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Recurrence of esophageal varices following endoscopic treatment and its impact on rebleeding: comparison of sclerotherapy and ligation
Journal of ~epaio~ogyZWO;3t: 202-208 Printed in Denmark All rights reserved Munksgaard Copenhagen
Journal of Hepatology ISSi’I 0168-8278
Recurrence of esophageal varices fo~o~g endoscopic reagent and its impact on rebleeding:comparison of sclerotherapy and ligation Ming-Chih
Hou, Han-Chieh
Lin, Fa-Yauh Lee, Full-Young
Chang and Shou-Dong
Lee
Division of Gastroenterology, Department of Medicine, Veterans General Hospital-Taipei and National Yang-Ming University School of Medicine, Taipei, Taiwan
R~ekg~o~n~A~~s: Endoscopic variceal ligation is superior to sclerotherapy because of its lower rebleeding and complication rates However, ligation is not without drawbacks due to a higher tendency to variceal recurrence. We conducted a randomized cohort study to delineate the long-term history of variceal recurrence following ligation and sclerotherapy, and to clarify the impact of recurrence on rebleeding and on the consumption of endoscopic treatment resources. Methods: Two hundred cirrhotic patients with esophageal variceal bleeding were ~ndo~d to undergo maintenance endoscopic variceal selerotherapy or ligation. Results: One hundred and forty-one patients achieved variceal eradication and were regularly followed up for 2.2 to 6.7 (mean: 5.1-1-1.2) years. The demographic data, hepatic reserve, bleeding severity, and endoscopic features of both sclerotherapy (tt=70) and ligation (n=71) showed no difference. Forty (57.1%) patients who underwent sclerotherapy experienced 58 recurrences of esophageal varices, in contrast to the 46 (64.8%) patients who underwent ligation and experienced 81 episodes of recurrence. Kaplan-Meier analysis showed that within 2 years variceal recur-
rence was more frequent for ligation than sclerotherapy, and the difference decreased thereafter. Multiple recurrence appeared more common with ligation (l/2/ 31415 episodes of recurrence: ~l23lg~3l~ vs. 40~14/3l~/ 0, p=O.OS). On multifactorial analysis, the endoscopic treatment method and red wale markings were the two factors determining variceal recurrence. Rebleeding from recurrent esophageal variees was unusual and showed no difference between the two groups (7158 vs. 6/U, p>O.O5). Rebleeding from gastric varices was more logon after eradication by sclerotherapy (7/ 19 vs. 1116, p=O.OSS) than by ligation. The number of sessions required for eradication of recurrent varices was no different between the two groups. Co~cZ~s~o~s; Early recurrence and m~tiple recurrence of esophageal varices are more likely in patients undergoing endoscopic ligation, compared to sclerotherapy; however, the recurrence did not lead to a higher risk of rebleeding or require more endoscopic treatment.
E
many reports, is the greater probability of variceal recurrence (5-7). These reports were based on a shortterm follow-up (5,6), but the recurrence rate of varices depends on the length of the follow-up. So far, no longterm follow-up studies or details regarding variceal recurrence after EVL have been recorded. Combined EVL and EVS, however, has been attempted to reduce variceal recurrence (89). Although recurrence appeared to decrease (8,9), combined EVL and EVS cannot be recommended because it offers no benefit over EVL alone, and is associated with a higher rate of complications (10,ll). Therefore, it is more appropriate to clarify whether or not the variceal recurrence
variceal ligation (EVL) and sclerotherapy (EVS) are widely used to treat esophageal variceal hemorrhage (1). Because of the lower rebleeding and complication rates of ligation (2-Q it has replaced sclerotherapy as the optimum endoscopic treatment to prevent recurrent bleeding from esophageal varices (1). However, one of the shortcomings of EVL, claimed in NDOSCOPIC
Received 4 June; revised I8 August: accepted 25 August 1999
Correspondence: Ming-Chih Hou, Division of Gastroenterology, Department of Medicine, Veterans General Hospital-Taipei, No. 201, Set 2, Shih-Pai Road, Taipei, Taiwan 11217. Tel: 886 2 28757308. Fax: 886 2 28739318.
202
Key words: Esophageal varices; Ligation; Long-term; Rebleediug; Recurrence; Sclerotherapy.
Impact of variceal recurrence
tendency of EVL carries a higher rebleeding risk than EVS. We conducted a long-term follow-up study to discover the difference in variceal recurrence between EVL and EVS, and to clarify the impact of variceal recurrence on rebleeding and on the consumption of endoscopic treatment resources.
Materials and Methods Patients
From June 1992, to April 1998, all cirrhotic patients entering this hospital with active or recent esophageal variceal hemorrhage were recruited for study, after obtaining informed consent from the patients or their families. Patients with clinical evidence of hepatoma or other malignancies, terminal illness, fundal varices, or a previous history of surgical or endoscopic treatment for esophageal varices were excluded. At the time of endoscopy, patients meeting the inclusion criteria were randomized to undergo EVS or EVL, based on computerized random digit allocation. Patients who continued to receive maintenance EVS or EVL, and who achieved variceal eradication, were included for study. Cirrhosis was diagnosed or suggested by liver biopsy or image study9 and clinical assessment. The study was approved by the Clinical Research Committee of this hospital. Endoscopic treatment procedures
EVS was performed using a free-hand method, with an Olympus XK10 endoscope (Olympus Optical Co., Ltd., Tokyo, Japan) and a 25gauge disposable injection needle, by means of an intravariceal injection. The sclerosant used was 1.5% sodium tetradecyl sulfate (ElkinsSinn, Inc., Cherry Hill, NJ, USA). EVL was performed using an Olympus XQ-20 endoscope with endoscopic ligating devices (Bard
on rebleeding
International Products, Tewksbury, MA, USA), and an overtube, or multi-band ligators (Wilson-Cook Medical Inc., Winston-Salem, NC, USA).
