Endoscopic advances in the management of non-variceal upper gastrointestinal bleeding: A review

Table 1 Etiologies of non-variceal upper gastrointestinal bleeding

Etiologies of non-variceal upper gastrointestinal bleeding
Ulcer/ inflammation	Peptic ulcer disease
	Erosive esophagitis, gastritis or duodenitis
	Anastomotic ulcers (post gastric bypass)
Vascular lesions	Gastric antral vascular ectasia
	Dieulafoy’s lesion
	Angiodysplasia/ Arteriovenous malformation
	Aorto-enteric fistula
Congestive gastropathy	Portal hypertensive gastropathy
Malignant lesions	Gastrointestinal stromal tumors (GIST)
	Non-GIST (e.g., Lipoma, schwannoma)
	Gastric and esophageal cancer
	Metastatic lesions in the upper GI tract
Post procedural	Endoscopic mucosal and submucosal dissection
	Post sphincterotomy
Others	Mallory Weis tear
	Cameron ulcers

GI: Gastrointestinal; GIST: Gastrointestinal stromal tumors.

Table 2 Summary of emerging endoscopic modalities for the management of non-variceal upper gastrointestinal bleeding

Emerging endoscopic modalities
Injection	Endoscopic ultrasound guided angiotherapy
Thermal therapies	Coagulation grasper, radiofrequency ablation, cryotherapy
Mechanical	Over the scope clip system, endoscopic suturing, flexible linear stapler (experimental)
Topical	Hemospray, endoclot, pure-Stat, ankaferd blood stopper, oxidized cellulose

Table 3 Summary of the pros and cons of new emerging endoscopic treatment modalities for non-variceal gastrointestinal bleeding

Emerging endoscopic treatment	Pros	Cons
Over the scope clips	1 Simple to use	1 Difficult to close hard, chronic, and severely fibrotic lesions with OTSC
	2 Special endoscopic skills are not required to implant the clip	2 Time consuming especially in the emergency situations (after identifying the bleeding source, the scope must be removed to mount OTSC system on the scope and reintroduce to deploy clips
	3 Effective for the ulcers larger than 2 cm in diameter, or with bleeding vessel > 2 mm
Endoscopic suturing	1 Technically more feasible and efficacious for larger, deep, and fibrotic ulcers	1 Double channel endoscope and expert endoscopic skills are required to operate endoscopic suturing device
Endoscopic band ligation (EVL)	1 Associated with the reduction of treatment sessions, control of bleeding and need for transfusion	Few cases of Hyperplastic gastric polyps
	2 EVL is safe, technically straightforward, and highly effective in this patient with complete eradication of GAVE
Coagrasper	1 One of the safest and most efficacious hemostasis modalities due to large surface area of the forceps and anti-slip jaw design provides mechanical tamponade effect to the surrounding tissue	1 Coagulation may be incomplete because of electrical leakage if the lesion submerged in water or lesion with large tissue volume or surface area
	2 The risk of perforation is extremely low because coagrasper works at a lower voltage as compared to other thermal treatments coagulates tissues without any carbonization and does not extend to deeper tissue	2 Because the devices used for soft coagulation, including disposable hemostatic forceps, are relatively expensive, the method may be appropriate only for centers that perform ESD frequently
	3 The forceps can be used to treat multiple bleeding sites proving to be cost-effective	3 Few cases of aspiration pneumonia reported
Radiofrequency ablation	1 Feasible and safe in ablating GAVE lesions	1 Endoscopic skills are required to perform RFA
	2 Able to deliver high energy captive coagulation of superficial mucosa including blood vessels	2 Exact apposition of the gastric antral mucosa with electrode is required to allow effective delivery of the electric energy which means the endoscope may have to be removed, the electrode rotated, and reintroduced multiple times The newer through-the-scope internally rotatable ablating catheter may sidestep this disadvantage but has smaller surface area
	3 Wider surface area coverage of mucosa owing to the various electrode sizes
	4 Contact technique with uniform zone of energy distribution and penetration such that deeper ectatic submucosal vascular channels are coagulated
Endoscopic ultrasound guided angiotherapy	1 EUS-guided therapy of nonvariceal bleeding has been shown to be feasible and safe for peptic ulcer disease, Dieulafoy's lesions, bleeding tumors, and pseudoaneurysms due to the ability to directly visualize and target the bleeding vessel with a specific therapy and subsequently confirm hemostasis with real-time Doppler ultrasound are significant advantages of EUS-guided therapy	1 Endoscopic skills are required to perform endoscopic ultrasound
		2 EUS guided angiotherapy more resource intensive than other routine hemostasis endoscopic procedures
Topical therapies, i.e., Hemospray and Endoclot	Easy to use, safe and effective Cost effective. Can be used for malignant GI hemorrhage	1 Theoretically possible side effects of Hemospray include embolization, intestinal obstruction, and allergic reaction to the powder
		2 If hemostasis fails, there is the disadvantage that the powder attached to the mucous membrane may limit the use of other hemostatic modalities
		3 Hemospray works only on active bleeding

