Over-the-scope Clips and Standard Treatments in Endoscopic Control of Acute Bleeding From Non-variceal Upper GI Causes
Condition: Acute Upper Gastrointestinal Bleeding; Tumor Bleeding
MeSH terms: Gastrointestinal Hemorrhage; Hemorrhage
Study type: Interventional

Summary: 
      In the management of patients with acute upper gastrointestinal bleeding from non-variceal
      causes, endoscopic treatment and acid suppression are now the standard of care. Current
      endoscopic treatment in the form of either thermo-coagulation or clipping to the bleeding
      arteries is highly efficacious in the stopping bleeding. Unfortunately in 5 to 10% of
      patients, bleeding cannot be controlled during index endoscopy or recurs after initial
      hemostasis. These patients are often elderly with significant co-morbidities. Their bleeding
      lesions are large eroding into major sub-serosal arteries. In the few who need surgical
      salvage, mortality increases to around 30%. The Over-the-scope-Clip (OTSC) is a device, which
      allows endoscopists to capture a large amount of tissue and compress on the bleeding artery.
      The OTSC also has a high retention rate. Recurrent bleeding with the use of standard
      hemo-clips can occur because of their low retention rate. We reported the use of OTSC with a
      high success rate in a case series of patients with refractory bleeding after standard
      endoscopic treatment. We have also used OTSC in the treatment of bleeding from
      pseudo-aneurysm arising from large eroded arteries in ulcer base. A multicenter randomized
      controlled trial that compares OTSC to standard endoscopic treatment in the endoscopic
      treatment of refractory bleeding lesions has just been completed. The use of OTSC has been
      shown to be superior in achieving hemostatic control and reducing further bleeding. In this
      proposed randomized controlled trial, we would test the hypothesis that the use of OTSC, when
      used as the first or primary treatment, is superior to standard treatment in achieving
      hemostasis and thereby improve patients' outcomes.
    

Detailed description: 
      Endoscopic therapy has improved outcomes to patients with acute non-variceal upper
      gastrointestinal bleeding. Acid suppression therapy as an adjunct to endoscopic therapy
      further reduces recurrent bleeding and interventions. There remains a small subgroup of
      patients who continue to bleed or re-bleed after initial endoscopic hemostasis. These
      patients are often elderly with significant comorbid illnesses. In the 2007 National United
      Kingdom Audit, mortality was 30% in those after salvage surgery for refractory bleeding [1].
      The current standard in endoscopic treatment is the use of either hemo-clips or thermal
      coagulation with or without pre-injection with diluted adrenaline. The two modalities are
      similar in their efficacies [2]. Their use is associated with a small but significant failure
      rate. Anatomically, the failed cases are usually larger deep ulcers with erosion into thick
      subserosal arteries [3]. In an ex vivo model, control of bleeding becomes inconsistent in
      arteries > 2mm in diameter in size with 3.2 mm contact thermal devices [4]. The investigators
      have few reports on in vivo data. Using thin barium angiography in 27 gastrectomy specimens
      from patients who underwent surgery for control of bleeding from their gastric ulcers, Swain
      and colleagues found vessels of varying sizes and disposition [5]. It was felt that artery
      beyond 1 mm would be difficult to control during endoscopy in a clinical setting. In a series
      of fatal deaths from bleeding gastroduodenal ulcers from Hong Kong [6], these arteries were
      around 3 mm in diameter at post-mortem examination.

      Over-the-scope clips or the Bear Claws were developed for the purpose of closure of GI
      luminal defects created at Natural orifice trans-luminal surgery. In clinical practice, OTSC
      are widely used for closure of GI perforations and anastomotic dehiscence. There have been
      anecdotal reports over the use of OTSC in the control of refractory bleeding from peptic
      ulcers [7, 8]. The investigators reported our experience in 9 such patients with successful
      hemostasis in all of them [9]. Further bleeding occurred in 2 patients. The investigators
      subsequently illustrated its use in difficult ulcers that failed standard endoscopic
      treatments; one of them showed a pseudo-aneurysm to a branch of the gastro-duodenal artery
      [10]. In our hospital, indication for OTSC use has been failure with conventional endoscopic
      treatments.

      The OTSC have several advantages over existing treatments. First, tissue compression on the
      bleeding artery is critical in control of bleeding. OTSC captures tissue size to that of an
      endoscope at least 9 mm in diameter. In theory, OTSC can compress arteries of significant
      size, beyond what can be achieved with standard treatment. Second, clip retention rate with
      OTSC is extremely and recurrent bleeding from clip loss or dislodgement can be avoided.
      Third, local complication from their applications is negligible. As a comparison, contact
      thermal coagulation carries a small risk (around 1%) of perforation.

      Investigator group has participated in a multicenter randomized trial [11] that compares OTSC
      to standard therapies in endoscopic management of refractory non-variceal bleeders. OTSC has
      been shown to be superior in the control of bleeding (30/33 patients, 91% vs. 15/26 patients
      57.6%, P=0.005) and is associated with fewer re-bleeding after hemostasis 6/33, 18% vs.
      10/26, 38%, P=0.14).

      In the current proposed randomized controlled trial, the investigators compare OTSC and
      standard therapies (hemo-clipping or thermal coagulation) as the primary endoscopic treatment
      in the control of bleeding from non-variceal causes in patients who present with acute upper
      gastrointestinal bleeding. The investigators argue that OTSC should be used as the first
      treatment given its promise in better bleeding control over other treatment methods.
      Rebleeding patients are exposed to excessive risks in organ failure and death. Furthermore,
      management of recurrent bleeding is expensive e.g. cost of angiographic embolization, surgery
      and intensive care stay.

