Use of over-the-scope clip (OTSC) versus standard

therapy for the prevention of rebleeding in large

peptic ulcers (size ≥1.5 cm): an open-labelled,
multicentre international randomised controlled trial
INTERN TIANPATTRA POTCHANA
 PICO

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 INTRODUCTION

Acute upper GI bleeding is a common and life-threatening condition.

Non-variceal bleeding -> 80%–90% of the cause with GU, DU, peptic ulcer being the major cause.
Endoscopic haemostasis has significantly improved the outcome of these patients.
Acid suppression and endoscopic tx -> 10%–20% of patients continue bleed or develop rebleeding.
Endoscopic haemostasis in the high-risk group to prevent rebleeding and mortality by injection therapy,
thermocoagulation or mechanical therapy such as haemostatic clips.
Currently recommended international guidelines : combine ≥2 techniques for haemostasis in PU bleeding.
There are limitations to thermocoagulation and conventional haemostatic clips.
Application of clips can also sometimes be difficult in chronic ulcers with fibrotic bases.
 INTRODUCTION

A novel endoscopic clipping device, the over-the-scope clip (OTSC)has become available. The efficacy of
OTSC was shown on a validated bleeding model to be superior to other clips.
Initial case series on OTSC for recurrent peptic ulcer bleeding rate is 0% - 22%.
Data on the use of OTSC on primary haemostasis of peptic ulcers are lacking.
In a subgroup analysis of a RCT, prophylactic transarterial embolisation (TAE) to peptic ulcers with a size of
≥1.5 cm decreased 30-day rebleeding rate compared with standard therapy alone.
In that study, the 30-day rebleeding rate for conventional arm without TAE was up to 23%.
This study compare the efficacy of the OTSC as primary haemostasis to standard therapy in this
particular high-risk group of ulcers with a size of ≥1.5 cm.
Inclusion criteria, the target population accounts for only 2.5% of all upper GI bleeders.
 METHODS

Trial design :
Randomised controlled trial
Comparing OTSC with standard endoscopic therapy for primary treatment of patients with peptic ulcer
bleeding that are at high risk of rebleeding.
Recruited patients were randomised to receive OTSC or standard endoscopic therapy.
 METHODS
Participants: Inclusion criteria Participants : Exclusion
1. Included actively bleeding PU (Forrest Ia and Ib), ulcers with a 1. Patients who are pregnant or lactating; and moribund patients
non-bleeding visible vessel or Forrest IIa ulcer with a size≥15 mm. or patients with terminal malignancy or end-stage non-
2. Patients aged <18 with PU with concomitant perforation, tumor malignant conditions, in whom life expectancy is less than 30
bleeding, variceal bleeding, stricture of the esophagus, stomach or days.
pylorus that could not be dilated to allow passage of a 11 mm
endoscope or an 11 mm OTSC
3. Participating centres include the Chinese U. of Hong Kong , North
District Hospital (Hong Kong), Chulalongkorn U. (Thailand), National
Taiwan U. (Taiwan), Taipei Tzu Chi Hospital (Taiwan) and ChengDu
Second People’s Hospital (China).
4. All procedures were performed by expert endoscopists defined as
having performed more than 20 endoscopic haemostatic
procedures with OTSC.

Research staff screened all patients presented with UGIB requiring EGD at the endoscopy centre and obtained consents.
On confirmation on EGD that patients fitted the inclusion criteria, randomisation was performed.
 METHODS

Interventions
Standard therapy group
Combining two standard treatment options. Possibilities included injection with diluted epinephrine
(1:10,000–1:20 000) with the application of standard clips/contact thermal coagulation technique (heater
probe 25 J four continuous pulses per station).
The decision to for the type of standard therapy was decided by the endoscopist.
OTSC group
Pretreatment with diluted epinephrine (1:10,000) injection and the use of the anchor device was optional.
Postendoscopy treatment All patients were treated with PPI infusion for 72 hours (80 mg+8 mg/hour)
after endoscopic haemostasis according to international guidelines.
 METHODS

Oral PPI was prescribed for 6–8 weeks after the procedure.
H. pylori was eradicated based on rapid urease test or histology results.
Antithrombotic drugs for cardiovascular disease or prevention of thromboembolic event were resumed
3–5 days after index endoscopy.
Clinical outcomes were recorded for 30 days.
 Outcomes
The primary endpoint was clinical rebleeding within 30 days.
Clinical rebleeding was defined
1. Fresh haematemesis, fresh melena, haematochezia, signs of hypovolaemic shock (SBP <90 mmHg and
PR >110 bpm), or a drop in Hb of ≥ 2 g/dL per 24 hours despite adequate transfusion.
2. Rebleeding was confirmed by an immediate endoscopy showing fresh blood in the stomach or active
bleeding from a previously seen ulcer.
3. A clinical rebleeding was independently reviewed by an adjudication panel.
Secondary endpoints death from all causes within 30 days, transfusion requirement within 30 days , hospital
and ICU, failure of achieving primary haemostasis and further interventions required, such as repeat
endoscopy, surgery or TAE.
Failure of achieving primary haemostasis was defined as persistent bleeding despite application of therapy
in the randomised arm with the need for additional endoscopic therapy.
Sample size estimation and statistical analysis