C%nical assessment and foltow-up
Endoscopic treatment was performed weekly for the first 3 weeks, when possible, and then every 3 weeks until the esophageal varices were eradicated. Follow-up endoscopic examinations were later performed twice on a 3-month basis, then on a 6-month basis if there was no recurrence. If rebleeding was suspected, emergency endoscopy was performed to identify the bleeding site. Patients were instructed to return to the hospital immediately if any symptoms or signs suggestive of rebleeding were noticed. If rebleeding occurred, the amount of blood transfused was recorded. If varices recurred, the previous method of eradication was again used. Hepatoma surveillance by serum a-fetoprotein and image study was performed every 3-4 months.
Definition
The severity of esophageal varices was graded, following the system suggested by Beppu et al. (12). Severity of cirrhosis was classified according to Pugh’s modification of Child’s classification (13). Variceal eradication was defined as nonvisualization of varices, or varices that could not be ligated or injected. Variceal recurrence was defined as the development of new varices which could be injected or ligated. The final decision between varices eradication or recurrence had to be agreed upon by two experienced endoscopists. Bebleeding was defined as a new onset of hematemesis, coffee-ground vomitus, hematochezia, or melena with an increasing pulse rate over 110 bpm, and decreasing blood pressure below 90 mmHg. Hepatoma that was found more than 6 months after the index endoscopic treatment was arbitrarily defined as newly developed, clinically detectable hepatoma.
TABLE 1 Clinical characteristics of patients with liver cirrhosis and esophageal variceal hemorrhage undergoing endoscopic variceal sclerotherapy or ligation Clinical characteristics
Age (year) Sex(m/f) Etiology (alcoholi~vira~combine~others) Child (A/B/C) Child-Pugh’s score Albumin (g/dl) Bilirubin (mgldl) Blood urea nitrogen (mgldl) Creatinine (mg/dl) Platelet (K/mm3) Hematocrit (%) Hematemesislnon-hematemesis Ascites f-i+) Encepha’topathy (-I+) Shock(-/+) Blood transfusion (units) Active/inactive bleeding Bed wale marking (<2+/~2+) Variceal form (F,, F$Fs) Number of rebleeding patients before eradication Total sclerosant volume (ml) or rubber bands (n) Eradication sessions* Eradication time (day) Occurrence of hepatoma’ Time of follow-up (month)
(n=70)
Ligation (n=71)
60.0211.9 57113 131441518 17/34/19 8.021.9 3.020.5 2.522.7 18.&9.1 1.121.2 87.1250.2 27526.1 44125 29140 59/l 1 62/S 3.924.4 15J5.5 42128 19151 27 53.6222.5 5.122.1 78.2232.2 12 63.4tll.6
60.4212.1 5605 1l/41/12/7 20126125 8.4~2.4 2.9205 2.822.3 21.2*13.7 1.1t0.5 81.2256.6 26.8265 52119 29142 58/13 61110 4.425.0 23148 38133 14157 18 21.2?9.5 3.7rt1.6 85.6252.9 9 60.1217.5
Sclerotherapy
* p
203
M-C.
Hou et al.
Child-Pugh’s
ment analysis between observers with regard to the eradication and recurrence of esophageal varices. Kaplan-Meier analysis was used to examine the time to first variceal recurrence and the time to death, and the log rank test was used to compare the difference between groups. Multivariate analyses were performed to assess the risk factors of variceal recurrence, using the Cox logistic regression with SPSS. The significance level was p
A
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Results
20
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Follow-up (years) Child-Pugh’s ';; P 3 .L L
B
100 60
Two hundred patients with liver cirrhosis and esophageal variceal hemorrhage were randomized to undergo EVS (n=99) or EVL (n=lOl). Twenty-five patients with poor compliance or lost to follow-up were excluded (12 in EVS, 13 in EVL). Also excluded were eight patients with development of clinically detectable hepatoma within 6 months of endoscopic treatment (4 in EVS and 4 in EVL); six patients with a change of treatment method (2 in EVS and 4 in EVL); and 20 patients with non-eradication of varices (11 in EVS,
60
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Follow-up (years) Fig. 1. Survival in patients with liver cirrhosis and eradication of esophageal varices after endoscopic variceal sclerotherapy and ligation. There was no statistical difference between the two groups, even after stratifying patients by hepatic reserve.
Ligation P=O.O718
o! 0
B Statistical
analysis
The results were expressed as mean?SD. Each continuous parameter between the two treatment groups was analyzed with two-sample Student’s t-tests. Categorical data were examined using the x2 test with Yates’ correction. The 95% confidence interval in their difference was computed using the assumption of Z distribution. The secular trend to multiple variceal recurrences and endoscopic treatment were evaluated by the x2 test for trends. The kappa statistic was used for agree-
204
.,.,.,.,.,.,., 1
2
3
4
5
6
7
Follow-up (years)
Fig. 2A. Absence of variceal recurrence within 2 years of eradication after endoscopic variceal sclerotherapy and ligation. The difference between the two groups was signtficant (p=O.O4). B. Absence of variceal recurrence within 6 years of eradication after endoscopic variceal sclerotherapy and ligation. There was no statistical difference between the two groups.
