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“The only thing necessary for these diseases to the triumph is for good people and governments to do nothing.”

  

 

Pharmacological Treatment of Portal Hypertension:
An Evidence-Based Approach


 
Gennaro D'Amico, M.D., Luigi Pagliaro, M.D., and Jaime Bosch, M.D., From Department of Liver
Transplantation and Hepatobiliary Medicine, Royal Free Hospital, London, United Kingdom
Semin Liver Dis 19(4):475-505, 1999. © 1999 Thieme Medical Publishers
http://www.medscape.com/viewarticle/416617_print
Abstract and Introduction
Abstract
Continuing advances in the knowledge of the pathophysiology of portal hypertension result in the progressive expansion of the spectrum of drugs with a potential role for clinical practice, with objectives that now tend to include the prevention of the enlargement or even the development of esophageal varices. This systematic review summarizes the evidence of efficacy of drug therapy for portal hypertension and draws recommendations for clinical practice. Although there is not yet enough evidence to support the treatment for the prevention of the development or enlargement of varices, nonselective beta-blockers are the first-choice therapy to prevent the first bleeding in patients with medium or large-sized varices and rebleeding in patients surviving a bleeding episode. The clinical role of isosorbide-5-mononitrate either alone or in association with beta-blockers still remains unsettled. Vasoactive drugs are generally effective and safe in controlling acute variceal bleeding, although the evidence is not equivalent for each of them.
Introduction
The continuous development of the knowledge in pathophysiology of portal hypertension has substantially expanded the spectrum of potentially effective drugs. The first step in the pharmacological treatment of portal hypertension was the reduction of the portal blood inflow. This is abnormally increased because of splanchnic and systemic vasodilatation that result in the hyperdynamic circulation. This causes a progressively increasing amount of blood to enter in the splanchnic bed and hence in the portal vein. Several vasoconstrictors have been shown to be effective in reducing portal blood inflow and, as a consequence, portal pressure. Because the hyperdynamic circulation is accompanied and maintained by hypervolemia, a low-sodium diet and spironolactone have also been shown to reduce portal pressure, even in compensated patients without sodium retention. Most importantly, in the last decade it has been established that, contrary to what was previously thought, the increase in hepatic vascular resistance is not only a mechanical consequence of the distortion of the hepatic structure but also the result of a dynamic component due to the active contraction of vascular smooth muscle cells in the liver vasculature and of extravascular cells, such as myofibroblasts or activated hepatic stellate cells surrounding the sinusoidal endothelial cells.[1] This dynamic component is enhanced by endothelin and a-adrenergic stimulation and is reduced by nitric oxide, prostacyclin, and several vasodilating drugs. Thus, vasodilators have become another important category of drugs for portal hypertension.
Combination therapy (associating a nonselective beta-blocker with a nitrovasodilator) and the identification of hemodynamic markers of long-term clinical efficacy of the treatment is opening the clinical scene to the tailoring of drug therapy to the individual patient, similarly to what is currently done to treat arterial hypertension. In that regard, it is now well established that the risk of bleeding from varices is nil when the portal pressure gradient (usually evaluated as the hepatic vein pressure gradient [HVPG]) is reduced to 12 mm Hg or below. Even without reaching this target, the risk of bleeding is extremely low when the HVPG is decreased by at least 20% from its baseline value.[2,3]
Although the pathophysiological basis for pharmacological treatment of portal hypertension is discussed elsewhere in this issue, here the evidence of clinical efficacy of drugs is summarized and recommendations for clinical practice are drawn.
Objectives Of Treatment
The principal objectives of pharmacological treatment for portal hypertension have been for many years the prevention of bleeding or rebleeding and the control of acute bleeding, aiming at improving survival by reducing bleeding-related deaths. More recently, the hypothesis that drug therapy may prevent varices from developing or becoming large enough to be at risk of rupture has been tested in one trial reported in abstract and in another still in progress.
Here, we review the body of evidence of clinical effectiveness of drug therapy for portal hypertension according to the baseline risk in different clinical scenarios to provide reliable estimates of the treatment effects for clinical practice.
Review Of Randomized Clinical Trials
To synthesize the evidence of efficacy of treatments, we pooled data from relevant groups of trials according to a random effects model and reported treatment effects as absolute rate difference (ARD) and number of patients needed to be treated (NNT = 1/absolute rate difference).[4-6] The number of patients needed to be treated to save a harmful treatment effect (NNH = 1/ absolute rate difference of harmful events due to treatment) is also reported when appropriate. ARD is always calculated as the event rate in the experimental group minus the event rate in the control group. In this way, a negative value indicates a beneficial effect of the experimental treatment. Ninety-five percent confidence intervals (CI) are also reported. When the confidence limits are both negative, the favorable experimental treatment effect is statistically significant, whereas an entirely positive CI indicates a significantly harmful effect of the experimental treatment. Cumulative meta-analysis is used to graphically represent the modification of the pooled estimate of the treatment effect at any time a new randomized clinical trial (RCT) has been reported.
Recommendations for clinical practice are derived from the evidence of efficacy of treatments. They are graded in six levels according to the strenght of evidence (validity and consistency of the studies), from A1 to C2 (Table 1). This grading of recommendations has been recently suggested by a Consensus Conference of the American College of Chest Physicians.[7]
Prevention Of First Bleeding
Relevant information from the natural history of portal hypertension has been recently thoroughly reviewed,[8] and the following key points may be considered as a basis for the definition of the objectives of treatment before the first bleeding.
Information on the incidence of esophageal varices is insufficient. One study reported a 10-year incidence of 90%[5-]; however, in that study the 5-year cumulative proportion of patients with varices was near 50% but half of these patients had varices when they entered the study. Thus, the net 5-year incidence was near 25% (about 5% per year). After 5 years of observation only 50 of the 532 patients originally included were still at risk, and confidence intervals of estimates were very large after that point. More recently, we reported cumulative data from two prospective studies of the natural history of cirrhosis performed at our unit including 1,123 patients without varices when first diagnosed. After a 10-year follow-up, the cumulative proportion of patients with esophageal varices was 44% with 123 patients still at risk at the beginning of the 10th year of observation.[8] The incidence of varices was quite constant and near to 4.4% per year. Because the incidence of varices observed in the former study[9] during the first 5 years was very close to that observed at our unit and no other data are available, we should assume the best available estimate of the incidence of varices is between 4 and 5% per year. This would require a sample size of 170 patients per group in a trial for the prevention of varices with a 5-year follow up, to show a 50% difference between the treatment and control group (a = 0.05 and b = 0.80).
From transversal studies we also know that esophageal varices develop only in patients with HVPG >10 mm Hg, although we do not know the incidence of varices in patients with HVPG above this level or whether the risk of developing varices increases with increasing values of HVPG above this threshold value. It may be expected that worsening of liver function and continuing exposure to alcohol are related to the risk of developing varices, but it has also been shown, in a prospective study, that HVPG increases with worsening of liver function and continuing alcohol abuse and decreases when liver function improves and with interrupting alcohol abuse.[10] Thus, to the best of our knowledge, HVPG is the only risk factor for developing esophageal varices and should be the parameter to select patients for preprimary prophylaxis of esophageal varices.
Once developed, varices increase in size from small to large in approximately 12% patients per year in the first 2 years after endoscopic diagnosis of varices. This is the median value from the four studies reporting this information.[8-11]
The following have been reported as risk indicators of bleeding from esophageal varices: variceal size, red marks on the variceal wall, Child-Pugh class, HVPG increasing with time, variceal pressure, and variceal wall tension. No bleeding has been reported in patients with HVPG <12 mm Hg, and this value is considered the threshold value for variceal bleeding.[8]
The 2-year bleeding incidence is near 30% in patients with medium or large-sized varices and near 10% in patients with small varices.[12]
Nonselective beta-blockers, nitrates, and spironolactone are the only drugs assessed for primary prophylaxis of variceal bleeding. Although several risk factors for variceal bleeding have been identified, clinical trials assessing pharmacological treatments for prophylaxis of first bleeding selected patients mainly on the basis of variceal size.[13] Information on the treatment effect according to the presence of ascites is also reported in some studies. Thus, the prevention of first variceal bleeding has been assessed in clinical scenarios mainly identified by the variceal size and clinical decompensation.
Nonselective Beta-Blockers
As discussed elsewhere in this issue, these drugs reduce portal pressure through a reduction in portal and collateral blood flow. This is a consequence in part of the reduction of cardiac output through the blockade of b1-cardiac receptors and in part of the splanchnic vasoconstriction due to the blockade of b2-splanchnic receptors with unopposed a-adrenergic activity.
Twelve RCTs assessing nonselective beta-blockers for the prophylaxis of the first variceal bleeding and 1 for the prevention of varices have been reported.[14-26] One[23] is not included in this review because although it included 319 patients, the results cannot be interpreted in a clinically useful way. In fact, in this study, patients with chronic liver disease were included, with or without cirrhosis, or with or without unknown varices (endoscopy in 45%, barium swallow test in 25%, and no information at all in 30%). Overall, only 11 patients bled and, although a very heterogeneous patient population was included, no attempt was done to perform a reliable subgroup analysis.
Nine of the remaining 11 RCTs were described in detail in previous meta-analyses.[13,27] Propranolol was assessed in nine studies and nadolol in two. Placebo or nonactive treatment was given to the control groups in all trials. The principal characteristics and results of the 11 studies, which included 1,189 patients, are reported in Table 1 and Figure 1. The methodological quality of the seven trials published as full reports was considered to be fair to good.[27] In nine RCTs, the bleeding rate was reduced and in one was not modified by beta-blockers. One RCT,[19] considered an outlier[27] because propranolol was associated with a significant increase in bleeding risk, was excluded from the pooled estimate of the treatment effect for bleeding (Table 2, Fig. 1). Overall, the bleeding rate was 25% in controls and 15% in treated patients, after a median follow-up of 24 months. The ARD was 210% (CI, 216 to 25; NNT = 10). Also, a small reduction in mortality, approaching statistical significance (Table 2, Fig. 1), was found (ARD = 24%; CI, 29% to 0%)
.

