588 Original article
Long-term treatment outcome of patients with gastric vascular ectasia treated with argon plasma coagulation Doron Boltin, Rachel Gingold-Belfer, Lev Lichtenstein, Zohar Levi and Yaron Niv Background Gastric vascular ectasia (VE) is an uncommon cause of upper gastrointestinal bleeding. Long-term data on the efficacy of argon plasma coagulation (APC) for the treatment of gastric VE are lacking. Methods We retrospectively identified consecutive patients, between January 2005 and December 2010, treated with APC for an index diagnosis of gastric VE. Clinical and endoscopic features and APC treatment success were recorded. Treatment success was determined by resolution of symptoms and stabilization of the hemoglobin level at 30% above baseline. Results A total of 62 patients [28 (45.2%) male] with a mean age of 72.6±12.8 years, who had undergone 159 upper endoscopies (mean 2.6, range 1–10), including 140 APC sessions (mean 2.3, range 1–10), were identified. The duration of follow-up was 46.9±26.5 months. Treatment success was achieved in 16 (25.8%) patients. Predictors of success included older age, focal pattern, lack of comorbid liver failure or collagen vascular disease, use of antiplatelet or
Introduction Gastric vascular ectasia (VE) is an uncommon but welldescribed cause of upper gastrointestinal (GI) bleeding. Presentation is usually acute GI bleeding or iron deficiency anemia. Gastric VEs have been classified endoscopically as gastric antral VE (GAVE; with a ‘watermelon’ or ‘honeycomb’ pattern) or focal VE (FVE) [1,2]. Microscopically, VEs appear as distorted, thin-walled blood vessels, thought to arise from submucosal venules, with characteristic histological findings, including spindle cell proliferation, fibrohyalinosis, and fibrin thrombi [3]. Gastric VEs may be associated with various chronic disease states including liver failure (30%) and collagen vascular disease, particularly Raynaud’s syndrome (30%) [4,5]. Most remaining cases are idiopathic. Symptomatic lesions may be treated endoscopically with a range of modalities. Argon plasma coagulation (APC) has emerged as first-line therapy because of its effectiveness, availability, ease of application, low complication rate, and lower cost [6,7]. APC is a noncontact technique with a controllable depth of coagulation (0.5–3 mm), whereby high-frequency current is applied to the gastric mucosa through an ionized and electrically conductive gas. Alternative modalities include neodymium:yttrium– c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0954-691X
anticoagulant drugs, and lower baseline hemoglobin level. Of the patients, 26 (41.9%) died during follow-up. Conclusion APC is safe and effective for the initial management of gastric VE; however, most patients do not experience long-term resolution of upper gastrointestinal bleeding and anemia. Eur J Gastroenterol c 2014 Wolters Kluwer Health | Hepatol 26:588–593 Lippincott Williams & Wilkins. European Journal of Gastroenterology & Hepatology 2014, 26:588–593 Keywords: angioectasia, argon plasma coagulation, endoscopic treatment, gastric vascular ectasia, gastric antral vascular ectasia Department of Gastroenterology, Rabin Medical Center, Beilinson Campus, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Correspondence to Doron Boltin, MBBS, Department of Gastroenterology, Rabin Medical Center, Beilinson Campus, 39 Jabotinski Street, Petah Tikva 49100, Israel Tel: + 972 3 9377236; fax: + 972 3 9210313; e-mail: [email protected] Received 14 November 2013 Accepted 19 December 2013
aluminum–garnet (Nd:YAG) laser, sclerotherapy, cryotherapy, electrocoagulation, band ligation, hemoclips, and radiofrequency ablation [8–11]. Small retrospective cohorts have described short-term and intermediate-term outcomes following APC for the treatment of gastric VE [6,7,12–14]. The aim of this study is to determine the long-term treatment success of APC for the management of gastric VE, in the largest reported cohort to date.
Methods Data source and population
This retrospective study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice and was approved by the Human Subjects Protection Program of Rabin Medical Center. Consecutive patients presenting for esophagogastroduodenoscopy or enteroscopy at our tertiary center between 1 January 2005 and 31 December 2010, with an endoscopic diagnosis of gastric VE, were identified. Patients treated with APC for gastric VE were included. This single-center study was performed at an endoscopy unit affiliated with Clalit Health Services (CHS). CHS is the largest health maintenance organization in Israel and the second largest health maintenance organization in the DOI: 10.1097/MEG.0000000000000047
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APC success in gastric VE Boltin et al. 589
world, with over 3.8 million enrollees. Demographic and clinical data were retrieved from clinic visits and the centralized clinical database managed by CHS, and include data on comorbidities (cirrhosis, renal failure, heart disease, and collagen vascular disease), medications (antiplatelet and anticoagulation), and laboratory parameters (hemoglobin level). Endoscopic data were obtained from an established computerized endoscopy reporting system. Patients were excluded if they had an additional lesion showing evidence of active or recent bleeding. All data were obtained by two independent reviewers. Any discrepancy was resolved by a third party (D.B.). Endoscopic diagnosis
