- Email: [email protected]
First meta-analysis of octreotide for variceal bleeding. A lost opportunity
Journal of Hepatology 36 (2002) 574–577 www.elsevier.com/locate/jhep
BEYOND THE JOURNAL Associate Editors: Guadalupe Garcia-Tsao and Ronald Oude Elferink
First meta-analysis of octreotide for variceal bleeding. A lost opportunity Octreotide for acute esophageal variceal bleeding: a meta-analysis. Corley DA, Cello JP, Adkisson W, Ko WF, Kerlikowske K. Division of Gastroenterology, University of California, San Francisco 94143-0538, USA BACKGROUND & AIMS: Studies of octreotide have not demonstrated a consistent benefit in efficacy or safety compared with conventional therapies. This study statistically pooled existing trials to evaluate the safety and efficacy of octreotide for esophageal variceal hemorrhage. METHODS: We identified randomized trials of octreotide for variceal hemorrhage from computerized databases, scientific meeting abstracts, and the manufacturer of octreotide. Blinded reviewers abstracted the data, and a meta-analysis was performed. RESULTS: Octreotide improved control of esophageal variceal hemorrhage compared with all alternative therapies combined (relative risk [RR], 0.63; 95% confidence interval [CI], 0.51–0.77); vasopressin/terlipressin (RR, 0.58; 95% CI, 0.42–0.81); or no additional intervention/placebo (among patients that received initial sclerotherapy/banding before randomization) (RR, 0.46; 95% CI, 0.32–0.67). Octreotide had comparable efficacy to immediate sclerotherapy for control of bleeding (RR, 0.94; 95% CI, 0.55–1.62), fewer major complications than vasopressin/terlipessin (RR, 0.31; 95% CI, 0.11– 0.87), and a complication profile comparable to no intervention/placebo (RR, 1.06; 95% CI, 0.72–1.55). No specific alternative therapy demonstrated a mortality benefit. CONCLUSIONS: These results favor octreotide over vasopressin/terlipressin in the control of esophageal variceal bleeding and suggest it is a safe and effective adjunctive therapy after variceal obliteration techniques. Trials are needed to determine the optimal dose, route, and duration of octreotide treatment. Gastroenterology 2001; 120: 946–954 PII: S01 68- 8278(02)0004 6-6
A meta-analysis recently reported in Gastroenterology by Corley et al. [1] showed that, in cirrhotic patients, octreotide improved control of variceal bleeding compared to all alternative therapies, to placebo/non-intervention and to vasopressin/terlipressin, whereas it was comparable to emergency sclerotherapy. Furthermore, the complication profile of octreotide was comparable to non-intervention/ placebo. However, these advantages were not associated with a survival benefit [1]. Several methodological issues in this meta-analysis call for caution before one can accept these results and apply them to clinical practice.
1. Aim of the meta-analysis The aim of the meta-analysis was to compare octreotide with alternative intervention, for acute variceal bleeding. A major measure of treatment efficacy was ‘sustained control of bleeding’. This was defined as ‘absence of rebleeding, as defined in each article’. However, these definitions were not reported in the meta-analysis and, in fact, were not reported also in seven of the 13 original reports (Table 1). It is of interest that although rebleeding was defined in only 6/13 studies, it was assessed in 12/13 and the time of assessment ranged from 24 h to 60 days after admission. Furthermore, in two studies rebleeding was assessed at different time intervals (Table 1) and no information was reported in the meta-analysis about which of these different assessments was used. Clearly, the uncertainty about the meaning of ‘rebleeding’ in this meta-analysis, makes it difficult to apply its results to clinical practice. In this context, it is important to note that recent consensus conferences [2–4] stated distinct definitions for control of bleeding and rebleeding. This is important in clinical practice, because achieving control of bleeding saves time for definitive therapy to prevent rebleeding. Therefore, in clinical trials and in meta-analyses, separate assessment of ‘control of bleeding’ and of ‘rebleeding’ should be reported.
