Dig Dis Sci (2015) 60:275–277 DOI 10.1007/s10620-014-3412-z
CORRESPONDENCE
Reply ‘‘Endoscopic Therapy with 2-Octyl-Cyanoacrylate for the Treatment of Gastric Varices’’: Optimizing the Cyanoacrylate Injection in the Treatment of Gastric Varices Javier Martinez-Gonzalez • Marta Aicart Ramos Agustin Albillos Martinez
•
Received: 15 October 2014 / Accepted: 23 October 2014 / Published online: 5 November 2014 Ó Springer Science+Business Media New York 2014
We have read with great interest the study published by Kahloon et al. [1] in this journal. All studies about the management of gastric varices (GV) are relevant due to the paucity of data. Apart from the limitations explained by the authors [1], there are some important aspects we would like to notice. First. An important heterogeneity of the patients included in the study (primary prophylaxis, secondary prophylaxis and active bleeders) has been noticed. Moreover, 5 % of them have non-cirrhotic portal hypertension and/or splenic vein thrombosis. It is well known that these patients usually have a preserved liver function compared with decompensated cirrhotic patients (95 % of the study population). This heterogeneous population has different burden of liver disease and certainly different hepatic venous pressure gradient, which may have influenced the results. Some special limitations exist with patients on primary prophylaxis (5 % of study population): (1) Among all study endpoints, only ‘‘complications’’ are applicable to them; (2) there is high controversy in the strategy of primary prophylaxis. A recent study of Sarin et al. [2] evaluated the primary prophylaxis comparing CAI versus beta-blockers versus no treatment. Significant differences were observed favouring CAI versus no treatment in terms of prevention of bleeding and survival. But when compared with propranolol, CAI only showed significant benefits in the prevention of rebleeding. This study has been criticized due to important limitations as highlighted by Tripathi [3]. In fact, the international consensus on portal hypertension (Baveno
J. Martinez-Gonzalez (&) M. A. Ramos A. A. Martinez Servicio de Gastroenteroloia y Hepatologia, Hospital Universitario Ramo´n y Cajal, IRYCIS, Universidad de Alcala´, Alcala de Henares, Madrid, Spain e-mail: [email protected]
V) only recommends beta-blockers for primary prophylaxis [4]. (3) Risk factors associated with bleeding from fundic varices were analyzed by Kim et al. [5]. They are all those listed by the authors except for ‘‘the need of anticoagulation,’’ which is not described in the literature. In our opinion, as secondary prophylaxis patients were 78 % of all the study population, in addition to all limitations of the primary prophylaxis group, a more homogeneous study cohort might have yielded more consistent results. Second. A main point is the subtype of GV included in the study. Only GOV1 and GOV2 are reported (Table 2) [1]. IGV2 are rare, but IGV1 are fundic varices, as well as GOV2. Both of them have the same venous origin and drainage and share many aspects of its pathophysiology and management. Thus, both are considered fundic varices as a whole [6]. IGV1 have been left out this study, unless the authors have considered GOV2 as a synonym of all fundic varices. Apart from that, although GOV1 is a subtype of gastric varix [2], it shares many characteristics with esophageal varices [4, 6]. In fact, many guidelines and international consensus recommend a similar management to that of esophageal varices [4, 6]. Therefore, although other historical series included GOV1, they might have excluded them following recent evidence [5, 6]. Third. Although 75 % of procedures were performed with one injection and median number of GV treated in one session were only one, endoscopists have used much more CA (mean dose of 3.4 cc) than recommended (0.5–1 cc) [7–9]. It is unknown how results could be influenced, as the authors do not explain how varix obliteration was confirmed. Despite it is not universally recommended in the management of gastric varices, endoscopy ultrasound can be easily used to check the varix flow [10]. Finally, one on the endpoints was death (19.5 % of study population). Apart from other causes, it included
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infections (3) and bleeding (2). Authors assert that any death was related to the injection procedure, although these two complications have been clearly related to CAI [9]. We do not know whether these patients are from active bleeders or from secondary or primary prophylaxis. Because of these complications can be related to CAI and large amount of CA has been used, authors should specify when these advert events occurred and which kind of patients were affected, as death cannot be admissible for primary prophylaxis with CAI when beta-blockers are the only recommended strategy [4, 6]. As a conclusion, CAI is a safe and effective procedure for active GV bleeding and for secondary prophylaxis. In this study, a more homogeneous study cohort, a better explanation of the GV subtypes included, a more accurate dose of CA and the use of endoscopy ultrasound to confirm varices obliteration might yield more consistent and comparable results with other studies.