EVL: Endoscopic band ligation; GAVE: Gastric antral vascular ectasia; EUS: Endoscopic ultrasound; GI: Gastrointestinal; RFA: Radiofrequency ablation; ESD: Endoscopic submucosal dissection; OTSC: Over-The-Scope Clip.

Table 4 Efficacy and safety of over the scope clips in the management of non-variceal upper gastrointestinal bleeding (2009-2018)

Authors and year of publication	Study design	Study participants	Sample size	Duration	Outcomes of the study	Success rate
Repici et al[33], 2009	Retrospective	Mean age, 70 yr, gender (M/F): 5/2	7	Unknown	Success rates with the first endoscopic therapy	Success rates with the first endoscopic therapy
Kirschniak et al[34], 2011	Retrospective	Mean age, 68 yr, gender (M/F): 18/9	27	2006-2010	1 Success rates with the first endoscopic therapy	Primary hemostasis was achieved in all cases (100%) Rebleeding was observed in 2 cases
					2 Rebleeding episodes
Albert et al[35], 2011	Retrospective	Mean age, 62 yr, gender (M/F): 5/2	7	Unknown	1 Success rates with the first endoscopic therapy	Primary success rate was observed in 100%
					2 Rebleeding episodes
Skinner et al[36], 2014	Retrospective	Mean age, 59 yr, gender (M/F): 8/5	12	2012-2013	1 Success rates with the first endoscopic therapy	Hemostasis was achieved in all patients. Rebleeding occurred in two patients 1 d and 7 d after OTSC placement
					2 Rebleeding episodes
Nishiyama et al[37], 2013	Retrospective	Mean age, 77 yr, gender (M/F): 5/4	9	2011-2012	Success rates with the first endoscopic therapy	Primary success rate was observed in 77.8%
Manta et al[39], 2013	Retrospective	Mean age, 64 yr, gender (M/F): 14/16	30	2011-2012	1 Success rates with the first endoscopic therapy	Primary hemostasis was achieved in 29 of 30 cases (97%) Rebleeding was observed in two cases (one duodenal bulb and one gastric ulcer)
					2 Rebleeding episodes
Manno et al[38], 2016	Retrospective	Mean age, 69 yr, gender (M/F): 33/7	40	2013-2014	1 Success rates with the first endoscopic therapy	Technical success and primary haemostasis were achieved in all patients (100%). No re-bleeding need for surgical or radiological embolization treatment or other complications were observed during the follow-up period of 30 d
					2 Rebleeding episodes
Richter-Schrag et al[40], 2016	Retrospective	Mean age, 72 yr, gender (M/F): 58/35	93	2012-2016	1 Success rates with the first endoscopic therapy	Primary hemostasis and clinical success of bleeding lesions (without rebleeding) was achieved in 88/100 (88%) and 78/100 (78%), respectively
					2 Rebleeding episodes
Wedi et al[41], 2016	Retrospective	Mean age, 71 yr, gender (M/F): 50/34	84	2009-2012	Success rates with the first endoscopic therapy	Success rate 35/41 (85.36%)
Lamberts et al[42], 2017	Retrospective	Mean age, 71.7 yr, gender (M/F): 55/20	75	February 2011 and June 2014	1 Success rates with the first endoscopic therapy	Application of the OTSC resulted in immediate hemostasis (primary success rate) in all 75 patients. However, in 34.7 % a rebleeding episode was noted that could be treated by further endoscopic interventions. Only 3 patients had to be sent to the operating room because of failure of endoscopic therapy. In the rebleeding group the use of antiplatelet therapies was higher (73.1% vs 48.9%)
					2 Rebleeding episodes
Brandler et al[43], 2018	Retrospective	Mean age, 71 yr, gender (M/F): 38/29	67	2011-2015	OTSC safety and efficacy in GI bleeding	OTSC success rate of 81.3%
Schmidt et al[44], 2018	Prospective, randomized, controlled multicenter trial	Mean age: 77 yr, gender (M/F): 37/29	67	March 2013 to September 2016	1 Persistent bleeding despite endoscopic therapy according to the protocol or	Persistent bleeding after per-protocol hemostasis was observed in 14 patients (42.4%) in the standard therapy group and 2 patients (6.0%) in the OTSC group (P < 0.001) Recurrent bleeding within 7 d occurred in 5 patients (16.1%) in the standard therapy group vs 3 patients (9.1%) in the OTSC group (P = 0.468)
					2 Recurrent bleeding within 7 d after initial successful endoscopic therapy

