Impact of long-term trends on outcomes in the management of colonic diverticular bleeding: mediation analyses in a large multicenter study

Omori J., Kaise M., Nagata N., Aoki T., Kobayashi K., Yamauchi A., Yamada A., Ikeya T., Aoyama T., Tominaga N., Sato Y., Kishino T., Ishii N., Sawada T., Murata M., et. al.

Current evidence on the surgical rate, indication, procedure, risk factors, mortality, and postoperative rebleeding for acute lower gastrointestinal bleeding (ALGIB) is limited. We constructed a retrospective cohort of 10,342 patients admitted for acute hematochezia at 49 hospitals (CODE BLUE J-Study) and evaluated clinical data on the surgeries performed. Surgery was performed in 1.3% (136/10342) of the cohort with high rates of colonoscopy (87.7%) and endoscopic hemostasis (26.7%). Indications for surgery included colonic diverticular bleeding (24%), colorectal cancer (22%), and small bowel bleeding (16%). Sixty-four percent of surgeries were for hemostasis for severe refractory bleeding. Postoperative rebleeding rates were 22% in patients with presumptive or obscure preoperative identification of the bleeding source and 12% in those with definitive identification. Thirty-day mortality rates were 1.5% and 0.8% in patients with and without surgery, respectively. Multivariate analysis showed that surgery-related risk factors were transfusion need ≥ 6 units (P < 0.001), in-hospital rebleeding (P < 0.001), small bowel bleeding (P < 0.001), colorectal cancer (P < 0.001), and hemorrhoids (P < 0.001). Endoscopic hemostasis was negatively associated with surgery (P = 0.003). For small bowel bleeding, the surgery rate was significantly lower in patients with endoscopic hemostasis as 2% compared to 12% without endoscopic hemostasis. Our cohort study elucidated the outcomes and risks of the surgery. Extensive exploration including the small bowel to identify the source of bleeding and endoscopic hemostasis may reduce unnecessary surgery and improve the management of ALGIB.

Kishino T., Aoki T., Sadashima E., Kobayashi K., Yamauchi A., Yamada A., Omori J., Ikeya T., Aoyama T., Tominaga N., Sato Y., Ishii N., Sawada T., Murata M., Takao A., et. al.

AbstractAimNo studies have compared the clinical outcomes of early and delayed feeding in patients with acute lower gastrointestinal bleeding (ALGIB). This study aimed to evaluate the benefits and risks of early feeding in a nationwide cohort of patients with ALGIB in whom haemostasis was achieved.MethodsWe reviewed data for 5910 patients with ALGIB in whom haemostasis was achieved and feeding was resumed within 3 days after colonoscopy at 49 hospitals across Japan (CODE BLUE‐J Study). Patients were divided into an early feeding group (≤1 day, n = 3324) and a delayed feeding group (2–3 days, n = 2586). Clinical outcomes were compared between the groups by propensity matching analysis of 1508 pairs.ResultsThere was no significant difference between the early and delayed feeding groups in the rebleeding rate within 7 days after colonoscopy (9.4% vs. 8.0%; p = 0.196) or in the rebleeding rate within 30 days (11.4% vs. 11.5%; p = 0.909). There was also no significant between‐group difference in the need for interventional radiology or surgery or in mortality. However, the median length of hospital stay after colonoscopy was significantly shorter in the early feeding group (5 vs. 7 days; p < 0.001). These results were unchanged when subgroups of presumptive and definitive colonic diverticular bleeding were compared.ConclusionThe findings of this nationwide study suggest that early feeding after haemostasis can shorten the hospital stay in patients with ALGIB without increasing the risk of rebleeding.

Aoki T., Yamada A., Kobayashi K., Yamauchi A., Omori J., Ikeya T., Aoyama T., Tominaga N., Sato Y., Kishino T., Ishii N., Sawada T., Murata M., Takao A., Mizukami K., et. al.

Shiratori Y., Ishii N., Aoki T., Kobayashi K., Yamauchi A., Yamada A., Omori J., Aoyama T., Tominaga N., Sato Y., Kishino T., Sawada T., Murata M., Takao A., Mizukami K., et. al.

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

Sengupta N., Feuerstein J.D., Jairath V., Shergill A.K., Strate L.L., Wong R.J., Wan D.

Gobinet-Suguro M., Nagata N., Kobayashi K., Yamauchi A., Yamada A., Omori J., Ikeya T., Aoyama T., Tominaga N., Sato Y., Kishino T., Ishii N., Sawada T., Murata M., Takao A., et. al.