In a recent RCT on prophylactic transarterial embolisation to PU with high rebleeding risk, rebleeding rate
ulcers ≥ 1.5 cm was 23.3%.
Rebleeding rate high-risk patients with standard treatment in this study was estimated to be 23%.
There were only scanty case reports and series on the efficacy of OTSC in primary treatment of bleeding PU.
The average rebleeding rate following application of the OTSC in the literature was 5%. Therefore, OTSC
was assumed to reduce the rebleeding rate from 23% to 5%.
Using a two-sided log-rank test with 5% significance level, 100 patients are required to achieve 80% power.
Since the primary outcome was 30-day clinical rebleeding, it was decided to be a short-term endpoint,
so a 0% dropout rate was assumed.
Randomisation and blinding
Informed consent was obtained before endoscopy for eligible patients.
Once the endoscopist confirmed that the patient fulfilled inclusion criteria, the patient was randomised
with an online randomisation form in the form of a computer-generated random sequence in blocks of 10.
The method of haemostasis was performed according to the allocation. In patients who are incapable of
consent, consent from their legal representatives was obtained.
It was not possible to blind the endoscopist, given the different therapies required during the endoscopy.
Also, given the objective outcomes measured, blinding was deemed not necessary. On technical failure of
haemostasis of the randomised group, other methods of haemostasisws allowed, including crossover to the
other group, TAE or surgery.
Statistical analysis
The data were analysed with intention-to- treat analysis.
χ2 test was used to calculate the rates of recurrent bleeding while the Kaplan-Meier method with the log-
rank test was used to compare differences in death within 30 days after randomisation.
The effect of OTSC as compared with that of standard therapy was calculated with relative risks and the
corresponding 95% CI.
The χ2 test (or Fisher’s exact test when appropriate), Student’s t-test and Mann-Whitney U test were used
to compare categorical, parametric and non-parametric data, respectively.
All tests of significant were two-tailed, and a p value of <0.05 was considered statistically significant.
Statistical analyses were performed using SPSS V.24.0 statistical software.
RESULTS
RESULTS
Clinical rebleeding
Clinical rebleeding occurred in 5/50 (10%) cases in the OTSC and 9/50 (18%) in the conventional arm.
In the intention-to-treat analysis, no statistically significant difference (p=0.23, OR=1.98, 95% CI 0.61 to 6.38).
The Kaplan-Meier curve for 30-day clinical rebleeding with log-rank test
Success in achieving primary haemostasis was achieved in 46/50 (92%) and 48/50 (96%) in the OTSC and
conventional arm, respectively.
Among patients who had success in primary haemostasis, 2/46 (4.35%) patients in the OTSC arm rebleed
within 30 days, while 9/48 (18.75%) patients in the conventional arm developed rebleeding (p=0.03)
Clinical rebleeding
Two cases in the conventional arm failed primary haemostasis and required OTSC as salvage. Both did not
rebleed. Four cases in the OTSC arm failed primary haemostasis.
Persistent bleeding was noted after OTSC application in all four cases from the base of the ulcer.
In two cases, the OTSC was applied to cover half of the bleeding vessel. OTSC was applied at the end of the
vessel in two other cases but still persistent oozing from the base.
For all four cases, additional epinephrine injection and heater probe were used as salvage. Three out of four
(75%) rebled and required TAE.
The one case that did not rebleed had empirical TAE performed. All four of these ulcers were located in the
junction between the first and second parts of the duodenum.
There was also no difference in early rebleeding, defined as within 72 hours of the index procedure (p=1.00,
OR=1.53,95% CI 0.25 to 9.59)
Secondary endpoints
The all-cause mortality was 2/50 (4%) and 4/50 (8%) in the OTSC and conventional arm (p=0.68, OR=2.09,
95% CI 0.37 to 11.95).
In the OTSC arm, one patient died of multiorgan failure. The other patient had a known intracranial
haemorrhage, who presented with cardiac arrest with massive melaena 1 day after endoscopy. The patient
died despite cardiopulmonary resuscitation.
For the conventional arm, there was one patient who died of rebleeding. The patient presented with
massive melaena and cardiac arrest. Cardiopulmonary resuscitation was given and the patient was revived.
Emergency laparotomy with open surgical application was performed. The patient subsequently died of
ischaemic bowel and multiorgan failure. The other three patients died of medical causes including
respiratory failure, multiorgan failure and hospital-acquired pneumonia.
Secondary endpoints
A mean of 3.13 (S 3.64) units of blood was transfused in the OTSC group, and a mean of 2.90 (D4.07) units
was required for the conventional group (p=0.31).
Hospital stay and need for ICU admission were also similar.
6% of the OTSC group required further intervention compared with 2% in the standard arm.
Three patients in the OTSC group required further TAE after endoscopic haemostasis.
One was done after primary failure of OTSC with further epinephrine injection and heater probe, but
haemostasis was deemed insecure.
Empirical TAE was performed and there was no rebleeding.