Endoscopy was performed by seven expert endoscopists using a single-channel endoscope (GIF-1T140L; Olympus Optical Co. Ltd, Tokyo, Japan), with patients under moderate sedation with midazolam and fentanyl or under general anesthesia. On endoscopy, lesions were stratified into two groups: FVE and GAVE (Fig. 1). FVE was identified on the basis of the presence of one or more flat red spots or reticulated vascular areas in any area of the stomach. GAVE was identified on the basis of the presence of typical punctuate-type (honeycomb) or striped (watermelon) VEs emanating from the antrum [2]. Biopsy specimens were not obtained, except when the diagnosis was unclear. The presence of gastroesophageal varices and portal hypertensive gastropathy was noted. The presence of additional VEs in the duodenum was recorded. Enteroscopy and capsule endoscopy were performed according to clinical judgment. The presence of concomitant VEs in the small bowel was recorded. Electrocoagulation technique
Treatment was applied by a probe introduced through the working channel of the endoscope using a high-frequency electrosurgical generator (ERBE APC300; ERBE Elektromedizin GmbH, Tubingen, Germany) coupled to
an argon gas delivery unit. The electrical power output setting varied from 30 to 70 W and the argon gas flow varied from 0.8 to 2.0 l/min. VEs were treated with either axial or lateral probes. A combination of focal pulse and spray-painting methods was used. Luminal gases were regularly aspirated during the session, and the probe was cleansed as deemed necessary by the endoscopist. The aim of each electrocoagulation session was treatment of all visualized bleeding and nonbleeding gastric VEs. All patients were prescribed proton pump inhibitors to facilitate mucosal healing. Follow-up
All patients were monitored at a dedicated clinic within 6 weeks of the index APC treatment or hospital discharge, and thereafter they were monitored on an individualized basis. All patients were monitored closely by their primary care physician. Hemoglobin levels were recorded in all cases, at least at baseline and at 3 months after the index APC session. In the case of persistent GI bleeding or transfusiondependent anemia, another APC session was conducted. APC sessions were repeated until complete symptom resolution. Several endoscopists recommended routine follow-up endoscopy to document treatment success. Treatment success was defined as the absence of further GI bleeding, coupled with a 30% increase in the hemoglobin level on follow-up. Patients with a normal baseline hemoglobin level did not require a 30% increase in the hemoglobin level for the treatment to be considered a success. Treatment was said to have failed in patients who continued to experience GI bleeding, who did not show resolution of iron deficiency anemia, and who continued to require blood transfusions. Follow-up was continued until 31 December 2012, death, emigration, or disenrollment from CHS. Statistical analysis
All analyses were carried out using SPSS version 21.0 statistical analysis software (IBM Inc., Chicago, Illinois,
Fig. 1
Endoscopic appearance of gastric vascular ectasia: (a) focal vascular ectasia; (b) gastric antral vascular ectasia (‘watermelon’ type).
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590 European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 6
Fig. 2
Table 1
18 733 upper endoscopies
APC treatment (143 patients) Gastric polypectomy∗ (34 patients)
Gastric vascular ectasia (62 patients)
Duodenal angioectasia (45 patients) Other∗∗ (2 patients)
Patient characteristics
Total Age (years) Mean (SD) Median (range) Male [n (%)] Etiology [n (%)] Idiopathic Liver disease Collagen vascular disease Gastric irradiation HHT Antiplatelet therapy [n (%)] Anticoagulant therapy [n (%)] Hb baseline (g/dl) Mean (SD) Median (range) Hb 3 months (g/dl) Mean (SD) Median (range)
62 (100) 72.6 (12.8) 76.4 (26.0–97.9) 28 (45.2) 42 12 6 1 1 23 9
(67.7) (19.4) (9.7) (1.6) (1.6) (37.1) (14.5)
8.86 (2.08) 8.6 (4.8–15.1) 11.27 (1.91) 11.3 (6.4–15.7)
Hb, hemoglobin; HHT, hereditary hemorrhagic telangiectasia.
FGE n = 31
GAVE n = 31
Study flowchart. *Hemostasis immediately after polypectomy. **Anastamotic bleed, one patient; Dieulafoy’s lesion, one patient. APC, argon plasma coagulation; FGE, focal gastric ectasia; GAVE, gastric antral vascular ectasia.
USA). Distributions of continuous variables were assessed for normality using the Kolmogorov–Smirnov test (cutoff at P < 0.1). Distributions of all continuous variables deviated significantly from normal; hence, they were described as median (min–max), in addition to mean±SD. Continuous variables were compared using the t-test or the Mann– Whitney U-test as appropriate. Nominal variables were described as frequency counts and presented as n (%). Nominal variables were compared using the w2-test. Survival was analyzed using Kaplan–Meier estimates. Treatment success and survival were modeled using Cox regression analysis to develop odds ratios (ORs) with 95% confidence intervals (CIs). All tests were two-sided and considered significant at P less than 0.05.
