Dig Dis 1992;10(suppl 1):38— 45
Department oflntcrnal Medicine and Department of Surgery, University of Texas Health Science Center at San Antonio, Tex., USA
Keyw ords Sclerotherapy Portosystemic shunt Portal hypertension
The Role of Endoscopic Sclerotherapy in the Management of Esophageal Varices
Abstract
Endoscopic sclerotherapy of esophageal varices has gained worldwide popularity. There is a consensus that sclerotherapy is an effective treatment for temporarily controlling acute variceal hemorrhage. Sclerotherapy has no place in the routine prophylaxis before the index bleed. The role of long-term scle rotherapy to prevent rebleeding is debatable. It is our bias that once patients with cirrhosis suffer a variceal hemorrhage, they should be considered for liver transplantation. If they are not suitable candidates for transplantation and have mild to mod erate hepatic dysfunction, then portosystemic shunting pro vides definitive secondary prophylaxis against rebleeding. Sclerotherapy should be reserved for patients with advanced decompensated cirrhosis.
Introduction
Crafoord and Frenckner [1] first described endoscopic sclerotherapy (EST) using a rigid esophagoscope in 1939. However, the proce dure did not gain wide acceptance over the subsequent three decades, probably because of the availability of portal decompressive surgery, which was quite effective in prevent ing rebleeding. The 1980s witnessed a rise in the popularity of EST because it became ap
parent that shunt surgery did not significantly improve survival and occasionally precipi tated encephalopathy. Moreover, uncon trolled European studies on EST published in the 1970s reported favorable results [2], This review will focus on the current role of EST in: (1) the prophylactic therapy of esophageal varices prior to the index bleed (primary prophylaxis); (2) the management of acute bleeding; (3) the long-term therapy to prevent recurrent bleeding (secondary pro-
Fuad Hasan, MD. Assistant Professor Department oflntcrnal Medicine University of Texas Health Science Center at San Antonio San Antonio. TX 78284-7878 (USA)
© 1992 S. Karger AG, Basel 0257-2753/92/ 0107-003852.75/0
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Fuad Hasan Barry A. Levine
Prevention of the First Variceal Hemorrhage
It is estimated that one third of patients with cirrhosis and esophageal varices will bleed from those varices during their lifetime [3], The index bleed carries a mortality of 40% [4], Therefore, some form of interven tion to prevent the first bleed and thereby reduce mortality seems logical. However, one should bear in mind that the remaining two thirds of patients will not bleed from varices and thus will not benefit from prophylactic therapy. More importantly, they may suffer from its potential complications. Hence, it is conceivable that the reduction in bleeding and mortality in a small subpopulation of patients may be offset by the mortality and morbidity caused by the prophylactic treat ment in the majority who are not at risk. This concept is crucial in analyzing the results of various studies of prophylactic therapy. Surgical portal decompression, (3-blockers and EST have been studied in controlled trials. Prophylactic shunting was efficacious in preventing bleeding but did not prolong life. The role of (3-blockers is controversial and is beyond the scope of this discussion. Eleven randomized controlled trials [5-15] comparing EST with placebo were published in English.The results were mixed, but for the most part discouraging (table 1). The first two European trials showed a reduction in bleed ing and mortality rates [5. 6], These studies were criticized because of the high incidence of bleeding in controls. A third European study by Piai et al. [10] also reported a benefi cial effect in the EST group with respect to
bleeding and survival. The frequency of vari ceal hemorrhage in controls was high perhaps because the investigators selected only those patients with endoscopic features predictive of an increased risk of bleeding. Such features, proposed by Beppu et al. [16] in a retro spective study include: cherry red spots, red wale marks, and blue varices. Yet in a fourth study of ‘high-risk patients’, the reduction in bleeding rate became statistically significant only after 36 months of follow-up and the mortality was not reduced [12], Seven other studies failed to show a significant reduction in the frequency of bleeding or improvement in survival in those who received prophylactic EST [7-9. 11, 13-15]. Two of the seven stud ies were terminated when it became apparent that the EST group had a higher bleeding rate [9, 15] and mortality [15] than did controls. In conclusion, based on the currently avail able data, prevention of the first variceal hem orrhage is not an acceptable routine indica tion for EST. Patients at high risk for bleed ing. as suggested by Japanese and more re cently Italian studies [17], may be candidates for enrollment in randomized controlled trials to assess the usefulness of these endo scopic and clinical criteria.
Acute Variceal Hemorrhage
There is little disagreement regarding the efficacy of EST in controlling acute variceal hemorrhage although available data arc far from clear-cut. Table 2 summarizes the re sults of the seven published randomized clini cal trials comparing EST with conventional medical treatment [18-24], These studies lacked uniformity in design. For instance, there were differences in the etiology of portal hypertension, technique and timing of EST, duration of follow-up and the kind of medical treatment given to ‘controls'. Furthermore, as
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phylaxis). Our discussion will be based on the results of published randomized clinical trials comparing EST with medical therapy and shunt surgery.
Table 1. Results o f eleven random ized controlled trials using sclerotherapy in preventing the first episode o f variceal bleeding Investigators
Paquet Witzel et al.
Reference
5 6
Therapy
Number of patients
Bleeding rate, % *
2-Ycar survival, % 94* 58
EST C
31 32
66
EST C
59 56
57
77* 45
6
9*
Koch et al.