Impact of variceal recurrence on rebleeding TABLE
2
Outcome of rebleeding and variceal sclerotherapy or ligation
recurrence
in patients
with liver cirrhosis
and esophageal
Characteristics
Rebleeding Rebleeding
patients after variceal eradication episodes after variceal eradication
Rebleeding sources Esophageal varix Esophageal ulcer Gastric varix Portal hypertensive gastropathy Gastric vascular ectasia Undetermined Patients with recurrent varices No. of sessions required to eradicate recurrent esophageal varices Blood transfusion for bleeding from recurrent varices (unit) Blood transfusion for bleeding from portal-hypertension-related sources * No patients died of recurrent esophageal varices with bleeding. + Including 58 episodes of recurrence in the sclerotherapy group, and 81 episodes
9 in EVL). Of 20 patients who died before variceal eradication, there were l/2/8 with Child-Pugh’s A/B/C in the EVS group and l/1/7 in the EVL group. According to Child-Pugh’s A/B/C, the mortality rates before eradication were 6% (l/18), 6% (2/36), 30% (8/27) in the EVS group and 5% (l/21), 4% (l/27) and 22% (7/32) in the ligation group. Therefore, one hundred and forty-one patients (70 in EVS, 71 in EVL) who had achieved variceal eradication and had had a regular follow-up of 2.2 to 6.7 (mean: 5.1~ 1.2) years, were analyzed. The interobserver agreement rate for eradication and recurrence of esophageal varices was excellent (kappa index of 0.79 and 0.75, respectively). Clinical characteristics of patients
With the exception that fewer sessions of EVL than of EVS were required to eradicate varices, the demographic data, underlying etiology of liver cirrhosis, hepatic function, endoscopic features, bleeding severity, follow-up period (Table l), and survival (Fig. 1) between the two groups were not different. Recurrence of esophageal varices after endoscopic eradication in patients undergoing sclerotherapy or ligation
Kaplan-Meier analysis showed that variceal recurrence within 2 years of variceal eradication was more frequent with ligation than sclerotherapy (Fig. 2A); however, the difference decreased as follow-up extended to 6 years (Fig. 2B). The number of patients experiencing variceal recurrence in the EVS and EVL groups was not different (Table 2). Of 24 pure alcoholic cirrhotics, esophageal varices recurred in six of ten patients abstaining from drinking, five in eight patients not ab-
(unit)
variceal
hemorrhage
after
endoscopic
Sclerotherapy (n=70)
Ligation (n=71)
p-value
10 19
6 16
NS NS
7* 2 7 0 1 2 40+ 1.620.9 2.622.4 3.825.5
6* 3 1 3 1 2 46+ 1.4kl.O 2.7k3.0 1822.4
NS NS 0.085 NS NS NS NS NS NS NS
of recurrence
in the ligation
variceal
group.
staining from drinking, and four in six patients with an uncertain drinking history. Multiple recurrence appeared to be more common with ligation (l/2/3/4/5 episodes of recurrence: 46/23/8/3/l vs. 40/14/3/1/O, p= 0.08). On multifactorial analysis of all the factors in Table 1, the endoscopic treatment method (EVL vs. EVS; odds ratio: 1.56; 95% confidence interval: 1.0% 2.43) and red wale markings ?2+ vs. <2+; odds ratio: 1.71; 95% confidence interval: 1.10-2.65) were the two factors determining recurrence. Rebleeding after eradication of esophageal varices in patients undergoing sclerotherapy or ligation
Patients might bleed from a variety of sources (Table 2). In both the EVS and EVL groups, the rebleeding rate before variceal eradication was higher than that after variceal eradication (27170 vs. 10170, ~~0.01 for EVS; 18171 vs. 6171, ~~0.05 for EVL). Rebleeding occurred 480.1 k439.3 (15 to 1220) days after variceal eradication with EVS and 328.4k213.0 (18 to 840) days after variceal eradication with EVL. Rebleeding from recurrent esophageal varices was unusual and no different in the EVS and EVL groups (7158 vs. 6181, p>O.O5). Rebleeding from gastric varices appeared more common in patients in whom esophageal variceal eradication was achieved with EVS than in those in whom eradication was achieved with EVL (7119 vs. 11 16,p=O.O85). The interval between esophageal variceal eradication and rebleeding of these eight patients was 39, 163, 323, 507, 1065, 1220, and 1250 days in the EVS group and 280 days in the EVL group. The number of units of blood transfused for rebleeding from recurrent esophageal varices or from any portal-hypertension-related sources, and the number of sessions re20.5
M.-C. Hou et al.
quired to eradicate recurrent varices, were similar in the two groups. The total number of treatment sessions required for eradication of initial varices and recurrent varices showed no difference between the EVS (total: 450, average: 6.43k2.72 sessions) and EVL groups (total: 378, average: 5.32k2.40 sessions). Death due to rebleeding occurred in four patients including three patients who died of gastric variceal bleeding in the EVS group and one patient who died of esophageal ulcer bleeding precipitated by hepatic failure in the EVL group. Complications before and after eradication of esophageal varices in patients undergoing sclerotherapy or ligation
Before eradication, the EVS-related complications were esophageal stricture in nine, intramural hematoma in one, aspiration pneumonia in one, spontaneous bacterial peritonitis in two and sepsis in one patient. The EVL-related complications before eradication were esophageal stricture in one, spontaneous bacterial peritonitis in one, deep neck infection in one and rectal variceal bleeding in one patient. The complication rate before variceal eradication was higher in the EVS than the EVL group (14/70 vs. 4/71, ~~0.05). In contrast, the only complication in a patient undergoing EVS for recurrent esophageal varices was esophaged stricture, and there were no complications with EVL.