Background and AimsTreatment strategies for colonic diverticular bleeding (CDB) based on stigmata of recent hemorrhage (SRH) remain unstandardized, and no large studies have evaluated their effectiveness. We sought to identify the best strategy among combinations of SRH identification and endoscopic treatment strategies.MethodsWe retrospectively analyzed 5823 CDB patients who underwent colonoscopy at 49 hospitals throughout Japan (CODE-BLUE J-Study). Three strategies were compared: find SRH (definitive CDB) and treat endoscopically, find SRH (definitive CDB) and treat conservatively, and without finding SRH (presumptive CDB) treat conservatively. In conducting pairwise comparisons of outcomes in these groups, we used propensity score–matching analysis to balance baseline characteristics between the groups being compared.ResultsBoth early and late recurrent bleeding rates were significantly lower in patients with definitive CDB treated endoscopically than in those with presumptive CDB treated conservatively (

Kishino T., Nagata N., Kobayashi K., Yamauchi A., Yamada A., Omori J., Ikeya T., Aoyama T., Tominaga N., Sato Y., Ishii N., Sawada T., Murata M., Takao A., Mizukami K., et. al.

Direct and indirect clipping treatments are used worldwide to treat colonic diverticular bleeding (CDB), but their effectiveness has not been examined in multicenter studies with more than 100 cases.We sought to determine the short- and long-term effectiveness of direct versus indirect clipping for CDB in a nationwide cohort.We studied 1041 patients with CDB who underwent direct clipping (n = 360) or indirect clipping (n = 681) at 49 hospitals across Japan (CODE BLUE-J Study).Multivariate analysis adjusted for age, sex, and important confounding factors revealed that, compared with indirect clipping, direct clipping was independently associated with reduced risk of early rebleeding (

Kobayashi K., Nagata N., Furumoto Y., Yamauchi A., Yamada A., Omori J., Ikeya T., Aoyama T., Tominaga N., Sato Y., Kishino T., Ishii N., Sawada T., Murata M., Takao A., et. al.

Abstract Background Prior studies have shown the effectiveness of both endoscopic band ligation (EBL) and clipping for colonic diverticular hemorrhage (CDH) but have been small and conducted at single centers. Therefore, we investigated which was the more effective and safe treatment in a multicenter long-term cohort study. Methods We reviewed data for 1679 patients with CDH who were treated with EBL (n = 638) or clipping (n = 1041) between January 2010 and December 2019 at 49 hospitals across Japan (CODE BLUE-J study). Logistic regression analysis was used to compare outcomes between the two treatments. Results In multivariate analysis, EBL was independently associated with reduced risk of early rebleeding (adjusted odds ratio [OR] 0.46; P < 0.001) and late rebleeding (adjusted OR 0.62; P < 0.001) compared with clipping. These significantly lower rebleeding rates with EBL were evident regardless of active bleeding or early colonoscopy. No significant differences were found between the treatments in the rates of initial hemostasis or mortality. Compared with clipping, EBL independently reduced the risk of needing interventional radiology (adjusted OR 0.37; P = 0.006) and prolonged length of hospital stay (adjusted OR 0.35; P < 0.001), but not need for surgery. Diverticulitis developed in one patient (0.16 %) following EBL and two patients (0.19 %) following clipping. Perforation occurred in two patients (0.31 %) following EBL and none following clipping. Conclusions Analysis of our large endoscopy dataset suggests that EBL is an effective and safe endoscopic therapy for CDH, offering the advantages of lower early and late rebleeding rates, reduced need for interventional radiology, and shorter length of hospital stay.

Nagata N., Kobayashi K., Yamauchi A., Yamada A., Omori J., Ikeya T., Aoyama T., Tominaga N., Sato Y., Kishino T., Ishii N., Sawada T., Murata M., Takao A., Mizukami K., et. al.

