- Email: [email protected]
Reply to Dr. Lo’s letter
GASTROENTEROLOGY 2004;126:933–945
CORRESPONDENCE Readers are encouraged to write letters to the editor concerning articles that have been published in GASTROENTEROLOGY. Short, general comments are also considered, but use of the Correspondence section for publication of original data in preliminary form is not encouraged. Letters should be typewritten and submitted electronically to www.gastro-central.org. Please be sure to send 2 hardcopies of any figures to the editorial office.
Are Vasoactive Drugs Truly the Treatment of Choice for Acute Esophageal Variceal Hemorrhage? Dear Sir: We read with interest the meta-analysis performed by D’Amico et al. that was published in the May 2003 issue of GASTROENTEROLOGY.1 The authors concluded that available evidence did not support emergency sclerotherapy as the first-line treatment for variceal bleeding in cirrhosis when compared with vasoactive drugs, which controlled bleeding in 83% of patients. They further pointed out that this consideration may also be extended to banding ligation. However, this is contrary to what is used in general practice.2 We would like to make some comments. As shown in the meta-analysis, most studies have shown that vasoactive drugs have the advantage of a good safety profile with similar effectiveness to endoscopic injection sclerotherapy (EIS) in stopping acute bleeding. However, vasopressin has been associated with potentially severe complications and the efficacy has been proven to be inferior to somatostatin.3 If we believe that EIS is as effective as somatostatin, then the study4 which showed that EIS was superior to vasopressin in controlling bleeding should not be simply regarded as flawed with detection bias. It is very unlikely that the use of endoscopic surveillance induced a serious observation bias. The hemostatic rate of 83% for vasoconstrictors was the results just observed for a short period. Based on the studies that proved the effectiveness and safety of vasoconstrictors, we can only infer that the vasoactive drugs are a good alternative when endoscopists are not available and emergency sclerotherapy should be performed with caution. Vasoactive drugs are not a definitive therapy and should be always followed by a definitive form of treatment such as EIS.5 The vasoconstrictors are valuable as a first-line approach for acute bleeding but cannot replace the role of emergency EIS in the prevention of variceal rebleeding. If EIS should be delayed until the use of vasoconstrictor for a few days, the expense of the vasoconstrictors and hospitalization would increase. Thus, the question of how the medical costs can be reduced arises. Endoscopic variceal ligation (EVL) has been shown to be comparable to EIS in controlling acute bleeding and long-term EVL is associated with fewer complications when compared with EIS.6 –7 The results of our previous trial demonstrated the superiority of emergency EVL over EIS in terms of hemostatic rates and complication rates.8 We cannot understand how D’Amico et al. ignored the fact that EVL is associated with fewer complications and suggested that EVL is not favored as the first-line therapy because of the equivalent hemostatic rate to EIS. Our study showed that emergency EVL arrested 97% of active variceal bleeding without serious complications. If complications are a serious concern, then EVL is a good alternative for patients with acute variceal hemorrhage. Studies comparing EVL with vasoconstrictors in the management of acute variceal bleeding are required before we can conclude that emergency EVL is not favored as a first-line therapy. A careful interpretation of the results using controlled studies is needed while performing a metaanalysis. We believe that endoscopic therapies and vasoconstrictors
are complementary to each other rather than competitive as the first-line therapy in the management of acute variceal hemorrhage. GIN-HO LO KWOK-HUNG LAI Division of Gastroenterology Department of Medicine Kaohsiung Veterans General Hospital National Yang-Ming University Kaohsiung, Taiwan, Republic of China 1. D’Amico G, Pietrosi G, Tarantino I, Pagliaro L. Emergency sclerotherapy versus vasoactive drugs for variceal bleeding in cirrhosis: a Cochrane meta-analysis. Gastroenterology 2003;124:1277– 1291. 2. Jalan R, Hayes PC. UK guidelines on the management of variceal hemorrhage in cirrhotic patients. Gut 2000;46(Suppl. III):1–15. 3. Hsai HC, Lee FY, Tsai YT, Lee SD, Lai KH, Lin WJ, Lin HC, Lay CS, Wang SS, Lo KJ. Comparison of somatostatin and vasopressin in the control of acute variceal hemorrhage. A randomized controlled study. Chin J Gastroenterol 1990;7:71–78. 