Reply to Martinez-Gonzalez et al. We would like to thank Martinez-Gonzalez et al. for their detailed comments on our manuscript. We agree that for patients in whom cyanoacrylate injection (CAI) was used for primary prophylaxis, only complications should be used as an endpoint. Both patients treated with cyanoacrylate for primary prophylaxis had intolerance or failure of nonselective beta-blocker therapy (i.e., congestive heart failure on ACE inhibitor and progression of gastric varices despite the use of beta-blockade) in our study [1]. We agree that ‘‘need for anticoagulation’’ is not an accepted indication for primary prophylaxis. However, in referral centers, we often encounter complex clinical situations when a risk–benefit decision has to be made without scientific evidence or expert opinion-based guidelines. Since gastric variceal bleeding is often a devastating complication in subjects who are not anticoagulated, we surmised that outcomes may be worse in patients who are on anticoagulation therapy. As the authors are likely aware of, there are no data on outcomes of bleeding from gastroesophageal varices in patients who are anticoagulated without portal vein thrombosis. In the retrospective study by Thomopoulos et al. [11], no variceal bleeding was reported among 111 patients who bled while on anticoagulation therapy (vs. 14 % among controls), which suggests that this is an uncommon practice or a publication bias. With regard to the type of gastric varices reported in our study [1], the distinction between gastric-esophageal varices type 2 (GOV2) and isolated gastric varices type 1 (IGV1) varices is somewhat arbitrary based on the presence or absence of esophageal varices [12]. This may be subjective particularly in patients with recent bleeding. Consequently, a
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Dig Dis Sci (2015) 60:275–277
better term to classify these collaterals would be ‘‘fundic varices.’’ However, contrary to the statement by MartinezGonzalez et al., we have not excluded GOV1 varices as seen in Table 2 [1]. As far as the endoscopic method, we used a slight modification of the endoscopic technique previously reported by Rengstorff et al. [13]. Thus, we injected CAI in 1 mL aliquots until we encountered resistance to injection (i.e., the varix felt ‘‘hard’’ to palpation with the catheter or bleeding ceased in patients who had active hemorrhage). Since some of the glue may spill out of the varix, the overall volume injected may exceed 3 mL. There are no data to support the use of smaller or larger volumes of glue outside the recommendations, which are strictly based on expert suggestions without an evidence. In fact, recent series describe volumes of injectate in excess of 2 mL/session even in patients treated for primary prophylaxis [13, 14]. Similarly, there is no qualified evidence that EUS-guided glue injection is superior to standard endoscopy in improving outcomes of therapy for gastric variceal bleeding [15]. We do agree that further comparison studies are needed before the added costs of EUS per se and associated with scope malfunction related to cyanoacrylate use can be advocated as standard of care. Finally, we entirely agree that some of the causes of death in our study could be attributed to glue injection. However, deaths from infection/sepsis and rebleeding occurred more than 8 weeks after the episode of endoscopic therapy, and therefore, they were unlikely to be related to the endoscopic procedure. No deaths from bleeding or infection were reported by the end of follow-up in patients who underwent primary prophylaxis. We apologize for omitting this information from the manuscript. Arslan Kahloon Naga Chalasani John DeWitt Suthat Liangpunsakul Rakesh Vinayek Raj Vuppalanchi Marwan Ghabril Michael Chiorean, MD Digestive Disease Institute, Division of Gastroenterology and Hepatology, Virginia Mason Medical Center, Seattle, WA 98101, USA e-mail: [email protected]
References 1. Kahloon A, Chalasani N, DeWitt J, et al. Endoscopic therapy with 2-Octyl-cyanoacrylate for the treatment of gastric varices. Dig Dis Sci. 2014;59:2178–2183. 2. Mishra S, Sharma B, Kumar A, Sarin S. Primary prophylaxis of gastric varices bleeding comparing cyanoacrylate and betablockers. J Hepatol. 2011;54:1161–1167.