Discussion Although sclerotherapy and ligation are of comparable efficiency in controlling active esophageal variceal bleeding, the rebleeding rate and post-treatment morbidity are lower with ligation (2-5). The advent of the speedband ligator, which obviates the need for an overtube, has provided better compliance and lessened the discomfort of EVL (14). Ligation has therefore become more popular with practitioners for treating esophageal variceal hemorrhage. Accumulated evidence suggests that the patency of feeder vessels of varices, such as paraesophageal varices and periesophageal varices, predisposes to variceal recurrence (15-l 8). These feeder vessels are occluded more efficiently by sclerotherapy than ligation, which is usually confined to the mucosal and submucosal collaterals (18,19). Ligation is thus not without the drawback of a higher tendency to variceal recurrence (5-7), but the details of variceal recurrence after ligation are still unknown. Furthermore, the recurrence of varices may become more frequent with time, and therefore a long-term follow-up is required to delineate the difference in variceal recurrence between ligation and sclerotherapy. It is also important to determine the impact of variceal re-
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currence on rebleeding and the usage of medical resources. Previous studies have shown that about 60% of patients have experienced recurrence of esophageal varices, and that most recurrences were within 1 year of sclerotherapy (15,20-22). We found that most recurrences were within 2 years of eradication, regardless of the treatment method. It is possible that varices rarely recur beyond 2 years after eradication when an opening of new porto-systemic collaterals elsewhere might take the place of esophageal varices in releasing portal hypertension. Although the number of patients experiencing variceal recurrence was similar in both groups, esophageal varices tended to recur earlier among EVL patients. Since feeder vessels in deeper layers could always be missed, even after repeated ligation for recurrence (18), varices continually recurred. These findings further support the crucial role of feeder vessels in determining the recurrence of esophageal varices (1.5-18). Besides the treatment method, we found that red wale markings are another determinant of variceal recurrence. Esophageal varices with red wale markings were found to have higher variceal pressure (23,24), which is an important hemostatic force for varices formation (25) and might contribute to recurrent varices. Rebleeding after variceal eradication was unusual (26). The rebleeding rate before variceal eradication was about 2 to 3 times higher than that after variceal eradication. The rebleeding risk was much higher if the follow-up period before and after variceal eradication was taken into consideration. Rebleeding from recurrent esophageal varices was even rarer if patients had regular endoscopic surveillance. Therefore, in spite of a higher recurrence rate of esophageal varices in the EVL group than in the EVS group, no higher rebleeding risk was found in the EVL group. Instead, rebleeding from secondary gastric varices appeared more likely in patients undergoing EVS in this longterm study, in contrast to our previous short-term study and others which showed no difference in rebleeding from gastric varices (2-6). It is possible that EVS causes a more complete occlusion of esophageal varices, and thus, with time, blood is shunted to other collaterals such as the gastric varices, those nearest to esophageal varices. However, no definite conclusion about the tendency of gastric variceal rebleeding with sclerotherapy in the long-term can be drawn from the small number of events in this study and requires further investigation. The amount of blood transfused for rebleeding from either recurrent esophageal varices or other portal-hypertension-related sources was not different after either EVS or EVL. Furthermore, the
Impact of variceal recurrence on rebleeding
number of treatment sessions required to eradicate the recurrent varices was similar in both groups. This result indicates that recurrent varices in the individual patient undergoing EVL requires no more eradication sessions than in the patient undergoing EVS. This also holds true for all patients in the EVL group, in which the total number of sessions of endoscopic treatment required was no higher than in the EVS group. This suggests that EVL did not increase the consumption of endoscopic treatment resources, in spite of the rate of variceal recurrence being higher than with EVS. A meta-analysis showed that shortterm survival (mean follow-up period 10 to 12 months) was improved in patients with EVL (27). Long-term survival (mean follow-up period 5.1 years) was not different between EVL and EVS in our patients achieving variceal eradication. More long-term studies are required to draw a definite conclusion. However, because there is no control arm (patients without long-term endoscopic follow-up) for comparison of rebleeding morbidity and cost/benefit, it will be necessary to investigate whether long-term follow-up is really useful. Primary prophylaxis of esophageal variceal bleeding with beta-blockers is a well-documented issue (28,29). However, whether treatment with beta-blockers should be added to endoscopic treatment to obtain extra benefit in reducing variceal recurrence and rebleeding is still controversial (22,29). Further studies are required to justify the long-term use of combined EVL and betablockers. In summary, earlier recurrence and multiple recurrences of esophageal varices were more likely in patients undergoing endoscopic ligation than in those undergoing sclerotherapy; however, the recurrences did not impose any higher risk of rebleeding or require more sessions for further eradication, if patients underwent regular endoscopic surveillance. Therefore, EVL still appears to be the optimum endoscopic method for the long-term treatment of esophageal variceal hemorrhage despite the higher tendency to recurrence.
Acknowledgements This work was supported in part by a grant (VGH-88B-251) from the Veterans General Hospital-Taipei and in part by a grant (NSC 88-2314-B-075-031) from the National Science Council, Taiwan. We thank Ms. PuiChing Lee for preparing the manuscript.