7
EST C
30 30
13 30
67 63
Sauerbruch et al.
8
EST C
68
65
28 37
65 54
9
EST C
49 45
35 15
76' 76
Piai et al.
10
EST C
71 69
18* 57
70* 44
Potzi et al.
11
EST C
45 42
29 34
76 54
Kobe et al.
12
EST C
30 33
24 50
73 63
Adreani et al.
13
EST C
42 41 43
37 32 5
52 54 66
Santangelo et al.
Triger et al.
14
EST C
33 35
39 40
80 43
Gregory et al.
15
EST C
143 138
28* 17
68
C = Control. * p < 0.05. 1 2 month survival.
most patients treated in these series were no longer bleeding at the time of EST. it is not surprising that the results were mixed. The success rate of EST in controlling acute bleeding is reportedly 74-95%. But variceal bleeding stops spontaneously in the majority of patients anyway. Thus, the superi ority of EST over conventional medical treat ment reached statistical significance in only
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Hasan/Levine
three of the five trials where this information is provided [18. 23. 24], Three trials reported a significant reduction in early rcblecding [ 18, 22.23] and only two showed better short-term survival [18, 20]. Despite these problems, it is the experience of most if not all endoscopists that EST slops bleeding from spurting varices. Since most patients with upper gastrointestinal bleeding
The Role of Endoscopic Sclerotherapy in the Management of Esophageal Varices
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1
83
Table 2. Results o f random ized controlled trials com paring EST and medical treatm ent in the m anagem ent o f acute variccal hemorrhage Investigator
Referencc
Therapy
Number of patients
Barsoum ct at.
18
EST EST followed by BT BT only
25 25 50
EST BT ± VP
93 94
EST BT
21 22
EST after VP VP or BT
Sorensen et al.
19
Paquet and Feussner
20
Soderlund and Ihre
21
Larson et al.
22
Moreto et al. Westaby et al.
23 24
Early rebleeding, %
Survival, % (0-42 days)
26*
74*
42
58
58
—
37 30
52 55
95 73
20
44
90* 73
57 50
95 84
30 34
66
EST after BT or VP BT or VP
44 38
_
23* 53
95 87
EST BT
23
100*
20
8
18* 55
69 70
EST VP + NG
33 31
88
31 31
73 61
Control of bleeding, % 74
*
-
-
65
*
74
will undergo diagnostic endoscopy, it seems prudent to perform EST if other causes of bleeding are ruled out. In this regard EST should be viewed as a temporizing measure until more definitive therapy can be provided (see below).
Prevention of Recurrent Bleeding
Patients who survive the index bleed are at an increased risk for rebleeding. In one series 70% rebled within 5 years with the majority of bleeding episodes occurring within the first year. The overall 5-year survival was 40% [25]. Therefore, patients who have had a variceal bleed should be considered for secondary
prophylaxis to prevent recurrent bleeding. Currently, there are several therapeutic op tions. EST aims at the obliteration of varices by 'local treatment’, but varices are a reflec tion of underlying portal hypertension which EST does not address. Thus, other manifesta tions of portal hypertension which can cause gastrointestinal bleeding, such as gastric varices, and congestive gastropathy remain untreated. Measures to reduce portal pressure medically (p-blockcrs) or surgically (portosys temic shunts) make more 'physiologic’ sense. Moreover, because a main cause of death in patients who bleed from varices is liver fail ure. it would seem even more logical to treat both portal hypertension and hepatocellular dysfunction by liver transplantation. In prac-
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BT = Balloon tamponade: VP = vasopressin: NG = nitroglycerin. * p < 0.05.
Table 3. Results o f random ized controlled trials com paring long-term sclerotherapy with medical therapy in the prevention o f recurrent variceal hem orrhage Investigator
Refer ence
Therapy
Number of Rebleeding Rebleeding Survial % episodes patients
Follow-up. months
Barsoum et al.
18
EST C
50 50
26* 58
70* 48
12-48
43* 73
38 37
12-60
24*
68
Terblanche et al.
26
EST C
37 38
38 52
Sorensen et al.
19
EST C
48 52
31 60
EST C
21
19 32
-
-
67* 33
36
22
Paquet and Feussner
20
Soderlund and Ihre
21
Korula et al.
27
Westaby et al. El-Zayadi et al.
28 29
*
9-52
50
101
EST C
-
56 66
50* 99
49 34
22
-
EST C
63 57
_
—
-
-
50 60
12 ± 9 14 ± 6
EST C
56 60
55* 80
EST C
63 55
19* 33
66
125
*
68
*
19-68 (median = 37)
*
21
47
-
86
-
71
tice, however, a given form of therapy may not be suitable for all patients. In other words, treatment should be tailored to individual pa tients. So how does EST fare among other options with regard to the prevention of rebleeding and the impact on survival? Unfortunately, this is a complex question that remains unan swered despite a plethora of uncontrolled and controlled studies. The lack of reliable data is in part due to the diversity of study designs, patient populations, and EST techniques. These problems not withstanding, we will briefly review these trials and try to come with some sensible conclusions. Table 3 depicts the results of eight con trolled trials comparing long-term EST with
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Hasan/Levine
conventional medical treatment [ 18-21, 2629], Three of the eight studies showed a statis tically significant reduction in the number of patients who experience rebleeding [18, 28, 29], Five of the studies showed a reduction in mortality. Meta-analysis of 7 studies [1-21. 26-28] showed a 25% reduction in mortality [30]. However, these results should be inter preted with extreme caution. Rebleeding rate was high (26-55%) and improvement in sur vival was marginal. Non-bleeding complica tions of EST occurred in 23% of patients. The results of seven controlled trials [3137] comparing EST with operative shunting are summarized in table 4. In all trials, shunt operations were superior to EST in prevent ing rebleeding. Three studies analyzed the
The Role of Endoscopic Sclerotherapy in the Management of Esophageal Varices
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C = Control. * p < 0.05
Table 4. Results o f random ized controlled trials com paring long-term sclerotherapy with shunt surgery in the prevention o f recurrent variceal hem orrhage Investigator
Referencc
Therapy
Number of patients
Rebleeding %
Survival Salvage operation, % %
Warren et al.