Dig Dis Sci (2015) 60:275–277 3. Tripathi D. Primary prophylaxis against gastric variceal bleeding: is there a sticky solution at last? Hepatology. 2011;54: 1994–1996. 4. Franchis R. Report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol. 2010;53:762–768. 5. Kim T, Shijo H, Kokawa H, et al. Risk factors for hemorrhage from gastric fundal varices. Hepatology. 1997;25:307–312. 6. Garcia-Paga´n JC, Barrufet M, Cardenas A, Escorsell A. Management of gastric varices. Clin Gastroenterol Hepatol. 2014; 12:919–928. 7. Bhat Y, Banerjee S, Barth B, et al. Tissue adhesives: cyanoacrylate glue and fibrin sealant. Gastrointest Endosc. 2013;78: 209–215. 8. Seewald S, Ang T, Imazu H, et al. A standardized injection technique and regimen ensures success and safety of cyanoacrylate injection for the treatment of gastric fundal varices. Gastrointest Endosc. 2008;68:447–454. 9. Cameron R, Binmoeller K. Cyanoacrylate applications in the GI tract. Gastrointest Endosc. 2013;77:846–857.
277 10. Romeroo R, Ellrichmann M, Ortiz C, et al. Endoscopic ultrasound-guided therapy of gastric varices: results from a prospective multicenter study. Gastrointest Endosc. 2013;78:711–721. 11. Thomopoulos KC, Mimidis KP, Theocharis GJ, et al. Acute upper gastrointestinal bleeding in patients on long-term oral anticoagulation therapy: endoscopic findings, clinical management and outcome. World J Gastroenterol. 2005;11:1365–1368. 12. Sarin SK, Kumar A. Gastric varices: profile, classification, and management. Am J Gastroenterol. 1989;84:1244–1249. 13. Rengstorff DS, Binmoeller KF. A pilot study of 2-octyl cyanoacrylate injection for treatment of gastric fundal varices in humans. Gastrointest Endosc. 2004;59:553–558. 14. Chang YJ, Park JJ, Joo MK, et al. Long-term outcomes of prophylactic endoscopic histoacryl injection for gastric varices with a high risk of bleeding. Dig Dis Sci. 2010;55:2391–2397. 15. Girotra M, Raghavapuram S, Abraham RR, et al. Management of gastric variceal bleeding: role of endoscopy and endoscopic ultrasound. World J Hepatol. 2014;6:130–136.
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CORRESPONDENCE
Reply ‘‘Endoscopic Therapy with 2-Octyl-Cyanoacrylate for the Treatment of Gastric Varices’’: Optimizing the Cyanoacrylate Injection in the Treatment of Gastric Varices Javier Martinez-Gonzalez • Marta Aicart Ramos Agustin Albillos Martinez
•
Received: 15 October 2014 / Accepted: 23 October 2014 / Published online: 5 November 2014 Ó Springer Science+Business Media New York 2014
We have read with great interest the study published by Kahloon et al. [1] in this journal. All studies about the management of gastric varices (GV) are relevant due to the paucity of data. Apart from the limitations explained by the authors [1], there are some important aspects we would like to notice. First. An important heterogeneity of the patients included in the study (primary prophylaxis, secondary prophylaxis and active bleeders) has been noticed. Moreover, 5 % of them have non-cirrhotic portal hypertension and/or splenic vein thrombosis. It is well known that these patients usually have a preserved liver function compared with decompensated cirrhotic patients (95 % of the study population). This heterogeneous population has different burden of liver disease and certainly different hepatic venous pressure gradient, which may have influenced the results. Some special limitations exist with patients on primary prophylaxis (5 % of study population): (1) Among all study endpoints, only ‘‘complications’’ are applicable to them; (2) there is high controversy in the strategy of primary prophylaxis. A recent study of Sarin et al. [2] evaluated the primary prophylaxis comparing CAI versus beta-blockers versus no treatment. Significant differences were observed favouring CAI versus no treatment in terms of prevention of bleeding and survival. But when compared with propranolol, CAI only showed significant benefits in the prevention of rebleeding. This study has been criticized due to important limitations as highlighted by Tripathi [3]. In fact, the international consensus on portal hypertension (Baveno
J. Martinez-Gonzalez (&) M. A. Ramos A. A. Martinez Servicio de Gastroenteroloia y Hepatologia, Hospital Universitario Ramo´n y Cajal, IRYCIS, Universidad de Alcala´, Alcala de Henares, Madrid, Spain e-mail: [email protected]