The bleeding source of hematochezia is unknown without performing colonoscopy. We sought to identify whether colonoscopy is a risk-stratifying tool to identify etiology and predict outcomes and whether presenting symptoms can differentiate the etiologies in patients with hematochezia.This multicenter retrospective cohort study conducted at 49 hospitals across Japan analyzed 10,342 patients admitted for outpatient-onset acute hematochezia.Patients were mostly elderly population, and 29.5% had hemodynamic instability. Computed tomography was performed in 69.1% and colonoscopy in 87.7%. Diagnostic yield of colonoscopy reached 94.9%, most frequently diverticular bleeding. Thirty-day rebleeding rates were significantly higher with diverticulosis and small bowel bleeding than with other etiologies. In-hospital mortality was significantly higher with angioectasia, malignancy, rectal ulcer, and upper gastrointestinal bleeding. Colonoscopic treatment rates were significantly higher with diverticulosis, radiation colitis, angioectasia, rectal ulcer, and postendoscopy bleeding. More interventional radiology procedures were needed for diverticulosis and small bowel bleeding. Etiologies with favorable outcomes and low procedure rates were ischemic colitis and infectious colitis. Higher rates of painless hematochezia at presentation were significantly associated with multiple diseases, such as rectal ulcer, hemorrhoids, angioectasia, radiation colitis, and diverticulosis. The same was true in cases of hematochezia with diarrhea, fever, and hemodynamic instability.This nationwide data set of acute hematochezia highlights the importance of colonoscopy in accurately detecting bleeding etiologies that stratify patients at high or low risk of adverse outcomes and those who will likely require more procedures. Predicting different bleeding etiologies based on initial presentation would be challenging.

Triantafyllou K., Gkolfakis P., Gralnek I.M., Oakland K., Manes G., Radaelli F., Awadie H., Camus Duboc M., Christodoulou D., Fedorov E., Guy R.J., Hollenbach M., Ibrahim M., Neeman Z., Regge D., et. al.

Main Recommendations 1 ESGE recommends that the initial assessment of patients presenting with acute lower gastrointestinal bleeding should include: a history of co-morbidities and medications that promote bleeding; hemodynamic parameters; physical examination (including digital rectal examination); and laboratory markers. A risk score can be used to aid, but should not replace, clinician judgment.Strong recommendation, low quality evidence. 2 ESGE recommends that, in patients presenting with a self-limited bleed and no adverse clinical features, an Oakland score of ≤ 8 points can be used to guide the clinician decision to discharge the patient for outpatient investigation.Strong recommendation, moderate quality evidence. 3 ESGE recommends, in hemodynamically stable patients with acute lower gastrointestinal bleeding and no history of cardiovascular disease, a restrictive red blood cell transfusion strategy, with a hemoglobin threshold of ≤ 7 g/dL prompting red blood cell transfusion. A post-transfusion target hemoglobin concentration of 7–9 g/dL is desirable.Strong recommendation, low quality evidence. 4 ESGE recommends, in hemodynamically stable patients with acute lower gastrointestinal bleeding and a history of acute or chronic cardiovascular disease, a more liberal red blood cell transfusion strategy, with a hemoglobin threshold of ≤ 8 g/dL prompting red blood cell transfusion. A post-transfusion target hemoglobin concentration of ≥ 10 g/dL is desirable.Strong recommendation, low quality evidence. 5 ESGE recommends that, in patients with major acute lower gastrointestinal bleeding, colonoscopy should be performed sometime during their hospital stay because there is no high quality evidence that early colonoscopy influences patient outcomes.Strong recommendation, low quality of evidence. 6 ESGE recommends that patients with hemodynamic instability and suspected ongoing bleeding undergo computed tomography angiography before endoscopic or radiologic treatment to locate the site of bleeding.Strong recommendation, low quality evidence. 7 ESGE recommends withholding vitamin K antagonists in patients with major lower gastrointestinal bleeding and correcting their coagulopathy according to the severity of bleeding and their thrombotic risk. In patients with hemodynamic instability, we recommend administering intravenous vitamin K and four-factor prothrombin complex concentrate (PCC), or fresh frozen plasma if PCC is not available.Strong recommendation, low quality evidence. 8 ESGE recommends temporarily withholding direct oral anticoagulants at presentation in patients with major lower gastrointestinal bleeding.Strong recommendation, low quality evidence. 9 ESGE does not recommend withholding aspirin in patients taking low dose aspirin for secondary cardiovascular prevention. If withheld, low dose aspirin should be resumed, preferably within 5 days or even earlier if hemostasis is achieved or there is no further evidence of bleeding.Strong recommendation, moderate quality evidence. 10 ESGE does not recommend routinely discontinuing dual antiplatelet therapy (low dose aspirin and a P2Y12 receptor antagonist) before cardiology consultation. Continuation of the aspirin is recommended, whereas the P2Y12 receptor antagonist can be continued or temporarily interrupted according to the severity of bleeding and the ischemic risk. If interrupted, the P2Y12 receptor antagonist should be restarted within 5 days, if still indicated.Strong recommendation, low quality evidence.