31
EST DSRS
36 35
53* 3
31
75* 51
26 26
Cello et al.
32
EST PCVS
28 24
50*
11
32 17
17 17
EST DSRS
48 42
38* 14
6
68
71
27 27
Teres et al.
33
21
Follow-up months
Rikkers et al.
34
EST S
30 27
57* 19
7
61 56
25 25
Henderson el al.
35
EST DSRS
37 35
59* 3
35
65* 43
61 (median)
Spina et al.
36
EST DSRS
20
-
95
20
35* 5
100
29 24
EST PCVS
35 34
40* 2.9
-
79 83
21
Planas et al.
37
19
cost of both forms of therapy but did not find a difference [32. 34. 37], Likewise, in five of seven studies there was no significant differ ence in survival. In the remaining two studies [31.35]. both from the Emory group, the EST group had an improved survival. However, in both of these studies, approximately one third of the EST patients had to undergo salvage shunting for uncontrollable rebleeding. In fact, surgery appeared to play the most impor tant role in reducing mortality! The authors conlcuded that EST with surgical back-up provides the best results with regards to sur vival. Finally, three trials compared [i-blockers with EST [38-40]. The results were also mixed, with one study demonstrating EST to
be superior to propranolol in reducing re bleeding rate and two studies showing no dif ference in the efficacy (or inefficacy). There were no significant differences with regard to survival in any of the trials. In addition to these mixed results the three trials enrolled a highly selected group of patients with only one third of the total number of bleeders satis fying the inclusion criteria. Clearly, more studies are needed to elucidate the role of Pblockers in secondary prophylaxis. Based on the above data, how should we manage cirrhotics after their initial variceal hemorrhage? One cannot be dogmatic about the answer, but certain observations deserve thoughtful consideration. First, surgical shunting is extremely effective in preventing
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EST = Endoscopic sclerotherapy: DSRS = distal splenorenal shunt; PCVS = porto-caval shunt; S = DSRS 23 patients, nonselectivc shunt 4. * p < 0.05.
rebleeding, EST is not. Second. EST is not suitable for patients who reside far away from where this procedure is available. Third, nei ther EST nor shunting seem to exhibit a clearcut benefit on survival. Fourth, further stud ies are needed regarding the impact of various modalities of therapy on the quality of patient life. EST is an unpleasant procedure not only for the endoscopist but also for the patient. Shunt surgery on the other hand can result in precipitating hepatic encephalopathy. PBlockers require a high degree of compliance and motivation which may be lacking in many patients with alcoholic cirrhosis. Liver
transplantation has not been compared to the above forms of therapy in a prospective ran domized fashion but appears to be the logical treatment of choice. It takes care of both por tal hypertension and underlying liver disease and is likely to prolong and improve the qual ity of life. However, the psychosocial profile as well as the medical condition of many cir rhotics may be prohibitive. In this situation, it is our bias that EST should be reserved for patients who have advanced decompensated cirrhosis (i.e. Child’s class C). Other patients should be considered for portosystemic shunting.
1 Crafoord C, Frcnckncr P: New sur gical treatmenl of varicose veins of the esophagus. Acta Otolaryngol (Stockh) 1939;27:422-429. 2 Johnston GW. Rodgers HW: A re view of 15 years experience in the use of sclerotherapy in the control of acute hemorrhage from esophageal varices. Br J Surg 1973:60:797-800. 3 Burroughs AK, D'Hcygere F. McIn tyre N: Pitfalls in studies of prophy lactic therapy of variceal bleeding in cirrhotics. Hepatology 1986:6: 1407-1413. 4 Graham DY. Smith JL: The course of patients after variceal hemor rhage. Gastroenterology 19 8 1:80: 800-809. 5 Paquel KJ: Prophylactic endoscopic sclerosing treatmenl of the esopha geal wall in varices - A prospective controlled randomized trial. Endos copy 1982:14:4-5. 6 Witzel L. Wolbergs E. Merki H: Pro phylactic endoscopic sclerotherapy of esophageal varices: A prospective controlled study. Lancet I985;i: 773-775. 7 Koch H. Henning H. Grimm H. Soehendra N: Prophylactic scleros ing of esophageal varices - Results of a prospective controlled study. Endoscopy 1986;18:40-43.