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Journal of Hepatology ISSi’I 0168-8278
Recurrence of esophageal varices fo~o~g endoscopic reagent and its impact on rebleeding:comparison of sclerotherapy and ligation Ming-Chih
Hou, Han-Chieh
Lin, Fa-Yauh Lee, Full-Young
Chang and Shou-Dong
Lee
Division of Gastroenterology, Department of Medicine, Veterans General Hospital-Taipei and National Yang-Ming University School of Medicine, Taipei, Taiwan
R~ekg~o~n~A~~s: Endoscopic variceal ligation is superior to sclerotherapy because of its lower rebleeding and complication rates However, ligation is not without drawbacks due to a higher tendency to variceal recurrence. We conducted a randomized cohort study to delineate the long-term history of variceal recurrence following ligation and sclerotherapy, and to clarify the impact of recurrence on rebleeding and on the consumption of endoscopic treatment resources. Methods: Two hundred cirrhotic patients with esophageal variceal bleeding were ~ndo~d to undergo maintenance endoscopic variceal selerotherapy or ligation. Results: One hundred and forty-one patients achieved variceal eradication and were regularly followed up for 2.2 to 6.7 (mean: 5.1-1-1.2) years. The demographic data, hepatic reserve, bleeding severity, and endoscopic features of both sclerotherapy (tt=70) and ligation (n=71) showed no difference. Forty (57.1%) patients who underwent sclerotherapy experienced 58 recurrences of esophageal varices, in contrast to the 46 (64.8%) patients who underwent ligation and experienced 81 episodes of recurrence. Kaplan-Meier analysis showed that within 2 years variceal recur-
rence was more frequent for ligation than sclerotherapy, and the difference decreased thereafter. Multiple recurrence appeared more common with ligation (l/2/ 31415 episodes of recurrence: ~l23lg~3l~ vs. 40~14/3l~/ 0, p=O.OS). On multifactorial analysis, the endoscopic treatment method and red wale markings were the two factors determining variceal recurrence. Rebleeding from recurrent esophageal variees was unusual and showed no difference between the two groups (7158 vs. 6/U, p>O.O5). Rebleeding from gastric varices was more logon after eradication by sclerotherapy (7/ 19 vs. 1116, p=O.OSS) than by ligation. The number of sessions required for eradication of recurrent varices was no different between the two groups. Co~cZ~s~o~s; Early recurrence and m~tiple recurrence of esophageal varices are more likely in patients undergoing endoscopic ligation, compared to sclerotherapy; however, the recurrence did not lead to a higher risk of rebleeding or require more endoscopic treatment.
E
many reports, is the greater probability of variceal recurrence (5-7). These reports were based on a shortterm follow-up (5,6), but the recurrence rate of varices depends on the length of the follow-up. So far, no longterm follow-up studies or details regarding variceal recurrence after EVL have been recorded. Combined EVL and EVS, however, has been attempted to reduce variceal recurrence (89). Although recurrence appeared to decrease (8,9), combined EVL and EVS cannot be recommended because it offers no benefit over EVL alone, and is associated with a higher rate of complications (10,ll). Therefore, it is more appropriate to clarify whether or not the variceal recurrence
variceal ligation (EVL) and sclerotherapy (EVS) are widely used to treat esophageal variceal hemorrhage (1). Because of the lower rebleeding and complication rates of ligation (2-Q it has replaced sclerotherapy as the optimum endoscopic treatment to prevent recurrent bleeding from esophageal varices (1). However, one of the shortcomings of EVL, claimed in NDOSCOPIC
Received 4 June; revised I8 August: accepted 25 August 1999
Correspondence: Ming-Chih Hou, Division of Gastroenterology, Department of Medicine, Veterans General Hospital-Taipei, No. 201, Set 2, Shih-Pai Road, Taipei, Taiwan 11217. Tel: 886 2 28757308. Fax: 886 2 28739318.
202
Key words: Esophageal varices; Ligation; Long-term; Rebleediug; Recurrence; Sclerotherapy.
Impact of variceal recurrence
tendency of EVL carries a higher rebleeding risk than EVS. We conducted a long-term follow-up study to discover the difference in variceal recurrence between EVL and EVS, and to clarify the impact of variceal recurrence on rebleeding and on the consumption of endoscopic treatment resources.
Materials and Methods Patients
From June 1992, to April 1998, all cirrhotic patients entering this hospital with active or recent esophageal variceal hemorrhage were recruited for study, after obtaining informed consent from the patients or their families. Patients with clinical evidence of hepatoma or other malignancies, terminal illness, fundal varices, or a previous history of surgical or endoscopic treatment for esophageal varices were excluded. At the time of endoscopy, patients meeting the inclusion criteria were randomized to undergo EVS or EVL, based on computerized random digit allocation. Patients who continued to receive maintenance EVS or EVL, and who achieved variceal eradication, were included for study. Cirrhosis was diagnosed or suggested by liver biopsy or image study9 and clinical assessment. The study was approved by the Clinical Research Committee of this hospital. Endoscopic treatment procedures
EVS was performed using a free-hand method, with an Olympus XK10 endoscope (Olympus Optical Co., Ltd., Tokyo, Japan) and a 25gauge disposable injection needle, by means of an intravariceal injection. The sclerosant used was 1.5% sodium tetradecyl sulfate (ElkinsSinn, Inc., Cherry Hill, NJ, USA). EVL was performed using an Olympus XQ-20 endoscope with endoscopic ligating devices (Bard
on rebleeding
International Products, Tewksbury, MA, USA), and an overtube, or multi-band ligators (Wilson-Cook Medical Inc., Winston-Salem, NC, USA).
