Endoscopic esophageal sclerotherapy: long-term results of the elective procedure.

Dig Dis 1992; 10(suppl 1):65—73

Antonio Russo Antonio Magnano Guido Passanisi Nunziata Giannone

Endoscopic Esophageal Sclerotherapy: Long-Term Results of the Elective Procedure

Chair of Surgical Endoscopy. University of Catania, Italy

Abstract Chronic endoscopic esophageal sclerotherapy represents a pri mary technique for the prevention of recurrent bleeding in cir rhotic patients who have already experienced one variceal bleeding episode. 131 patients with portal hypertension and a history of esophageal variceal bleeding underwent endoscopic sclerotherapy. 74 of these patients constituted a subgroup which was singled out for special analysis. In these patients, treatment had been started after conservative management of an acute bleeding episode had stopped the bleeding and fol low-up data for at least 6 months were available. 90.5% of these patients had nonalcoholic etiology for their portal hyper tension. 60.8% of patients developed recurrent varices and 11.1% had recurrent bleeding from esophageal varices. The bleeding risk index, calculated as the number of hemorrhages/patient/months of follow-up, correlated strongly with the number of previous hemorrhages and inversely with hepatic reserve (Child’s class). The bleeding risk index de creased tenfold after sclerotherapeutic obliteration of varices. These data suggest that chronic elective endoscopic sclerother apy may play a primary role in the management of patients who have bled from esophageal varices.

Bleeding esophageal varices are one of the most important causes of death in patients with portal hypertension [1], The cumulative prevalence of this complication is approxi mately 33% (17.4-43.3%). This value de

creases to 29% if only the first episode of bleeding is considered but it rises to 70% because of recurrent bleeding. The mortality caused by variceal bleeding suggests the dramatic importance of this

A. Russo Chair of Surgical Kndoscopy University of Catania 1-95100 Catania (Italy)

©1992 S. Karger AG. Basel 0257-2753/92/ 0107-006552.75/0

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KeyWords Sclerotherapy Cirrhosis Portal hypertension Esophageal varices

n

%

Etiology of portal hypertension Non-alcoholic cirrhosis Alcoholic cirrhosis Portal thrombosis

65 7 2

87.8 9.5 2.7

Child's classification Class A Class B Class C

35 29 10

47.3 39.1 13.6

Table 2. Outcome of patients submitted to chronic elective EST

N umber of patients Deaths Drop out Patients with eradicated varices

n

%

87 6 7 74

6.9 8.0 85.1

Mean post-eradication follow-up 23.2 months (6-72).

event in the natural history of the disease. Thirty-seven percent of the bleeders succumb to the first variceal hemorrhage. Thirty-one percent of the survivors will eventually die of bleeding recurrences. Cumulatively, 36.5% of cirrhotics die of variceal bleeding [2]. These data motivate therapeutic efforts aimed at preventing the initial episode of var iceal bleeding (prophylaxis) and recurrent bleeding (long-term management), or stop ping an active variceal hemorrhage (emergen cy). We report here on long-term results ob tained in a population of cirrhotics submitted to chronic esophageal sclerotherapy after one or more episodes of variceal bleeding.

66

Patients and Methods Between March 1983 and August 1989. I3l pa tients underwent endoscopic sclerotherapy (EST). In 87 of these patients, treatment was started after active variceal bleeding had been stopped by conservative procedures (vasoactive drugs or Sengstaken-Blakemore tamponade). Seventy-four of this subgroup were followed for at least 6 months. All patients (55 males. 19 females): median age 58.1 years) had third- and fourth-grade esophageal varices according to Paquet's classification. The causes of portal hypertension were: non-alcoholic cirrhosis (87.8%). alcoholic cirrhosis (9.5%) and portal vein thrombosis (2.7%). 47.3% of the patients were in Child’s class A. 39.1% in class B and 13.6% in class C (table 1). All patients had experienced one or more variceal hemorrhages. Forty-three had experienced one episode of bleeding, 21 two episodes and 10 three or more epi sodes. EST w'as always started at least 24 h after the control of bleeding. It was performed with standard or wide-channel fiberscopes, by the free-hand technique of injection. Multiple para- and intravascular injec tions of 1% Polidocanol were given in the last 5-8 cm of the lower esophagus for a total amount of 22.5 ml (6-42). Sclerotherapy sessions were performed every 7-10 days until complete obliteration of varices had been achieved. Subsequently, patients with eradicated varices were submitted to regular clinical, laboratory, ultrasonographic and endoscopic controls every 3 months during the first year and every 6 months there after. Recurrent varices detected during follow-up were all treated during a same-day hospital procedure. Results have been analyzed for: ( I ) incidence of variceal and bleeding recurrences and evolution of the bleeding risk index, calculated as incidence of blceding/patient/months of follow up: (2) evolution of residual hepatic reserve; (3) survival of patients, and (4) incidence of side clTccts and complications of the treatment.