FIG. 1. Cumulative meta-analysis (random effects model) of randomized clinical trials of beta-blockers compared with placebo or nonactive treatment for prevention of variceal bleeding in cirrhosis. The treatment effects on bleeding (top) and mortality (bottom) are reported. Solid circles represent the absolute risk difference (treated minus controls) obtained by pooling the results of every new trial with all those reported previously. The horizontal bars represent the 95% confidence intervals of each estimate. The vertical line represents the zero difference (the equivalence between the treatments). Negative values (on the left of the equivalence line) favor beta-blockers; positive values favor control treatment (CT). A significant bleeding risk reduction was evident after the second study and was consistently confirmed by adding all the subsequent studies; the important death risk reduction shown by the first three studies was reduced by the others but it is consistent and nearly significant.

 

In the following sections, beta-blockers efficacy is assessed according to the most important clinical characteristics of patients included in the RCTs to extract more sound information for clinical practice.
The Patient with Varices, Independent of Size
In four RCTs, 374 patients with varices of any size were included (Table 3). In two of these RCTs, however, only patients with HVPG, respectively, >10 mm Hg19 or >12 mm Hg21 were included. It is surprising that the baseline risk (the incidence of bleeding in untreated patients) in these two studies was similar or even lower compared with the two studies selecting patients only on the presence of varices. Also, excluding the outlier trial of Colman et al.,[19] there is a significant heterogeneity across these studies with a bleeding risk reduction ranging from 0 to 227%. If we accept this heterogeneity as a qualitative one (i.e., in the size and not in the direction of the treatment effect), the pooled risk reduction is 214%, but it fails to reach statistical significance with a CI including 0 (from 230 to 0) (Table 2). Overall mortality rate was also not significantly reduced (ARD = 29%; CI 217 to 0), without heterogeneity across trials.
The Patient with Medium or Large-Sized Varices, Independent of Signs of Clinical Decompensation of Cirrhosis
Six of 11 RCTs of beta-blockers included patients with medium or large-sized varices.[14-18,24] Moreover, in two RCTs including patients with varices of any size, a separate bleeding analysis was reported for patients with medium or large varices.[20,21] The experimental drug was propranolol in six studies and nadolol in two. A total of 811 patients were assessable in these eight studies. The mean weighted bleeding rate in control patients was 30% after a mean follow-up near to 2 years. The corresponding bleeding rate in treated patients was 14% (ARD = 216%; CI from 224% to 28%; NNT = 6). No significant treatment effect on mortality was detected (Table 3; Fig. 2).
 

FIG. 2. Cumulative meta-analysis (random effects model) of randomized clinical trials of beta-blockers compared with placebo or nonactive treatment for prevention of variceal bleeding in cirrhosis with medium or large esophageal varices. The treatment effects on bleeding (top) and mortality (bottom) are reported. Solid circles represent the absolute risk difference (treated minus controls) obtained by pooling the results of every new trial with all those reported previously. The horizontal bars represent the 95% confidence intervals of each estimate. The vertical line represents the zero difference (the equivalence between the treatments). Negative values (on the left of the equivalence line) favor beta-blockers; positive values favor control treatment (CT). An important bleeding risk reduction with beta-blockers is consistently confirmed in all the studies, whereas the favorable effect on mortality shown in the first studies disappeared by increasing the number of studied patients.

 

FIG. 3. Meta-analysis (random effects model) of randomized clinical trials of IMN compared with propranolol (first and second panels, top) and of IMN plus nadolol (Nad) compared with nadolol alone (third and fourth panels, bottom), for the prevention of first variceal bleeding in cirrhosis. Solid circles represent the absolute risk difference (treated minus controls) for each trial and the overall estimates. The horizontal bars represent the 95% confidence intervals of each estimate. The vertical line represents the zero difference (the equivalence between the treatments). Negative values (on the left of the equivalence line) favor beta-blockers; positive values favor control treatment (CT). No differences were found either for bleeding or for mortality in both groups of RCTs.

Four of these eight studies were pooled in a meta-analysis based on individual patient data, including 589 patients.[28] The mean 2-year baseline risk of bleeding was significantly reduced from 27% to 17% by the treatment (ARD = 210%; CI, 217% to 23%; NNT = 10) (Table 3). No reduction in overall mortality was found with the treatment, although mortality from bleeding was reduced from 14% in control patients to 7% in treated patients (ARD = 27%; CI, 212% to 22%; NNT = 14).
The Patient with Medium or Large Varices, Without Ascites
The meta-analysis based on individual patient data above reported[28] is the largest available dataset providing information on this point and includes all the relevant information. Overall, 280 patients without ascites were included in the four RCTs. The 2-year bleeding rate was 25% in the control patients and 12% in treated patients (ARD = 213%; CI, 222% to 24%; NNT = 8) (Table 3). No mortality data were reported.
The Patient with Medium or Large Varices with Ascites
Again, the relevant information comes from the meta-analysis based on individual patient data, reported above.[28] In the four trials included, there were 305 patients with ascites. The 2-year bleeding rate was 31% in the control patients and 22% in treated patients (ARD = 29%; CI, 218% to 0%; NNT = 11) (Table 3). Therefore, either the absolute or the relative risk reduction in patients with ascites is appreciably lower than in patients without ascites. Moreover, the ARD in patients with ascites fails to reach statistical significance because the CI includes 0. However, when assessed by the log-rank test on the Kaplan-Meyer cumulative estimates, the 2-year bleeding risk reduction is statistically significant also in patients with ascites (from 41% to 27%, p = 0.002). No mortality data were reported.
The Patient with Small Varices
Among four RCTs including patients with varices of any size, three[20-22] reported separate results in 166 patients with small varices and showed no benefit from propranolol (n = 81) compared with placebo (n = 85). No mortality data were reported in this subset of patients. More recently, preliminary results from a trial of nadolol compared with placebo only in patients with small varices has been reported.[25] After a mean follow-up of 16 months, 2 of 54 patients given placebo and none of 50 given nadolol bled. The difference was not significant. No difference in mortality was observed between the treatment groups (four deaths with placebo and three with nadolol).
 