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8 Sauerbruch T. Wotzka R. Kopcke W. Harlin M. Hcldwein W. BayerdorlTcr E. Sander R. Ansari H. Starz I. PaumgartnerG: Prophylactic scle rotherapy before the first episode of variceal hemorrhage in patients with cirrhosis. N Engl J Med 1988; 319:8-15. 9 Santangelo WC. Dueno Ml, Estes BL. Krejs G.I: Prophylactic sclero therapy of large esophageal varices. N Engl J Med 1988:318:814-818. 10 Piai G. Cipolletta L. Claar M. Maronc G. Bianco MA. Forte G. lodice G. Mattera D. Minicri M. Rocco P. Santoro LM. Mazzacca G: Prophy lactic sclerotherapy of high risk esophageal varices: Results of multi centric prospective controlled trial. Hepatology 1988:8:1495-1500. 11 Potzi R. Bauer P. Rcichcl W. et al: Prophylactic endoscopic sclerother apy of esophageal varices in liver cirrhosis: A multicenter prospective controlled randomized trial in Vien na. Gut 1989;30:873-879. 12 Kobe E, Zipprich B, Schentke KU. Nilius R: Prophylactic endoscopic sclerotherapy of esophageal varices - A prospective randomized trial. Endoscopy 1990:22:245-248.
13 Adreani T. Poupon RE. Balkau BJ. Trinchet JC. Grange JD. Peigney N, Bcaugrand M. Poupon R: Pre ventive therapy of first gastrointesti nal bleeding in patients with cirrho sis: Results o f a controlled trial com paring propranolol, endoscopic scle rotherapy and placebo. Hepatology 1990:12:1413-1419. 14 Triger DR. Smart IIL. HoskingSW. Johnson AG: Prophylactic sclero therapy for esophageal varices: Long-term results of a single-center trial. Hepatology 19 9 1: 13:117 - 123. 15 Gregory PB. Hartigan P. Amodeo DJ, ct al: Prophylactic sclerotherapy for esophageal varices in men with alcoholic liver disease. The Veterans AITfairs Cooperative Variceal Scle rotherapy Group. N Engl J Med 1991:324:1779-1784. 16 Beppu K. Inokuchi K. Koyanagi N. Nakayama S, Sakata H, Kitano S. Kobayashi M: Prediction o f variceal hemorrhage by esophageal endosco py. Gastrointest Endosc 1981:4: 213-218.
Hasan/Levine
The Role of Endoscopic Sclerotherapy in the Management of Esophageal Varices
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References
26 Terblanche J. Bomman PC. Kahn D. Jonker MA. Campbell JAH. Wright J. Kirsch R: Failure of re peated injection sclerotherapy to improve longterm survival after oe sophageal variceal bleeding. Lancet 1983;ii: 1328-1332. 27 Korula J. Balart LA. Radvan G. Zweiban BE. Larson W. Kao HW. Yamada S: A prospective random ized controlled trial of chronic esophageal variceal sclerotherapy. Hepatology 1985:5:584-589. 28 Westaby D, MacDougall BRD. Wil liams R: Improved survival follow ing injection sclerotherapy for oe sophageal varices: Final analysis of a controlled trial. Hepatology 1985:5: 827-830. 29 El-Zayadi. El-Din SS. Kabil SM: En doscopic sclerotherapy versus medi cal treatment for bleeding esopha geal varices in patients with schis tosomal liver disease. Gastrointest Endosc 1988:34:314-317. 30 Infante-Rcviard C. Esnaola S. Vil leneuve JP: Role of endoscopic vari ceal sclerotherapy in the longterm management of variceal bleeding: A metaanalysis. Gastroenterology 1989:96:1087-1092. 31 Warren WD. Henderson JM, Milli kan WJ, Galambos JT. Brooks WS, Riepe SP. Salam AA. Kutner Mil: Distal splenorenal shunt versus en doscopic sclerotherapy for longterm management of variceal bleeding. Ann Surg 1986:203:454-462. 32 Cello JP. Grendcll JH. Crass RA. Weber TE, Turnkey DD: Endo scopic sclerotherapy versus porta caval shunt in patients with severe cirrhosis and acute variceal hemor rhage. Longterm followup. N Engl J Med 1987:316:11-15. 33 TeresJ. BordasJM. Bravo D. VisaJ. Grande L. Garcia-Valdecasas JC, Pera C. Rodes J: Sclerotherapy ver sus distal splenorenal shunt in the elective treatment of variceal hem orrhage. A randomized controlled trial. Hepatology 1987;7:430-436.