V) only recommends beta-blockers for primary prophylaxis [4]. (3) Risk factors associated with bleeding from fundic varices were analyzed by Kim et al. [5]. They are all those listed by the authors except for ‘‘the need of anticoagulation,’’ which is not described in the literature. In our opinion, as secondary prophylaxis patients were 78 % of all the study population, in addition to all limitations of the primary prophylaxis group, a more homogeneous study cohort might have yielded more consistent results. Second. A main point is the subtype of GV included in the study. Only GOV1 and GOV2 are reported (Table 2) [1]. IGV2 are rare, but IGV1 are fundic varices, as well as GOV2. Both of them have the same venous origin and drainage and share many aspects of its pathophysiology and management. Thus, both are considered fundic varices as a whole [6]. IGV1 have been left out this study, unless the authors have considered GOV2 as a synonym of all fundic varices. Apart from that, although GOV1 is a subtype of gastric varix [2], it shares many characteristics with esophageal varices [4, 6]. In fact, many guidelines and international consensus recommend a similar management to that of esophageal varices [4, 6]. Therefore, although other historical series included GOV1, they might have excluded them following recent evidence [5, 6]. Third. Although 75 % of procedures were performed with one injection and median number of GV treated in one session were only one, endoscopists have used much more CA (mean dose of 3.4 cc) than recommended (0.5–1 cc) [7–9]. It is unknown how results could be influenced, as the authors do not explain how varix obliteration was confirmed. Despite it is not universally recommended in the management of gastric varices, endoscopy ultrasound can be easily used to check the varix flow [10]. Finally, one on the endpoints was death (19.5 % of study population). Apart from other causes, it included
123
276
infections (3) and bleeding (2). Authors assert that any death was related to the injection procedure, although these two complications have been clearly related to CAI [9]. We do not know whether these patients are from active bleeders or from secondary or primary prophylaxis. Because of these complications can be related to CAI and large amount of CA has been used, authors should specify when these advert events occurred and which kind of patients were affected, as death cannot be admissible for primary prophylaxis with CAI when beta-blockers are the only recommended strategy [4, 6]. As a conclusion, CAI is a safe and effective procedure for active GV bleeding and for secondary prophylaxis. In this study, a more homogeneous study cohort, a better explanation of the GV subtypes included, a more accurate dose of CA and the use of endoscopy ultrasound to confirm varices obliteration might yield more consistent and comparable results with other studies.
Reply to Martinez-Gonzalez et al. We would like to thank Martinez-Gonzalez et al. for their detailed comments on our manuscript. We agree that for patients in whom cyanoacrylate injection (CAI) was used for primary prophylaxis, only complications should be used as an endpoint. Both patients treated with cyanoacrylate for primary prophylaxis had intolerance or failure of nonselective beta-blocker therapy (i.e., congestive heart failure on ACE inhibitor and progression of gastric varices despite the use of beta-blockade) in our study [1]. We agree that ‘‘need for anticoagulation’’ is not an accepted indication for primary prophylaxis. However, in referral centers, we often encounter complex clinical situations when a risk–benefit decision has to be made without scientific evidence or expert opinion-based guidelines. Since gastric variceal bleeding is often a devastating complication in subjects who are not anticoagulated, we surmised that outcomes may be worse in patients who are on anticoagulation therapy. As the authors are likely aware of, there are no data on outcomes of bleeding from gastroesophageal varices in patients who are anticoagulated without portal vein thrombosis. In the retrospective study by Thomopoulos et al. [11], no variceal bleeding was reported among 111 patients who bled while on anticoagulation therapy (vs. 14 % among controls), which suggests that this is an uncommon practice or a publication bias. With regard to the type of gastric varices reported in our study [1], the distinction between gastric-esophageal varices type 2 (GOV2) and isolated gastric varices type 1 (IGV1) varices is somewhat arbitrary based on the presence or absence of esophageal varices [12]. This may be subjective particularly in patients with recent bleeding. Consequently, a
123
Dig Dis Sci (2015) 60:275–277