4. Westaby D, Hayes P, Gimson AES, Polson R, Williams R. Controlled clinical trial of injection sclerotherapy for active variceal bleeding. Hepatology 1989;9:274 –277. 5. De Franchis R, Banares R, Silvain C. Emergency endoscopy strategies for improved outcomes. Scand J Gastroenterol 1998; 33(Suppl. 226):25–36. 6. Laine L. Ligation: endoscopic treatment of choice for patients with bleeding esophageal varices? Hepatology 1995;22:663– 665. 7. Lo GH, Lai KH, Cheng JS, Hwu JH, Chang CF, Chen SM, Chiang HT. A prospective, randomized trial of sclerotherapy versus ligation in the management of bleeding esophageal varices. Hepatology 1995;22:466 – 471. 8. Lo GH, Lai KH, Cheng JS, Lin CK, Huang JS, Hsu PI, Chiang HT. Emergency banding ligation versus sclerotherapy for the control of active bleeding from esophageal varices. Hepatology 1997;25: 1101–1104. doi:10.1053/j.gastro.2004.01.033
Reply. We are most grateful to Dr. Lo for his considerations on our meta-analysis of emergency sclerotherapy compared with vasoactive drugs for acute variceal bleeding, although some of these might have been raised by some inadvertent misinterpretation of the message conveyed by our article. The conclusion of our meta-analysis was that “Available evidence does not support emergency sclerotherapy as the first line treatment of variceal bleeding in cirrhosis compared with vasoacitve drugs which control bleeding in 83% patients.” Moreover, we pointed out that it is conceivable that this consideration may be extended to banding ligation since, by combining the reults of 9 randomized controlled trials (RCTs) including 288 patients, it has been recently shown that endoscopic sclerotherapy and banding ligation are equivalent for hemostasis and survival of active variceal bleeding.1 Dr. Lo argues that this consideration is not accepted in UK2 where endoscopic treatment is recommended as the first-line therapy. However, we would like to point out that the UK guidelines for the management of variceal hemorrhage2 were set before our meta-analysis and
934
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also before the publication of many of the trials included in our meta-analysis. On the other hand, a large consensus conference3 also held before this meta-analysis recommended vasoactive treatment as soon as possible and then endoscopic therapy. Our meta-analysis provides scientific evidence to consider the hypothesis that patients might benefit more from endoscopic therapy when pharmacological therapy fails. Of course, this hypothesis should be proven in appropriate RCTs before it may be translated into a recommendation for clinical practice. Dr. Lo suggests that since sclerotherapy is equivalent to somatostatin and this is superior to vasopressin, then the superiority of sclerotherapy to vasopressin shown in an RCT potentially flawed by a detection bias should be accepted without considering this potential bias. We agree with Dr. Lo that indirect comparisons may provide useful information when several conditions are verified4 –5; however, great caution is suggested when interpreting indirect comparisons4 –5 and this is the reason why we abstained from exploring indirect comparisons and preferred to show the objective evidence shown by RCTs. We agree with Dr. Lo that the vasoactive drugs used for controlling the acute bleed should always be followed by a definitive treatment for the prevention of rebleeding. However, the use of pharmacological treatment to control acute bleeding does not delay the definitive treatment with -adrenergic blockers or endoscopic band ligation, which are the best options for the prevention of rebleeding.6 Yet, it provides the opportunity to perform the diagnostic endoscopy in stable conditions in most patients, avoiding emergency endoscopic treatment in patients candidate to long-term -blockers and allowing for endoscopic therapy in a safer situation in patients candidate to long-term banding ligation. This approach, would optimize therapy and reduce costs. Banding ligation has not been compared with vasoactive drugs and our meta-analysis showed that sclerotherapy is not superior to pharmacological therapy while it is associated with a higher complication rate. Although adverse events are significantly less with long-term banding ligation than sclerotherapy, this has been shown in the emergency situation in only one RCT,7 which might be not a conclusive evidence that emergency banding ligation is safer than sclerotherapy. Therefore, available scientific evidence does not support endoscopic therapy as first-line therapy, and suggests that endoscopic and pharmacological therapy may be equivalent options. Since