Results Patient characteristics
During the inclusion period between 1 January 2005 and 31 December 2010, a total of 62 patients were subjected to APC treatment for gastric VE (Fig. 2). Of them, 28 (45.2%) were male, and the mean age of the patients was 72.6±12.8 years. Most patients did not have a predisposing condition (42, 67.7%); however, liver failure was evident in 12 (19.4%) patients and collagen vascular disease in six (9.7%) patients. Patient characteristics are shown in Table 1. Endoscopy
A total of 159 upper GI endoscopies were performed (mean 2.6, range 1–10), including 140 APC sessions
(mean 2.3, range 1–10). The mean time to retreatment, among patients who required retreatment, was 5.9±7.3 months. The mean time to the first retreatment was 4.6±6.4 months and the mean time to the final APC session was 7.0±15.1 months. The Kaplan–Meier curve for APC-free survival is shown in Fig. 3a. FVE was seen in 31 (50%) patients and GAVE was seen in 31 patients (50%; Fig. 1). Iron deficiency anemia and GI bleeding were the presenting features in 38 (61.3%) and 21 (33.9%) patients, respectively. Concomitant small intestinal VE was observed in 13 (21%) patients. The endoscopic features of gastric VE in our cohort are summarized in Table 2. Treatment success
Treatment success, as previously defined, was achieved in 16 (25.8%) patients. Predictors of success included older age, focal pattern (FVE), lack of comorbid liver failure or collagen vascular disease, use of antiplatelet or anticoagulant drugs, fewer APC sessions, and a lower baseline hemoglobin level. No relationship was observed between treatment success and presenting symptoms (acute vs. subacute presentation). The relationship between death and the presence of concomitant small intestinal VEs had borderline significance (P = 0.06). Multivariate regression analysis identified focal pattern (OR, 4.3; 95% CI, 1.2–16.1; P = 0.03) and antiaggregant or anticoagulant use (OR, 5.4; 95% CI, 1.3–22.4; P = 0.02) as independent predictors of treatment success (Tables 3 and 4). Survival
The mean duration of follow-up from the index APC session until one of the defined endpoints was 46.9±26.5 months. The mean duration of follow-up after the final APC session was 40.4±26.8 months. During follow-up, 26 (41.9%) patients died 29.5±23.9 months after the index APC session. The Kaplan–Meier curve for overall survival is shown in Fig. 3b. Predictors of death following APC
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APC success in gastric VE Boltin et al.
591
Fig. 3
(a) 1
(b) 1
0.9
0.9
0.8
0.8
0.7
0.7
0.6
0.6
0.5
0.5
0.4
0.4
0.3
0.3
0.2
0.2
0.1
0.1
0
0 0
100 200 300 400 500 600 700 800 900 1000 Days
0
500
1000
1500 Days
2000
2500
3000
Kaplan–Meier survival for primary outcomes: (a) APC-free survival; (b) overall survival. APC, argon plasma coagulation.
Table 2
APC. No patient required angiographic or surgical intervention for intractable GI hemorrhage.
Endoscopic features
Total EGD Mean (SD) Median (range) Total APC Mean (SD) Median (range) Number APC sessions [n (%)] 1 2 3 4 Z5 Pattern [n (%)] FGE GAVE Indication for index EGD [n (%)] GI bleeding Iron deficiency anemia Othera Associated SI angioectasia [n (%)]
159 (2.6) 2 (1–10) 140 (2.3) 2 (1–10) 37 8 3 7 7
(59.7) (12.9) (4.8) (11.3) (11.3)
31 (50) 31 (50) 21 38 3 13
(33.87) (61.3) (4.8) (21)
APC, argon plasma coagulation; EGD, esophagogastroduodenoscopy; FGE, focal gastric ectasia; GAVE, gastric antral vascular ectasia; GI, gastrointestinal; SI, small intestine. a Surveillance following surgery for adenocarcinoma of gastroesophaeal junction, one case; epigastric pain without anemia, one case; screening for premalignant lesions, one case.
treatment for gastric VE include advancing age, low baseline hemoglobin level, liver failure, and collagen vascular disease (Table 5). Treatment failure did not portend poor survival. None of the variables retained significance following multivariate regression analysis. Adverse events
There were no adverse events directly attributable to treatment by APC. One patient developed acute anaphylaxis to vancomycin, which was administered prophylactically for endocarditis. In all cases of acute upper GI bleeding initial hemostasis was achieved with
Discussion In the present study we demonstrate that, although APC is highly effective for the management of gastric VEs, three quarters of patients do not achieve symptom resolution and a sustained increase in the hemoglobin level. The 5-year survival following APC for gastric VE is 37%. This is by far the largest cohort ever reported and covers the longest ever reported follow-up period, with a mean duration of B4 years. Herrera et al. [15] reported 86% treatment success with APC in a recent prospective cohort of 29 patients with gastric VE. Treatment success was defined according to the criteria adopted in our study. The success rate in their study is significantly higher than that in ours, and this discrepancy cannot be accounted for solely by their prospective study design. Herrera and colleagues described patients presenting with overt upper GI bleeding, whereas our cohort included patients with iron deficiency anemia who may be less likely to achieve the requisite 30% hemoglobin increase. The results of Herrera and colleagues may also be biased by the lower proportion of GAVEs (associated with inferior outcomes in our study) and the inclusion of patients with portal hypertensive gastropathy in the absence of FVE or GAVE. Moreover, duration of follow-up in the cohort of Herrera and colleagues was 50% shorter than that in our study. Additional small, retrospective studies report the efficacy of APC to range from 70 to 100%; however, the criteria defining treatment success vary widely between cohorts, and follow-up is typically short [6,7,12–14,16].