The other two were performed due to clinical rebleeding.
One bleeding stopped; the other rebled and had multiple sessions of endoscopic haemostasis.
One case in the conventional arm required emergency surgery, but the patient died of ischaemic bowel and
multiorgan failure.
DISCUSSION
In bleeding PU >=15 mm in size, OTSC for primary haemostasis did not decrease 30-day clinical
rebleeding when compared with standard therapy.
Although there was no statistical difference between the rebleeding rates (10% vs 18% for OTSC and
standard therapy, respectively; p=0.234), this may be due to an underestimation of the sample size
leading to type II error.
The failure rate of achieving primary haemostasis was 8% (4/50) in the OTSC group.
All four ulcers were located at the junction of D1/2, which is notoriously difficult for haemostasis.
There are large fibrotic ulcers which increased difficulty of application to the base. In two out of the four
cases of failed primary haemostasis, there was persistent oozing despite end on application of the OTSC.
This was probably due to the fibrotic base. This illustrated that it is technically demanding to apply an
OTSC clip, especially in fibrotic ulcers at the junction between the first and second portions of the
duodenum.
DISCUSSION
Also, in situations of persistent bleeding despite OTSC application, endoscopic salvage was made even
more challenging due to the presence of the OTSC clip and resulted in a high rate of rebleeding (3/4
(75%)).
TAE is often required for salvage. A learning curve is associated with the successful use of the OTSC, and
technical expertise is mandatory in the application.
Moreover, careful preapplication assessment is necessary to avoid misfire because rebleeding rate after
misfire is exceptionally high and endoscopic salvage is not possible in most situations.
On the contrary, where primary haemostasis was successful, OTSC significantly decreased clinical
rebleeding when compared with standard therapy.
In the 46 cases (92%) of successful application of the OTSC, the rebleeding rate was only 4.35% when
compared with 18.75% with conventional therapy (p=0.03). This suggests that OTSC has its role in
decreasing rebleeding.
DISCUSSION
OTSC was first used for PU bleeding in recurrent bleeding after initial endoscopic haemostasis.
The initial case series for recurrent bleeding from our centre showed clinical effectiveness of 77.8%.
2/9 patients developed rebleeding requiring TAE.
A multicentre German randomised trial (STING-1study) on the use of OTSC in refractory peptic ulcer
bleeding showed that OTSC was more effective than standard therapy with less recurrent bleeding within
7 days (15.2% vs 57.6%, p<0.001).
In a retrospective analysis on the experience of OTSC for primary haemostasis in 67 patients by the Mayo
Clinic, high-risk ulcers were included
High risk defined as vessels > 2 mm in size, deep, penetrating/excavating fibrotic ulcers and who fail
other endoscopic treatment)
The clinical success rate was 81.3%, and patients with coronary artery disease have an increased risk
of rebrleeding even after OTSC, suggesting a need for escalating therapies.
The results of this study are similar to those of the current study.
DISCUSSION
In the current study, the clinical success rate of the OTSC group was 90% and that of the conventional arm
was 82%.
Both studies included large fibrotic ulcers, suggesting that even with OTSC, there is still a 10%–20%
chance of rebleeding.
In the first RCT for primary haemostasis by Jensen et al, 53 patients with bleeding peptic ulcers and
Dieulafoy’s lesions were randomised to receive either OTSC or standard treatment.
Recurrent bleeding occurred in only 1/25 (4%) patients treated by OTSC compared with 8/28 (28.6%) in
the standard treatment group (p=0.017).
Although this study did show a significant decrease in rebleeding in the OTSC group, the sample size was
relatively small; the study included both ulcers and Dieulafoy’s lesion; and the rebleeding rate for the
standard arm was exceptionally high.
Limitation
There are several limitations of this study.
Underestimation of the sample size leading to a type II error.
The OTSC group had a 10% rebleeding rate when compared with a predicted 5%.
Our study included only giant ulcers, which may explain the higher rebleeding rate. May be publication bias
leading to an underestimation of the rebleeding rate.
The second is the technical failure rate for OTSC was high. Endoscopists with experience of more than 20
cases of OTSC for haemostasis were included. To date, there are no studies regarding the learning curve
of OTSC application. The optimal cut-off point for an experience endoscopist for OTSC is still
undetermined.
Although this study did not show significant results, it reflected on the real-life scenario on the use of
OTSC in giant ulcers.
Limitation
Technical success of OTSC application was associated with decreased rebleeding, suggesting that OTSC
may be beneficial in selected cases.
This study showed that the routine use of OTSC as primary haemostasis in large bleeding peptic ulcers was
not associated with a significant decrease in 30-day rebleeding.
There may be a role of OTSC in expert hands where OTSC can be successfully applied. It also highlighted that
there is a learning curve to the use of OTSC and that salvage after a misplaced OTSC could be challenging.
Critical Appraisal