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Be “routinely selective” when performing second-look endoscopy in peptic ulcer bleeding!

      Abbreviations:

      CI (confidence interval), IV (intravenous), NSAID (nonsteroidal anti-inflammatory drug), OR (odds ratio), PPI (proton pump inhibitor), RCT (randomized controlled trial), RR (relative risk)
      Routine second-look endoscopy is defined as a “scheduled” repeated endoscopic assessment performed within 24 hours after the index endoscopy regardless of the type of bleeding lesion at index endoscopy, perceived rebleeding risk, or clinical signs of rebleeding.
      • Barkun A.N.
      • Bardou M.
      • Kuipers E.J.
      • et al.
      International consensus recommendations on the management of patients with nonvariceal upper gastrointestinal bleeding.
      • Gralnek I.M.
      • Dumonceau J.M.
      • Kuipers E.J.
      • et al.
      Diagnosis and management of nonvariceal upper gastrointestinal hemorrhage: European Society of Gastrointestinal Endoscopy (ESGE) Guideline.
      At scheduled second-look endoscopy, repeated endoscopic hemostasis therapy is performed in patients found to have high-risk endoscopic stigmata that include active bleeding or a nonbleeding visible vessel, and in some studies adherent clot. This clinical strategy has been proposed to reduce the risk of recurrent hemorrhage and thus improve patient outcomes. However, with the optimization of endoscopic hemostasis techniques and medical therapies (no more use of diluted epinephrine as monotherapy, increased use of combination hemostasis, and provision of posthemostasis high-dose intravenous [IV] proton pump inhibitors [PPIs]), current evidence-based guidelines and expert reviews on nonvariceal upper GI hemorrhage and peptic ulcer bleeding do not recommend routine second-look endoscopy.
      • Barkun A.N.
      • Bardou M.
      • Kuipers E.J.
      • et al.
      International consensus recommendations on the management of patients with nonvariceal upper gastrointestinal bleeding.
      • Gralnek I.M.
      • Dumonceau J.M.
      • Kuipers E.J.
      • et al.
      Diagnosis and management of nonvariceal upper gastrointestinal hemorrhage: European Society of Gastrointestinal Endoscopy (ESGE) Guideline.
      • Gralnek I.M.
      • Barkun A.N.
      • Bardou M.
      Management of acute bleeding from a peptic ulcer.
      • Laine L.
      • Jensen D.M.
      Management of patients with ulcer bleeding.
      • Lau J.Y.W.
      • Barkun A.N.
      • Fan D.M.
      • et al.
      Challenges in the management of acute peptic ulcer bleeding.
      Repeated endoscopy is reserved for cases in which there is clinical evidence for recurrent bleeding, where poor visualization at the index endoscopy precluded a thorough and complete examination with failure to identify a clear source of hemorrhage, or where at index endoscopy the endoscopist was concerned that the applied hemostasis was inadequate.
      • Barkun A.N.
      • Bardou M.
      • Kuipers E.J.
      • et al.
      International consensus recommendations on the management of patients with nonvariceal upper gastrointestinal bleeding.
      • Gralnek I.M.
      • Dumonceau J.M.
      • Kuipers E.J.
      • et al.
      Diagnosis and management of nonvariceal upper gastrointestinal hemorrhage: European Society of Gastrointestinal Endoscopy (ESGE) Guideline.
      • Gralnek I.M.
      • Barkun A.N.
      • Bardou M.
      Management of acute bleeding from a peptic ulcer.
      • Laine L.
      • Jensen D.M.
      Management of patients with ulcer bleeding.
      • Lau J.Y.W.
      • Barkun A.N.
      • Fan D.M.
      • et al.
      Challenges in the management of acute peptic ulcer bleeding.
      In this issue of Gastrointestinal Endoscopy, Park and colleagues
      • Park S.J.
      • Park H.
      • Lee Y.C.
      • et al.
      Effect of scheduled second-look endoscopy on peptic ulcer bleeding: a prospective randomized multicenter trial.
      report on the efficacy of scheduled second-look endoscopy in preventing recurrent bleeding in ambulatory adults presenting to the hospital with peptic ulcer bleeding. This was a multicenter (7 medical centers participated), randomized, noninferiority study from Korea. The investigators also attempted to identify predictors of recurrent bleeding to identify those patients at highest risk for recurrent bleeding and in whom scheduled second-look endoscopy might be most beneficial. After undergoing index endoscopy with the identification of high-risk peptic ulcer (defined as active bleeding: Forrest Ia and Ib, nonbleeding visible vessel; Forrest IIa, or adherent clot; Forrest IIb) and successful primary hemostasis, 319 patients were randomly assigned to receive scheduled second-look endoscopy 24 to 36 hours after index endoscopy (intervention group) or “close observation” (control group). The use of diluted epinephrine or fibrin glue as endoscopic monotherapy at index endoscopy was not permitted, and they were given only as part of combination hemostasis therapy. All patients received twice-daily bolus IV PPI. The primary outcomes of this study were ulcer rebleeding within 7 and 30 days, with clinical signs and symptoms of recurrent bleeding a priori strictly defined by the investigators.
      • Park S.J.
      • Park H.
      • Lee Y.C.
      • et al.
      Effect of scheduled second-look endoscopy on peptic ulcer bleeding: a prospective randomized multicenter trial.