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Table 3
Treatment outcomes following argon plasma coagulation for gastric vascular ectasia GI bleeding
N (%) Follow-up duration [mean (SD)] (months) Treatment success [n (%)]b Time to retreatment [mean (SD)] (months)c Time to final APC [mean (SD)] (months) Death [n (%)] Time to death [mean (SD)] (months) Adverse events [n (%)]
21 33.8 7 3.5 1.6 12 20.6 0
Iron deficiency anemia
(33.8) (21.9) (33.3) (3.2) (4.2) (57.1) (15.1) (0)
38 54.9 9 6.5 9.7 13 37.6 1
(61.3) (26.3) (23.7) (8.2) (18.0) (34.2) (28.0) (2.6)
Totala
Pd
62 46.9 (26.5) 16 (25.8) 5.9 (7.3) 7.0 (15.1) 26 (41.9) 29.5 (23.9) 1 (1.6)
< 0.01 NS NS NS NS < 0.01 NS
APC, argon plasma coagulation; GI, gastrointestinal; IDA, iron deficiency anemia. Included all patients presenting with GI bleeding and IDA, as well as three patients with other presenting signs, see Table 2 subtext. No further GI bleeding and 30% increase in hemoglobin level at follow-up. c Patients who underwent only one APC session were excluded from this calculation. d Compares GI bleeding and IDA groups. a
b
Table 4
Predictors of treatment successa
Variables
P
Older age Absence of predisposing comorbidityb Number of APC treatments FGEc Antiplatelet or antiaggregantc Low baseline Hb
0.038 0.019 0.005 0.02 0.006 0.004
APC, argon plasma coagulation; FGE, focal gastric ectasia; Hb, hemoglobin. No further GI bleeding and 30% increase in hemoglobin level at follow-up. b Absence of liver disease, collagen vascular disease, hereditary hemorrhagic telangiectasia, or gastric irradiation. c Retains significance on multivariate regression analysis. a
Table 5
Predictors of death
Variables Older age Sex Liver disease Collagen vascular disease SI angioectasia Low baseline Hb
P 0.049 0.201 0.009 0.027 0.096 0.01
spindle cell proliferation, and fibrohyalinosis [3,17]. The pathogenesis of FVE may involve humoral or hemodynamic alterations [18]. GAVE may involve additional factors including mechanical stress (mucosal prolapse) or autoimmunity [19]. We can speculate that a lower baseline hemoglobin level was associated with treatment success because of earlier presentation and lower absolute increase in hemoglobin level necessary to attain a 30% increase in these patients. Our finding that antiaggregant and anticoagulant use was associated with treatment success might also be related to earlier presentation. Of the patients, 16/32 (50%) receiving antiaggregant or anticoagulant medication presented with overt GI bleeding, compared with 5/30 (16.7%) patients not receiving these medications (P < 0.01). Patients with overt bleeding are likely to present earlier. Therefore, treatment with antiaggregants and anticoagulants is likely to be related to earlier presentation and might not be a truly independent predictor of treatment success.
Hb, hemoglobin; SI, small intestine.
We found that patients with FVE have a favorable prognosis compared with patients with GAVE. Subgroup analysis revealed that patients with FVE more often present with acute GI bleeding (16/31 vs. 4/31, P < 0.01), require fewer APC sessions (1.2±0.8 vs. 3.3±2.5, P < 0.01), more often have an associated small intestinal angioectasia (12/31 vs. 0/31, P < 0.01), and are less likely to have comorbid liver or collagen vascular disease (5/31 vs. 13/31, P = 0.04), compared with patients with GAVE. Age did not differ between patients with FVE and those with GAVE, nor did overall survival. Although FVE and GAVE clearly represent two distinct entities, for the purpose of this study we chose to group them together; the focus of our study is the efficacy of APC, not the clinical features of VE per se. FVE may be more amenable to APC than GAVE, because of the lower surface area involved and possibly its histopathology. Whereas FVEs are derived from submucosal venules, GAVEs are thought to involve mucosal capillaries and exhibit focal thrombosis,
Although we found that older age is predictive of treatment success, age is probably a confounding factor related to the etiology of gastric VE. Patients without liver or collagen vascular disease were significantly older than patients with these comorbidities (74.8±11.9 vs. 67.03±13.4 years, P < 0.01). Similarly, older age was predictive of poor overall survival. This finding is selfevident and is probably unrelated to GI bleeding. The fact that no endoscopic features were found to predict overall survival is consistent with our finding that APC treatment is effective for initial hemostasis. Limitations of this study include its single-center design and the retrospective nature of data acquisition. For example, misclassification of treatment failure could occur in patients receiving undocumented blood transfusions. Misclassification of treatment success could occur in patients subjected to routine follow-up endoscopy and treated with APC for persistent VE in the absence of observable symptoms. Nevertheless, we believe that such error is minimal because of the nature of our
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APC success in gastric VE Boltin et al.
computerized database and the high corroboration between the two independent reviewers. Although oral iron supplementation was routinely recommended after index endoscopy, we could not reliably assess compliance because of the availability of over-the-counter preparations. Iron supplementation could not be adequately controlled for and was not included as a variable in the data analysis. Finally, although loss to follow-up is a legitimate concern, the nature of the CHS reimbursement policy makes it unlikely that patients would undergo APC at other centers. Alternatives to APC for the treatment of VE include cryotherapy, endoscopic band ligation, and endoscopic clipping. Sclerotherapy and Nd:YAG laser are rarely used nowadays because of adverse events. There has been recent interest in radiofrequency ablation of GAVE using the HALO(90) ULTRA ablation catheter (Covidien, Mansfield, Massachusetts, USA) [20]. Although preliminary results are encouraging, larger, prospective and comparative studies are needed. Placement of a transjugular intrahepatic portosystemic shunt is ineffective for the treatment of bleeding in cirrhotic patients with GAVE and is associated with a substantial risk for hepatic encephalopathy [21]. Conclusion
APC is safe and effective for the management of gastric VE. Nevertheless, resolution of GI bleeding and anemia in the long term is not seen in most treated patients. Further, prospective studies are required to confirm our findings and to explore a role for alternative treatment modalities in refractory patients.
Acknowledgements
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The authors acknowledge Nili Golan and Tali Movshovitz for their assistance with data acquisition and analysis. All authors have approved the final version of this manuscript.