better term to classify these collaterals would be ‘‘fundic varices.’’ However, contrary to the statement by MartinezGonzalez et al., we have not excluded GOV1 varices as seen in Table 2 [1]. As far as the endoscopic method, we used a slight modification of the endoscopic technique previously reported by Rengstorff et al. [13]. Thus, we injected CAI in 1 mL aliquots until we encountered resistance to injection (i.e., the varix felt ‘‘hard’’ to palpation with the catheter or bleeding ceased in patients who had active hemorrhage). Since some of the glue may spill out of the varix, the overall volume injected may exceed 3 mL. There are no data to support the use of smaller or larger volumes of glue outside the recommendations, which are strictly based on expert suggestions without an evidence. In fact, recent series describe volumes of injectate in excess of 2 mL/session even in patients treated for primary prophylaxis [13, 14]. Similarly, there is no qualified evidence that EUS-guided glue injection is superior to standard endoscopy in improving outcomes of therapy for gastric variceal bleeding [15]. We do agree that further comparison studies are needed before the added costs of EUS per se and associated with scope malfunction related to cyanoacrylate use can be advocated as standard of care. Finally, we entirely agree that some of the causes of death in our study could be attributed to glue injection. However, deaths from infection/sepsis and rebleeding occurred more than 8 weeks after the episode of endoscopic therapy, and therefore, they were unlikely to be related to the endoscopic procedure. No deaths from bleeding or infection were reported by the end of follow-up in patients who underwent primary prophylaxis. We apologize for omitting this information from the manuscript. Arslan Kahloon Naga Chalasani John DeWitt Suthat Liangpunsakul Rakesh Vinayek Raj Vuppalanchi Marwan Ghabril Michael Chiorean, MD Digestive Disease Institute, Division of Gastroenterology and Hepatology, Virginia Mason Medical Center, Seattle, WA 98101, USA e-mail: [email protected]
References 1. Kahloon A, Chalasani N, DeWitt J, et al. Endoscopic therapy with 2-Octyl-cyanoacrylate for the treatment of gastric varices. Dig Dis Sci. 2014;59:2178–2183. 2. Mishra S, Sharma B, Kumar A, Sarin S. Primary prophylaxis of gastric varices bleeding comparing cyanoacrylate and betablockers. J Hepatol. 2011;54:1161–1167.
Dig Dis Sci (2015) 60:275–277 3. Tripathi D. Primary prophylaxis against gastric variceal bleeding: is there a sticky solution at last? Hepatology. 2011;54: 1994–1996. 4. Franchis R. Report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol. 2010;53:762–768. 5. Kim T, Shijo H, Kokawa H, et al. Risk factors for hemorrhage from gastric fundal varices. Hepatology. 1997;25:307–312. 6. Garcia-Paga´n JC, Barrufet M, Cardenas A, Escorsell A. Management of gastric varices. Clin Gastroenterol Hepatol. 2014; 12:919–928. 7. Bhat Y, Banerjee S, Barth B, et al. Tissue adhesives: cyanoacrylate glue and fibrin sealant. Gastrointest Endosc. 2013;78: 209–215. 8. Seewald S, Ang T, Imazu H, et al. A standardized injection technique and regimen ensures success and safety of cyanoacrylate injection for the treatment of gastric fundal varices. Gastrointest Endosc. 2008;68:447–454. 9. Cameron R, Binmoeller K. Cyanoacrylate applications in the GI tract. Gastrointest Endosc. 2013;77:846–857.
277 10. Romeroo R, Ellrichmann M, Ortiz C, et al. Endoscopic ultrasound-guided therapy of gastric varices: results from a prospective multicenter study. Gastrointest Endosc. 2013;78:711–721. 11. Thomopoulos KC, Mimidis KP, Theocharis GJ, et al. Acute upper gastrointestinal bleeding in patients on long-term oral anticoagulation therapy: endoscopic findings, clinical management and outcome. World J Gastroenterol. 2005;11:1365–1368. 12. Sarin SK, Kumar A. Gastric varices: profile, classification, and management. Am J Gastroenterol. 1989;84:1244–1249. 13. Rengstorff DS, Binmoeller KF. A pilot study of 2-octyl cyanoacrylate injection for treatment of gastric fundal varices in humans. Gastrointest Endosc. 2004;59:553–558. 14. Chang YJ, Park JJ, Joo MK, et al. Long-term outcomes of prophylactic endoscopic histoacryl injection for gastric varices with a high risk of bleeding. Dig Dis Sci. 2010;55:2391–2397. 15. Girotra M, Raghavapuram S, Abraham RR, et al. Management of gastric variceal bleeding: role of endoscopy and endoscopic ultrasound. World J Hepatol. 2014;6:130–136.
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