FIG. 4. Meta-analysis (random effects model) of randomized clinical trials of terlipressin compared with placebo for acute variceal bleeding: treatment effect on overall mortality. Top, traditional meta-analysis; bottom, cumulative meta-analysis. Solid circles represent the absolute risk difference (treated minus controls) for each trial and the overall estimates. The horizontal bars represent the 95% confidence intervals of each estimate. The vertical line represents the zero difference (the equivalence between the treatments). Negative values (on the left of the equivalence line) favor terlipressin; positive values favor placebo. Cumulative meta-analysis shows that mortality was consistently reduced since the first study and that the effect reached statistical significance with the third study in 1990.

When the results on bleeding of this RCT are pooled with two [20,21] of the three above mentioned studies (the third[22] reports only the relative risk of bleeding and not the number of observed events), the bleeding rate was 7 in 100 with placebo and 2 in 91 with nadolol or propranolol (ARD = 25%; CI, from 211% to 2%).
The Patient Without Varices
There is only one trial reported in abstract form[26] and another still in progress.[29] In the study reported in abstract form and not yet published as a full report, 207 patients among whom 41% were without varices and 59% with small varices were randomized to propranolol (n = 103) or placebo (n = 104). After a mean follow-up of 18 months, the actuarial proportion of patients with large varices was 41% in the propranolol group and 17% in the placebo group (p < 0.01). The authors did not provide any plausible explanation for this surprising result, and any conclusion must be delayed until the study is published as a full report. For the moment, in the absence of reliable information, there is no reason to prescribe propranolol for the prevention of varices.
Contraindications and Side Effects
Several contraindications remarkably reduce the number of patients suitable for beta-blocker treatment. The most frequent are chronic pulmonary obstructive disease, heart failure or heart diseases in which heart function may be worsened by beta-blockers, atrioventricular heart block, and peripheral arterial insufficiency. Sinusal bradycardia and insulin-dependent diabetes are relative contraindications. Because of these contraindications, 15-20% of patients are excluded from beta-blockers. If these contraindications are carefully checked, the incidence of side effects among treated patients is in the order of 15%. The most frequent are dyspnea, bronchospasm, asthenia, and reduction of sexual activity. No more than 5% of side effects require treatment discontinuation.
Organic Nitrates
Short-acting (nitroglycerin [NTG]) or long-acting (isosorbide dinitrate, or isosorbide-5-mononitrate [IMN]) organic nitrates produce vasodilatation, mainly venous. They act by forming nitric oxide that induces a reduction of intracellular calcium concentration.[30] Several studies have shown that organic nitrates reduce portal pressure in cirrhotic patients. Moreover, the association of NTG with vasopressin enhances the reduction in portal pressure while counteracting the adverse systemic hemodynamic effects.[31] Similarly, adding IMN to propranolol enhances the reduction of portal pressure and allows a significant portal pressure reduction also in nonresponders to propranolol.[32]This is probably because IMN decreases hepatic resistance and prevents the increase in portal collateral resistance caused by propranolol.
Among long-acting nitrates, only IMN has been evaluated in clinical trials for the prevention of variceal bleeding.
IMN Compared with Beta-Blockers
In one RCT, 118 patients with varices of any size were randomized to IMN (20 mg three times a day; n = 57) or propranolol (maximum tolerated dose or to reduce heart rate to 55 beats/min; n = 61).[33] The bleeding rate was low, and no difference was found between the two groups after a median follow-up of 29 months. It was concluded that IMN is equivalent to propranolol, although the study appeared to be underpowered. After 7 years the bleeding incidence was still low (30/118 patients), and there were no differences between the two treatment groups. However, there was an increased mortality in the IMN group that was significant among the patients over 50; these patients were 90 of the 118 randomized (76%). In the IMN group there was also a significantly higher mortality without bleeding. If this increase in mortality reflected a harmful long-term effect of IMN or a beneficial effect of propranolol remains to be clarified.
In another small RCT34 including 30 patients with ascites, 6 of 15 patients given IMN (40 mg twice a day) and none of 15 given nadolol (to reduce heart rate by 25%) bled (p = 0.02). No differences in mortality were found. Sodium excretion was almost halved by IMN (201 6 28 vs. 114 6 15 mEq/min, p < 0.05).
Pooling the results of these two RCTs, a nonsignificant increase in bleeding rate and mortality with IMN was found (Table 1, Fig. 3). However, the number of patients included in the two RCTs is insufficient to draw conclusions even by meta-analysis.

 

    