both may control bleeding in over 80% of patients and the association has been proven superior to endoscopic therapy alone,8 we consider it clinically sound to use first vasoactive drugs which are less invasive and safer than emergency sclerotherapy and to add the endoscopic therapy (banding ligation whenever available) in pharmacological treatment failures. However, whether this approach is more effective and safe than the immediate combination of endoscopic and pharmacological therapy, should be proven in appropriately designed and conducted clinical trials. GENNARO D’AMICO GIADA PIETROSI ILARIA TARANTINO Department of Medicine Ospedale V Cervello Palermo, Italy LUIGI PAGLIARO Institute of Medicina Generale e Pneumologia University of Palermo Palermo, Italy
GASTROENTEROLOGY Vol. 126, No. 3
1. de Franchis R, Primignani M. Endoscopic treatments for portal hypertension. Sem Liv Dis 1999;19:439 – 455. 2. Jalan R, Hayes PC. UK guidelines on the management of variceal hemorrhage in cirrhotic patients. Gut 2000;46(Suppl. III):1–15. 3. de Franchis R. Updating consensus in portal hypertension: report of the Baveno III Consensus Workshop on definitions, methodology and therapeutic strategies in portal hypertension. J Hepatol 2000;33:846 – 852. 4. Bucher HC, Guyatt GH, Griffith LE, Walter SD. The results of direct and indirect treatment comparisons in meta-analysis of randomised controlled trials. J Clin Epidemiol 1997;50:683– 691. 5. Song F, Altman D, Glenny AM, Deeks JJ. Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analyses. BMJ 2003;326:472– 475. 6. Bosch J, Abraldes JC, Groszmann R. Current management of portal hypertension. J Hepatol 2003;38:S54 –S68. 7. Lo GH, Lai KH, Cheng JS, Lin CK, Huang JS, Hsu PI, Chiang HT. Emergency banding ligation versus sclerotherapy for the control of active bleeding from esophageal varices. Hepatology 1997;25: 1101–1104. 8. Banares R, Albillos A, Rincon D, Alonso S, Gonzalez M, Ruiz-delArbol L, Salcedo M, Molinero LM. Endoscopic treatment versus endoscopic plus pharmacologic treatment for acute variceal bleeding. A meta-analysis. Hepatology 2002;35:609 – 615. doi:10.1053/j.gastro.2004.01.034
Binding Activities of Infliximab and Etanercept to Transmembrane Tumor Necrosis Factor-␣ Dear Sir: We read with interest the article entitled “Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn’s disease” by van den Brande et al.1 The 2 types of TNF antagonists, infliximab (chimeric anti-TNF-␣ antibody), and etanercept (recombinant TNF receptor/immunoglobulin G fusion protein), have been shown to be equally effective against rheumatoid arthritis; however, only infliximab was effective in Crohn’s disease, the other TNF-mediated disease. The authors concluded that infliximab, but not etanercept, binds to the transmembrane TNF-␣ on lamina propria T cells from patients with Crohn’s disease, and only infliximab-induced apoptosis of activated lymphocytes. In the article, the inability of etanercept on the binding to transmembrane TNF-␣ was suggested to explain the difference in the biological effects of these 2 types of TNF antagonists in the clinical settings. There are 2 points we would like to discuss. First is on the mechanism of infliximab-induced T cell apoptosis. As they implicated, outside-toinside (reverse) signal from transmembrane TNF-␣ is likely the cause of infliximab-induced apoptosis. Our group and others have shown that stimulation of transmembrane TNF-␣ with polyclonal anti-TNF-␣ induced several biological effects including calcium mobilization,2,3 cytokine production,2,4 and E-selectin expression on T cells.5 These lines of evidence support the presence of reverse signal through transmembrane TNF-␣ in infliximab-induced apoptosis as well. Second, we suppose that etanercept binds to transmembrane TNF-␣ as well as infliximab, which does not agree with the data by van den Brande et al.1 Binding of etanercept as well as infliximab to uncleavable form of transmembrane TNF-␣ (amino acids 1–12 of mature TNF deleted) on mouse myeloma K2 cells has already been demonstrated,6 although more infliximab bound to the transmembrane TNF-␣ with higher avidity than etanercept. In addition, we here show that etanercept and infliximab bound to
CORRESPONDENCE Readers are encouraged to write letters to the editor concerning articles that have been published in GASTROENTEROLOGY. Short, general comments are also considered, but use of the Correspondence section for publication of original data in preliminary form is not encouraged. Letters should be typewritten and submitted electronically to www.gastro-central.org. Please be sure to send 2 hardcopies of any figures to the editorial office.