      Investigators hypothesize that OTSC as the first treatment during index endoscopy is superior
      to standard endoscopic therapy in the overall rate of hemostasis. Knowledge from this
      clinical trial will enable us to choose the correct treatment for bleeding lesions.

      Research plan and methodology Trial Design - A randomized controlled trial The trial will be
      executed in accordance with Good Clinical Practice guidelines Randomization - Patients with
      overt signs of acute upper GIB (melena, hematemesis, drop in haemoglobin with or without
      hypotension) are invited to participate in the trial. Investigators or research nurses
      approach patients and obtain their written consents. During endoscopy, if they have bleeding
      lesions suitable for standard endoscopic treatment and OTSC, the endoscopist then requests
      the next number sealed envelope to be opened by an endoscopy nurse. Patients are randomized
      to receive either standard endoscopic treatment (contact thermal methods or hemoclips with or
      without pre injection with diluted epinephrine), or the use of OTSC. Indications for
      endoscopic treatment are active bleeding (pulsatile or Forrest Ia bleeding, oozing from a
      visible vessel or a protuberance otherwise referred to as Forrest I b bleeding, or a non
      bleeding visible vessel or Forrest IIa lesion). Clots overlying bleeding lesions are
      irrigated or elevated using a cheese wiring technique with a minisnare. If a vessel is
      unveiled, randomization can then proceed and the assigned treatment is then carried out. The
      random number list is generated by computer software.

      Blinding - no blinding

      Participants - Consecutive patients admitted with overt signs of acute upper GIB (melena,
      hematemesis, drop in hemoglobin with or without hypotension) and documented bleeding (Forrest
      I) from a non-variceal upper gastrointestinal sourcegastro-duodenal ulcers, Mallory Weiss
      tear, cancers, Dieulafoy's and other vascular lesions) at endoscopy.

      Interventions - Patients are randomly assigned at endoscopy to receive;

      Patients are randomized in a 1:1 ratio to receive; endoscopic treatment using OTSC or
      standard therapies.

      No cross over to treatment of the other arm is allowed. A full description of the bleeding
      lesion and the success of endoscopic therapy are provided and documented in the electronic
      endoscopy report. It is unrealistic and impossible to completely blind ward staff as a plain
      abdomen x-ray will readily an OTSC or indeed most hemo-clips.

      After successful endoscopy, patients are started on an intravenous infusion with proton pump
      inhibitor (PPI) for 72 hours. Thereafter, patients go onto receive an oral PPI or standard
      PPI H. pylori eradication therapy should the patient is infected. It is generally recommended
      that patients be transfused to a hemoglobin level of around 7 or 8 g/dl. In patients with
      significant cardiac co-morbidities, a higher transfusion threshold is allowed.

      The management of antiplatelet agents and anticoagulation in these patients is based on ASGE
      guidelines.

      Further bleeding is defined by failure to control bleeding during first endoscopy or
      recurrent bleeding after initial control. Recurrent bleeding is defined by fresh hematemesis,
      fresh melena or hematochezia with hemodynamic instability (systolic blood pressure lower than
      90mmHg, heart rate greater than 110 per minute) and/or drop in hemoglobin > 2g/dl in 24 hours
      after transfusion to around 8 g/dl. An episode of recurrent bleeding has to be confirmed by
      repeat endoscopy showing fresh blood in stomach or active bleeding from the previously
      treated lesion.

      Statistics analysis An independent data monitoring and safety panel will be formed by senior
      physicians from our Clinical Trial Centre at the Chinese University of Hong Kong to
      adjudicate over the occurrence of primary outcome events.

      Analyses are by intention-to-treat and then per protocol principles. The primary outcome
      between groups over 30 days is compared using a time-to-event type analysis with a log rank
      test. An adjusted analysis or Cox regression model will be used in the presence of
      significant difference in the baseline covariates. Initial rate of hemostasis and recurrent
      bleeding within 30 days are independently reported and compared using a chi-square test.
      Categorical data in secondary outcome measures are compared between groups again using
      chi-square test. Parametric and non-parametric data are compared using student's t test and
      Mann-Whitney U test respectively.
    

Intervention name(s): Over-the-scope Clips; Hemo-clipping; thermo-coagulation; Epinephrine
Intervention type(s): Device; Device; Device; Drug
Intervention description(s): Over-the-scope Clips is mounted onto a transparent cap, which is attached to the tip of the endoscope. To deploy the claw device, a cogwheel at the scope head is turned pulling a trip string. This in turn retracts the cap releasing the OTSC onto tissue.; Hemo-clipping <=20 clips; contact thermo-coagulation < = 8 pulses; epinephrine injection (diluted 1:1000) beneath peptic ulcer <20 mls
Other intervention name(s): OTSC; quick clips; contact thermo-coagulation; adrenaline
Intervention MeSH terms: Epinephrine
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Patients are randomized in a 1:1 ratio to receive; endoscopic treatment using OTSC or standard therapies Stratified randomization according to size of ulcers and non-ulcer lesions
size smaller than10mm in diameter
size equal to 10mm and less than 20mm in diameter
size equal or greater than 20mm in diameter
non-ulcer lesions
Masking: None (Open Label)
Primary purpose: Treatment