Beta-Blockers and IMN Compared with Beta-Blockers
Three RCTs have been reported,35-37 only one as full report[35] (Table 2). Two studies used nadolol[35,36] and one propranolol.[37] The first open study included 146 patients, all but 6 with medium or large-sized varices. Overall, 13 of 74 (18%) patients bled in the nadolol group and 7 of 72 (10%) bled in the combination therapy group (p = 0.17). If only variceal bleeding is considered, corresponding figures were 11 of 74 (15%) and 4 of 72 (6%; p = 0.064). Both differences were statistically significant when assessed by the log-rank test on Kaplan-Meyer cumulative rates. Deaths were 14 (19%) and 8 (11%), respectively (p = 0.19). The incidence of side effects was 8 of 74 (11%) in the nadolol group and 37 of 72 (51%) in the combination therapy group (p < 0.00001). Side effects were severe enough to require treatment withdrawal in three (4%) and eight (11%) patients, respectively (p = 0.10). The incidence of ascites was similar in the treatment groups after 6 months of follow-up,[38] but no information is reported in the long term.[35]
The other two studies[36,37] were double blind and placebo controlled. Of these, one[36] was a small single-center study including [57] patients with large varices and red color sign. Ten of 27 patients (37%) in the placebo-nadolol group and 5 of 30 (17%) in the IMN (40 mg twice a day) nadolol group bled within the 2-year study period (p = 0.08) (Table 2). Variceal bleeding was, respectively, 8 of 27 (30%) and 4 of 30 (13%; p = 0.13). Deaths were three and five, respectively. Overall, 7 of 27 patients (26%) in the placebo and nadolol group and 16 of 30 (53%) in the IMN and nadolol group developed side effects (p = 0.03). Among them, 4 (15%) and 12 (40%) patients, respectively, had to be withdrawn from the treatment (p = 0.034). A statistically insignificant higher incidence of ascites was found with the combination therapy (4/27 vs. 8/30), and the study was prematurely interrupted, because of a statistically significant excess mortality in patients treated with IMN and nadolol in a parallel identical trial for the prevention of rebleeding.[39]
In the third multicenter study,[37] 349 patients were included (199 with large varices): 174 were given propranolol with placebo and 175 propranolol with IMN. The 2-year bleeding rate was low and similar in the treatment groups (10% and 13%, respectively), even when only the 199 patients with large varices were considered (13% in both groups). Side effects were significantly more frequent in the propranolol and IMN group (37% vs. 25%, p < 0.05). There were no differences in the number of patients developing or worsening ascites (16% vs. 17%). Neither treatment caused deleterious effects on renal function.
Overall, 552 patients were included in the three studies. Bleeding rate was 15% in the beta-blockers-treated patients and 10% in the combination therapy patients (ARD = 25%, CI, 216% to 6%). Mortality rate was 10% in both groups (Table 2, Fig. 3). Side effects were remarkably more frequent with the combination therapy.
Spironolactone and Beta-Blockers Compared with Beta-Blockers Alone
Spironolactone, by preventing or reducing the increase in plasma volume that sustains the hyperdynamic circulation in portal hypertension, lowers HVPG in patients with cirrhosis.40 Its association with nadolol has been compared with nadolol alone for the prevention of first variceal bleeding and of ascites in compensated cirrhotic patients in an RCT still in progress.[41] Preliminary results on the first 67 patients show no differences in the bleeding or in the ascites incidences (Table 1).
Beta-Blockers Compared with Endoscopic Therapy
Two studies[20,22] with a three-arm design (placebo or no treatment vs. propranolol vs. sclerotherapy) included 226 patients in the arms comparing propranolol with sclerotherapy. Patients were not selected for variceal size. No differences were found in the risk of variceal bleeding (ARD = 25%; CI, 214% to 4%). However, in one study20 a significant favorable effect with propranolol was found when bleeding from any portal hypertensive source were considered (2/43 vs. 9/42; p < 0.03). In one recent study,42 propranolol was compared with variceal band ligation in 89 patients with medium or large varices with red signs and showed a significant benefit with ligation. However, this study has been criticized[42]b because of the unusually high rate of bleeding with propranolol; lower mean dose of propranolol with respect to previous RCTs (70 vs. 123 mg/day[28]), and lack of information on bleeding from nonvariceal sources. Furthermore, no differences in mortality were observed. Therefore, these results should be validated in further studies before they are accepted for clinical practice.
Monitoring of Treatment Response
In prospective cohort studies and clinical trials[2,3,42-45] it has been shown that the risk of bleeding is virtually abolished when HVPG or the variceal pressure is reduced by $20% of baseline values or HVPG is reduced below 12 mm Hg. Failure to reach a treatment response according to one of these parameters indicates the need for a different therapy. Although the efficacy of such hemodynamic monitoring has not been directly proven in an RCT, it may be predicted in patients treated for the prevention of rebleeding, whose baseline risk is 60% in 1 year. However, it is largely uncertain if it may be effective in patients treated for prevention of first bleeding, whose baseline risk is much lower, being in the order of 15% per year in the presence of large varices.
Conclusions and Recommendations for Clinical Practice
Patients without varices should be screened for appearance of varices every 2 years (grade C1). They should not receive treatment for prevention of development of varices (grade C2).
Patients with small varices should be screened for enlargement of varices every year (grade C2). At present, there is not evidence to recommend treatment for prevention of variceal bleeding in these patients, who have a low risk of bleeding (grade A2).
Patients with medium or large varices should be treated with a nonselective beta-blocker (grade A1) either in the absence of ascites (grade A1) or in the presence of ascites (grade A2). The expected benefit is higher in patients without ascites.
Available evidence does not support the use of combination therapy with nonselective beta-blockers and IMN in the prevention of firts bleeding, because no benefit has been shown from this therapy in comparison with beta-blockers alone (grade A2). This seems to depend on the low risk of bleeding, even with large varices, in patients treated with beta-blockers. This conclusion might change in the future if more accurate indicators of the risk of bleeding will allow to select patients with higher risk.
Patients with medium or large varices with contraindications or who are intolerant to beta-blockers may be treated with IMN (grade B2). Patients aged over 50 should be strictly monitored for liver and renal function (grade B2).
Treatment Of Acute Bleeding
The following key points of the clinical course of variceal bleeding[8] should be considered when defining the principal objectives for treatment.
Hemorrhage spontaneously stops in as much as 40-50% of patients.[13]
Immediate mortality because of uncontrolled bleeding is about 8% and occurs within 1-2 days from admission. This is the median rate from eight studies including 1,488 patients. Bacterial infection is independently associated with failure to control bleeding.[46] No other prognostic indicators of this very early death risk have been identified.
Rebleeding occurs in 40% of patients within 6 weeks. About half of rebleeding episodes occur within 1 week from start of bleeding. Indicators of early rebleeding are poorly defined: Low albuminemia, gastric varices, high blood urea nitrogen, active bleeding at emergency endoscopy, and HVPG >16 mm Hg measured the first or second day after hospital admission, have been proposed.
Six-week mortality is about 30%. The most consistently reported death risk indicators are Child-Pugh classification or its components, age, active alcohol abuse, blood urea nitrogen or creatininemia, active bleeding on endoscopy, early rebleeding, and HVPG >20 mm Hg.
Based on these observations, the principal objectives of therapy for acute variceal bleeding are control of bleeding, prevention of early rebleeding, and reduction of mortality. Because the bleeding is a stop and start event, there has been some difficulty in the past to distinguish the initial bleeding from early rebleeding either in clinical practice or in clinical trials. Therefore, it is often difficult to extract from clinical trials a reliable measure of the treatment effect on each of these two end points. Moreover, in some trials, a unified end point has been considered: failure to control bleeding or early rebleeding within 5 days. Two recent large consensus conferences[47,48] proposed the following definitions for time events in variceal bleeding:
The time of admission to the first hospital the patient is taken to is time zero.
Bleeding is the occurrence of hematemesis and/or melena.
Clinically significant bleeding is any bleeding requiring two units of blood or more within 24 hours of time zero, together with a systolic blood pressure <100 mm Hg or a postural change = 20 and/or pulse rate = 100/min at time zero.
The acute bleeding episode is represented by an interval of 48 hours from time zero with no evidence of clinically significant bleeding between 24 and 48 hours. Evidence of any bleeding after 48 hours is the first rebleeding episode.
Failure to control acute variceal bleeding within 6 hours is defined as any of the following three factors: transfusion of four units of blood or more, inability to achieve an increase in systolic blood pressure by 20 mm Hg or to 70 mm Hg or more, and/or pulse reduction to less than 100/min or a reduction of 10/min from baseline pulse rate.
Failure to control acute variceal bleeding after 6 hours is defined as any of the following four factors: the occurrence of hematemesis; reduction of blood pressure = 20 mm Hg from the 6-hour point, increase in pulse rate = 20/min from the 6-hour point on two consecutive readings an hour apart, and/or transfusion of two units of blood or more (over and above the previous transfusions) required to increase the hematocrit = 27% or hemoglobin = 9 g/dL.
Because these definitions were not adopted in most published trials, we consider the following measures of treatment efficacy, to extract more homogeneous data from RCTs: failure to control bleeding within 24-48 hours of treatment, rebleeding after bleeding control before definitive therapy for long-term prevention of rebleeding, and mortality within 6 weeks or during the stay in hospital.
The drugs assessed for acute bleeding are vasopressin and its analogue terlipressin and somatostatin and its analogue octreotide. Vasopressin and terlipressin have been associated with NTG in some trials.
Vasopressin
Vasopressin causes a marked splanchnic vasoconstriction and hence reduces portal blood flow and portal pressure.[49] It also reduces portocollateral blood flow and variceal pressure.[50] However, it also causes systemic vasoconstriction that may result in serious complications such as myocardial ischemia or infarction, arrhythmias, mesenteric ischemia, limb ischemia, and cerebrovascular accidents.
Ten RCTs assessing vasopressin for acute variceal bleeding have been published.[13] In nine of these studies, the time of infusion of vasopressin or control treatment ranged from 12 to 48 hours and the assessment of failure to control bleeding was done during the drug infusion (need to change therapy) or at the end of the infusion (continuing bleeding). Only in one RCT,[51] vasopressin was infused over a 20-minute period and treatment failure was assessed 60 minutes after starting therapy. Details of these RCTs have been recently reviewed,[13] and because no other trials have been subsequently reported, they will not be discussed further here. Briefly, four RCTs including 157 patients compared vasopressin with nonactive treatment. Although failure to control bleeding was reduced from 82% in control patients to 50% in treated patients (ARD = 232%; CI, from 259% to 26%; NNT = 3), no differences in mortality were found. Side effects in vasopressin-treated patients ranged from 32% to 64% and were severe enough to require withdrawal of therapy in 25% of cases. Mortality from complications of vasopressin was 3 of 85 treated patients. Intraarterial was compared with intravenous vasopressin in three RCTs including 73 patients and no differences were found either in the rates of failure to control bleeding or in mortality. Therefore, the use of intraarterial vasopressin was abandoned.
Aiming at reducing side effects, vasopressin has been combined with NTG and compared with vasopressin alone in three RCTs including 176 patients. Failure rate in controlling bleeding was 57% with vasopressin alone and 35% with the combination (ARD = 222%; CI, 236% to 28%; NNT = 4.5) without differences in mortality (34% and 33%, respectively).
Although the only double-blind study[50] did not show significant differences in side effects between the treatments, the pooled incidence of side effects in the three RCTs was 61% wih vasopressin and 31% with the combination therapy (ARD = 230%; CI, 254% to 26%). The number of patients needed to be treated with vasopressin and NTG to save a harmful event (NNH) was 3. However, the number of patients in which treatment was withdrawn because of side effects was not significantly different between the treatment groups (ARD = 210%; CI, 227% to 7%).
Among the 10 RCTs, rebleeding rate was only reported in 2 studies comparing intraarterial with intravenous vasopressin and no differences were found.
Terlipressin
This synthetic analogue of vasopressin is composed of three glycyl residues and lysine-vasopressin. When administered intravenously it causes immediate vasoconstriction by intrinsic activity followed by prolonged hemodynamic effects because it is slowly converted into vasopressin by enzymatic cleavage of the glycyl residues. Like vasopressin, it causes portal and portocollateral blood flow reduction and parallel decrease in portal and variceal pressure. It was speculated that the low blood levels consequent to the slow release of the active agent would result in less frequent side effects. Clinical studies[13] have consistently shown less frequent and severe side effects with terlipressin than with vasopressin even when vasopressin is associated with NTG. Terlipressin, unlike vasopressin, does not activate fibrinolysis and has a longer biological activity that allows its administration every 4-6 hours.
To assess its efficacy, terlipressin was compared with placebo or nonactive treatment in five RCTs,[265,66] to vasopressin in five,[57-61] to somatostatin in three,[55,62-64] to octreotide in 265,[265,66] (see next section), to sclerotherapy in 1,[265,66] and to esophageal tamponade in 3.[265,66]
Terlipressin Compared with Placebo or Nonactive Treatment
Four[52-54,56] of the five available RCTs are published as full reports (Table 4) and were double-blind placebo-controlled studies. The fifth is reported as a letter[55] and was an open three-arm trial comparing terlipressin with somatostatin and with conventional therapy (i.e., no active drugs, no sclerotherapy). Overall, 256 patients were included. Treatment duration ranged from 8 to 36-48 hours. In one study, treatment was started at the patient's home if variceal bleeding was suspected.[56] Overall, the rate of failure to control bleeding was 50% in control patients and 26% in treated patients (ARD = 224%; CI, 236 to 213; NNT = 4) (Table 4). Rebleeding rate was reported only in three studies and was difficult to interpret because no information on treatments for prevention of rebleeding was reported and some patients, after failure of the experimental treatment, were treated by endoscopic sclerotherapy. With these limitations, the overall estimate did not show a significant difference between treatment groups. Mortality was significantly and remarkably reduced with terlipressin (ARD = 218%; CI, 228% to 27%; NNT = 6). The reduction in mortality was found in all the studies but was clinically important in three and statistically significant in one.
Some of these studies have been criticized. One[52] included other therapies, the timing of which is unclear, and in another[56] no difference in the transfusion requirement at the end of the 12-hour therapy was found between the two groups, although a significant mortality reduction was found in Child C patients (which were 81% of the trial population).[71] However, cumulative meta-analysis (Fig. 4) shows that since the first RCT, the reduction in mortality with terlipressin was about 20%, remained stable by adding the following studies, and became statistically significant after the third, when only 141 patients had been randomized. It is extremely unlikely that this result comes from some inapparent bias affecting mortality always in the same direction across five RCTs, four of which were double-blind placebo-controlled studies.
 