34 Rikkers LF. Burnettt DA, Volentine GD. Buchi KN. Cormier RA: Shunt surgery' versus endoscopic sclero therapy for long-term treatment of variceal bleeding. Early results of a randomized trial. Ann Surg 1987: 206:261-271. 35 Henderson JM . Kutner MH. Milli kan WJ, Galambos JT, Riepe SP, Brooks WS. Bryan FC. Warren WD: Endoscopic variceal sclerosis com pared with distal splenorenal shunt to prevent recurrent variceal bleed ing in cirrhosis. A prospective ran domized trial. Ann Intern Med 1990:112:262-269. 36 Spina GP. Santambrogio R. Opocher E, Consentino F. Zambelli A. Passoni GR, Cucchiaro G. Macri M. Morandi E, Bruno S. Pezzuoli G: Distal splenorenal shunt versus en doscopic sclerotherapy in the pre vention o f variceal rebleeding. First stage of a randomized controlled trial. Ann Surg 1990;211:178-185. 37 Planas R. Boix J. Broggi M. Cabrc E. Gomes-Vieira MC. Morillas R, Armengol M. De Leon R. Humbert P. Salva JA. Gassull MA: Portacaval shunt versus endoscopic sclerother apy in the elective treatment of variceal hemorrhage. Gastroenterol ogy 1991:100:1078-1086. 38 Fleig WE. Stangc EF. Ilunecke R. Schonborn W, Hurler U. Rainer K. Gaus W, Ditschuneit H: Prevention of recurrent bleeding in cirrhotics with recent variceal hemorrhage: Prospective randomized compari son of propranolol and slcerotherapv. Hepatology 1987:7:355-361. 39 Alcxandrino PT. Alves MM. Cor reia JP: Propranolol or endoscopic sclerotherapy in the prevention of recurrence of variceal bleeding. A prospective randomized controlled trial. J Hepatol 1988:7:175-185. 40 Westaby D. Poison RJ. Gimson AES. Hayes PC. Hayllar K. Wil liams R: A controlled trial of oral propranolol compared with injec tion sclerotherapy for long-term management of variceal bleeding. Hepatology 1990:11:353-359.
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17 The North Italian Endoscopic Club for the Study and Treatment of Esophageal Varices. Prediction of the first variceal hemorrhage in pa tients with cirrhosis of the liver and esophageal varices. A prospective multicenter study. N Engl J Med 1988;319:983-989. 18 Barsoum MS. Bolous FI. El-Rooby AA. Rizk-Allah MA. Ibrahim AS: Tamponade and injection sclero therapy in the management of bleeding oesophageal varices. Br J Surg 1982:69:76-78. 19 Sorensen T, Andersen B. Backer O. et al: Sclerotherapy after first vari ceal hemorrhage in cirrhosis. N Engl J Med 1984:311:1594-1600. 20 Paquet KJ. Eeussner H: Endoscopic slcerosis and esophageal balloon tamponade in acute hemorrhage from esophagogastric varices: A pro spective controlled randomized trial. Hepatology 1985:5:580-583. 21 Soderlund C. litre T: Endoscopic sclerotherapy vs. conservative man agement of bleeding oesophageal varices. Acta C'hir Scand 1985:151: 449-456. 22 Larson AW. Cohen H. Zweiban B. Chapman D. Gourdji M. Korula J, Weiner J: Acute esophageal variceal sclerotherapy. Results of a prospec tive randomized controlled trial. JAMA 1986:225:497-500. 23 Moreto M. Zaballa M. Bernal A. Ibanez S. Ojembarrena E. Rodri guez A: A randomized trial of tam ponade or sclerotherapy as imme diate treatment for bleeding esopha geal varices. Surg Gynecol Obstet 1988:167:303-306. 24 Westaby D. Hayes PC. Gimson AE. Poison PJ. Williams R: Controlled clinical trial of injection sclerother apy for active variceal bleeding. He patology 1989:9:274-277. 25 Rcsnick RH. Iber FL. Ishihara AM. Chalmers TC. Zimmerman IT. Bos ton Interhospital Liver Group: A controlled study of the therapeutic portacaval shunt. Gastroenterology 1974;67:843-857.
Department oflntcrnal Medicine and Department of Surgery, University of Texas Health Science Center at San Antonio, Tex., USA
Keyw ords Sclerotherapy Portosystemic shunt Portal hypertension
The Role of Endoscopic Sclerotherapy in the Management of Esophageal Varices
Abstract
Endoscopic sclerotherapy of esophageal varices has gained worldwide popularity. There is a consensus that sclerotherapy is an effective treatment for temporarily controlling acute variceal hemorrhage. Sclerotherapy has no place in the routine prophylaxis before the index bleed. The role of long-term scle rotherapy to prevent rebleeding is debatable. It is our bias that once patients with cirrhosis suffer a variceal hemorrhage, they should be considered for liver transplantation. If they are not suitable candidates for transplantation and have mild to mod erate hepatic dysfunction, then portosystemic shunting pro vides definitive secondary prophylaxis against rebleeding. Sclerotherapy should be reserved for patients with advanced decompensated cirrhosis.