Beyond the Journal
575
Table 1 Relevant characteristics of RCTs included in the Corley’s meta-analysis Study (reference in Corley’s article)
Definition of rebleeding
Time of assessment of rebleeding
Duration of octreotide infusion
Sclerotherapy associated with octreotide
Hwang [1]
Blood in naso-gastric tube after initial control of bleeding Any recurrence of bleeding after initial hemostasis Not reported Recurrent hematemesis after initial control of bleeding Not reported (definition for failure to control bleeding, reported) Not reported Hematemesis/melena plus systemic disturbance Not reported (definition for failure to control bleeding, reported) Not reported Not reported (definition for failure to control bleeding, reported) Hematemesis or fall in blood pressure ,90 mmHg plus pulse rate .100 Not reported Not reported
24 h
24 h
No
24 h Not reported 24 h; 7 days; 60 days Not reported (failure to control bleeding assessed at 12 h) 48 h 48 h 120 h; 15 days
24 h 8–24 h 168 h 24 h
No No No No
48 h 48 h 120 h
No No Yes, before octreotide
120 h 120 h
120 h 120 h
Yes, before octreotide Yes, before octreotide
Hospital stay
120 h
120 h 48 h
120 h 48 h
Band ligation before octreotide Yes, before octreotide No
Huang [1] Kasumobroto [1] Pedretti [1] Silvain [1] Sung [1] a Jenkins [1] Besson [1] Signorelli [1] b Zuberi [1] Sung [1] c Signorelli [1] McKee [1] a b c d
d
Ref. [15] in Corley’s article. Ref. [9] in Corley’s article. Ref. [16] in Corley’s article. Ref. [37] in Corley’s article.
2. Study selection In the methods section of the article by Corley et al. [1] it is reported that “full manuscripts… were evaluated” however, three randomized controlled trials (RCTs) only available in abstract form were included (Refs. [9,36,37] in Ref. [1]). In contrast four other abstracts [5–8] available at the time of the selection of studies for this meta-analysis were not included. Their inclusion would have increased the total number of patients available for the meta-analysis from 1016 to 1474. This publication bias [9] is particularly relevant because one of the excluded trials [5] was the only available double-blind study of octreotide compared with placebo. In fact, the studies included in the meta-analysis and presented as comparisons of octreotide with placebo were actually RCTs of sclerotherapy (or band ligation) associated with octreotide and compared with sclerotherapy (or band ligation) plus placebo or alone. 3. Search strategy Although the search was limited to studies published within 1999, one study published in March 2000 (Ref. [38] in [1]) was also included. The inclusion of this study introduced another remarkable bias because if studies published in 2000 had to be included then there were three more studies to be considered, published, respectively, in March [10] April [11] and September [12] 2000. The inclusion of these three studies would have increased the total number of patients included in the meta-analysis by 339 patients. When also the four missed abstracts are consid-
ered, the total number of available patients would have been 1813 (19 RCTs) instead of the 1016 included.
4. Combinability of trials RCTs of octreotide compared with any alternative treatment were combined showing a significant benefit from octreotide regarding sustained control of bleeding (RR 0.63; CI 0.42–0.81). However, since alternative treatments (placebo or no active intervention, vasopressin/glipressin, balloon tamponade and sclerotherapy) are markedly different from each other, it is hard to interpret this pooled estimate. In fact, separate analyses by type of control treatment revealed that octreotide was superior to placebo or no treatment and to vasopressin/glipressin but not to sclerotherapy, and we know from previous reviews that it is not superior to balloon tamponade [13]. Also the combinability of studies using vasopressin or terlipressin as a control treatment is somehow questionable. In fact, although terlipressin is a vasopressin analogue, it is the only vasoactive drug which has been shown to significantly reduce mortality compared with placebo [14], whereas such an effect has never been shown for vasopressin.
5. Quality of trials Although the quality of trials has been assessed, no details were reported on the quality of each trial. Quality was assessed by a validated method [15] based on adequacy of randomization and blinded treatment alloca-
576
Beyond the Journal
tion. However, several other methodological issues for clinical trials in portal hypertension have been discussed and agreed upon in recent consensus conferences [2–4,16]. Even though a trial may be well randomized and have an adequate concealment of treatment assignment it may be poorly undertaken, and this issue should also be explored in meta-analyses.