 

Terlipressin Compared with Vasopressin

Five unblinded trials[57-61] compared terlipressin with vasopressin, which was associated with transdermal or sublingual nitroglycerin in two studies.[59,61] Relevant characteristics and results of these studies are reported in Table 4. No statistically significant differences were found in the rate of failure to control bleeding, rebleeding, or mortality. There was a significant heterogeneity for the failure to control bleeding that disappeared (x2 for heterogeneity, 5.26; p = 0.15; ARD = 22; CI, 217% to 13%) by removing an outlier RCT57 where an extremely high failure rate with vasopressin (91%) was found (far out of the range of all other RCTs of vasopressin[13]). The larger[61] of these RCTs reported detailed information on side effects, which were significantly less frequent and less severe with terlipressin compared with vasopressin plus transdermal nitroglycerin.

Terlipressin Compared with Emergency Endoscopic Variceal Sclerotherapy

There is only one RCT comparing terlipressin with endoscopic variceal sclerotherapy (EVS) (Table 4). It is reported in abstract form[67] and included 219 patients. Failure of treatment was defined as failure to control bleeding or early rebleeding within 5 days after initial control of bleeding. Treatment failures were 36 of 114 patients (32%) with EVS and 39 of 105 patients (37%) with terlipressin (p = 0.39). Failure rate in control of bleeding was, respectively, 17% and 21% (p = 0.45), rebleeding within 5 days 13% and 15% (p = 0.67), and 6-week mortality 16% and 23% (p = 0.19). Side effects were 29% with EVS and 30% with terlipressin and were serious in 5% and 6%, respectively. Although the full report of the study is needed to draw definitive conclusions, these results indicate that terlipressin may be considered an equivalent alternative to emergency sclerotherapy for acute variceal bleeding.

Terlipressin Compared with Balloon Tamponade

Three RCTs[68-70] including 141 patients compared terlipressin with esophageal tamponade. Although a trend was found toward a higher failure rate in the control of bleeding with terlipressin, the difference was not significant (ARD = 8%; CI, 28% to 24%). Early rebleeding rate (4-7 days) and hospital mortality were similar with the two treatments (Table 4). These results may not be considered as a conclusive indication of equivalence between the two treatments because of the insufficient number of patients included in the three RCTs. However, further studies would not be justified because it is now well established that esophageal tamponade is a temporary salvage therapy for otherwise uncontrollable bleeding.