Are Vasoactive Drugs Truly the Treatment of Choice for Acute Esophageal Variceal Hemorrhage? Dear Sir: We read with interest the meta-analysis performed by D’Amico et al. that was published in the May 2003 issue of GASTROENTEROLOGY.1 The authors concluded that available evidence did not support emergency sclerotherapy as the first-line treatment for variceal bleeding in cirrhosis when compared with vasoactive drugs, which controlled bleeding in 83% of patients. They further pointed out that this consideration may also be extended to banding ligation. However, this is contrary to what is used in general practice.2 We would like to make some comments. As shown in the meta-analysis, most studies have shown that vasoactive drugs have the advantage of a good safety profile with similar effectiveness to endoscopic injection sclerotherapy (EIS) in stopping acute bleeding. However, vasopressin has been associated with potentially severe complications and the efficacy has been proven to be inferior to somatostatin.3 If we believe that EIS is as effective as somatostatin, then the study4 which showed that EIS was superior to vasopressin in controlling bleeding should not be simply regarded as flawed with detection bias. It is very unlikely that the use of endoscopic surveillance induced a serious observation bias. The hemostatic rate of 83% for vasoconstrictors was the results just observed for a short period. Based on the studies that proved the effectiveness and safety of vasoconstrictors, we can only infer that the vasoactive drugs are a good alternative when endoscopists are not available and emergency sclerotherapy should be performed with caution. Vasoactive drugs are not a definitive therapy and should be always followed by a definitive form of treatment such as EIS.5 The vasoconstrictors are valuable as a first-line approach for acute bleeding but cannot replace the role of emergency EIS in the prevention of variceal rebleeding. If EIS should be delayed until the use of vasoconstrictor for a few days, the expense of the vasoconstrictors and hospitalization would increase. Thus, the question of how the medical costs can be reduced arises. Endoscopic variceal ligation (EVL) has been shown to be comparable to EIS in controlling acute bleeding and long-term EVL is associated with fewer complications when compared with EIS.6 –7 The results of our previous trial demonstrated the superiority of emergency EVL over EIS in terms of hemostatic rates and complication rates.8 We cannot understand how D’Amico et al. ignored the fact that EVL is associated with fewer complications and suggested that EVL is not favored as the first-line therapy because of the equivalent hemostatic rate to EIS. Our study showed that emergency EVL arrested 97% of active variceal bleeding without serious complications. If complications are a serious concern, then EVL is a good alternative for patients with acute variceal hemorrhage. Studies comparing EVL with vasoconstrictors in the management of acute variceal bleeding are required before we can conclude that emergency EVL is not favored as a first-line therapy. A careful interpretation of the results using controlled studies is needed while performing a metaanalysis. We believe that endoscopic therapies and vasoconstrictors
are complementary to each other rather than competitive as the first-line therapy in the management of acute variceal hemorrhage. GIN-HO LO KWOK-HUNG LAI Division of Gastroenterology Department of Medicine Kaohsiung Veterans General Hospital National Yang-Ming University Kaohsiung, Taiwan, Republic of China 1. D’Amico G, Pietrosi G, Tarantino I, Pagliaro L. Emergency sclerotherapy versus vasoactive drugs for variceal bleeding in cirrhosis: a Cochrane meta-analysis. Gastroenterology 2003;124:1277– 1291. 2. Jalan R, Hayes PC. UK guidelines on the management of variceal hemorrhage in cirrhotic patients. Gut 2000;46(Suppl. III):1–15. 3. Hsai HC, Lee FY, Tsai YT, Lee SD, Lai KH, Lin WJ, Lin HC, Lay CS, Wang SS, Lo KJ. Comparison of somatostatin and vasopressin in the control of acute variceal hemorrhage. A randomized controlled study. Chin J Gastroenterol 1990;7:71–78. 4. Westaby D, Hayes P, Gimson AES, Polson R, Williams R. Controlled clinical trial of injection sclerotherapy for active variceal bleeding. Hepatology 1989;9:274 –277. 