adjunctive therapy to endoscopic variceal sclerotherapy or band ligation in the treatment of acute variceal hemorrhage. G. D’Amico* Inst. di Med. Generale e Pneumologia, Universita degli Studi di Palermo, Ospedale V. Cervello, Via Trabucco 180, 90146 Palermo, Italy
6. Results E-mail address: [email protected] (G. D’Amico).
In general, the results of this meta-analysis are difficult to follow, particularly because the relevant data for each study are not shown. Therefore, it is impossible to assess the reproducibility of the pooled estimates. Specific guidelines to improve the quality of reports of meta-analyses of RCTs (the QUORUM statement) [17] have been reported, but unfortunately they were not followed by Corley et al. The comparison of octreotide with any alternative therapy is clinically meaningless given the marked differences among control treatments. The comparison between octreotide and placebo or no therapy was not actually assessed. The meta-analysis only evaluated octreotide (vs. placebo/no therapy) as an adjunct to endoscopic sclerotherapy or band ligation. In this context, it is important to note that the only available double blind study of octreotide vs. placebo [5] included 262 patients and failed to show any benefit from octreotide. The superiority of octreotide over vasopressin/ glypressin should be confirmed before it is accepted in clinical practice. It is of interest, in this regard that previous separate analyses of RCTs of octreotide vs. vasopressin and terlipressin, showed that octreotide is superior to vasopressin but not to terlipressin [13–14]. That octreotide is as effective as sclerotherapy had already been shown in a larger meta-analysis [18]. Although octreotide appears to be a safe drug [19], the meta-analysis presented by Corley et al. is also difficult to follow, in this respect. In Table 3 of Ref. [1] it is not specified whether numbers refer to number of complications or number of patients. It is also surprising that post-sclerotherapy ulcers, irrespective of severity, were not included as a complication and that bleeding from post-sclerotherapy ulcers, which is the most frequent and severe complication of emergency sclerotherapy [18] was not mentioned. With all these drawbacks, it is difficult to draw conclusions from this meta-analysis particularly regarding the usefulness of octreotide as single first line therapy for variceal hemmorrhage. Also, the biological plausibility of octreotide’s clinical efficacy is somewhat weak given its inconsistent hemodynamic effects [19] and the recent demonstration of a rapid desensitization to its portal pressure-reducing effects [20]. Blunting of postprandial splanchnic hyperemia, the most consistently reported hemodynamic effect of octreotide [19] may be, however, its main mechanism of action [1,13]. Therefore, for now, octreotide should only be used as an
References [1] Corley DA, Cello PJ, Adkisson W, Ko WF, Kerlikowske K. Octreotide for acute esophageal variceal bleeding: a meta-analysis. Gastroenterology 2001;120:946–954. [2] de Franchis R. Portal hypertension II. Proceedings of the second Baveno International Consensus Workshop on definitions, methodology, and therapeutic strategies. In: de Franchis R, editor. Oxford: Blackwell Science, 1996. [3] Grace N, Groszman RJ, Garcia-Tsao G, Burroughs AK, Pagliaro L, Makuch RW, et al. Portal hypertension and variceal bleeding: an AASLD single topic symposium. Hepatology 1998;28:868–880. [4] 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. [5] Burroughs AK. Double blind RCT of 5 day octreotide versus placebo, associated with sclerotherapy for trial failures. Hepatology 1996;24(Suppl):352A. [6] Poo JL, Bosques S, Guarduno R, Marin E, Mora`n MA, Bobadilla J, et al. Octreotide versus emergency sclerotherapy in acute variceal hemorrhage in liver cirrhosis. A randomized multicenter study. Gastroenterology 1996;110:A1297. [7] Lopez F, Vargas R, Margarita G, Rizo T, Arguelles D. Octreotide vs sclerotherapy in the treatment of acute variceal bleeding. Hepatology 1999;30:574A. [8] Signorelli S, Paris B, Negrin F, Cesareni P, Minola E, Auriemma L. Octreotide and endoscopic variceal sclerotherapy in the management of acute variceal haemorrhage. Endoscopy 1999;31:E66. [9] Egger E, Smith GD. Meta-analysis. Bias in location and selection of studies. BMJ 1998;316:61–66. [10] Sivri B, Oksuzoglu G, Bayraktar Y, Kayhan B. A prospective randomized trial from Turkey comparing octreotide versus injection sclerotherapy in acute variceal bleeding. Hepatogastroenterology 2000;47:166–173. [11] Bildozola M, Kravetz, Argonz J, Romero G, Suarez A, Jmelnitzky A, et al. Efficacy of octreotide and sclerotherapy in the treatment of acute variceal bleeding in cirrhotic patients. A prospective, multicenter, and randomized clinical trial. Scand J Gastroenterol 2000;35:419–425. [12] Freitas D, Sofia C, Pontres JM, Gregorio C, Cabral JP, Andrade P, et al. Octreotide in acute bleeding esophageal varices: a prospective randomized study. Hepatogastroenterology 2000;47:1310–1314. [13] D’Amico G, Pagliaro L, Bosch J. Pharmacological treatment of portal hypertension: an evidence based approach. Semin Liver Dis 1999;19: 475–506. [14] Ioannau G, Doust J, Rockey DC. Terlipressin for acute esophageal variceal hemorrage (Cochrane Review). Oxford: The Cochrane Library; Update Software, Issue 1; 2001. [15] Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al. Does quality of reports of randomized trials affect estimates of intervention efficacy reported in meta-analyses? Lancet 1998;352:609–613.