Introduction
Crafoord and Frenckner [1] first described endoscopic sclerotherapy (EST) using a rigid esophagoscope in 1939. However, the proce dure did not gain wide acceptance over the subsequent three decades, probably because of the availability of portal decompressive surgery, which was quite effective in prevent ing rebleeding. The 1980s witnessed a rise in the popularity of EST because it became ap
parent that shunt surgery did not significantly improve survival and occasionally precipi tated encephalopathy. Moreover, uncon trolled European studies on EST published in the 1970s reported favorable results [2], This review will focus on the current role of EST in: (1) the prophylactic therapy of esophageal varices prior to the index bleed (primary prophylaxis); (2) the management of acute bleeding; (3) the long-term therapy to prevent recurrent bleeding (secondary pro-
Fuad Hasan, MD. Assistant Professor Department oflntcrnal Medicine University of Texas Health Science Center at San Antonio San Antonio. TX 78284-7878 (USA)
© 1992 S. Karger AG, Basel 0257-2753/92/ 0107-003852.75/0
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Fuad Hasan Barry A. Levine
Prevention of the First Variceal Hemorrhage
It is estimated that one third of patients with cirrhosis and esophageal varices will bleed from those varices during their lifetime [3], The index bleed carries a mortality of 40% [4], Therefore, some form of interven tion to prevent the first bleed and thereby reduce mortality seems logical. However, one should bear in mind that the remaining two thirds of patients will not bleed from varices and thus will not benefit from prophylactic therapy. More importantly, they may suffer from its potential complications. Hence, it is conceivable that the reduction in bleeding and mortality in a small subpopulation of patients may be offset by the mortality and morbidity caused by the prophylactic treat ment in the majority who are not at risk. This concept is crucial in analyzing the results of various studies of prophylactic therapy. Surgical portal decompression, (3-blockers and EST have been studied in controlled trials. Prophylactic shunting was efficacious in preventing bleeding but did not prolong life. The role of (3-blockers is controversial and is beyond the scope of this discussion. Eleven randomized controlled trials [5-15] comparing EST with placebo were published in English.The results were mixed, but for the most part discouraging (table 1). The first two European trials showed a reduction in bleed ing and mortality rates [5. 6], These studies were criticized because of the high incidence of bleeding in controls. A third European study by Piai et al. [10] also reported a benefi cial effect in the EST group with respect to
bleeding and survival. The frequency of vari ceal hemorrhage in controls was high perhaps because the investigators selected only those patients with endoscopic features predictive of an increased risk of bleeding. Such features, proposed by Beppu et al. [16] in a retro spective study include: cherry red spots, red wale marks, and blue varices. Yet in a fourth study of ‘high-risk patients’, the reduction in bleeding rate became statistically significant only after 36 months of follow-up and the mortality was not reduced [12], Seven other studies failed to show a significant reduction in the frequency of bleeding or improvement in survival in those who received prophylactic EST [7-9. 11, 13-15]. Two of the seven stud ies were terminated when it became apparent that the EST group had a higher bleeding rate [9, 15] and mortality [15] than did controls. In conclusion, based on the currently avail able data, prevention of the first variceal hem orrhage is not an acceptable routine indica tion for EST. Patients at high risk for bleed ing. as suggested by Japanese and more re cently Italian studies [17], may be candidates for enrollment in randomized controlled trials to assess the usefulness of these endo scopic and clinical criteria.
Acute Variceal Hemorrhage
There is little disagreement regarding the efficacy of EST in controlling acute variceal hemorrhage although available data arc far from clear-cut. Table 2 summarizes the re sults of the seven published randomized clini cal trials comparing EST with conventional medical treatment [18-24], These studies lacked uniformity in design. For instance, there were differences in the etiology of portal hypertension, technique and timing of EST, duration of follow-up and the kind of medical treatment given to ‘controls'. Furthermore, as
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phylaxis). Our discussion will be based on the results of published randomized clinical trials comparing EST with medical therapy and shunt surgery.
Table 1. Results o f eleven random ized controlled trials using sclerotherapy in preventing the first episode o f variceal bleeding Investigators
Paquet Witzel et al.
Reference
5 6
Therapy
Number of patients
Bleeding rate, % *
2-Ycar survival, % 94* 58
EST C
31 32
66
EST C
59 56
57
77* 45
6
9*
Koch et al.
7
EST C
30 30
13 30
67 63
Sauerbruch et al.
8
EST C
68
65
28 37
65 54
9
EST C
49 45
35 15
76' 76
Piai et al.
10
EST C
71 69
18* 57
70* 44
Potzi et al.
11
EST C
45 42
29 34
76 54
Kobe et al.
12
EST C
30 33
24 50
73 63
Adreani et al.
13
EST C
42 41 43
37 32 5
52 54 66
Santangelo et al.
Triger et al.
14
EST C
33 35
39 40
80 43
Gregory et al.
15
EST C
143 138
28* 17
68
C = Control. * p < 0.05. 1 2 month survival.
most patients treated in these series were no longer bleeding at the time of EST. it is not surprising that the results were mixed. The success rate of EST in controlling acute bleeding is reportedly 74-95%. But variceal bleeding stops spontaneously in the majority of patients anyway. Thus, the superi ority of EST over conventional medical treat ment reached statistical significance in only
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three of the five trials where this information is provided [18. 23. 24], Three trials reported a significant reduction in early rcblecding [ 18, 22.23] and only two showed better short-term survival [18, 20]. Despite these problems, it is the experience of most if not all endoscopists that EST slops bleeding from spurting varices. Since most patients with upper gastrointestinal bleeding
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1
83
Table 2. Results o f random ized controlled trials com paring EST and medical treatm ent in the m anagem ent o f acute variccal hemorrhage Investigator
Referencc
Therapy
Number of patients
Barsoum ct at.
18
EST EST followed by BT BT only
25 25 50
EST BT ± VP
93 94
EST BT
21 22
EST after VP VP or BT
Sorensen et al.
19
Paquet and Feussner
20
Soderlund and Ihre
21
Larson et al.
22
Moreto et al. Westaby et al.