5. De Franchis R, Banares R, Silvain C. Emergency endoscopy strategies for improved outcomes. Scand J Gastroenterol 1998; 33(Suppl. 226):25–36. 6. Laine L. Ligation: endoscopic treatment of choice for patients with bleeding esophageal varices? Hepatology 1995;22:663– 665. 7. Lo GH, Lai KH, Cheng JS, Hwu JH, Chang CF, Chen SM, Chiang HT. A prospective, randomized trial of sclerotherapy versus ligation in the management of bleeding esophageal varices. Hepatology 1995;22:466 – 471. 8. Lo GH, Lai KH, Cheng JS, Lin CK, Huang JS, Hsu PI, Chiang HT. Emergency banding ligation versus sclerotherapy for the control of active bleeding from esophageal varices. Hepatology 1997;25: 1101–1104. doi:10.1053/j.gastro.2004.01.033
Reply. We are most grateful to Dr. Lo for his considerations on our meta-analysis of emergency sclerotherapy compared with vasoactive drugs for acute variceal bleeding, although some of these might have been raised by some inadvertent misinterpretation of the message conveyed by our article. The conclusion of our meta-analysis was that “Available evidence does not support emergency sclerotherapy as the first line treatment of variceal bleeding in cirrhosis compared with vasoacitve drugs which control bleeding in 83% patients.” Moreover, we pointed out that it is conceivable that this consideration may be extended to banding ligation since, by combining the reults of 9 randomized controlled trials (RCTs) including 288 patients, it has been recently shown that endoscopic sclerotherapy and banding ligation are equivalent for hemostasis and survival of active variceal bleeding.1 Dr. Lo argues that this consideration is not accepted in UK2 where endoscopic treatment is recommended as the first-line therapy. However, we would like to point out that the UK guidelines for the management of variceal hemorrhage2 were set before our meta-analysis and
934
CORRESPONDENCE
also before the publication of many of the trials included in our meta-analysis. On the other hand, a large consensus conference3 also held before this meta-analysis recommended vasoactive treatment as soon as possible and then endoscopic therapy. Our meta-analysis provides scientific evidence to consider the hypothesis that patients might benefit more from endoscopic therapy when pharmacological therapy fails. Of course, this hypothesis should be proven in appropriate RCTs before it may be translated into a recommendation for clinical practice. Dr. Lo suggests that since sclerotherapy is equivalent to somatostatin and this is superior to vasopressin, then the superiority of sclerotherapy to vasopressin shown in an RCT potentially flawed by a detection bias should be accepted without considering this potential bias. We agree with Dr. Lo that indirect comparisons may provide useful information when several conditions are verified4 –5; however, great caution is suggested when interpreting indirect comparisons4 –5 and this is the reason why we abstained from exploring indirect comparisons and preferred to show the objective evidence shown by RCTs. We agree with Dr. Lo that the vasoactive drugs used for controlling the acute bleed should always be followed by a definitive treatment for the prevention of rebleeding. However, the use of pharmacological treatment to control acute bleeding does not delay the definitive treatment with -adrenergic blockers or endoscopic band ligation, which are the best options for the prevention of rebleeding.6 Yet, it provides the opportunity to perform the diagnostic endoscopy in stable conditions in most patients, avoiding emergency endoscopic treatment in patients candidate to long-term -blockers and allowing for endoscopic therapy in a safer situation in patients candidate to long-term banding ligation. This approach, would optimize therapy and reduce costs. Banding ligation has not been compared with vasoactive drugs and our meta-analysis showed that sclerotherapy is not superior to pharmacological therapy while it is associated with a higher complication rate. Although adverse events are significantly less with long-term banding ligation than sclerotherapy, this has been shown in the emergency situation in only one RCT,7 which might be not a conclusive evidence that emergency banding ligation is safer than sclerotherapy. Therefore, available scientific evidence does not support endoscopic