1. The role of vasoactive drugs used in esophageal variceal bleeding Date: 94.03.09 ( 三 ) Reporter: 張秀美 藥師

2. Population (P) Intervention (I) Comparison (C) Outcome (O) Esophageal variceal- bleeding Vasoactive drugs PlaceboEfficacy

3. Database Cochrane Library key word: Esophageal variceal bleeding found: 3 related results => Somatostatin analogues for acute bleeding oesophageal varices. => Terlipressin for acute esophageal variceal hemorrhage. => Emergency sclerotherapy versus medical interventions for bleeding oesophageal varices in cirrhotic patients.

6. Bandolier => knowledge library => not found. ACP Journal Club key word: Esophageal variceal bleeding found: 1 related result => Octreotide reduces rebleeding more than dose vasopressin or terlipressin in patients with esophageal varices.

9. National Guideline Clearinghouse (NGC) key word: Esophageal variceal bleeding found: No related result The American Gastroenterological Association => not found related guideline

11. HINT database => Medline, Cochrane Systematic Reviews, Cochrane of Abstracts of Reviews, Cochrane Central Register of Controlled Trials, OVID Full Text Collection. key word => Esophageal variceal bleeding Somatostatin, Octreotide, Vasopressin, Terlipressin found => …..

16. Results…..

17. 學名 SomatostatinOctreotideVasopressinTerlipressin 商名 SomatosanSandostatinPitressinGlypressin 規格 3mg/Amp0.1mg/1ml/Amp20U/1ml/Amp1mg/vial (in 5ml N/S) 性質 與 來源 Naturally tetra- decapeptide identical to human Somatotropin release inhibiting factor Somatostatin analogue Octapeptide analogue Natural antidiuretic hormone Synthetic analogue of vasopressin (triglycyl lysine vasopressin) 作用 機制 Inhibit secretion of growth hormone, glucagon, insulin, secretin, gastrin, and TSH. Clinical indications included GI bleeding. Inhibits growth hormone, insulin and glucagon secretion. More selective suppression of growth hormone than insulin or glucagon. Acts vascular smooth muscle to cause vasoconstriction. Portal blood pressure is reduced with contraction of esophageal smooth muscles. Increases vascular and nonvascular smooth muscle tone, resulting in vasoconstriction and decreased splanchnic blood flow. ref: micromedex

18. 學名 SomatostatinOctreotideVasopressinTerlipressin 商名 SomatosanSandostatinPitressinGlypressin 適應 症 Carcinoid syndrome Pancreatitis Gastrointestinal hemorrhage Acromegaly Carcinoid syndrome Secretory diarrhea Variceal bleeding Diabetes insipidus GI, EV-bleeding Class IIb (vasodilatory shock) EV-bleeding 劑量 ( 出血 ) Initial bolus: 250mcg then Continuous infus: 250-500mcg/hr x 2-5 d. SC: 50-100mcg; bid-tid/day IV infusion: 25-50mcg/hr x 5d IV: 0.2-1U/min, increased each hr by 0.2U/min until bleeding controled. IV: 2-4mg then 1mg q4-6h x 2-3d. 注意 事項 半衰期短 (1-3mins), 只能 IV continuous infusion. 半衰期較長 (90-110 mins), 可 SC 3-4 次 /day. IV infusion dilute: N/S (1-2mcg/ml) 室溫可存放 2 天 半衰期 10-20mins 必須稀釋才可 IVF: D5W: 0.1-1U/ml 0.9%N/S: 0.1-1U/ml IV NTG 降低 S.E t 1/2 51-66mins Antidiuretic effect: 3% of native Not cause cardiotoxic effect. ref: micromedex

19. Terlipressin for acute esophageal variceal hemorrhage G Ioannou, J Doust, DC Rockey The Cochrane Database of Systematic Reviews 2003, Issue 1. Art. No.: CD002147. DOI: 10.1002/14651858.CD002147.

20. Objectives To determine if treatment with terlipressin improves outcome in acute esophageal variceal hemorrhage and is safe. Selection criteria All randomized clinical trials, which compared terlipressin with: (a) placebo or no treatment, (b) balloon tamponade, (c) endoscopic treatment, (d) octreotide, (e) somatostatin and (f) vasopressin, in the setting of acute variceal hemorrhage. Data collection and analysis primary outcome measure was mortality. Secondary outcomes were failure of initial hemostasis, rebleeding, procedures required for uncontrolled bleeding or rebleeding, transfusion requirements and length of hospitalization. Main results The Cochrane Database of Systematic Reviews 2003, Issue 1.