GI: Gastrointestinal; OTSC: Over-The-Scope Clip.

Table 5 Efficacy and safety of hemospray in the management of non-variceal upper gastrointestinal bleeding (2013-2018)

Study	Type of study	Sample size	Bleeding source	Modality	Outcomes	Results
Leblanc et al[72], 2013	Case series, single arm (July 2011-March 2012)	17 patients	Procedural (12/17) and malignancy related bleeding (5/17)	Monotherapy or rescue therapy	Immediate hemostasis, recurrent bleeding and mortality at 7 and 30 d, and related adverse events	Immediate hemostasis achieved in 100% patient in both groups; 2 patients with recurrent bleeding with 1 of 2 with treatment failure. No adverse events. No related complications
Sakai et al[73], 2016	Case report	1 patient	Ulcer related bleeding	Monotherapy	Immediate hemostasis	Immediate hemostasis achieved. No recurrent bleeding. No adverse events
Chen et al[55], 2015	Retrospectiv single center study; (July 2011-July 2013)	60 patients	21 for nonmalignant nonvariceal upper gastrointestinal bleeding, 19 for malignant upper gastrointestinal bleeding, 11 for lower gastrointestinal bleeding, and 16 for intra-procedural bleeding	Monotherapy	Immediate hemostasis and early rebleeding (≤  72 h)	Immediate hemostasis achieved in 66 cases including upper and lower (98.5 %), with 6 cases (9.5 %) of early rebleeding
Arena et al[74], 2017	Retrospective cohort study; (January 2014-December 2015)	A total of 15 patients, 8 males, mean age 74 yr ± 7.7	Malignancy related bleeding	Monotherapy	Immediate hemostasis, bleeding recurrence, adverse events, clinical outcome at 1 and 6 mo	Immediate hemostasis achieved in 93% (14/15). 3 (21%) patients with recurrent bleeding. 12/14 (80%) with good clinical outcome at 30 d and 50% (6/12) at 6 mo. No related adverse events
Pittayanon et al[75], 2018	Retrospective study; (2011-2016)	99 patients (70.5% were male, age 65 ± 14 yr	Malignancy related bleeding	Monotherapy and adjuvant therapy	Immediate hemostasis, early (≤ 3 d) and late (> 3 d) recurrent bleeding	Immediate hemostasis was 97.7%, with recurrent bleeding in 15% (early) and 17% (delayed). Six-month survival was 53.4%
Baracat et al[76], 2017	Case report	1 patient	Post-sphincterotomy bleeding	Rescue therapy	Hemostasis	Immediate hemostasis achieved
González et al[77], 2016	Case report	1 patient	Post-sclerotherapy bleeding	Monotherapy	Hemostasis	Immediate hemostasis achieved
Sung et al[78], 2011	Prospective single-arm	20 patients (18 men, 2 women; mean age 60.2 yr)	Peptic ulcer bleeding (Forrest score Ia or Ib)	Monotherapy	Immediate hemostasis (max of 2 applications allowed), bleeding recurrence post-operatively, after 72 h endoscopically, and after 30 d via phone; mortality, need for surgery, and complications	Immediate hemostasis in 95 % (19 / 20) of patients; (1/20) with a pseudoaneurysm requiring arterial embolization. Bleeding recurred in 2 patients ≤ 72 h (hemoglobin drop); neither had active bleeding at the 72-h endoscopy. No mortality, adverse events, or procedural-related complications at 30-d