Somatostatin

Natural somatostatin is a tetradecapeptide that causes splanchnic vasoconstriction within a few seconds after intravenous administration. The hormone has no direct effect on splanchnic vascular smooth muscle at low levels,[72] but it increases the vascular tone by inhibiting secretion of gut-derived vasodilatory peptides, such as glucagon, vasoactive intestinal peptide, and substance P.[73-75] It causes splanchnic vasoconstriction, thereby decreasing portal and collateral blood flow and portal pressure without the adverse effects of vasopressin on the systemic circulation.[75] However, vasoconstriction is probably not confined to the splanchnic circulation because bolus injections cause a transient increase in mean arterial pressure and systemic vascular resistance.[76]

Somatostatin consistently reduces azygous blood flow, suggesting an effect on portocollateral circulation.[77] Bolus injections of somatostatin cause rapid and marked reduction of both portal pressure and azygous blood flow, greater than those induced by continuous infusions.[76] Somatostatin has been compared with placebo or nonactive treatment in eight RCTs,[55,78-84] with vasopressin in seven,[85-91] with terlipressin in three,[55,62-64] with endoscopic sclerotherapy in four,[92-95] and with esophageal tamponade in two.[96,97]

Somatostatin Compared with Placebo or Nonactive Treatment

Three double-blind placebo-controlled trials of somatostatin[78-80] including 290 patients showed contrasting results with a favorable treatment effect in one[79] not confirmed in the others.[78,80] It is of interest that one[78] of the two negative RCTs found an unusually high rate of spontaneous bleeding cessation (83%, the highest ever reported) and the other[80] did not assess failure to control bleeding. None of the three studies found any beneficial effect on survival.

Four unblinded RCTs compared somatostatin with a nonactive treatment[55,81-83] and showed a trend to ward benefit from somatostatin. A recent double-blind placebo-controlled study,[84] showed that somatostatin administered before emergency variceal sclerotherapy makes the endoscopic procedure significantly more easy and reduces failure to control bleeding.

Overall, failure to control bleeding was assessed in seven RCTs (Table 5, Fig. 5) including 552 patients. The pooled estimate of treatment effect shows a significant qualitative heterogeneity (i.e., in the direction, not in the size of the effect), which disappears by removing the study by Valenzuela et al.,[78] which seems to be an outlier because of the very high rate of bleeding control in the placebo group. The remaining six studies (468 patients) show a significant reduction of failure to control bleeding with somatostatin (ARD = 217%; CI, 229% to 26%; NNT = 6) (Fig. 5). This result did not change in a sensitive analysis by also removing the most favorable trial82 (ARD = 214%; CI, 224% to 24%; NNT = 7) (Fig. 5). It is important to note that the two double-blind placebo-controlled RCTs[79,84] consistently showed a marked and significant benefit from somatostatin (Table 5). Rebleeding rate after control of bleeding is reported in three studies (Table 5), but the time of assessment was different, and details on other therapies after control of bleeding were insufficient, making pooling meaningless. Mortality is reported in eight RCTs (638 patients), homogeneously showing no treatment effect (Table 5).

FIG. 5. Meta-analysis (random effects model) of randomized clinical trials of somatostatin compared with placebo or nonactive treatment for acute variceal bleeding: treatment effect on failure to control bleeding. Top, traditional meta-analysis including all the available RCTs; middle, cumulative meta-analysis by excluding the Valenzuela et al.1 RCT78 and showing significant benefit from somatostatin since the last two studies; bottom, sensitivity meta-analysis (cumulative) by excluding the trial with the most favorable treatment effect82 from the set of RCTs shown in the midle panel. Solid circles represent the absolute risk difference (treated minus controls) for each trial and the overall estimates. The horizontal bars represent the 95% confidence intervals of each estimate. The vertical line represents the zero difference (the equivalence between the treatments). Negative values (on the left of the equivalence line) favor somatostatin; positive values favor placebo or nonactive treatment (CT).

Somatostatin Compared with Vasopressin

There are seven RCTs including 301 patients[85-91] (Table 5). Failure to definitively control bleeding is not different between the two treatments (ARD = 29%; CI, 225% to 8%), whereas a recent meta-analysis98 showed that immediate control of bleeding is significantly higher with somatostatin. The lack of benefit from somatostain in the definitive control of bleeding is explained by the higher rebleeding rate after initial control (ARD = 18%; CI, 8% to 27%). Mortality is almost equal (ARD = 21%; CI, 211% to 9%). However, side effects are significantly reduced with somatostatin (from 57% to 10%: ARD = 247%, CI, 269% to 225%; NNH = 2) as well as major side effects requiring drug dosage reduction or treatment withdrawal (from 20% to 2%: ARD = 218%, CI, 230% to 26 %; NNH = 6) (Fig. 6). In conclusion, the overall balance indicates that somatostatin is equivalent in efficacy to vasopressin, with significantly less frequent and less severe side effects.

FIG. 6. Cumulative meta-analysis (random effects model) of randomized clinical trials of somatostatin compared with vasopressin for acute variceal bleeding: total (top) and major (bottom) side effects. Solid circles represent the absolute risk difference (treated minus controls) for each trial and the overall estimates. The horizontal bars represent the 95% confidence intervals of each estimate. The vertical line represents the zero difference (the equivalence between the treatments). Negative values (on the left of the equivalence line) favor somatostatin; positive values favor vasopressin. A marked and consistent reduction of total and major side effects was found with somatostatin since the first studies.

Somatostatin Compared with Terlipressin

Somatostatin has been compared with terlipressin in three studies,[55,62-64] two of which were double blind placebo controlled,62-64 including 302 patients. Overall, no differences were found for failure to control bleeding, rebleeding, and mortality (Table 5). Total side effects were not significantly reduced with somatostatin from 29% to 21%, and major side effects (requiring withdrawal of treatment or specific therapy) were 4% in both treatment groups. Most frequently reported side effects with somatostatin were bradycardia, hypertension, hyperglicemia, and diarrhea and with terlipressin abdominal cramps, diarrhea, bradycardia, hypertension, arrythmias, and angina.

Somatostatin Compared with Emergency Sclerotherapy

Four RCTs,[92-95] including 367 patients compared somatostatin with sclerotherapy. Two[92,95] are still in abstract form (Table 5); one[95] included patients after control of bleeding and compared the two treatments for 6-week rebleeding and mortality. No significant differences were found in failure to control bleeding (ARD = 7%; CI, 24% to 18%) (Fig. 7), rebleeding (ARD = 4%; CI, 25% to 13%), and mortality (ARD = 4%; CI, 23% to 12%) (Table 5), although complications were significantly less frequent and less severe with somatostatin. It should be remarked that early rebleeding was assessed before starting definitive treatment for long-term prevention of rebleeding in the three RCTs available for this outcome (including 305 patients), and although assessment times varied widely across studies (6 weeks,[95] 7 days,[94] 5 days[93]), no heterogeneity in the treatment effect was found (Table 5).

FIG. 7. Cumulative meta-analysis (random effects model) of randomized clinical trials of somatostatin (top) or octreotide (bottom) compared with emergency sclerotherapy for acute variceal bleeding: treatment effects on failure to control bleeding. Solid circles represent the absolute risk difference (treated minus controls) for each trial and the overall estimates. The horizontal bars represent the 95% confidence intervals of each estimate. The vertical line represents the zero difference (the equivalence between the treatments). Negative values (on the left of the equivalence line) favor somatostatin or octreotide; positive values favor sclerotherapy. A not significant trend favoring sclerotherapy compared with somatostatin was found (top). The equivalence of sclerotherapy and octreotide shown by the overall estimate in the bottom panel is not acceptable for clinical practice because of a statistically significant heterogeneity both in the direction and in the size of the effect across trials.

Somatostatin Compared with Balloon Tamponade

Two RCTs[96,97] failed to show differences between somatostatin and balloon tamponade for variceal bleeding (Table 5), although they were largely underpowered. However, side effects were significantly less frequent and less severe with somatostatin.

Octreotide

Octreotide is a synthetic octapeptide which by a shared four-amino acid segment retains most of the effects of somatostatin with a longer half-life. The affinity of octreotide for the somatostatin S2 receptors is 3- to 10-fold higher than the natural hormone.[99] Thus, octreotide mimicks part of the effects of somatostatin.