Beyond the Journal [16] Burroughs AK, editor. Methodology and review of clinical trials in portal hypertension Amsterdam: Excerpta Medica, 1987. [17] Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF, for the QUORUM Group. Improving the quality of reports of meta-analysis of randomised controlled trials: the Quorum statement. Lancet 1999;354:1896–1900. [18] D’Amico G, Pietrosi G, Tarantino I, Pagliaro L. Emergency sclerotherapy versus medical interventions for bleeding esophageal varices in cirrhosis (Cochrane Review). Oxford: The Cochrane Library; Update Software, Issue 1; 2002.
577
[19] Garcia-Pagan JC, Escorsell A, Moitinho E, Bosch J. Influence of pharmacological agents on portal hemodynamics: basis for its use in the treatment of portal hypertension. Semin Liver Dis 1999;19: 427–437. [20] Escorsell A, Bandi JC, Andreu V, Moitinho E, Garcia-Pagan JC, Bosch J, Rodes J. Desensitization to the effects of intravenous octreotide in cirrhotic patients with portal hypertension. Gastroenterology 2001;120:161–169.
BEYOND THE JOURNAL Associate Editors: Guadalupe Garcia-Tsao and Ronald Oude Elferink
First meta-analysis of octreotide for variceal bleeding. A lost opportunity Octreotide for acute esophageal variceal bleeding: a meta-analysis. Corley DA, Cello JP, Adkisson W, Ko WF, Kerlikowske K. Division of Gastroenterology, University of California, San Francisco 94143-0538, USA BACKGROUND & AIMS: Studies of octreotide have not demonstrated a consistent benefit in efficacy or safety compared with conventional therapies. This study statistically pooled existing trials to evaluate the safety and efficacy of octreotide for esophageal variceal hemorrhage. METHODS: We identified randomized trials of octreotide for variceal hemorrhage from computerized databases, scientific meeting abstracts, and the manufacturer of octreotide. Blinded reviewers abstracted the data, and a meta-analysis was performed. RESULTS: Octreotide improved control of esophageal variceal hemorrhage compared with all alternative therapies combined (relative risk [RR], 0.63; 95% confidence interval [CI], 0.51–0.77); vasopressin/terlipressin (RR, 0.58; 95% CI, 0.42–0.81); or no additional intervention/placebo (among patients that received initial sclerotherapy/banding before randomization) (RR, 0.46; 95% CI, 0.32–0.67). Octreotide had comparable efficacy to immediate sclerotherapy for control of bleeding (RR, 0.94; 95% CI, 0.55–1.62), fewer major complications than vasopressin/terlipessin (RR, 0.31; 95% CI, 0.11– 0.87), and a complication profile comparable to no intervention/placebo (RR, 1.06; 95% CI, 0.72–1.55). No specific alternative therapy demonstrated a mortality benefit. CONCLUSIONS: These results favor octreotide over vasopressin/terlipressin in the control of esophageal variceal bleeding and suggest it is a safe and effective adjunctive therapy after variceal obliteration techniques. Trials are needed to determine the optimal dose, route, and duration of octreotide treatment. Gastroenterology 2001; 120: 946–954 PII: S01 68- 8278(02)0004 6-6
A meta-analysis recently reported in Gastroenterology by Corley et al. [1] showed that, in cirrhotic patients, octreotide improved control of variceal bleeding compared to all alternative therapies, to placebo/non-intervention and to vasopressin/terlipressin, whereas it was comparable to emergency sclerotherapy. Furthermore, the complication profile of octreotide was comparable to non-intervention/ placebo. However, these advantages were not associated with a survival benefit [1]. Several methodological issues in this meta-analysis call for caution before one can accept these results and apply them to clinical practice.