therapy as first-line therapy, and suggests that endoscopic and pharmacological therapy may be equivalent options. Since both may control bleeding in over 80% of patients and the association has been proven superior to endoscopic therapy alone,8 we consider it clinically sound to use first vasoactive drugs which are less invasive and safer than emergency sclerotherapy and to add the endoscopic therapy (banding ligation whenever available) in pharmacological treatment failures. However, whether this approach is more effective and safe than the immediate combination of endoscopic and pharmacological therapy, should be proven in appropriately designed and conducted clinical trials. GENNARO D’AMICO GIADA PIETROSI ILARIA TARANTINO Department of Medicine Ospedale V Cervello Palermo, Italy LUIGI PAGLIARO Institute of Medicina Generale e Pneumologia University of Palermo Palermo, Italy
GASTROENTEROLOGY Vol. 126, No. 3
1. de Franchis R, Primignani M. Endoscopic treatments for portal hypertension. Sem Liv Dis 1999;19:439 – 455. 2. Jalan R, Hayes PC. UK guidelines on the management of variceal hemorrhage in cirrhotic patients. Gut 2000;46(Suppl. III):1–15. 3. de Franchis R. Updating consensus in portal hypertension: report of the Baveno III Consensus Workshop on definitions, methodology and therapeutic strategies in portal hypertension. J Hepatol 2000;33:846 – 852. 4. Bucher HC, Guyatt GH, Griffith LE, Walter SD. The results of direct and indirect treatment comparisons in meta-analysis of randomised controlled trials. J Clin Epidemiol 1997;50:683– 691. 5. Song F, Altman D, Glenny AM, Deeks JJ. Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analyses. BMJ 2003;326:472– 475. 6. Bosch J, Abraldes JC, Groszmann R. Current management of portal hypertension. J Hepatol 2003;38:S54 –S68. 7. Lo GH, Lai KH, Cheng JS, Lin CK, Huang JS, Hsu PI, Chiang HT. Emergency banding ligation versus sclerotherapy for the control of active bleeding from esophageal varices. Hepatology 1997;25: 1101–1104. 8. Banares R, Albillos A, Rincon D, Alonso S, Gonzalez M, Ruiz-delArbol L, Salcedo M, Molinero LM. Endoscopic treatment versus endoscopic plus pharmacologic treatment for acute variceal bleeding. A meta-analysis. Hepatology 2002;35:609 – 615. doi:10.1053/j.gastro.2004.01.034
Binding Activities of Infliximab and Etanercept to Transmembrane Tumor Necrosis Factor-␣ Dear Sir: We read with interest the article entitled “Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn’s disease” by van den Brande et al.1 The 2 types of TNF antagonists, infliximab (chimeric anti-TNF-␣ antibody), and etanercept (recombinant TNF receptor/immunoglobulin G fusion protein), have been shown to be equally effective against rheumatoid arthritis; however, only infliximab was effective in Crohn’s disease, the other TNF-mediated disease. The authors concluded that infliximab, but not etanercept, binds to the transmembrane TNF-␣ on lamina propria T cells from patients with Crohn’s disease, and only infliximab-induced apoptosis of activated lymphocytes. In the article, the inability of etanercept on the binding to transmembrane TNF-␣ was suggested to explain the difference in the biological effects of these 2 types of TNF antagonists in the clinical settings. There are 2 points we would like to discuss. First is on the mechanism of infliximab-induced T cell apoptosis. As they implicated, outside-toinside (reverse) signal from transmembrane TNF-␣ is likely the cause of infliximab-induced apoptosis. Our group and others have shown that stimulation of transmembrane TNF-␣ with polyclonal anti-TNF-␣ induced several biological effects including calcium mobilization,2,3 cytokine production,2,4 and E-selectin expression on T cells.5 These lines of evidence support the presence of reverse signal through transmembrane TNF-␣ in infliximab-induced apoptosis as well. Second, we suppose that etanercept binds to transmembrane TNF-␣ as well as infliximab, which does not agree with the data by van den Brande et al.1 Binding of etanercept as well as infliximab to uncleavable form of transmembrane TNF-␣ (amino acids 1–12 of mature TNF deleted) on mouse myeloma K2 cells has already been demonstrated,6 although more infliximab bound to the transmembrane TNF-␣ with higher avidity than etanercept. In addition, we here show that etanercept and infliximab bound to