C%nical assessment and foltow-up
Endoscopic treatment was performed weekly for the first 3 weeks, when possible, and then every 3 weeks until the esophageal varices were eradicated. Follow-up endoscopic examinations were later performed twice on a 3-month basis, then on a 6-month basis if there was no recurrence. If rebleeding was suspected, emergency endoscopy was performed to identify the bleeding site. Patients were instructed to return to the hospital immediately if any symptoms or signs suggestive of rebleeding were noticed. If rebleeding occurred, the amount of blood transfused was recorded. If varices recurred, the previous method of eradication was again used. Hepatoma surveillance by serum a-fetoprotein and image study was performed every 3-4 months.
Definition
The severity of esophageal varices was graded, following the system suggested by Beppu et al. (12). Severity of cirrhosis was classified according to Pugh’s modification of Child’s classification (13). Variceal eradication was defined as nonvisualization of varices, or varices that could not be ligated or injected. Variceal recurrence was defined as the development of new varices which could be injected or ligated. The final decision between varices eradication or recurrence had to be agreed upon by two experienced endoscopists. Bebleeding was defined as a new onset of hematemesis, coffee-ground vomitus, hematochezia, or melena with an increasing pulse rate over 110 bpm, and decreasing blood pressure below 90 mmHg. Hepatoma that was found more than 6 months after the index endoscopic treatment was arbitrarily defined as newly developed, clinically detectable hepatoma.
TABLE 1 Clinical characteristics of patients with liver cirrhosis and esophageal variceal hemorrhage undergoing endoscopic variceal sclerotherapy or ligation Clinical characteristics
Age (year) Sex(m/f) Etiology (alcoholi~vira~combine~others) Child (A/B/C) Child-Pugh’s score Albumin (g/dl) Bilirubin (mgldl) Blood urea nitrogen (mgldl) Creatinine (mg/dl) Platelet (K/mm3) Hematocrit (%) Hematemesislnon-hematemesis Ascites f-i+) Encepha’topathy (-I+) Shock(-/+) Blood transfusion (units) Active/inactive bleeding Bed wale marking (<2+/~2+) Variceal form (F,, F$Fs) Number of rebleeding patients before eradication Total sclerosant volume (ml) or rubber bands (n) Eradication sessions* Eradication time (day) Occurrence of hepatoma’ Time of follow-up (month)
(n=70)
Ligation (n=71)
60.0211.9 57113 131441518 17/34/19 8.021.9 3.020.5 2.522.7 18.&9.1 1.121.2 87.1250.2 27526.1 44125 29140 59/l 1 62/S 3.924.4 15J5.5 42128 19151 27 53.6222.5 5.122.1 78.2232.2 12 63.4tll.6
60.4212.1 5605 1l/41/12/7 20126125 8.4~2.4 2.9205 2.822.3 21.2*13.7 1.1t0.5 81.2256.6 26.8265 52119 29142 58/13 61110 4.425.0 23148 38133 14157 18 21.2?9.5 3.7rt1.6 85.6252.9 9 60.1217.5
Sclerotherapy
* p
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Hou et al.
Child-Pugh’s
ment analysis between observers with regard to the eradication and recurrence of esophageal varices. Kaplan-Meier analysis was used to examine the time to first variceal recurrence and the time to death, and the log rank test was used to compare the difference between groups. Multivariate analyses were performed to assess the risk factors of variceal recurrence, using the Cox logistic regression with SPSS. The significance level was p
A
100 T L 3
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Results
20
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Follow-up (years) Child-Pugh’s ';; P 3 .L L
B
100 60
Two hundred patients with liver cirrhosis and esophageal variceal hemorrhage were randomized to undergo EVS (n=99) or EVL (n=lOl). Twenty-five patients with poor compliance or lost to follow-up were excluded (12 in EVS, 13 in EVL). Also excluded were eight patients with development of clinically detectable hepatoma within 6 months of endoscopic treatment (4 in EVS and 4 in EVL); six patients with a change of treatment method (2 in EVS and 4 in EVL); and 20 patients with non-eradication of varices (11 in EVS,
60
z
g 100 6E
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2
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Follow-up (years) Child-Pugh’s T P z .>, L
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Follow-up (years) Fig. 1. Survival in patients with liver cirrhosis and eradication of esophageal varices after endoscopic variceal sclerotherapy and ligation. There was no statistical difference between the two groups, even after stratifying patients by hepatic reserve.
Ligation P=O.O718
o! 0
B Statistical
analysis
The results were expressed as mean?SD. Each continuous parameter between the two treatment groups was analyzed with two-sample Student’s t-tests. Categorical data were examined using the x2 test with Yates’ correction. The 95% confidence interval in their difference was computed using the assumption of Z distribution. The secular trend to multiple variceal recurrences and endoscopic treatment were evaluated by the x2 test for trends. The kappa statistic was used for agree-
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.,.,.,.,.,.,., 1
2
3
4
5
6
7
Follow-up (years)
Fig. 2A. Absence of variceal recurrence within 2 years of eradication after endoscopic variceal sclerotherapy and ligation. The difference between the two groups was signtficant (p=O.O4). B. Absence of variceal recurrence within 6 years of eradication after endoscopic variceal sclerotherapy and ligation. There was no statistical difference between the two groups.