Results Of the 87 patients. 74 were followed for more than 6 months. Seven were lost to fol low-up and 6 patients died of recurrent vari ceal bleeding before EST was completed (ta ble 2). Of the 74 patients with eradicated var ices, 20 died during subsequent follow-up.

Russo/Magnano/Passanisi/Giannonc

Endoscopic Esophageal SclerotherapyLong-Term Results of the Elective Procedure


Table 1. Chronic Elective EST: clinical findings in eradicated patients (n = 74)

Recurrences o f Varices and Bleeding Forty-five of the 74 patients with eradi cated varices (60.8%) had recurrent varices: these were detected within the first 6 months after eradication in 77.8% of the cases. Recur rent varices were grade 1, according to Paquet. in 33 patients (73.3%) and grade 2 in the remaining 12 (26.7%). Recurrent varices were detected in the gastric fundus in only 2 cases. No correlation between the severity of hepatic decompensation and variceal recurrence rate emerged (table 3). Twelve out of the 74 patients included in this study had a total of 12 recurrent episodes of bleeding. Bleeding was caused by recurrent esophageal varices in 8 cases, gastric fundic varices in 2 cases and duodenal ulcer and jeju nal ulcer in 1 case each. Out of the 12 hemor rhages (8 variceal. 4 non-variceal) which oc curred during the course of the follow-up. 8 were controlled, while 4 were lethal (table 4). In order to quantify the effectiveness of EST in reducing the probability of hemor rhagic events, we have calculated a bleeding risk index, expressed as the number of hemorrhages/patient/months of follow-up. We cor related the number of episodes of variceal bleeding observed before and after EST, with the cumulative period (in months) of post eradication follow-up. Bleeding risk index was similar before EST (0.08). and during eradication (0.07. but the bleeding risk de creased index ten-fold after the obliteration of varices (index = 0.007) (table 5). We also evaluated the bleeding risk in cor relation with the number of episodes of vari ceal bleeding which patients had experienced prior to EST. For patients with one or two

Table 3. Correlation between variceal recurrences and degree of hepatic decompensation Child’s class

Patients

A B C

35 29 10

Variceal recurrences n

%

23 18 4

65.7 (n.s.) 62.1 (n.s.) 40.0 (n.s.)

Table 4. Outcome of 12 variceal rebleedings in patients with eradicated varices

Deaths Controlled by Medical treatment Emergency EST

n

%

4

33.3

6 2

50.0 16.7

Table 5. Evaluation of the bleeding risk index

Months/ Bleedings Index patient value Before EST After EST Before eradication After eradication

1.748 1.748 241 1.507

138 29 17 12

0.08 0.016 0.07 0.007

previous hemorrhages, the index value during follow-up was 0.019. For patients with a his tory of three or more previous events, the index rose to 0.039. Finally, we correlated the incidence of re current bleeding with the severity of hepatic decompensation. Among Child A-B patients. 12.5% rebled while 40% of Child C patients rebled. This difference was not statistically

67


while the remaining 54 survivors continued to be followed regularly. On average, 4.2 ses sions of EST (range 2-7), were necessary to obliterate the varices, with a mean hospitali zation of 17.5 days (range 12-25).

Evolution o f Residual Hepatic Reserve To verify the influence of treatment on the long-term evolution of liver disease, we cate gorized our patients according to the ChildHobbs classification before EST and annually after EST was completed. In our experience, EST did not exert any influence on the long term evolution of hepatic reserve. Survival There were 20 deaths among the 74 pa tients who survived until eradication. Five deaths were related to a bleeding episode (4 variceal, 1 non-variceal). 8 to liver failure and 7 to other causes (6 malignancies, 1 stroke) (table 7). In our experience, the probability of sur vival appeared to be affected by the degree of hepatic decompensation. After 48 months of follow-up. cumulative survival was 61.6%. However, the survival rate was 79.3% for Child class A-B patients compared to 40% for Child class C. Therefore, a good hepatic re serve seems to be associated with a better long-term outcome (x2 = 4.59: p < 0.05). Complications We observed 20 severe complications. Out of 17 episodes. 11 were controlled by medical and/or endoscopic means while 6 were lethal. Three post-injection esophageal strictures oc curred. One mild stricture recovered sponta neously while the remaining two required en doscopic dilation. The most common side effects were retro sternal pain and esophageal ulcerations, both probably due to extravasation of the sclero sant. Patients complained less commonly of transient dysphagia and fever. These symp toms always disappeared spontaneously within 24-48 h [3].

