early vs electiveElective vs lateEarly vs lateEarly vs electiveElective vs lateEarly vs late
      Colonic diverticular bleeding
      Colonic diverticular bleeding included definitive and presumptive. Enterocolitis included infectious colitis, inflammatory bowel disease, drug-induced colitis, nonspecific ulcer, and nonspecific colitis. Anal bleeding included hemorrhoids and anal lesions such as anal laceration. Small-bowel bleeding included definitive small-bowel bleeding, presumptive small-bowel bleeding, and Meckel's diverticulum. Other diseases included miscellaneous and unknown lesions.
      .219.159.381.157.041.213
      Ischemic colitis.143.221.356.115.07.136
      Enterocolitis
      Colonic diverticular bleeding included definitive and presumptive. Enterocolitis included infectious colitis, inflammatory bowel disease, drug-induced colitis, nonspecific ulcer, and nonspecific colitis. Anal bleeding included hemorrhoids and anal lesions such as anal laceration. Small-bowel bleeding included definitive small-bowel bleeding, presumptive small-bowel bleeding, and Meckel's diverticulum. Other diseases included miscellaneous and unknown lesions.
      .089.133.219.047.021.060
      Rectal ulcer.042.010.052.036.029.032
      Anal bleeding
      Colonic diverticular bleeding included definitive and presumptive. Enterocolitis included infectious colitis, inflammatory bowel disease, drug-induced colitis, nonspecific ulcer, and nonspecific colitis. Anal bleeding included hemorrhoids and anal lesions such as anal laceration. Small-bowel bleeding included definitive small-bowel bleeding, presumptive small-bowel bleeding, and Meckel's diverticulum. Other diseases included miscellaneous and unknown lesions.
      .036.016.021.052.003.064
      Small-bowel bleeding
      Colonic diverticular bleeding included definitive and presumptive. Enterocolitis included infectious colitis, inflammatory bowel disease, drug-induced colitis, nonspecific ulcer, and nonspecific colitis. Anal bleeding included hemorrhoids and anal lesions such as anal laceration. Small-bowel bleeding included definitive small-bowel bleeding, presumptive small-bowel bleeding, and Meckel's diverticulum. Other diseases included miscellaneous and unknown lesions.
      .013.012.001.007.014.012
      Vascular ectasia.046.052.006.054.069.039
      Radiation colitis.016.051.067.003.072.054
      Varices.047.048.002.057.066.025
      Dieulafoy's ulcer.033.038.006.002.003.015
      Other diseases
      Colonic diverticular bleeding included definitive and presumptive. Enterocolitis included infectious colitis, inflammatory bowel disease, drug-induced colitis, nonspecific ulcer, and nonspecific colitis. Anal bleeding included hemorrhoids and anal lesions such as anal laceration. Small-bowel bleeding included definitive small-bowel bleeding, presumptive small-bowel bleeding, and Meckel's diverticulum. Other diseases included miscellaneous and unknown lesions.
      .178.027.151.120.027.198
      The proportion of colonic diverticular bleeding was not well balanced before and after the inverse probability of treatment weighting.
      Colonic diverticular bleeding included definitive and presumptive. Enterocolitis included infectious colitis, inflammatory bowel disease, drug-induced colitis, nonspecific ulcer, and nonspecific colitis. Anal bleeding included hemorrhoids and anal lesions such as anal laceration. Small-bowel bleeding included definitive small-bowel bleeding, presumptive small-bowel bleeding, and Meckel's diverticulum. Other diseases included miscellaneous and unknown lesions.

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