Kherad O., Restellini S., Almadi M., Strate L.L., Ménard C., Martel M., Roshan Afshar I., Sadr M.S., Barkun A.N.

Background The optimal timing of colonoscopy in acute lower gastrointestinal bleeding (LGIB) remains controversial. Aim To characterise the utility of early colonoscopy (within 24 hours) in managing acute LGIB. Methods A systematic literature search to October 2019 identified fully published articles and abstracts of randomised controlled trials (RCTs) and observational studies with control groups assessing early colonoscopy in acute LGIB. The primary outcome was rebleeding. Secondary outcomes included mortality, surgery, length of stay (LOS), definite cause of bleeding and adverse events. Odds ratios (ORs) and mean differences (MD) were calculated. Results Of 1116 citations, 4 RCTs (466 patients) and 13 observational studies with elective colonoscopy (>24 hours) as control group (1 061 281 patients) were included. No differences in rebleeding were noted between early and elective colonoscopy groups among RCTs alone (OR = 1.70; 0.79; 3.64), or observational studies alone (OR = 1.20; 0.69; 2.09). No other significant between-group differences in outcomes were found when restricting the analysis to RCTs. Among observational studies only, early colonoscopy was associated with lower rates of all-cause mortality (OR = 0.86; 0.75; 0.98), surgery (OR = 0.52; 0.42; 0.64), blood transfusion (OR = 0.81; 0.75; 0.87), units of blood transfusion (MD = -4.30; -6.24; -2.36) and shorter LOS (MD = -1.70; -1.70; -1.70 days). Conclusion In contradistinction to observational studies, data from RCTs do not support a role for early colonoscopy in the routine management of acute LGIB with regards to the most important clinical outcomes. Further research is needed to better identify patients with high-risk LGIB who may benefit from early colonoscopy.

Kishino T., Kanemasa K., Kitamura Y., Fukumoto K., Okamoto N., Shimokobe H.

Abstract Background and study aims The efficacy of endoclips for colonic diverticular hemorrhage remains unclear. The aim of the current study was to evaluate the safety and efficacy of endoclips versus endoscopic band ligation (EBL) for the treatment of colonic diverticular hemorrhage. Patients and methods At Nara City Hospital, 93 patients with colonic diverticular hemorrhage with stigmata of recent hemorrhage (SRH) were treated using endoclips or EBL between January 2013 and December 2018. We classified the patients treated by endoclips into the direct clipping group and indirect clipping group. Endoclips were placed directly onto the vessel if technically feasible (direct clipping). When direct placement of endoclips onto the vessel was not possible, the diverticulum was closed in a zipper fashion (indirect clipping). Patient demographics, rate of early rebleeding within 30 days after initial treatment, and complications were retrospectively evaluated. Results Of the 93 patients, 34, 28, and 31 were in the direct clipping group, indirect clipping group, and EBL group, respectively. Rates of early rebleeding in the direct clipping, indirect clipping, and EBL groups were 5.9 % (2/34), 35.7 % (10/28), and 6.5 % (2/31), respectively (P = 0.006: direct clipping vs indirect clipping, P = 1: direct clipping vs EBL). No complications occurred in any groups. All patients who had early rebleeding in the direct clipping group underwent EBL, and no further bleeding occurred after repeat therapy. Conclusions Direct clip placement is acceptable as the first treatment choice for colonic diverticular hemorrhage. When direct placement of endoclips is not possible, EBL should be performed instead of indirect clipping.

Niikura R., Nagata N., Yamada A., Honda T., Hasatani K., Ishii N., Shiratori Y., Doyama H., Nishida T., Sumiyoshi T., Fujita T., Kiyotoki S., Yada T., Yamamoto K., Shinozaki T., et. al.