1. Aim of the meta-analysis The aim of the meta-analysis was to compare octreotide with alternative intervention, for acute variceal bleeding. A major measure of treatment efficacy was ‘sustained control of bleeding’. This was defined as ‘absence of rebleeding, as defined in each article’. However, these definitions were not reported in the meta-analysis and, in fact, were not reported also in seven of the 13 original reports (Table 1). It is of interest that although rebleeding was defined in only 6/13 studies, it was assessed in 12/13 and the time of assessment ranged from 24 h to 60 days after admission. Furthermore, in two studies rebleeding was assessed at different time intervals (Table 1) and no information was reported in the meta-analysis about which of these different assessments was used. Clearly, the uncertainty about the meaning of ‘rebleeding’ in this meta-analysis, makes it difficult to apply its results to clinical practice. In this context, it is important to note that recent consensus conferences [2–4] stated distinct definitions for control of bleeding and rebleeding. This is important in clinical practice, because achieving control of bleeding saves time for definitive therapy to prevent rebleeding. Therefore, in clinical trials and in meta-analyses, separate assessment of ‘control of bleeding’ and of ‘rebleeding’ should be reported.
Beyond the Journal
575
Table 1 Relevant characteristics of RCTs included in the Corley’s meta-analysis Study (reference in Corley’s article)
Definition of rebleeding
Time of assessment of rebleeding
Duration of octreotide infusion
Sclerotherapy associated with octreotide
Hwang [1]
Blood in naso-gastric tube after initial control of bleeding Any recurrence of bleeding after initial hemostasis Not reported Recurrent hematemesis after initial control of bleeding Not reported (definition for failure to control bleeding, reported) Not reported Hematemesis/melena plus systemic disturbance Not reported (definition for failure to control bleeding, reported) Not reported Not reported (definition for failure to control bleeding, reported) Hematemesis or fall in blood pressure ,90 mmHg plus pulse rate .100 Not reported Not reported
24 h
24 h
No
24 h Not reported 24 h; 7 days; 60 days Not reported (failure to control bleeding assessed at 12 h) 48 h 48 h 120 h; 15 days
24 h 8–24 h 168 h 24 h
No No No No
48 h 48 h 120 h
No No Yes, before octreotide
120 h 120 h
120 h 120 h
Yes, before octreotide Yes, before octreotide
Hospital stay
120 h
120 h 48 h
120 h 48 h
Band ligation before octreotide Yes, before octreotide No
Huang [1] Kasumobroto [1] Pedretti [1] Silvain [1] Sung [1] a Jenkins [1] Besson [1] Signorelli [1] b Zuberi [1] Sung [1] c Signorelli [1] McKee [1] a b c d
d
Ref. [15] in Corley’s article. Ref. [9] in Corley’s article. Ref. [16] in Corley’s article. Ref. [37] in Corley’s article.
2. Study selection In the methods section of the article by Corley et al. [1] it is reported that “full manuscripts… were evaluated” however, three randomized controlled trials (RCTs) only available in abstract form were included (Refs. [9,36,37] in Ref. [1]). In contrast four other abstracts [5–8] available at the time of the selection of studies for this meta-analysis were not included. Their inclusion would have increased the total number of patients available for the meta-analysis from 1016 to 1474. This publication bias [9] is particularly relevant because one of the excluded trials [5] was the only available double-blind study of octreotide compared with placebo. In fact, the studies included in the meta-analysis and presented as comparisons of octreotide with placebo were actually RCTs of sclerotherapy (or band ligation) associated with octreotide and compared with sclerotherapy (or band ligation) plus placebo or alone. 3. Search strategy Although the search was limited to studies published within 1999, one study published in March 2000 (Ref. [38] in [1]) was also included. The inclusion of this study introduced another remarkable bias because if studies published in 2000 had to be included then there were three more studies to be considered, published, respectively, in March [10] April [11] and September [12] 2000. The inclusion of these three studies would have increased the total number of patients included in the meta-analysis by 339 patients. When also the four missed abstracts are consid-
ered, the total number of available patients would have been 1813 (19 RCTs) instead of the 1016 included.