21. Terlipressin v.s placeboBolloon tamponade endoscopicoctreotidesomatost atin vasopre ssin Mortality F: T NNNNN Failing initial hemostasis F: T NN F: O NN Rebleeding NNNNNN Procedures required for bleeding F: T- NNNN Blood transfusion NNNNNN Adverse event (death) NN Not estimable N N Adverse event (withdrawal) NN - NN F: T Length of hospitalization -- N - N - F: favor; N: no significant difference

22. ARR: 12.6%; NNT= 8 The Cochrane Database of Systematic Reviews 2003, Issue 1.

23. ARR: 17.7%; NNT= 6

24. The Cochrane Database of Systematic Reviews 2003, Issue 1. ARR: 12.8%; NNT= 8

25. The Cochrane Database of Systematic Reviews 2003, Issue 1. ARI: 14.3%; NNH= 7

26. The Cochrane Database of Systematic Reviews 2003, Issue 1. ARI: 4.7%; NNH= 21

27. CONCLUSION 1. Terlipressin may indeed be a safer drug than vasopressin and appears to be as safe as the other treatments used in variceal bleeding. 2. On the basis of a 34% relative risk reduction in mortality (NNT= 8), terlipressin should be considered to be effective in the treatment of acute variceal hemorrhage. (no other vasoactive agent has been shown to reduce mortality in single studies or meta-analyses) The Cochrane Database of Systematic Reviews 2003, Issue 1.

28. Somatostatin analogues for acute bleeding oesophageal varices (Review) Gtzsche PC, HrÛbjartsson A The Cochrane Database of Systematic Reviews 2005, Issue 1. Art. No.: CD000193.pub2. DOI: 10.1002/14651858.CD000193.pub2.

29. Objectives To study whether somatostatin or analogues improve survival or reduce the need for blood transfusions in patients with bleeding oesophageal varices. Selection criteria All randomised trials comparing somatostatin or analogues with placebo or no treatment in patients suspected of acute or recent bleeding from oesophageal varices. Data collection and analysis The effect variables extracted were: mortality, blood transfusions, use of balloon tamponade, initial haemostasis and rebleeding. Main results

30. Somatostatin analogues v.sPlacebo or no treatment MortalityNo significant difference RR 0.87 95%CI 0.72-1.04 P= 0.1 Blood transfusion favor Weighted mean difference= -0.98 95%CI -1.35--0.61 P< 0.00001 With balloon tamponade No significant difference RR 0.68 95%CI 0.37-1.24 P= 0.2 Failing initial hemostasis favor RR 0.67 95%CI 0.53-0.86 P= 0.001; NNT= 9 RebleedingNo significant difference RR 0.78 95%CI 0.58-1.05 P= 0.1 The Cochrane Database of Systematic Reviews 2005, Issue 1.

32. ARR: 11.1%; NNT= 9

33. CONCLUSION The drugs did not have a signicant effect on mortality whereas they had a signicant effect on number of blood transfusions. However, the total drug effect, combining the number of transfusions used during both the acute bleeding and during any rebleeds, corresponded to only one half unit of blood saved per patient in the high-quality trials. It is doubtful whether this effect is worthwhile. The Cochrane Database of Systematic Reviews 2005, Issue 1.

34. Emergency sclerotherapy versus medical interventions for bleeding oesophageal varices in cirrhotic patients G D'Amico, LLP Pagliaro, GGPI Pietrosi, IITA Tarantino The Cochrane Database of Systematic Reviews 2002, Issue 1. Art. No.: CD002233. DOI: 10.1002/14651858.CD002233.