23 24
Early rebleeding, %
Survival, % (0-42 days)
26*
74*
42
58
58
—
37 30
52 55
95 73
20
44
90* 73
57 50
95 84
30 34
66
EST after BT or VP BT or VP
44 38
_
23* 53
95 87
EST BT
23
100*
20
8
18* 55
69 70
EST VP + NG
33 31
88
31 31
73 61
Control of bleeding, % 74
*
-
-
65
*
74
will undergo diagnostic endoscopy, it seems prudent to perform EST if other causes of bleeding are ruled out. In this regard EST should be viewed as a temporizing measure until more definitive therapy can be provided (see below).
Prevention of Recurrent Bleeding
Patients who survive the index bleed are at an increased risk for rebleeding. In one series 70% rebled within 5 years with the majority of bleeding episodes occurring within the first year. The overall 5-year survival was 40% [25]. Therefore, patients who have had a variceal bleed should be considered for secondary
prophylaxis to prevent recurrent bleeding. Currently, there are several therapeutic op tions. EST aims at the obliteration of varices by 'local treatment’, but varices are a reflec tion of underlying portal hypertension which EST does not address. Thus, other manifesta tions of portal hypertension which can cause gastrointestinal bleeding, such as gastric varices, and congestive gastropathy remain untreated. Measures to reduce portal pressure medically (p-blockcrs) or surgically (portosys temic shunts) make more 'physiologic’ sense. Moreover, because a main cause of death in patients who bleed from varices is liver fail ure. it would seem even more logical to treat both portal hypertension and hepatocellular dysfunction by liver transplantation. In prac-
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BT = Balloon tamponade: VP = vasopressin: NG = nitroglycerin. * p < 0.05.
Table 3. Results o f random ized controlled trials com paring long-term sclerotherapy with medical therapy in the prevention o f recurrent variceal hem orrhage Investigator
Refer ence
Therapy
Number of Rebleeding Rebleeding Survial % episodes patients
Follow-up. months
Barsoum et al.
18
EST C
50 50
26* 58
70* 48
12-48
43* 73
38 37
12-60
24*
68
Terblanche et al.
26
EST C
37 38
38 52
Sorensen et al.
19
EST C
48 52
31 60
EST C
21
19 32
-
-
67* 33
36
22
Paquet and Feussner
20
Soderlund and Ihre
21
Korula et al.
27
Westaby et al. El-Zayadi et al.
28 29
*
9-52
50
101
EST C
-
56 66
50* 99
49 34
22
-
EST C
63 57
_
—
-
-
50 60
12 ± 9 14 ± 6
EST C
56 60
55* 80
EST C
63 55
19* 33
66
125
*
68
*
19-68 (median = 37)
*
21
47
-
86
-
71
tice, however, a given form of therapy may not be suitable for all patients. In other words, treatment should be tailored to individual pa tients. So how does EST fare among other options with regard to the prevention of rebleeding and the impact on survival? Unfortunately, this is a complex question that remains unan swered despite a plethora of uncontrolled and controlled studies. The lack of reliable data is in part due to the diversity of study designs, patient populations, and EST techniques. These problems not withstanding, we will briefly review these trials and try to come with some sensible conclusions. Table 3 depicts the results of eight con trolled trials comparing long-term EST with
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conventional medical treatment [ 18-21, 2629], Three of the eight studies showed a statis tically significant reduction in the number of patients who experience rebleeding [18, 28, 29], Five of the studies showed a reduction in mortality. Meta-analysis of 7 studies [1-21. 26-28] showed a 25% reduction in mortality [30]. However, these results should be inter preted with extreme caution. Rebleeding rate was high (26-55%) and improvement in sur vival was marginal. Non-bleeding complica tions of EST occurred in 23% of patients. The results of seven controlled trials [3137] comparing EST with operative shunting are summarized in table 4. In all trials, shunt operations were superior to EST in prevent ing rebleeding. Three studies analyzed the
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C = Control. * p < 0.05
Table 4. Results o f random ized controlled trials com paring long-term sclerotherapy with shunt surgery in the prevention o f recurrent variceal hem orrhage Investigator
Referencc
Therapy
Number of patients
Rebleeding %
Survival Salvage operation, % %
Warren et al.
31
EST DSRS
36 35
53* 3
31
75* 51
26 26
Cello et al.
32
EST PCVS
28 24
50*
11
32 17
17 17
EST DSRS
48 42
38* 14
6
68
71
27 27
Teres et al.
33
21
Follow-up months
Rikkers et al.
34
EST S
30 27
57* 19
7
61 56
25 25
Henderson el al.
35
EST DSRS
37 35
59* 3
35
65* 43
61 (median)
Spina et al.
36
EST DSRS
20
-
95
20
35* 5
100
29 24
EST PCVS
35 34
40* 2.9
-
79 83
21
Planas et al.