Impact of variceal recurrence on rebleeding TABLE
2
Outcome of rebleeding and variceal sclerotherapy or ligation
recurrence
in patients
with liver cirrhosis
and esophageal
Characteristics
Rebleeding Rebleeding
patients after variceal eradication episodes after variceal eradication
Rebleeding sources Esophageal varix Esophageal ulcer Gastric varix Portal hypertensive gastropathy Gastric vascular ectasia Undetermined Patients with recurrent varices No. of sessions required to eradicate recurrent esophageal varices Blood transfusion for bleeding from recurrent varices (unit) Blood transfusion for bleeding from portal-hypertension-related sources * No patients died of recurrent esophageal varices with bleeding. + Including 58 episodes of recurrence in the sclerotherapy group, and 81 episodes
9 in EVL). Of 20 patients who died before variceal eradication, there were l/2/8 with Child-Pugh’s A/B/C in the EVS group and l/1/7 in the EVL group. According to Child-Pugh’s A/B/C, the mortality rates before eradication were 6% (l/18), 6% (2/36), 30% (8/27) in the EVS group and 5% (l/21), 4% (l/27) and 22% (7/32) in the ligation group. Therefore, one hundred and forty-one patients (70 in EVS, 71 in EVL) who had achieved variceal eradication and had had a regular follow-up of 2.2 to 6.7 (mean: 5.1~ 1.2) years, were analyzed. The interobserver agreement rate for eradication and recurrence of esophageal varices was excellent (kappa index of 0.79 and 0.75, respectively). Clinical characteristics of patients
With the exception that fewer sessions of EVL than of EVS were required to eradicate varices, the demographic data, underlying etiology of liver cirrhosis, hepatic function, endoscopic features, bleeding severity, follow-up period (Table l), and survival (Fig. 1) between the two groups were not different. Recurrence of esophageal varices after endoscopic eradication in patients undergoing sclerotherapy or ligation
Kaplan-Meier analysis showed that variceal recurrence within 2 years of variceal eradication was more frequent with ligation than sclerotherapy (Fig. 2A); however, the difference decreased as follow-up extended to 6 years (Fig. 2B). The number of patients experiencing variceal recurrence in the EVS and EVL groups was not different (Table 2). Of 24 pure alcoholic cirrhotics, esophageal varices recurred in six of ten patients abstaining from drinking, five in eight patients not ab-
(unit)
variceal
hemorrhage
after
endoscopic
Sclerotherapy (n=70)
Ligation (n=71)
p-value
10 19
6 16
NS NS
7* 2 7 0 1 2 40+ 1.620.9 2.622.4 3.825.5
6* 3 1 3 1 2 46+ 1.4kl.O 2.7k3.0 1822.4
NS NS 0.085 NS NS NS NS NS NS NS
of recurrence
in the ligation
variceal
group.
staining from drinking, and four in six patients with an uncertain drinking history. Multiple recurrence appeared to be more common with ligation (l/2/3/4/5 episodes of recurrence: 46/23/8/3/l vs. 40/14/3/1/O, p= 0.08). On multifactorial analysis of all the factors in Table 1, the endoscopic treatment method (EVL vs. EVS; odds ratio: 1.56; 95% confidence interval: 1.0% 2.43) and red wale markings ?2+ vs. <2+; odds ratio: 1.71; 95% confidence interval: 1.10-2.65) were the two factors determining recurrence. Rebleeding after eradication of esophageal varices in patients undergoing sclerotherapy or ligation
Patients might bleed from a variety of sources (Table 2). In both the EVS and EVL groups, the rebleeding rate before variceal eradication was higher than that after variceal eradication (27170 vs. 10170, ~~0.01 for EVS; 18171 vs. 6171, ~~0.05 for EVL). Rebleeding occurred 480.1 k439.3 (15 to 1220) days after variceal eradication with EVS and 328.4k213.0 (18 to 840) days after variceal eradication with EVL. Rebleeding from recurrent esophageal varices was unusual and no different in the EVS and EVL groups (7158 vs. 6181, p>O.O5). Rebleeding from gastric varices appeared more common in patients in whom esophageal variceal eradication was achieved with EVS than in those in whom eradication was achieved with EVL (7119 vs. 11 16,p=O.O85). The interval between esophageal variceal eradication and rebleeding of these eight patients was 39, 163, 323, 507, 1065, 1220, and 1250 days in the EVS group and 280 days in the EVL group. The number of units of blood transfused for rebleeding from recurrent esophageal varices or from any portal-hypertension-related sources, and the number of sessions re20.5
M.-C. Hou et al.
quired to eradicate recurrent varices, were similar in the two groups. The total number of treatment sessions required for eradication of initial varices and recurrent varices showed no difference between the EVS (total: 450, average: 6.43k2.72 sessions) and EVL groups (total: 378, average: 5.32k2.40 sessions). Death due to rebleeding occurred in four patients including three patients who died of gastric variceal bleeding in the EVS group and one patient who died of esophageal ulcer bleeding precipitated by hepatic failure in the EVL group. Complications before and after eradication of esophageal varices in patients undergoing sclerotherapy or ligation
Before eradication, the EVS-related complications were esophageal stricture in nine, intramural hematoma in one, aspiration pneumonia in one, spontaneous bacterial peritonitis in two and sepsis in one patient. The EVL-related complications before eradication were esophageal stricture in one, spontaneous bacterial peritonitis in one, deep neck infection in one and rectal variceal bleeding in one patient. The complication rate before variceal eradication was higher in the EVS than the EVL group (14/70 vs. 4/71, ~~0.05). In contrast, the only complication in a patient undergoing EVS for recurrent esophageal varices was esophaged stricture, and there were no complications with EVL.