Octreotide infusions, at the doses used empirically to treat variceal hemorrhage or higher, have not been found to decrease portal pressure.[100,101] Bolus injections of octreotide produce marked but transient decreases in HVPG and variceal pressure, and a rapid desensitization to the drug has been hypothesized.[100] Like somatostatin, bolus injections of octreotide cause a transient increase in mean arterial pressure and systemic vascular resistance, suggesting a systemic effect.[100,102] The more consistently reported hemodynamic effect of octreotide is to prevent the increase in portal pressure associated with volume replacement after hemorrhagic shock[103] or induced by a meal.[104] Therefore, the net effect of octreotide on portal and systemic hemodynamics remains unclear.

Octreotide has been compared with placebo in four RCTs,[105-108] two still in abstract form[107,108] (Table 6). In the larger study,[107] sclerotherapy was used in octreotide or placebo failures. In the others, octreotide or placebo was given immediately after performing sclerotherapy[105,108] or band ligation.[106] Two RCTs were double blind.[105,107] A total of 639 patients were included in the four RCTs. Overall, failure to control bleeding was significantly reduced from 44% with placebo to 29% with octreotide (ARD = 215%; CI, 226% to 23%; NNT = 7). It may be noted that in the only study using octreotide or placebo as initial treatment,107 no benefit from octreotide was found, whereas when sclerotherapy or ligation were performed before or at the same time of octreotide administration, a significant benefit was found in two studies[105,106] and near significant in the third[108] (Table 6). These results suggest that octreotide may improve the outcome of endoscopic therapy but has no or little effect if used alone. However, further studies are needed to draw conclusions for clinical practice. No effects of octreotide on rebleeding or death were found (Table 6).

Octreotide was better than vasopressin for control of bleeding in two RCTs,[109,110] and equivalent to terlipressin in other two[65,66] (Table 6). Side effects were less frequent and severe with octreotide than with either vasopressin or terlipressin, but the difference was significant only for vasopressin.

Octreotide has also been compared with emergency sclerotherapy in four RCTs,[111-114] including 341 patients (Table 6, Fig. 7). Two are only available in abstract and were still ongoing at the time of the report.[112,113] No differences were found for failure to control bleeding, rebleeding, or mortality in the four studies; however, they were underpowered and also their meta-analysis was difficult to interpret because of a significant heterogeneity for the effect on failure to control bleeding and on rebleeding (Fig. 7). Therefore, no conclusions may be drawn from these studies at present. There is another RCT recently reported comparing octreotide with emergency sclerotherapy in 100 patients with schistosomal portal hypertension.[115] In Child classes A and B failure to control bleeding was 10% with octreotide and 0% with sclerotherapy (p > 0.05), whereas in class C was 42% and 6%, respectively (p < 0.05).

Only one RCT compared octreotide with balloon tamponade,116 showing a nonsignificant trend in favor of tamponade for control of bleeding (Table 6).

Finally, in a double-blind placebo-controlled pragmatic RCT,[117] including 262 patients, octreotide was administred subcutaneously (100 mg three times a day) over a period of 15 days, aiming at reducing early rebleeding in patients treated with beta-blockers or sclerotherapy for long-term prevention of rebleeding. Sixty-four patients did not receive long-term prophylaxis because of intolerance to beta-blockers, low compliance, or too advanced liver disease, and no effect of octreotide was found in this group. Among 198 patients treated for long-term prophylaxis, 15-day rebleeding rate was reduced from 26% to 16% (p = 0.05) with octreotide.

Conclusions and Recommendations for Clinical Practice

There is now a large number of RCTs, several of fair to good quality, showing that pharmacological treatment is effective in controlling variceal bleeding. Most importantly, for terlipressin and somatostatin there is growing evidence that they are equivalent to emergency sclerotherapy with a remarkably lower incidence and severity of side effects. Moreover, terlipressin significantly reduces mortality when compared with placebo. Although there is uncertainty on the mechanisms of action of somatostatin and octreotide and on their hemodynamic effects, RCTs have shown that somatostatin is more effective than placebo or nonactive treatment and equivalent to vasopressin, terlipressin, sclerotherapy, and balloon tamponade, whereas data are still insufficient for octreotide. Compared with placebo, octreotide has been consistently effective when associated with endoscopic therapy but not if used as a single therapy. It seems to be equivalent to vasopressin and terlipressin, but the available RCTs are few and underpowered, and the encouraging results of meta-analysis should be confirmed before this conclusion is assumed for clinical practice. The results of RCTs comparing octreotide with sclerotherapy are not convincing because of significant heterogeneity that is difficult to explain with two of four studies still available only in abstract. Serious side effects are acceptably few with terlipressin or vasopressin plus nitroglycerin and not significantly different from those of somatostatin or octreotide. This evidence suggests the following recommendations for clinical practice.

  • Pharmacological treatment should be started immediately when variceal bleeding is suspected, even before endoscopic confirmation of diagnosis (grade A1).
  • Terlipressin should be the first choice treatment because it may reduce mortality (grade A2).
  • Somatostatin may be considered alternative to terlipressin (grade A2). Additive bolus injections are advisable for patients actively bleeding on endoscopy.
  • Octreotide improves the efficacy of emergency sclerotherapy in controlling bleeding. Therefore, it should be given to patients initially treated with sclerotherapy or band ligation (grade A1), whereas, at present, there is no evidence supporting its use as a single therapy.
  • If vasopressin is used, it should be associated with nitroglycerin (grade A1).
  • Endoscopic sclerotherapy may be considered a further step after terlipressin or somatostatin failure (grade A1).

Prevention Of Rebleeding

Patients surviving a first episode of variceal bleeding have a very high risk of rebleeding and death. Median rebleeding incidence in untreated controls of 20 RCTs reported since 1981 of nonsurgical treatment for prevention of recurrent bleeding was 63% within 1 to 2 years.[13] The corresponding mortality figure is 33%. For this reason, in two recent consensus conferences[47,48] it has been agreed that all patients surviving a variceal bleeding need active treatments for prevention of rebleeding.

Pharmacological treatment for prevention of rebleeding has been based on nonselective beta-blockers since the late 1980s. Recently, their association with IMN has been proposed.

Beta-Blockers

The hemodynamic basis for the use of nonselective beta-blockers in the prevention of rebleeding and its contraindications and side effects are the same as for the prevention of first bleeding.

Beta-Blockers Compared with Placebo or Nonactive Treatment

Twelve RCTs including 809 patients have been reported[118-129] (Table 7, Fig. 8). One trial compared propranolol with atenolol and with placebo[125] and is analyzed as two separate RCTs. One trial assessed nadolol[123] and the remaining propranolol. Overall, beta-blockers reduced the rebleeding rate from 63% in controls to 42% (ARD = 221%; CI, 230% to 213%; NNT = 5) and mortality from 27% to 20% (ARD = 27%; CI, 212% to 22%; NNT = 14). A recent meta-analysis of these RCTs showed also that beta-blockers significantly reduce mortality fom bleeding.[130]

FIG. 8. Cumulative meta-analysis (random effects model) of randomized clinical trials of beta-blockers compared with placebo or nonactive treatment for prevention of rebleeding in cirrhosis. The treatment effects on rebleeding (top) and mortality (bottom) are reported. Solid circles represent the absolute risk difference (treated minus controls) obtained by pooling the results of every new trial with all those reported previously. The horizontal bars represent the 95% confidence intervals of each estimate. The vertical line represents the zero difference (the equivalence between the treatments). Negative values (on the left of the equivalence line) favor beta-blockers; positive values favor control treatment (CT). A significant rebleeding risk reduction with beta-blockers was evident since the fourth study in 1986 and was consistently confirmed thereafter (top). The smaller beneficial effect on mortality became statistically significant after seven studies and was consistently confirmed thereafter.