      The secondary outcomes included need for surgery or an interventional radiology procedure, blood transfusions, length of hospital stay, and mortality.
      There were no reported baseline differences between the study groups. Thus, randomization appears to have achieved its methodologic goal of equalizing the intervention and control arms of the study. Importantly, this included no observed significant differences in age, gender distribution, medical comorbidities, use of antithrombotic agents, type of ulcer (gastric or duodenal), presence of high-risk endoscopic stigmata, endoscopic hemostasis modality used at index endoscopy, or the endoscopist’s self-reported estimate of hemostasis success at index endoscopy.
      In an intention-to-treat analysis, Park and colleagues
      • Park S.J.
      • Park H.
      • Lee Y.C.
      • et al.
      Effect of scheduled second-look endoscopy on peptic ulcer bleeding: a prospective randomized multicenter trial.
      reported that one-time endoscopy was not inferior to a strategy of scheduled second-look endoscopy in reducing recurrent peptic ulcer bleeding, both at 7 days (relative risk [RR], 0.50; 95% confidence interval [CI], 0.21-1.21) and at 30 days (RR, 0.53; 95% CI, 0.23-1.23). Interestingly, in comparison with the published literature, the overall rate of peptic ulcer rebleeding in this study was low (6.4%), and there was more rebleeding in the second-look endoscopy group. There was no significant difference in need for surgery or interventional radiology, length of hospitalization, blood transfusions, or mortality. In their multivariate analysis, the investigators reported that endoscopist-perceived unsatisfactory endoscopic hemostasis at index endoscopy, ≥4 units of blood transfused, and use of nonsteroidal anti-inflammatory drugs (NSAIDs) were independent risk factors for recurrent bleeding.
      Before the publication of this present randomized trial, what was the evidence regarding the role of routine second-look endoscopy? In the most recent systematic review of this topic, El Ouali and colleagues
      • El Ouali S.
      • Barkun A.N.
      • Wyse J.
      • et al.
      Is routine second-look endoscopy effective after endoscopic hemostasis in acute peptic ulcer bleeding? A meta-analysis.
      published a meta-analysis of 8 randomized controlled trials (4 fully published papers and 4 in abstract form) published between 1994 and 2011 (n = 938 study participants) that evaluated scheduled second-look endoscopy in acute upper GI bleeding. In that meta-analysis, scheduled second-look endoscopy appeared to significantly reduce the rates of rebleeding (odds ratio [OR], 0.55; 95% CI, 0.37-0.81) and need for surgery (OR, 0.43; 95% CI, 0.19-0.96) but not mortality (OR, 0.65; 95% CI, 0.26-1.62). However, when the authors excluded the 2 studies that used modern-day combination endoscopic hemostasis therapy in concert with high-dose PPI therapy or that included a high percentage of patients presenting with hemodynamic shock and at very high risk of rebleeding (active bleeding found at index endoscopy), the benefit of routine second-look endoscopy in preventing rebleeding disappeared (OR, 0.65; 95% CI, 0.42-1.00). The authors of this meta-analysis concluded that second-look endoscopy may be efficacious in the subgroup of patients who are considered to be at very high risk of rebleeding (active bleeding at index endoscopy) or who do not receive high-dose PPI therapy after endoscopic hemostasis. The medical economics of scheduled second-look endoscopy has also been considered because most patients will not have recurrent bleeding and repeated endoscopy will not be warranted. When decision analysis is used, the cost effectiveness of scheduled second-look endoscopy in peptic ulcer bleeding has been questioned.
      • Spiegel B.M.
      • Ofman J.J.
      • Woods K.
      • et al.
      Minimizing recurrent peptic ulcer hemorrhage after endoscopic hemostasis: the cost-effectiveness of competing strategies.
      • Imperiale T.F.
      • Kong N.
      Second-look endoscopy for bleeding peptic ulcer disease: a decision-effectiveness and cost-effectiveness analysis.
      Spiegel and colleagues
      • Spiegel B.M.
      • Ofman J.J.
      • Woods K.
      • et al.
      Minimizing recurrent peptic ulcer hemorrhage after endoscopic hemostasis: the cost-effectiveness of competing strategies.
      reported that “selective” second-look endoscopy at 24 hours was more effective and less expensive only in patients at “high risk” for rebleeding. In a subsequent study, Imperiale and Kong
      • Imperiale T.F.
      • Kong N.
      Second-look endoscopy for bleeding peptic ulcer disease: a decision-effectiveness and cost-effectiveness analysis.
      reported that only when the rebleeding risk was ≥31% was routine second-look endoscopy cost effective.
      Does this study by Park and colleagues
      • Park S.J.
      • Park H.
      • Lee Y.C.
      • et al.
      Effect of scheduled second-look endoscopy on peptic ulcer bleeding: a prospective randomized multicenter trial.