4. Combinability of trials RCTs of octreotide compared with any alternative treatment were combined showing a significant benefit from octreotide regarding sustained control of bleeding (RR 0.63; CI 0.42–0.81). However, since alternative treatments (placebo or no active intervention, vasopressin/glipressin, balloon tamponade and sclerotherapy) are markedly different from each other, it is hard to interpret this pooled estimate. In fact, separate analyses by type of control treatment revealed that octreotide was superior to placebo or no treatment and to vasopressin/glipressin but not to sclerotherapy, and we know from previous reviews that it is not superior to balloon tamponade [13]. Also the combinability of studies using vasopressin or terlipressin as a control treatment is somehow questionable. In fact, although terlipressin is a vasopressin analogue, it is the only vasoactive drug which has been shown to significantly reduce mortality compared with placebo [14], whereas such an effect has never been shown for vasopressin.
5. Quality of trials Although the quality of trials has been assessed, no details were reported on the quality of each trial. Quality was assessed by a validated method [15] based on adequacy of randomization and blinded treatment alloca-
576
Beyond the Journal
tion. However, several other methodological issues for clinical trials in portal hypertension have been discussed and agreed upon in recent consensus conferences [2–4,16]. Even though a trial may be well randomized and have an adequate concealment of treatment assignment it may be poorly undertaken, and this issue should also be explored in meta-analyses.
adjunctive therapy to endoscopic variceal sclerotherapy or band ligation in the treatment of acute variceal hemorrhage. G. D’Amico* Inst. di Med. Generale e Pneumologia, Universita degli Studi di Palermo, Ospedale V. Cervello, Via Trabucco 180, 90146 Palermo, Italy
6. Results E-mail address: [email protected] (G. D’Amico).
In general, the results of this meta-analysis are difficult to follow, particularly because the relevant data for each study are not shown. Therefore, it is impossible to assess the reproducibility of the pooled estimates. Specific guidelines to improve the quality of reports of meta-analyses of RCTs (the QUORUM statement) [17] have been reported, but unfortunately they were not followed by Corley et al. The comparison of octreotide with any alternative therapy is clinically meaningless given the marked differences among control treatments. The comparison between octreotide and placebo or no therapy was not actually assessed. The meta-analysis only evaluated octreotide (vs. placebo/no therapy) as an adjunct to endoscopic sclerotherapy or band ligation. In this context, it is important to note that the only available double blind study of octreotide vs. placebo [5] included 262 patients and failed to show any benefit from octreotide. The superiority of octreotide over vasopressin/ glypressin should be confirmed before it is accepted in clinical practice. It is of interest, in this regard that previous separate analyses of RCTs of octreotide vs. vasopressin and terlipressin, showed that octreotide is superior to vasopressin but not to terlipressin [13–14]. That octreotide is as effective as sclerotherapy had already been shown in a larger meta-analysis [18]. Although octreotide appears to be a safe drug [19], the meta-analysis presented by Corley et al. is also difficult to follow, in this respect. In Table 3 of Ref. [1] it is not specified whether numbers refer to number of complications or number of patients. It is also surprising that post-sclerotherapy ulcers, irrespective of severity, were not included as a complication and that bleeding from post-sclerotherapy ulcers, which is the most frequent and severe complication of emergency sclerotherapy [18] was not mentioned. With all these drawbacks, it is difficult to draw conclusions from this meta-analysis particularly regarding the usefulness of octreotide as single first line therapy for variceal hemmorrhage. Also, the biological plausibility of octreotide’s clinical efficacy is somewhat weak given its inconsistent hemodynamic effects [19] and the recent demonstration of a rapid desensitization to its portal pressure-reducing effects [20]. Blunting of postprandial splanchnic hyperemia, the most consistently reported hemodynamic effect of octreotide [19] may be, however, its main mechanism of action [1,13]. Therefore, for now, octreotide should only be used as an