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Conflicts of interest
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There are no conflicts of interest. 20
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Long-term treatment outcome of patients with gastric vascular ectasia treated with argon plasma coagulation Doron Boltin, Rachel Gingold-Belfer, Lev Lichtenstein, Zohar Levi and Yaron Niv Background Gastric vascular ectasia (VE) is an uncommon cause of upper gastrointestinal bleeding. Long-term data on the efficacy of argon plasma coagulation (APC) for the treatment of gastric VE are lacking. Methods We retrospectively identified consecutive patients, between January 2005 and December 2010, treated with APC for an index diagnosis of gastric VE. Clinical and endoscopic features and APC treatment success were recorded. Treatment success was determined by resolution of symptoms and stabilization of the hemoglobin level at 30% above baseline. Results A total of 62 patients [28 (45.2%) male] with a mean age of 72.6±12.8 years, who had undergone 159 upper endoscopies (mean 2.6, range 1–10), including 140 APC sessions (mean 2.3, range 1–10), were identified. The duration of follow-up was 46.9±26.5 months. Treatment success was achieved in 16 (25.8%) patients. Predictors of success included older age, focal pattern, lack of comorbid liver failure or collagen vascular disease, use of antiplatelet or
Introduction Gastric vascular ectasia (VE) is an uncommon but welldescribed cause of upper gastrointestinal (GI) bleeding. Presentation is usually acute GI bleeding or iron deficiency anemia. Gastric VEs have been classified endoscopically as gastric antral VE (GAVE; with a ‘watermelon’ or ‘honeycomb’ pattern) or focal VE (FVE) [1,2]. Microscopically, VEs appear as distorted, thin-walled blood vessels, thought to arise from submucosal venules, with characteristic histological findings, including spindle cell proliferation, fibrohyalinosis, and fibrin thrombi [3]. Gastric VEs may be associated with various chronic disease states including liver failure (30%) and collagen vascular disease, particularly Raynaud’s syndrome (30%) [4,5]. Most remaining cases are idiopathic. Symptomatic lesions may be treated endoscopically with a range of modalities. Argon plasma coagulation (APC) has emerged as first-line therapy because of its effectiveness, availability, ease of application, low complication rate, and lower cost [6,7]. APC is a noncontact technique with a controllable depth of coagulation (0.5–3 mm), whereby high-frequency current is applied to the gastric mucosa through an ionized and electrically conductive gas. Alternative modalities include neodymium:yttrium– c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0954-691X
anticoagulant drugs, and lower baseline hemoglobin level. Of the patients, 26 (41.9%) died during follow-up. Conclusion APC is safe and effective for the initial management of gastric VE; however, most patients do not experience long-term resolution of upper gastrointestinal bleeding and anemia. Eur J Gastroenterol c 2014 Wolters Kluwer Health | Hepatol 26:588–593 Lippincott Williams & Wilkins. European Journal of Gastroenterology & Hepatology 2014, 26:588–593 Keywords: angioectasia, argon plasma coagulation, endoscopic treatment, gastric vascular ectasia, gastric antral vascular ectasia Department of Gastroenterology, Rabin Medical Center, Beilinson Campus, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Correspondence to Doron Boltin, MBBS, Department of Gastroenterology, Rabin Medical Center, Beilinson Campus, 39 Jabotinski Street, Petah Tikva 49100, Israel Tel: + 972 3 9377236; fax: + 972 3 9210313; e-mail: [email protected] Received 14 November 2013 Accepted 19 December 2013
aluminum–garnet (Nd:YAG) laser, sclerotherapy, cryotherapy, electrocoagulation, band ligation, hemoclips, and radiofrequency ablation [8–11]. Small retrospective cohorts have described short-term and intermediate-term outcomes following APC for the treatment of gastric VE [6,7,12–14]. The aim of this study is to determine the long-term treatment success of APC for the management of gastric VE, in the largest reported cohort to date.
Methods Data source and population
This retrospective study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice and was approved by the Human Subjects Protection Program of Rabin Medical Center. Consecutive patients presenting for esophagogastroduodenoscopy or enteroscopy at our tertiary center between 1 January 2005 and 31 December 2010, with an endoscopic diagnosis of gastric VE, were identified. Patients treated with APC for gastric VE were included. This single-center study was performed at an endoscopy unit affiliated with Clalit Health Services (CHS). CHS is the largest health maintenance organization in Israel and the second largest health maintenance organization in the DOI: 10.1097/MEG.0000000000000047
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APC success in gastric VE Boltin et al. 589
world, with over 3.8 million enrollees. Demographic and clinical data were retrieved from clinic visits and the centralized clinical database managed by CHS, and include data on comorbidities (cirrhosis, renal failure, heart disease, and collagen vascular disease), medications (antiplatelet and anticoagulation), and laboratory parameters (hemoglobin level). Endoscopic data were obtained from an established computerized endoscopy reporting system. Patients were excluded if they had an additional lesion showing evidence of active or recent bleeding. All data were obtained by two independent reviewers. Any discrepancy was resolved by a third party (D.B.). Endoscopic diagnosis