      add to the literature and provide us with important evidence? I submit that the answer is yes. All in all, this is a well-performed study because of its multicenter, prospective randomized design, clearly delineated study endpoints, strict a priori definitions of rebleeding, sound statistical plan including power calculations, and an “intention-to-treat” analysis. However, there are of course limitations that must be pointed out. These limitations include no subject or investigator blinding that could have led to unintended bias. Although the authors are to be commended for evaluating endoscopists’ self-reported satisfaction with success of hemostasis at index endoscopy, the questionnaire used to measure this variable was not a validated instrument, and thus its accuracy should be questioned. Because endoscopists’ self-reported satisfaction with success of hemostasis at index endoscopy is an important variable to measure in GI bleeding studies, it would be important for this questionnaire to be used in future studies to attain external validation. Last, although this was a multicenter study and multiple endoscopists participated, according to the authors all the endoscopists were considered “experts” in endoscopic hemostasis, and this may limit the study’s generalizability to nonexperts in endoscopic hemostasis. This may also at least partially explain the observed overall low rate of rebleeding.
      So should we be performing “routine” second-look endoscopy in patients with high-risk peptic ulcer bleeding? This editorialist says no. Current evidence does not support this practice, and up-to-date evidence-based guidelines and expert reviews are correct in their recommendation against routine second-look endoscopy. In the modern era of combination endoscopic hemostasis therapy for high-risk endoscopic stigmata, and with the now widespread use of high-dose post-hemostasis PPI therapy, routine second-look endoscopy is not warranted. We should, however, perform repeated endoscopy in patients who demonstrate clinical signs and symptoms of rebleeding, specifically, in patients with recurrent hematemesis (fresh blood, coffee-ground appearance, or both), recurrent melena after normalization of stool color, recurrent hemodynamic instability once hemodynamic stability has been normalized, and when there is a >2 g/dL drop in hemoglobin once the hemoglobin is stabilized after intravascular volume resuscitation. And we should perform repeated endoscopic hemostasis in patients in whom the high-risk stigmata of hemorrhage persist.
      • Barkun A.N.
      • Bardou M.
      • Kuipers E.J.
      • et al.
      International consensus recommendations on the management of patients with nonvariceal upper gastrointestinal bleeding.
      • Gralnek I.M.
      • Dumonceau J.M.
      • Kuipers E.J.
      • et al.
      Diagnosis and management of nonvariceal upper gastrointestinal hemorrhage: European Society of Gastrointestinal Endoscopy (ESGE) Guideline.
      • Gralnek I.M.
      • Barkun A.N.
      • Bardou M.
      Management of acute bleeding from a peptic ulcer.
      • Laine L.
      • Jensen D.M.
      Management of patients with ulcer bleeding.
      • Lau J.Y.W.
      • Barkun A.N.
      • Fan D.M.
      • et al.
      Challenges in the management of acute peptic ulcer bleeding.
      • Lau J.Y.W.
      • Sung J.J.Y.
      • Lam Y.H.
      • et al.
      Endoscopic retreatment compared with surgery in patients with recurrent bleeding after initial endoscopic control of bleeding ulcers.
      This editorialist does advocate performing “selective” second-look endoscopy in patients in whom poor endoscopic visualization at index endoscopy precludes a thorough and complete examination with failure to identify a clear source of hemorrhage, when the endoscopist is concerned that the applied hemostasis was inadequate or incomplete, and—on the basis of these present data from Park et al—possibly in patients with high blood transfusion requirements or those using NSAIDs. As recommended in current guidelines, the use of a prokinetic agent before performance of the index endoscopy to facilitate gastric emptying of blood and clots may be helpful in providing the endoscopist with a better field of view and allow for a more complete initial examination.
      • Barkun A.N.
      • Bardou M.
      • Kuipers E.J.
      • et al.
      International consensus recommendations on the management of patients with nonvariceal upper gastrointestinal bleeding.
      • Gralnek I.M.
      • Dumonceau J.M.
      • Kuipers E.J.
      • et al.
      Diagnosis and management of nonvariceal upper gastrointestinal hemorrhage: European Society of Gastrointestinal Endoscopy (ESGE) Guideline.
      • Gralnek I.M.
      • Barkun A.N.
      • Bardou M.
      Management of acute bleeding from a peptic ulcer.
      • Laine L.
      • Jensen D.M.
      Management of patients with ulcer bleeding.
      • Lau J.Y.W.
      • Barkun A.N.
      • Fan D.M.
      • et al.
      Challenges in the management of acute peptic ulcer bleeding.
      Unfortunately, the use of a preendoscopy prokinetic agent was not commented upon within the context of this present study.
      With the use of up-to-date endoscopic hemostasis techniques (eg, combination hemostasis therapy) along with the use of high-dose IV PPI therapy, routine second-look endoscopy in patients with high-risk peptic ulcer bleeding does not appear to be warranted. Selective second-look endoscopy should be considered in patients considered to be at very high risk of persisting or recurrent bleeding. Further research should focus on better identifying these very high-risk patients and investigating the effect of “selective” second-look endoscopy on them.

      Disclosure

      The author disclosed no financial relationships relevant to this publication.

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