37
19
cost of both forms of therapy but did not find a difference [32. 34. 37], Likewise, in five of seven studies there was no significant differ ence in survival. In the remaining two studies [31.35]. both from the Emory group, the EST group had an improved survival. However, in both of these studies, approximately one third of the EST patients had to undergo salvage shunting for uncontrollable rebleeding. In fact, surgery appeared to play the most impor tant role in reducing mortality! The authors conlcuded that EST with surgical back-up provides the best results with regards to sur vival. Finally, three trials compared [i-blockers with EST [38-40]. The results were also mixed, with one study demonstrating EST to
be superior to propranolol in reducing re bleeding rate and two studies showing no dif ference in the efficacy (or inefficacy). There were no significant differences with regard to survival in any of the trials. In addition to these mixed results the three trials enrolled a highly selected group of patients with only one third of the total number of bleeders satis fying the inclusion criteria. Clearly, more studies are needed to elucidate the role of Pblockers in secondary prophylaxis. Based on the above data, how should we manage cirrhotics after their initial variceal hemorrhage? One cannot be dogmatic about the answer, but certain observations deserve thoughtful consideration. First, surgical shunting is extremely effective in preventing
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EST = Endoscopic sclerotherapy: DSRS = distal splenorenal shunt; PCVS = porto-caval shunt; S = DSRS 23 patients, nonselectivc shunt 4. * p < 0.05.
rebleeding, EST is not. Second. EST is not suitable for patients who reside far away from where this procedure is available. Third, nei ther EST nor shunting seem to exhibit a clearcut benefit on survival. Fourth, further stud ies are needed regarding the impact of various modalities of therapy on the quality of patient life. EST is an unpleasant procedure not only for the endoscopist but also for the patient. Shunt surgery on the other hand can result in precipitating hepatic encephalopathy. PBlockers require a high degree of compliance and motivation which may be lacking in many patients with alcoholic cirrhosis. Liver
transplantation has not been compared to the above forms of therapy in a prospective ran domized fashion but appears to be the logical treatment of choice. It takes care of both por tal hypertension and underlying liver disease and is likely to prolong and improve the qual ity of life. However, the psychosocial profile as well as the medical condition of many cir rhotics may be prohibitive. In this situation, it is our bias that EST should be reserved for patients who have advanced decompensated cirrhosis (i.e. Child’s class C). Other patients should be considered for portosystemic shunting.
1 Crafoord C, Frcnckncr P: New sur gical treatmenl of varicose veins of the esophagus. Acta Otolaryngol (Stockh) 1939;27:422-429. 2 Johnston GW. Rodgers HW: A re view of 15 years experience in the use of sclerotherapy in the control of acute hemorrhage from esophageal varices. Br J Surg 1973:60:797-800. 3 Burroughs AK, D'Hcygere F. McIn tyre N: Pitfalls in studies of prophy lactic therapy of variceal bleeding in cirrhotics. Hepatology 1986:6: 1407-1413. 4 Graham DY. Smith JL: The course of patients after variceal hemor rhage. Gastroenterology 19 8 1:80: 800-809. 5 Paquel KJ: Prophylactic endoscopic sclerosing treatmenl of the esopha geal wall in varices - A prospective controlled randomized trial. Endos copy 1982:14:4-5. 6 Witzel L. Wolbergs E. Merki H: Pro phylactic endoscopic sclerotherapy of esophageal varices: A prospective controlled study. Lancet I985;i: 773-775. 7 Koch H. Henning H. Grimm H. Soehendra N: Prophylactic scleros ing of esophageal varices - Results of a prospective controlled study. Endoscopy 1986;18:40-43.
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8 Sauerbruch T. Wotzka R. Kopcke W. Harlin M. Hcldwein W. BayerdorlTcr E. Sander R. Ansari H. Starz I. PaumgartnerG: Prophylactic scle rotherapy before the first episode of variceal hemorrhage in patients with cirrhosis. N Engl J Med 1988; 319:8-15. 9 Santangelo WC. Dueno Ml, Estes BL. Krejs G.I: Prophylactic sclero therapy of large esophageal varices. N Engl J Med 1988:318:814-818. 10 Piai G. Cipolletta L. Claar M. Maronc G. Bianco MA. Forte G. lodice G. Mattera D. Minicri M. Rocco P. Santoro LM. Mazzacca G: Prophy lactic sclerotherapy of high risk esophageal varices: Results of multi centric prospective controlled trial. Hepatology 1988:8:1495-1500. 11 Potzi R. Bauer P. Rcichcl W. et al: Prophylactic endoscopic sclerother apy of esophageal varices in liver cirrhosis: A multicenter prospective controlled randomized trial in Vien na. Gut 1989;30:873-879. 12 Kobe E, Zipprich B, Schentke KU. Nilius R: Prophylactic endoscopic sclerotherapy of esophageal varices - A prospective randomized trial. Endoscopy 1990:22:245-248.
13 Adreani T. Poupon RE. Balkau BJ. Trinchet JC. Grange JD. Peigney N, Bcaugrand M. Poupon R: Pre ventive therapy of first gastrointesti nal bleeding in patients with cirrho sis: Results o f a controlled trial com paring propranolol, endoscopic scle rotherapy and placebo. Hepatology 1990:12:1413-1419. 14 Triger DR. Smart IIL. HoskingSW. Johnson AG: Prophylactic sclero therapy for esophageal varices: Long-term results of a single-center trial. Hepatology 19 9 1: 13:117 - 123. 15 Gregory PB. Hartigan P. Amodeo DJ, ct al: Prophylactic sclerotherapy for esophageal varices in men with alcoholic liver disease. The Veterans AITfairs Cooperative Variceal Scle rotherapy Group. N Engl J Med 1991:324:1779-1784. 16 Beppu K. Inokuchi K. Koyanagi N. Nakayama S, Sakata H, Kitano S. Kobayashi M: Prediction o f variceal hemorrhage by esophageal endosco py. Gastrointest Endosc 1981:4: 213-218.
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