Endoscopy was performed by seven expert endoscopists using a single-channel endoscope (GIF-1T140L; Olympus Optical Co. Ltd, Tokyo, Japan), with patients under moderate sedation with midazolam and fentanyl or under general anesthesia. On endoscopy, lesions were stratified into two groups: FVE and GAVE (Fig. 1). FVE was identified on the basis of the presence of one or more flat red spots or reticulated vascular areas in any area of the stomach. GAVE was identified on the basis of the presence of typical punctuate-type (honeycomb) or striped (watermelon) VEs emanating from the antrum [2]. Biopsy specimens were not obtained, except when the diagnosis was unclear. The presence of gastroesophageal varices and portal hypertensive gastropathy was noted. The presence of additional VEs in the duodenum was recorded. Enteroscopy and capsule endoscopy were performed according to clinical judgment. The presence of concomitant VEs in the small bowel was recorded. Electrocoagulation technique
Treatment was applied by a probe introduced through the working channel of the endoscope using a high-frequency electrosurgical generator (ERBE APC300; ERBE Elektromedizin GmbH, Tubingen, Germany) coupled to
an argon gas delivery unit. The electrical power output setting varied from 30 to 70 W and the argon gas flow varied from 0.8 to 2.0 l/min. VEs were treated with either axial or lateral probes. A combination of focal pulse and spray-painting methods was used. Luminal gases were regularly aspirated during the session, and the probe was cleansed as deemed necessary by the endoscopist. The aim of each electrocoagulation session was treatment of all visualized bleeding and nonbleeding gastric VEs. All patients were prescribed proton pump inhibitors to facilitate mucosal healing. Follow-up
All patients were monitored at a dedicated clinic within 6 weeks of the index APC treatment or hospital discharge, and thereafter they were monitored on an individualized basis. All patients were monitored closely by their primary care physician. Hemoglobin levels were recorded in all cases, at least at baseline and at 3 months after the index APC session. In the case of persistent GI bleeding or transfusiondependent anemia, another APC session was conducted. APC sessions were repeated until complete symptom resolution. Several endoscopists recommended routine follow-up endoscopy to document treatment success. Treatment success was defined as the absence of further GI bleeding, coupled with a 30% increase in the hemoglobin level on follow-up. Patients with a normal baseline hemoglobin level did not require a 30% increase in the hemoglobin level for the treatment to be considered a success. Treatment was said to have failed in patients who continued to experience GI bleeding, who did not show resolution of iron deficiency anemia, and who continued to require blood transfusions. Follow-up was continued until 31 December 2012, death, emigration, or disenrollment from CHS. Statistical analysis
All analyses were carried out using SPSS version 21.0 statistical analysis software (IBM Inc., Chicago, Illinois,
Fig. 1
Endoscopic appearance of gastric vascular ectasia: (a) focal vascular ectasia; (b) gastric antral vascular ectasia (‘watermelon’ type).
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590 European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 6
Fig. 2
Table 1
18 733 upper endoscopies
APC treatment (143 patients) Gastric polypectomy∗ (34 patients)
Gastric vascular ectasia (62 patients)
Duodenal angioectasia (45 patients) Other∗∗ (2 patients)
Patient characteristics
Total Age (years) Mean (SD) Median (range) Male [n (%)] Etiology [n (%)] Idiopathic Liver disease Collagen vascular disease Gastric irradiation HHT Antiplatelet therapy [n (%)] Anticoagulant therapy [n (%)] Hb baseline (g/dl) Mean (SD) Median (range) Hb 3 months (g/dl) Mean (SD) Median (range)
62 (100) 72.6 (12.8) 76.4 (26.0–97.9) 28 (45.2) 42 12 6 1 1 23 9
(67.7) (19.4) (9.7) (1.6) (1.6) (37.1) (14.5)
8.86 (2.08) 8.6 (4.8–15.1) 11.27 (1.91) 11.3 (6.4–15.7)
Hb, hemoglobin; HHT, hereditary hemorrhagic telangiectasia.
FGE n = 31
GAVE n = 31
Study flowchart. *Hemostasis immediately after polypectomy. **Anastamotic bleed, one patient; Dieulafoy’s lesion, one patient. APC, argon plasma coagulation; FGE, focal gastric ectasia; GAVE, gastric antral vascular ectasia.
USA). Distributions of continuous variables were assessed for normality using the Kolmogorov–Smirnov test (cutoff at P < 0.1). Distributions of all continuous variables deviated significantly from normal; hence, they were described as median (min–max), in addition to mean±SD. Continuous variables were compared using the t-test or the Mann– Whitney U-test as appropriate. Nominal variables were described as frequency counts and presented as n (%). Nominal variables were compared using the w2-test. Survival was analyzed using Kaplan–Meier estimates. Treatment success and survival were modeled using Cox regression analysis to develop odds ratios (ORs) with 95% confidence intervals (CIs). All tests were two-sided and considered significant at P less than 0.05.