Discussion Although sclerotherapy and ligation are of comparable efficiency in controlling active esophageal variceal bleeding, the rebleeding rate and post-treatment morbidity are lower with ligation (2-5). The advent of the speedband ligator, which obviates the need for an overtube, has provided better compliance and lessened the discomfort of EVL (14). Ligation has therefore become more popular with practitioners for treating esophageal variceal hemorrhage. Accumulated evidence suggests that the patency of feeder vessels of varices, such as paraesophageal varices and periesophageal varices, predisposes to variceal recurrence (15-l 8). These feeder vessels are occluded more efficiently by sclerotherapy than ligation, which is usually confined to the mucosal and submucosal collaterals (18,19). Ligation is thus not without the drawback of a higher tendency to variceal recurrence (5-7), but the details of variceal recurrence after ligation are still unknown. Furthermore, the recurrence of varices may become more frequent with time, and therefore a long-term follow-up is required to delineate the difference in variceal recurrence between ligation and sclerotherapy. It is also important to determine the impact of variceal re-
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currence on rebleeding and the usage of medical resources. Previous studies have shown that about 60% of patients have experienced recurrence of esophageal varices, and that most recurrences were within 1 year of sclerotherapy (15,20-22). We found that most recurrences were within 2 years of eradication, regardless of the treatment method. It is possible that varices rarely recur beyond 2 years after eradication when an opening of new porto-systemic collaterals elsewhere might take the place of esophageal varices in releasing portal hypertension. Although the number of patients experiencing variceal recurrence was similar in both groups, esophageal varices tended to recur earlier among EVL patients. Since feeder vessels in deeper layers could always be missed, even after repeated ligation for recurrence (18), varices continually recurred. These findings further support the crucial role of feeder vessels in determining the recurrence of esophageal varices (1.5-18). Besides the treatment method, we found that red wale markings are another determinant of variceal recurrence. Esophageal varices with red wale markings were found to have higher variceal pressure (23,24), which is an important hemostatic force for varices formation (25) and might contribute to recurrent varices. Rebleeding after variceal eradication was unusual (26). The rebleeding rate before variceal eradication was about 2 to 3 times higher than that after variceal eradication. The rebleeding risk was much higher if the follow-up period before and after variceal eradication was taken into consideration. Rebleeding from recurrent esophageal varices was even rarer if patients had regular endoscopic surveillance. Therefore, in spite of a higher recurrence rate of esophageal varices in the EVL group than in the EVS group, no higher rebleeding risk was found in the EVL group. Instead, rebleeding from secondary gastric varices appeared more likely in patients undergoing EVS in this longterm study, in contrast to our previous short-term study and others which showed no difference in rebleeding from gastric varices (2-6). It is possible that EVS causes a more complete occlusion of esophageal varices, and thus, with time, blood is shunted to other collaterals such as the gastric varices, those nearest to esophageal varices. However, no definite conclusion about the tendency of gastric variceal rebleeding with sclerotherapy in the long-term can be drawn from the small number of events in this study and requires further investigation. The amount of blood transfused for rebleeding from either recurrent esophageal varices or other portal-hypertension-related sources was not different after either EVS or EVL. Furthermore, the
Impact of variceal recurrence on rebleeding
number of treatment sessions required to eradicate the recurrent varices was similar in both groups. This result indicates that recurrent varices in the individual patient undergoing EVL requires no more eradication sessions than in the patient undergoing EVS. This also holds true for all patients in the EVL group, in which the total number of sessions of endoscopic treatment required was no higher than in the EVS group. This suggests that EVL did not increase the consumption of endoscopic treatment resources, in spite of the rate of variceal recurrence being higher than with EVS. A meta-analysis showed that shortterm survival (mean follow-up period 10 to 12 months) was improved in patients with EVL (27). Long-term survival (mean follow-up period 5.1 years) was not different between EVL and EVS in our patients achieving variceal eradication. More long-term studies are required to draw a definite conclusion. However, because there is no control arm (patients without long-term endoscopic follow-up) for comparison of rebleeding morbidity and cost/benefit, it will be necessary to investigate whether long-term follow-up is really useful. Primary prophylaxis of esophageal variceal bleeding with beta-blockers is a well-documented issue (28,29). However, whether treatment with beta-blockers should be added to endoscopic treatment to obtain extra benefit in reducing variceal recurrence and rebleeding is still controversial (22,29). Further studies are required to justify the long-term use of combined EVL and betablockers. In summary, earlier recurrence and multiple recurrences of esophageal varices were more likely in patients undergoing endoscopic ligation than in those undergoing sclerotherapy; however, the recurrences did not impose any higher risk of rebleeding or require more sessions for further eradication, if patients underwent regular endoscopic surveillance. Therefore, EVL still appears to be the optimum endoscopic method for the long-term treatment of esophageal variceal hemorrhage despite the higher tendency to recurrence.
Acknowledgements This work was supported in part by a grant (VGH-88B-251) from the Veterans General Hospital-Taipei and in part by a grant (NSC 88-2314-B-075-031) from the National Science Council, Taiwan. We thank Ms. PuiChing Lee for preparing the manuscript.
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