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Table 6. Correlation between rebleeding and de gree of hepatic decompensation Child’s class

Patients

A B C

35 29 10

Rebleeding n

%

5 3 4

14.3 (n.s.) 10.3 (n.s.) 40.0 (n.s.)

Table 7. Causes of death in patients with eradi cated varices

Liver failure Malignancies Bleeding variceal non-variceal Stroke Total

n

%

8 6 4 1 1

40.0 30.0 20.0 5.0 5.0

20

100.0

Discussion Until 10 years ago, surgery was the onlydefinitive therapeutic option either for active variceal bleeding or the prevention of reblceding. However, during the last decade poor long-term results of surgery have been pro gressively counterbalanced by promising re sults of two new therapeutic procedures: en doscopic sclerotherapy and the administra tion of |)-blockers. EST is increasingly recommended today either to stop active variceal bleeding or to prevent rebleeding [4-14], The utility of EST in the prevention of the first variceal hemor rhage has not yet been clearly demonstrated [15-22],

Russo/Magnano/Passanisi/Giannone

Endoscopic Esophageal Sclerotherapy: Long-Term Results o f the Elective Procedure


significant, however (%2 = 3.0: p: n.s.) (ta ble 6).

Table 8. Results of controlled trials on therapeutic EST

Copenhagen study [10] Westaby et al. [ 11 ] Korula ct al. [12] Terblanche et al. [13]

Controls

Mean/ median follow-up months

EST n

rebleeding mortality % %

n


24 37 13 48

93 56 63 37

48 55 50 58

94 60 57 38

54 80 80 77

The wide use of EST is due to its technical simplicity, its favorable cost-benefit ratio and the low availability of surgical centers specifi cally concerned with treatment of portal hy pertension. However, the role of EST as a ‘gold standard' for long-term management of variceal bleeding still requires further confir mation. Whatever the treatment considered is, two critical points of evaluation should be kept in mind: incidence of rebleeding and long-term survival of patients. In four controlled studies [10-13], EST has been shown to decrease bleeding compared to standard medical man agement (48-58 vs. 54-82%). In two of these trials [10, 11], the differences were of statisti cal significance (table 8). In our patients, 39.3% of whom rebled, a critical decrease (about ten-fold) in the bleed ing risk could be obtained only once complete obliteration of varices had been achieved. Be fore eradication, the probability of remaining bleeding-free was similar to that of untreated patients. Many factors may influence the risk of bleeding and, consequently, the effectiveness of treatment. The time between bleeding and initiation of treatment is probably the single most critical factor in determining the long term outcome of EST. The number of bleed ing episodes previously experienced by the

65 .32 33 62

78 53 .33 63

patient is also significant [23]. In our popula tion of cirrhotics, the rebleeding risk index/month was 0.019 for patients with 1 or 2 previous variceal bleedings and 0.039 for pa tients with a history of 3 or more episodes. Other variables may also affect the efficacy of the treatment. Technical factors include the type and concentration of sclerosant, the esophageal segment injected, the technique of injection (paravariceal, intravariceal or both), and the schedule of treatment. Clinical factors which may alter the efficacy of sclerotherapy include the etiology of portal hypertension (post-hepatic or alcoholic cirrhosis, extrahepatic portal obstruction), the gross appear ance and degree of pressure within varices, the presence of coexisting gastric varices or other mucosal lesions and the schedule of fol low-up. The skill of the endoscopist and of the medical team are also relevant. Finally, emphasis must be placed on the role of residual hepatic reserve [24. 25] which is, with few exceptions [26], considered of critical importance in determining the long term results of any treatment. In our experi ence. 40% of Child class C patients rebled compared to 12.5% in Child class A. More over, it has been shown that prognosis of vari ceal rebleeding in untreated patients is worse than that of patients submitted to EST [27],

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Author

Author

Dollct ct al. [29] Fleig ct al. [30] Alexandrino ct al. [31]

Whereas the role of EST in decreasing the probability of variceal rebleeding is well es tablished, its efficacy in improving long-term patient survival is less clear. Only one of the four controlled trials which have been per formed has shown a significant improvement of cumulative short-term survival [11]. An improvement in long-term survival was shown for Child class A patients only. The failure of EST to improve survival in the other three studies may be explained by a close examination of these trials. In the Lon don study, the control patients who experi enced bleeding were treated only by standard medical drugs. In the Cape Town and Los Angeles studies [12, 13], patients underwent emergency EST and portacaval shunt, respec tively. If rebleeders are excluded from both series, then a significant improvement in sur vival does become evident. The effectiveness of EST in decreasing the rebleeding rate and improving 1- and 2-year survival has been recently reaffirmed in a pro spective trial performed on Child class B-C post-hepatic cirrhotics. Survival was between 70 and 47% in the EST group and between 52 and 23% in the control group [14], In our pop ulation. predominantly composed of posthepatic cirrhotics, we obtained similar 2-year survival rates (Child A 80%. Child B 83.3%. Child C 57.1 %). The increase in mortality that we observed at 42 months for Child class