Beta-Blockers Compared with EVS

There are 10 RCTs including 862 patients[129,131-140] (Table 7, Fig. 9). Although the treatment for rebleeding was not the same in the two groups in several RCTs, in which emergency sclerotherapy was allowed in patients randomized to EVS and not in those randomized to beta-blockers,[13] no significant differences were found between the two treatments either for rebleeding rate (ARD = 7%; CI, 22% to 17%) or for mortality (ARD = 2%; CI, 25% to 8%) (Table 7). There is a nearly significant heterogeneity for the effect on rebleeding, which disappears by separately analyzing the treatment effect for rebleeding from varices or from any portal hypertensive source.[141] Because beta-blockers may reduce the risk of rebleeding from either varices or other sources, the effect on overall rebleeding is reported here (Table 7, Fig. 9). Side effects were significantly less frequent and severe with beta-blockers (ARD = 222%; CI, 238% to 26; NNH = 4).[141]

FIG. 9. Cumulative meta-analysis (random effects model) of randomized clinical trials of beta-blockers compared with sclerotherapy for the prevention of rebleeding in cirrhosis. The treatment effects on rebleeding (top) and mortality (bottom) are reported. Solid circles represent the absolute risk difference (treated minus controls) obtained by pooling the results of every new trial with all those reported previously. The horizontal bars represent the 95% confidence intervals of each estimate. The vertical line represents the zero difference (the equivalence between the treatments). Negative values (on the left of the equivalence line) favor beta-blockers; positive values favor sclerotherapy. A nonsignificant trend toward a beneficial effect of sclerotherapy over beta-blockers was found, but mortality was consistently equal with the two treatments since the fourth study.

    

Beta-Blockers Compared with EVS Plus Beta-Blockers

Beta-blockers have been compared with the combination of EVS and beta-blockers in three studies,[142-144] one still in abstract,[144] including 277 patients (Table 7). They consistently show a significantly higher rebleeding risk with beta-blockers (ARD = 19%; CI, 8% to 30%) without significant differences in mortality (ARD = 15%; CI 21% to 32%).

It is of interest that 10 RCTs comparing EVS with the combination of EVS and beta-blockers showed that the rebleeding rate was significantly lower with the combination therapy without differences in mortality,[13] suggesting that patients rebleeding under beta-blockers or EVS might benefit from associating the two treatments.

Combined Pharmacological Therapy

At present, the only combination therapy assessed in clinical trials is the association of nonselective beta-blockers with IMN. This drug combination has been compared with beta-blockers alone, with endoscopic therapy, and with transjugular intrahepatic partasystemic shunt (TIPS). Overall, seven RCTs have been reported,[43,145-150] but only one as a full report.[43]

Beta-Blockers Plus IMN Compared with Beta-Blockers Alone

There are two RCTs reported in abstract[145,146] (Table 7) including 199 patients. One is double blind was placebo controlled.[146] Neither shows benefit from the combination therapy. However, the full report of the two studies is needed to draw conclusions. In fact, although no significant heterogeneity was found, the results are largely inconsistent, particularly for survival, with one study[146] showing a statistically significant excess mortality with the combination therapy. In both studies, side effects were significantly more frequent with the combination therapy (mostly headache and weakness).

Beta-Blockers Plus IMN Compared with Endoscopic Therapy

The combination therapy has been compared with sclerotherapy in one RCT[43] and with band ligation in 2.[147,148] Only one of these studies is published as a full report.[43] Propranolol was used in one RCT[148] and nadolol in two.[43,147] A marked reduction of rebleeding with the combination therapy was found, which was statistically significant compared with sclerotherapy and nearly significant with band ligation (Table 7). The risk reduction was similar in the three studies (range, 221% to 228%), suggesting that they may be combined to assess the overall combination therapy effect size compared with endoscopic treatment. A total of 199 patients were included in the three studies. Rebleeding rate was reduced from 50% with endoscopic treatment to 25% with the combination therapy (ARD = 225%; CI, 23 to 212; NNT = 4), whereas mortality was similar with the two treatments (20% vs. 18%) (Table 7).

In one study comparing the combination therapy with sclerotherapy,[43] HVPG was measured before and 3 to 4 months after starting therapy in 31 of 43 patients in each treatment group. None of 14 patients (12 drug therapy, 2 sclerotherapy) with HVPG reduction to below 12 mm Hg and only 1 of 17 with HVPG reduction of >20% of baseline (13 drug therapy, 4 sclerotherapy) rebled. By contrast, 23 patients (8 drug therapy, 15 sclerotherapy) of 45 (18 and 27, respectively) with HVPG reduction of 20% or less rebled. This result confirms previous observations from a prophylactic trial of propranolol and from prospective cohort studies[39-40,42] suggesting that pharmacological treatment should be targeted to achieve an HVPG reduction >20% or to below 12 mm Hg.

Propranolol plus IMN has been compared with sclerotherapy (in Child-Pugh A and B patients) and with shunt surgery (Child-Pugh C patients) in one study still reported in abstract[149] and showing no significant differences either for rebleeding or for mortality between treatment groups (Table 7). However, a full understanding of the results must wait the full report of the study.

Beta-Blockers Plus IMN Compared with TIPS

There is only one study including 91 patients with Child-Pugh score >7 reported in abstract form.[150] The rebleeding rate was higher with the pharmacological therapy (Table 7), but there was no difference in mortality, and encephalopathy was significantly more frequent and severe with TIPS (requiring hospital admissions in 23 vs. 9 occasions). The estimated cost of TIPS therapy (16,903 U.S.$) was more than twice that of drug therapy.

Conclusions and Recommendations for Clinical Practice

Available evidence from RCTs shows that nonselective beta-blockers significantly reduce the risk of rebleeding and mortality. They are equivalent to endoscopic therapy with significantly less frequent and severe side effects. The association of beta-blockers and sclerotherapy is superior to either therapy alone. Although it is unclear whether the combination of beta-blockers with IMN is superior to beta-blockers alone, it is superior to endoscopic sclerotherapy and probably to endoscopic band ligation. The combination of beta-blockers with IMN has not been compared with the association of beta-blockers and endoscopic therapy. Benefit from drug therapy is expected to improve by tailoring the individual patient treatment to achieve HVPG reduction >20% of baseline or below 12 mm Hg. This evidence suggests the following recommendations for clinical practice.

  • Patients surviving a bleeding episode should be treated with nonselective beta-blockers if they were previously untreated (grade A1). Those intolerant or who have contraindications to beta-blockers should be treated with endoscopic therapy (band ligation is superior to sclerotherapy; see above) (grade A1).
  • Whenever possible, the hemodynamic effect of beta-blockers should be monitored. (This recommendation is indirectly drawn from RCTs that were not designed to prove the clinical efficacy of this intervention; therefore, it may not be graded according to the grading system for recommendations used in this review.) If a reduction of HVPG >20% or below 12 mm Hg is not achieved, IMN may be added.
  • The association of a beta-blocker with endoscopic sclerotherapy or band ligation may be used after beta-blocker failure (grade A1).
  • Patients with severe or repeat rebleeding while treated with beta-blockers associated with endoscopic therapy or IMN should be considered for "rescue" therapy with TIPS (preferably in candidates to liver transplantation) or shunt surgery.

Abbreviations Used

ARD: absolute rate difference
CI: confidence interval
EVS: endoscopic variceal scleratherapy
HVPG: hepatic vein pressure gradient
IMN: isosorbide-5-mononitrate
NTG: nitroglycerin
NNH: number of patients needed to save a harmful treatment effect
NNT: number of patients needed to treat
RCT: randomized clinical trials
TIPS: transjugular intrahepatic partasystemic shunt

Tables

Table 1.

 

 

Table 2.

 

 

Table 3.

 

 

Table 4.

 

 

Table 5.

 

 

Table 6.