We performed a large, multicenter, randomized controlled trial to determine the efficacy and safety of early colonoscopy on outcomes of patients with acute lower gastrointestinal bleeding (ALGIB).We performed an open-label study at 15 hospitals in Japan of 170 patients with ALGIB randomly assigned (1:1) to groups that underwent early colonoscopy (within 24 hours of initial visit to the hospital) or elective colonoscopy (24-96 hours after hospital admission). The primary outcome was identification of stigmata of recent hemorrhage (SRH). Secondary outcomes were rebleeding within 30 days, endoscopic treatment success, need for transfusion, length of stay, thrombotic events within 30 days, death within 30 days, and adverse events.SRH were identified in 17 of 79 patients (21.5%) in the early colonoscopy group vs 17 of 80 patients (21.3%) in the elective colonoscopy group (difference, 0.3; 95% confidence interval, -12.5 to 13.0; P = .967). Rebleeding within 30 days of hospital admission occurred in 15.3% of patients in the early colonoscopy group and 6.7% of patients in the elective colonoscopy group (difference, 8.6; 95% confidence interval, -1.4 to 18.7); there were no significant differences between groups in successful endoscopic treatment rate, transfusion rate, length of stay, thrombotic events, or death within 30 days. The adverse event of hemorrhagic shock occurred during bowel preparation in no patient in the early group vs 2 patients (2.5%) in the elective colonoscopy group.In a randomized controlled study, we found that colonoscopy within 24 hours after hospital admission did not increase SRH or reduce rebleeding compared with colonoscopy at 24-96 hours in patients with ALGIB. ClinicalTrials.gov, Numbers: UMIN000021129 and NCT03098173.

Oakland K., Chadwick G., East J.E., Guy R., Humphries A., Jairath V., McPherson S., Metzner M., Morris A.J., Murphy M.F., Tham T., Uberoi R., Veitch A.M., Wheeler J., Regan C., et. al.

This is the first UK national guideline to concentrate on acute lower gastrointestinal bleeding (LGIB) and has been commissioned by the Clinical Services and Standards Committee of the British Society of Gastroenterology (BSG). The Guidelines Development Group consisted of representatives from the BSG Endoscopy Committee, the Association of Coloproctology of Great Britain and Ireland, the British Society of Interventional Radiology, the Royal College of Radiologists, NHS Blood and Transplant and a patient representative. A systematic search of the literature was undertaken and the quality of evidence and grading of recommendations appraised according to the GRADE(Grading of Recommendations Assessment, Development and Evaluation) methodology. These guidelines focus on the diagnosis and management of acute LGIB in adults, including methods of risk assessment and interventions to diagnose and treat bleeding (colonoscopy, computed tomography, mesenteric angiography, endoscopic therapy, embolisation and surgery). Recommendations are included on the management of patients who develop LGIB while receiving anticoagulants (including direct oral anticoagulants) or antiplatelet drugs. The appropriate use of blood transfusion is also discussed, including haemoglobin triggers and targets.

Nagata N., Ishii N., Manabe N., Tomizawa K., Urita Y., Funabiki T., Fujimori S., Kaise M.

Colonic diverticular disease has been increasing in prevalence in Japan due to the rapidly aging population. Colonic diverticular bleeding can result in hemorrhagic shock requiring blood transfusion, and it carries a high risk of recurrence within 1 year. Colonic diverticulitis can cause abscess, fistula formation, and perforation of the colon that may require surgery, and it often recurs. As a result, patients with colonic diverticular disease are often bothered by required frequent examinations, re-hospitalization, and a consequent decrease in quality of life. However, the management of diverticular disease differs between Japan and Western countries. For example, computed tomography (CT) is readily accessible at Japanese hospitals, so urgent CT may be selected as the first diagnostic procedure for suspected diverticular disease. Endoscopic clipping or band ligation may be preferred as the first endoscopic procedure for diverticular bleeding. Administration of antibiotics and complete bowel rest may be considered as first-line therapy for colonic diverticulitis. In addition, diverticula occur mainly in the sigmoid colon in Western countries, whereas the right side or bilateral of the colon is more commonly involved in Japan. As such, diverticular disease in the right-side colon is more prevalent in Japan than in Western countries. Against this background, concern is growing about the management of colonic diverticular disease in Japan and there is currently no practice guideline available. To address this situation, the Japanese Gastroenterological Association decided to create a clinical guideline for colonic diverticular bleeding and colonic diverticulitis in collaboration with the Japanese Society of Gastroenterology, Japan Gastroenterological Endoscopy Society, and Japanese Society of Interventional Radiology. The steps taken to establish this guideline involved incorporating the concept of the GRADE system for rating clinical guidelines, developing clinical questions (CQs), accumulating evidence through a literature search and review, and developing the Statement and Explanation sections. This guideline includes 2CQs for colonic diverticulosis, 24 CQs for colonic diverticular bleeding, and 17 CQs for diverticulitis.