Results Patient characteristics
During the inclusion period between 1 January 2005 and 31 December 2010, a total of 62 patients were subjected to APC treatment for gastric VE (Fig. 2). Of them, 28 (45.2%) were male, and the mean age of the patients was 72.6±12.8 years. Most patients did not have a predisposing condition (42, 67.7%); however, liver failure was evident in 12 (19.4%) patients and collagen vascular disease in six (9.7%) patients. Patient characteristics are shown in Table 1. Endoscopy
A total of 159 upper GI endoscopies were performed (mean 2.6, range 1–10), including 140 APC sessions
(mean 2.3, range 1–10). The mean time to retreatment, among patients who required retreatment, was 5.9±7.3 months. The mean time to the first retreatment was 4.6±6.4 months and the mean time to the final APC session was 7.0±15.1 months. The Kaplan–Meier curve for APC-free survival is shown in Fig. 3a. FVE was seen in 31 (50%) patients and GAVE was seen in 31 patients (50%; Fig. 1). Iron deficiency anemia and GI bleeding were the presenting features in 38 (61.3%) and 21 (33.9%) patients, respectively. Concomitant small intestinal VE was observed in 13 (21%) patients. The endoscopic features of gastric VE in our cohort are summarized in Table 2. Treatment success
Treatment success, as previously defined, was achieved in 16 (25.8%) patients. Predictors of success included older age, focal pattern (FVE), lack of comorbid liver failure or collagen vascular disease, use of antiplatelet or anticoagulant drugs, fewer APC sessions, and a lower baseline hemoglobin level. No relationship was observed between treatment success and presenting symptoms (acute vs. subacute presentation). The relationship between death and the presence of concomitant small intestinal VEs had borderline significance (P = 0.06). Multivariate regression analysis identified focal pattern (OR, 4.3; 95% CI, 1.2–16.1; P = 0.03) and antiaggregant or anticoagulant use (OR, 5.4; 95% CI, 1.3–22.4; P = 0.02) as independent predictors of treatment success (Tables 3 and 4). Survival
The mean duration of follow-up from the index APC session until one of the defined endpoints was 46.9±26.5 months. The mean duration of follow-up after the final APC session was 40.4±26.8 months. During follow-up, 26 (41.9%) patients died 29.5±23.9 months after the index APC session. The Kaplan–Meier curve for overall survival is shown in Fig. 3b. Predictors of death following APC
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APC success in gastric VE Boltin et al.
591
Fig. 3
(a) 1
(b) 1
0.9
0.9
0.8
0.8
0.7
0.7
0.6
0.6
0.5
0.5
0.4
0.4
0.3
0.3
0.2
0.2
0.1
0.1
0
0 0
100 200 300 400 500 600 700 800 900 1000 Days
0
500
1000
1500 Days
2000
2500
3000
Kaplan–Meier survival for primary outcomes: (a) APC-free survival; (b) overall survival. APC, argon plasma coagulation.
Table 2
APC. No patient required angiographic or surgical intervention for intractable GI hemorrhage.
Endoscopic features
Total EGD Mean (SD) Median (range) Total APC Mean (SD) Median (range) Number APC sessions [n (%)] 1 2 3 4 Z5 Pattern [n (%)] FGE GAVE Indication for index EGD [n (%)] GI bleeding Iron deficiency anemia Othera Associated SI angioectasia [n (%)]
159 (2.6) 2 (1–10) 140 (2.3) 2 (1–10) 37 8 3 7 7
(59.7) (12.9) (4.8) (11.3) (11.3)
31 (50) 31 (50) 21 38 3 13
(33.87) (61.3) (4.8) (21)
APC, argon plasma coagulation; EGD, esophagogastroduodenoscopy; FGE, focal gastric ectasia; GAVE, gastric antral vascular ectasia; GI, gastrointestinal; SI, small intestine. a Surveillance following surgery for adenocarcinoma of gastroesophaeal junction, one case; epigastric pain without anemia, one case; screening for premalignant lesions, one case.
treatment for gastric VE include advancing age, low baseline hemoglobin level, liver failure, and collagen vascular disease (Table 5). Treatment failure did not portend poor survival. None of the variables retained significance following multivariate regression analysis. Adverse events
There were no adverse events directly attributable to treatment by APC. One patient developed acute anaphylaxis to vancomycin, which was administered prophylactically for endocarditis. In all cases of acute upper GI bleeding initial hemostasis was achieved with
Discussion In the present study we demonstrate that, although APC is highly effective for the management of gastric VEs, three quarters of patients do not achieve symptom resolution and a sustained increase in the hemoglobin level. The 5-year survival following APC for gastric VE is 37%. This is by far the largest cohort ever reported and covers the longest ever reported follow-up period, with a mean duration of B4 years. Herrera et al. [15] reported 86% treatment success with APC in a recent prospective cohort of 29 patients with gastric VE. Treatment success was defined according to the criteria adopted in our study. The success rate in their study is significantly higher than that in ours, and this discrepancy cannot be accounted for solely by their prospective study design. Herrera and colleagues described patients presenting with overt upper GI bleeding, whereas our cohort included patients with iron deficiency anemia who may be less likely to achieve the requisite 30% hemoglobin increase. The results of Herrera and colleagues may also be biased by the lower proportion of GAVEs (associated with inferior outcomes in our study) and the inclusion of patients with portal hypertensive gastropathy in the absence of FVE or GAVE. Moreover, duration of follow-up in the cohort of Herrera and colleagues was 50% shorter than that in our study. Additional small, retrospective studies report the efficacy of APC to range from 70 to 100%; however, the criteria defining treatment success vary widely between cohorts, and follow-up is typically short [6,7,12–14,16].