Sinha et al[79], 2016	Retrospective single center	20 patients (median age of 75 yr; 50% men)	Peptic ulcer related bleeding (forrest 1a and 1b)	Adjuvant therapy to adrenaline, or to adrenaline with clips or a thermal device	Immediate hemostasis, 7 and 30-d rebleeding; all-cause and GI-related 30-d mortality	Initial hemostasis was attained in 95% with an overall rebleeding rate (RBR) at 7 d of 16%. No difference between the 7 and 30-d RBR. Hemospray + adrenaline = 100% initial hemostasis and 25% 7-d RBR. Hemospray as third agent = 92% initial hemostasis and 9% RBR. All-cause mortality was 15% with 1 GI-related death (3%)
Haddara et al[80], 2016	Prospective registry; (published 2016)	202 patients	Ulcer related bleeding in 75 patients, malignancy related bleed in 61 patients, procedural related bleed in 35 patients, and other in 31 patients	Monotherapy or rescue therapy	Feasibility, efficacy, re-bleeding rate at day 8 and 30	Application of hemospray was found to be very easy or easy in 31.7 % and 55.4 %, respectively. Immediate hemostasis achieved in 96.5 %. Re-bleeding rate at day 8 and 30 were 26.7 % and 33.5 %, respectively
Yau et al[81], 2014	Retrospective (February 2012-July 2013)	19 patients (mean age 67.6 yr)	Peptic ulcers in 12 (63.2%) patients, Dieulafoy lesions in 2 (10.5%), mucosal erosion in 1 (5.3%), angiodysplastic lesion in 1 (5.3%), ampullectomy site in 1 (5.3%), polypectomy site in 1 (5.3%), and an unidentified lesion in 1 (5.3%)	Monotherapy, adjuvant therapy, and rescue therapy	Immediate hemostasis, recurrent bleeding at 7- and 30 d, mortality at 7 and 30 d (related to GIB), and adverse events (related to Hemospray)	Hemostasis in 14 of 15 (93.3%) patients; Rebleeding within 7 d in 7/18 (38.9%) patients. Potential adverse events in 2 (10.5%) patients (visceral perforation and splenic infarct). Mortality in 5 (26.3%) patients with 1 with hemoperitoneum
Smith et al[82], 2014	Multicenter registry (June 2011-September 2011)	63 patients (44 men; median age 65)	30 patients with ulcer related bleeding	Monotherapy or rescue therapy	Immediate hemostasis	47/55 (85%) patients in monotherapy group achieved immediate hemostasis
Sulz et al[83], 2014	Case series; (published in 2014)	16 patients	NVUGIB, unidentified	Monotherapy or rescue therapy	Immediate hemostasis	Immediate hemostasis of 93.75% (15/16)

NVUGIB: Non-variceal upper gastrointestinal bleeding; GI: Gastrointestinal; GIB: Gastrointestinal bleeding; RBR: Rebleeding rate.