References [1] Corley DA, Cello PJ, Adkisson W, Ko WF, Kerlikowske K. Octreotide for acute esophageal variceal bleeding: a meta-analysis. Gastroenterology 2001;120:946–954. [2] de Franchis R. Portal hypertension II. Proceedings of the second Baveno International Consensus Workshop on definitions, methodology, and therapeutic strategies. In: de Franchis R, editor. Oxford: Blackwell Science, 1996. [3] Grace N, Groszman RJ, Garcia-Tsao G, Burroughs AK, Pagliaro L, Makuch RW, et al. Portal hypertension and variceal bleeding: an AASLD single topic symposium. Hepatology 1998;28:868–880. [4] 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. [5] Burroughs AK. Double blind RCT of 5 day octreotide versus placebo, associated with sclerotherapy for trial failures. Hepatology 1996;24(Suppl):352A. [6] Poo JL, Bosques S, Guarduno R, Marin E, Mora`n MA, Bobadilla J, et al. Octreotide versus emergency sclerotherapy in acute variceal hemorrhage in liver cirrhosis. A randomized multicenter study. Gastroenterology 1996;110:A1297. [7] Lopez F, Vargas R, Margarita G, Rizo T, Arguelles D. Octreotide vs sclerotherapy in the treatment of acute variceal bleeding. Hepatology 1999;30:574A. [8] Signorelli S, Paris B, Negrin F, Cesareni P, Minola E, Auriemma L. Octreotide and endoscopic variceal sclerotherapy in the management of acute variceal haemorrhage. Endoscopy 1999;31:E66. [9] Egger E, Smith GD. Meta-analysis. Bias in location and selection of studies. BMJ 1998;316:61–66. [10] Sivri B, Oksuzoglu G, Bayraktar Y, Kayhan B. A prospective randomized trial from Turkey comparing octreotide versus injection sclerotherapy in acute variceal bleeding. Hepatogastroenterology 2000;47:166–173. [11] Bildozola M, Kravetz, Argonz J, Romero G, Suarez A, Jmelnitzky A, et al. Efficacy of octreotide and sclerotherapy in the treatment of acute variceal bleeding in cirrhotic patients. A prospective, multicenter, and randomized clinical trial. Scand J Gastroenterol 2000;35:419–425. [12] Freitas D, Sofia C, Pontres JM, Gregorio C, Cabral JP, Andrade P, et al. Octreotide in acute bleeding esophageal varices: a prospective randomized study. Hepatogastroenterology 2000;47:1310–1314. [13] D’Amico G, Pagliaro L, Bosch J. Pharmacological treatment of portal hypertension: an evidence based approach. Semin Liver Dis 1999;19: 475–506. [14] Ioannau G, Doust J, Rockey DC. Terlipressin for acute esophageal variceal hemorrage (Cochrane Review). Oxford: The Cochrane Library; Update Software, Issue 1; 2001. [15] Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al. Does quality of reports of randomized trials affect estimates of intervention efficacy reported in meta-analyses? Lancet 1998;352:609–613.
Beyond the Journal [16] Burroughs AK, editor. Methodology and review of clinical trials in portal hypertension Amsterdam: Excerpta Medica, 1987. [17] Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF, for the QUORUM Group. Improving the quality of reports of meta-analysis of randomised controlled trials: the Quorum statement. Lancet 1999;354:1896–1900. [18] D’Amico G, Pietrosi G, Tarantino I, Pagliaro L. Emergency sclerotherapy versus medical interventions for bleeding esophageal varices in cirrhosis (Cochrane Review). Oxford: The Cochrane Library; Update Software, Issue 1; 2002.
577
[19] Garcia-Pagan JC, Escorsell A, Moitinho E, Bosch J. Influence of pharmacological agents on portal hemodynamics: basis for its use in the treatment of portal hypertension. Semin Liver Dis 1999;19: 427–437. [20] Escorsell A, Bandi JC, Andreu V, Moitinho E, Garcia-Pagan JC, Bosch J, Rodes J. Desensitization to the effects of intravenous octreotide in cirrhotic patients with portal hypertension. Gastroenterology 2001;120:161–169.