35. Objectives To assess whether emergency sclerotherapy is superior to pharmacological treatment for variceal bleeding in cirrhosis. Selection criteria Randomised clinical trials comparing sclerotherapy with vasoactive treatments (vasopressin (± nitroglycerin), terlipressin, somatostatin, or octreotide) for acute variceal bleeding in cirrhotic patients. Data collection and analysis Outcome measures were failure to control bleeding, 5- day treatment failure, rebleeding before other elective treatments, mortality before other elective treatments, 42-day mortality, number of blood transfusions, and adverse events. Main results

36. Sclerotherapy v.s VasopressinTerlipressinSomatostatinOctreolideRCT trial total MortalityNNNNN RebleedingNNNNN Failing control bleeding F: EVSNNNN 5-day failureNNNNN Rebleeding before other elective treatment NNNNN Adverse eventsNNF: SomatoNF: Vaso Serious adverse events NNF: SomatoNF: Vaso transfusionsNNNNN The Cochrane Database of Systematic Reviews 2002, Issue 1. F: favor; N: no significant difference

37. The Cochrane Database of Systematic Reviews 2002, Issue 1.

38. ARI: 18.2%; NNH= 5 ARI: 10.5%; NNH= 10 The Cochrane Database of Systematic Reviews 2002, Issue 1.

39. ARI: 7.7%; NNH= 13 ARI: 5.9%; NNH= 17 The Cochrane Database of Systematic Reviews 2002, Issue 1.

40. CONCLUSION 1. This systematic review showed that emergency sclerotherapy is not signicantly superior to any of the pharmacological treatments - vasopressin (with or without nitroglycerin), terlipressin, somatostatin, or octreotide - with regard to any of the assessed efficacy outcomes and may even carry a higher burden of adverse events. 2. Sclerotherapy should not be used as a first line single therapy in cirrhotic patients with variceal bleeding. Sclerotherapy should only be used if pharmacological vasoactive therapy fails to control bleeding. The Cochrane Database of Systematic Reviews 2002, Issue 1.

41. Review: Octreotide reduces rebleeding more than does vasopressin or terlipressin in patients with esophageal varices ACP Journal Club and Best Evidence Copyright 2001 American College of Physicians - American Society of Internal Medicine 135(2): 51; 2001

42. Questions: In patients with upper gastrointestinal (GI) hemorrhage who have endoscopically confirmed esophageal varices as the probable cause of hemorrhage, does octreotide reduce all-cause mortality or control bleeding, and what are the major complications resulting from its use? Study selection: Randomized controlled trials (RCTs) were selected if octreotide was studied in patients with acute variceal bleeding confirmed by endoscopy as the probable source of bleeding, data were available on all-cause mortality or control of bleeding, and follow-up was >= 48 hours.

43. Main results: 1. Octreotide was not associated with a reduction in mortality for all studies; (RR 0.89, 95% CI 0.69 to 1.14) or compared with any other single therapy. 2. Patients who received octreotide had a lower incidence of rebleeding than did those receiving any other therapy, vasopressin or terlipressin (RR 0.58, CI 0.42 to 0.81), or placebo or no therapy (all patients received endoscopic therapy before randomization) (RR 0.46, CI 0.32 to 0.67). 3. Major complications were less common with octreotide than with vasopressin or terlipressin (RR 0.31, CI 0.11 to 0.87).

44. Table. Octreotide for patients with upper gastrointestinal hemorrhage probably caused by esophageal varices (duration of studies up to 60 d) From: ACP J Club, Volume 135(2).September/October 2001.51

45. Conclusion: Octreotide reduces rebleeding more than does vasopression or terlipressin in patients with upper gastrointestinal hemorrhage who have endoscopically confirmed esophageal varices as the probable cause of hemorrhage. ACP J Club, Volume 135(2).September/October 2001.51

46. 總 結 Terlipressin (Glypressin) 是目前 vasoactive drugs 中, 唯一顯示在治 療 acute variceal bleeding 可降低 mortality 的藥物, 同時也可降低 failing initial hemostasis 及 procedures required for uncontrolled bleeding/ rebleeding. Somatostatin analogues 治療 acute EV-bleeding, 並不能降低 mortality, 但可以降低 failing initial hemostasis, 減少 blood transfusion 必要性. Failing initial hemostasis : Octreotide(Sandostatin) 優於 Terlipressin. Adverse events causing withdrawal of treatment : Terlipressin 優於 Vasopressin(Pitressin). Sclerotherapy 副作用大於 Vasoactive drugs (adverse event, NNH= 10; serious adverse event, NNH= 17). => Cirrhotic p’t with variceal bleeding, sclerotherapy 不應用於 first line single therapy, 應用於 vasoactive drug 止血失敗之輔助治療.

47. Thanks for your attention…..