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European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 6
Table 3
Treatment outcomes following argon plasma coagulation for gastric vascular ectasia GI bleeding
N (%) Follow-up duration [mean (SD)] (months) Treatment success [n (%)]b Time to retreatment [mean (SD)] (months)c Time to final APC [mean (SD)] (months) Death [n (%)] Time to death [mean (SD)] (months) Adverse events [n (%)]
21 33.8 7 3.5 1.6 12 20.6 0
Iron deficiency anemia
(33.8) (21.9) (33.3) (3.2) (4.2) (57.1) (15.1) (0)
38 54.9 9 6.5 9.7 13 37.6 1
(61.3) (26.3) (23.7) (8.2) (18.0) (34.2) (28.0) (2.6)
Totala
Pd
62 46.9 (26.5) 16 (25.8) 5.9 (7.3) 7.0 (15.1) 26 (41.9) 29.5 (23.9) 1 (1.6)
< 0.01 NS NS NS NS < 0.01 NS
APC, argon plasma coagulation; GI, gastrointestinal; IDA, iron deficiency anemia. Included all patients presenting with GI bleeding and IDA, as well as three patients with other presenting signs, see Table 2 subtext. No further GI bleeding and 30% increase in hemoglobin level at follow-up. c Patients who underwent only one APC session were excluded from this calculation. d Compares GI bleeding and IDA groups. a
b
Table 4
Predictors of treatment successa
Variables
P
Older age Absence of predisposing comorbidityb Number of APC treatments FGEc Antiplatelet or antiaggregantc Low baseline Hb
0.038 0.019 0.005 0.02 0.006 0.004
APC, argon plasma coagulation; FGE, focal gastric ectasia; Hb, hemoglobin. No further GI bleeding and 30% increase in hemoglobin level at follow-up. b Absence of liver disease, collagen vascular disease, hereditary hemorrhagic telangiectasia, or gastric irradiation. c Retains significance on multivariate regression analysis. a
Table 5
Predictors of death
Variables Older age Sex Liver disease Collagen vascular disease SI angioectasia Low baseline Hb
P 0.049 0.201 0.009 0.027 0.096 0.01
spindle cell proliferation, and fibrohyalinosis [3,17]. The pathogenesis of FVE may involve humoral or hemodynamic alterations [18]. GAVE may involve additional factors including mechanical stress (mucosal prolapse) or autoimmunity [19]. We can speculate that a lower baseline hemoglobin level was associated with treatment success because of earlier presentation and lower absolute increase in hemoglobin level necessary to attain a 30% increase in these patients. Our finding that antiaggregant and anticoagulant use was associated with treatment success might also be related to earlier presentation. Of the patients, 16/32 (50%) receiving antiaggregant or anticoagulant medication presented with overt GI bleeding, compared with 5/30 (16.7%) patients not receiving these medications (P < 0.01). Patients with overt bleeding are likely to present earlier. Therefore, treatment with antiaggregants and anticoagulants is likely to be related to earlier presentation and might not be a truly independent predictor of treatment success.
Hb, hemoglobin; SI, small intestine.
We found that patients with FVE have a favorable prognosis compared with patients with GAVE. Subgroup analysis revealed that patients with FVE more often present with acute GI bleeding (16/31 vs. 4/31, P < 0.01), require fewer APC sessions (1.2±0.8 vs. 3.3±2.5, P < 0.01), more often have an associated small intestinal angioectasia (12/31 vs. 0/31, P < 0.01), and are less likely to have comorbid liver or collagen vascular disease (5/31 vs. 13/31, P = 0.04), compared with patients with GAVE. Age did not differ between patients with FVE and those with GAVE, nor did overall survival. Although FVE and GAVE clearly represent two distinct entities, for the purpose of this study we chose to group them together; the focus of our study is the efficacy of APC, not the clinical features of VE per se. FVE may be more amenable to APC than GAVE, because of the lower surface area involved and possibly its histopathology. Whereas FVEs are derived from submucosal venules, GAVEs are thought to involve mucosal capillaries and exhibit focal thrombosis,
Although we found that older age is predictive of treatment success, age is probably a confounding factor related to the etiology of gastric VE. Patients without liver or collagen vascular disease were significantly older than patients with these comorbidities (74.8±11.9 vs. 67.03±13.4 years, P < 0.01). Similarly, older age was predictive of poor overall survival. This finding is selfevident and is probably unrelated to GI bleeding. The fact that no endoscopic features were found to predict overall survival is consistent with our finding that APC treatment is effective for initial hemostasis. Limitations of this study include its single-center design and the retrospective nature of data acquisition. For example, misclassification of treatment failure could occur in patients receiving undocumented blood transfusions. Misclassification of treatment success could occur in patients subjected to routine follow-up endoscopy and treated with APC for persistent VE in the absence of observable symptoms. Nevertheless, we believe that such error is minimal because of the nature of our
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APC success in gastric VE Boltin et al.
computerized database and the high corroboration between the two independent reviewers. Although oral iron supplementation was routinely recommended after index endoscopy, we could not reliably assess compliance because of the availability of over-the-counter preparations. Iron supplementation could not be adequately controlled for and was not included as a variable in the data analysis. Finally, although loss to follow-up is a legitimate concern, the nature of the CHS reimbursement policy makes it unlikely that patients would undergo APC at other centers. Alternatives to APC for the treatment of VE include cryotherapy, endoscopic band ligation, and endoscopic clipping. Sclerotherapy and Nd:YAG laser are rarely used nowadays because of adverse events. There has been recent interest in radiofrequency ablation of GAVE using the HALO(90) ULTRA ablation catheter (Covidien, Mansfield, Massachusetts, USA) [20]. Although preliminary results are encouraging, larger, prospective and comparative studies are needed. Placement of a transjugular intrahepatic portosystemic shunt is ineffective for the treatment of bleeding in cirrhotic patients with GAVE and is associated with a substantial risk for hepatic encephalopathy [21]. Conclusion
APC is safe and effective for the management of gastric VE. Nevertheless, resolution of GI bleeding and anemia in the long term is not seen in most treated patients. Further, prospective studies are required to confirm our findings and to explore a role for alternative treatment modalities in refractory patients.
Acknowledgements
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The authors acknowledge Nili Golan and Tali Movshovitz for their assistance with data acquisition and analysis. All authors have approved the final version of this manuscript.
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Conflicts of interest
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There are no conflicts of interest. 20
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