70


p-Blockers

EST

n

rebleeding %

n

rebleeding %

36 -

27 34

41 28

28 36

64 29

29

34

62

31

23

C patients may be related to either a further deterioration of liver function or the small number of subjects included in this group. As an alternative to sclerotherapy, the ad ministration of p-blocking drugs has been re cently proposed [28]. Three controlled trials (table 9) have compared EST to the adminis tration of non-cardioselective P-blockers [29— 31], while a cardioseiective drug has been evaluated in another report [32]. In two of the first three studies, no differ ence emerged. In another [29], 23% of EST patients showed bleeding recurrences com pared to 62% of patients receiving proprano lol. However, this difference disappears if non-variceal hemorrhages are excluded from analysis of these data. In a comparison be tween EST and a cardioseiective (3-blocker (metoprolol), EST was able to decrease the incidence of rebleeding three-fold [32]. These conflicting results in terms of bleeding rate reduction are counterbalanced by similar short- and long-term survival rates observed in two of the aforementioned studies [29, 30], In evaluating the role of p-blockers in pa tients with esophageal varices, it should also be considered that only a restricted subgroup of cirrhotics may tolerate the chronic admin istration of these drugs. Among patients who initially tolerate P-blockade. about 25% must stop treatment because of severe side effects

Russo/Magnano/Passanisi/Giannonc



Table 9. Results of trials comparing propranolol and therapeutic EST

Table 10. Results of trials comparing selective shunt surgery (DSRS) and therapeutic EST

Rikkerset al. [47] Teres ct al. [48] Warren et al. [49]

EST


Surgery' n


n


25 27 26

27 57 35

19 14.3 3

30 55 36

57 37.5 53

[33], Furthemore, the effectiveness of (3blockade in improving the long-term outcome of patients has yet to be clearly demonstrated [33-37], Surgery is the third therapeutic option to which EST might be compared. At the begin ning of the 1970s. some studies on portal-tosystemic shunts showed a remarkable de crease of bleeding recurrence without equiva lent improvement of patient survival [38-40], In fact, this approach, while decompressing the portal system, resulted in a progressive deterioration of residual hepatic function and. in 15-45% of shunted patients disabling neurological sequelae [41.42], Further variations of portosystemic shunts (side-to-side portacaval, mesocaval. mesorenal) have failed to produce better results [43— 45], In an effort to obviate these problems. Warren [46] in 1967 proposed the distal sple norenal shunt (DSRS) aimed at selectively decompressing gastroesophageal varices, by simultaneously preserving the portal venous perfusion of the liver. Several controlled trials have confirmed the validity of the rationale for this operation. DSRS produced similar rates of operative mortality ( 11 %) and late mortality (31%) to standard portacaval shunt ing. However, the incidence and severity of encephalopathy were markedly diminished after DSRS [46]. The effectiveness of DSRS has been compared to EST in three studies

35 19 40

39 27 14

[47-49] (table 10). Rebleeding rates have al ways been lower after DSRS than after EST (11.5 vs. 47.4%). Survival rates after DSRS and EST have been similar in two studies [47. 48] and better after EST in the third [49], The latter result was obtained by surgically recov ering EST failures. Furthermore, this study emphasizes that EST improves liver function as assessed by galactose elimination capacity. Finally, with relation to the economic costs of each therapeutic option, it has been esti mated [47] that, in the initial phase, surgery is more expensive than EST (US$ 34.375 ± 5.499 vs. US$ 37.648 ± 6.392). However, the need for repeated therapy in EST patients subsequently increases the expense of this op tion. It is possible that EST might eventually maintain the most favorable cost-benefit ratio if follow-up of these patients is performed on an outpatient basis. In conclusion, chronic elective EST has assumed the major role in the long-term man agement of patients who have bled from esophageal varices. Compared to standard medical therapy, EST provides better results in terms of reduction of rebleeding and shortand long-term survival. EST is at least as effective as [3-blocking agents. These drugs, reserved for weel-selected subgroups of cir rhotics. are totally useless for patients with poor liver function (Child class C) [34],

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Author

The comparison between EST and surgery (in particular DSRS) also demonstrates sub stantial equivalence, although better results in EST patients might be obtained if the two procedures were performed in a complemen tary way. However, only a critical examina tion of available experience together with a more extensive evaluation will clearly delin

eate the role of EST in the management of the most severe complication of portal hyperten sion. To date, a multidisciplinary approach seems to be the most appropriate therapeutic strategy. This may improve the long-term out come of these patients, but the goal of chang ing the natural history of this disease will probably remain unrealized.

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