PERSPECTIVES IN CLINICAL HEPATOLOGY Somatostatin and Analogues in Portal Hypertension

Juan G. Abraldes and Jaime Bosch

omatostatin (SST) is a 14 amino acid peptide rst isolated 30 years ago from the hypothalamus as a growth hormoneinhibitory substance.1 Since then, SST has been extensively studied and has been found to exert a variety of biologic effects. SST inhibits the secretion of a number of hormones in the gastrointestinal tract and endocrine pancreas. Some of these hormones, particularly glucagon, have been shown to contribute to the maintenance of portal hypertension.2 This property provided the rationale for the introduction of SST in hepatology for the treatment of variceal bleeding.3 Five SST receptors (SSTR 1-5) have been cloned to date,4 but information about their tissue distribution is scarce. It has been suggested that human blood vessels and pancreatic islets express predominantly SSTR-2,5 but receptor pattern may vary between different vascular territories. This has not been thoroughly evaluated. Also, the recent nding that hepatic stellate cells express SSTR-1, -2, and -3 in cirrhotic rat liver, but not in normal liver,6 requires conrmation in humans because there are species differences in receptor distribution. SST has a very short half-life, 1 to 3 minutes in normal subjects,7 and must be administered as a continuous infusion. This prompted the search for analogues with longer half-lives. Several hundred were synthesized, but only the cyclic octapeptides octreotide (OCT), lanreotide, and vapreotide have become available.8 OCT, with a half-life of 2 hours, was the rst SST analogue introduced in clinical practice. It can be administered subcutaneously and it is much more potent than native SST inhibiting growth hormone, glucagon, and insulin.9

Half-lives of SST and OCT are prolonged in elderly patients and patients with renal and liver failure.7,10-12 SST analogues have different receptor afnities as compared with the natural compound (Fig. 1). Although SST binds equally to all 5 receptors, OCT binds with high afnity to SSTR-2 and -5, with moderate afnity to SSTR-3, and does not bind to SSTR-1 or -4. Vapreotide and lanreotide have a similar prole, but they bind to SSTR-4 with intermediate afnity.9 These distinct binding afnities may translate in some differences in their effects in cirrhotic patients.

Hemodynamic Effects
Somatostatin has been used for over 2 decades3 in the treatment of acute variceal bleeding based on its ability to decrease portal pressure and collateral blood ow.13 However, its hemodynamic effects and the best schedules and doses for its clinical use have not been adequately evaluated until recently.14 Besides, little investigation has focused on the mechanism mediating the effects of these drugs, and on the differences between SST and OCT.15 The clinical use of SST and its analogues has been largely empiric and not based on the results of hemodynamic studies, which might have hampered the optimization of these treatments in clinical practice.15,16 Splanchnic Circulation Somatostatin. In cirrhotic patients with portal hypertension, SST induces a dramatic decrease (around 50%) in portal pressure and azygos blood ow when given as a 250-g bolus.14 These changes are accompanied by a marked decrease in variceal pressure,17,18 but are transient and do not last beyond 5 minutes.14 Infusion of 250 g/h after bolus achieves an enduring but moderate decrease in hepatic venous pressure gradient (HVPG) (6%) and hepatic blood ow (10%), but azygos blood ow returns to values close to baseline.14 This dose has also proven to decrease HVPG in acute variceal bleeding.19 Higher doses (500 g/h) are associated with more consistent hemodynamic effects, decreasing signicantly HVPG (13%) and azygos blood ow (23%).14 SST infusion has been recently shown to prevent increases in HVPG induced by blood transfusion and by a test meal in the setting of acute variceal bleeding.19 Because the presence of blood in the gastrointestinal lumen and volume restitution may in1305

Abbreviations: SST, somatostatin; SSTR, somatostatin receptor; OCT, octreotide; HVPG, hepatic venous pressure gradient; RCT, randomized clinical trial. From the Hepatic Hemodynamic Laboratory, Liver Unit, Institut de Malaties Digestives, Hospital Clinic, Institut dInvestigacions Biome `diques August Pi i Sunyer, University of Barcelona, Spain. Received January 2, 2002; accepted March 11, 2002. Supported by grants from Comisio n Interministerial de Ciencia y Tecnolog a (CICYT SAF 99-0007) and Fondo de Investigaciones Sanitarias (FIS 00/0444). J.G.A. was a recipient of a grant from Fondo de Investigaciones Sanitarias (01/ 9356). Address reprint requests to: Jaime Bosch, M.D., Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Villarroel 170, 08036 Barcelona, Spain. E-mail: jbosch@medicina.ub.es; fax: (34) 93-451-52-72. Copyright 2002 by the American Association for the Study of Liver Diseases. 0270-9139/02/3506-0003$35.00/0 doi:10.1053/jhep.2002.33469

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Systemic Hemodynamics Bolus SST or OCT injections cause transient increases in mean arterial pressure and pulmonary artery pressure, and decrease heart rate and cardiac output.14,22,23,38 On the contrary, continuous infusion of SST or OCT is practically devoid from systemic effects,14,19,22,39 though it has been suggested that OCT infusion may increase pulmonary artery pressure.23
Fig. 1. Differences in SSTR afnities of SST and its analogues.

crease HVPG,20,21 SST may prevent early rebleeding by this mechanism. Octreotide. A 50-g OCT bolus has similar effects of a SST bolus.22,23 Unexpectedly, despite a 40-fold longer half-life, the hemodynamic effects of OCT are as shortlived as those of SST.22 Moreover, there is a rapid desensitization to the effects of OCT. Because of this, repeated bolus achieve less than half of the effects of the rst one, and injecting a higher dose (500 g) does not increase or prolong these effects.22 Continuous infusion, in contrast to SST, did not decrease portal pressure in most studies despite the use of a variety of doses (50, 100, or 250 g/h).22,24,25 To what extent these differences with native SST were owing to inappropriate dosage or way of administration, or to differences in afnity with SST receptors, is largely unknown. The more consistent effect of OCT in cirrhotic patients is its capacity to blunt postprandial hyperemia and the consequent increase in portal pressure.26-30 This effect is maintained, at least in part, on continued OCT administration,31 and may explain some of the effects of OCT on variceal bleeding.21 Besides, brisk increases in portal pressure and portal-collateral blood ow in response to meals are thought to be a major determinant of the progressive dilatation of the varices in patients with cirrhosis. Long-term OCT, thus, may have benecial effects, preventing variceal dilation. The hemodynamic effects of OCT have also been evaluated after repeated subcutaneous administration. Jenkins et al.32 reported a decrease in portal pressure in cirrhotic patients receiving subcutaneous octreotide twice per day for 6 months, but important questions such as the small sample size and the lack of control on alcohol withdrawal arose.33 Studies in animal models of cirrhosis have not claried this issue because some studies have shown lack of effect34,35 and others a decrease in portal pressure.36 Very recently, the new long-acting release formula of OCT failed to obtain a decrease in portal pressure in cirrhotic patients,37 but uneven randomization and, possibly, insufcient dosage make this study nonconclusive.

Renal Function In a single study, SST infusion reduced renal plasma ow, glomerular ltration rate, and sodium excretion, presumably by inducing renal vasoconstriction, and these effects were more marked in patients with ascites.39 In experimental models, long-term OCT administration caused benecial effects on renal function and sodium excretion by ameliorating the vasodilatory syndrome of portal hypertension.40,41 However, studies in humans failed to conrm these ndings.42 The long-acting release formula of OCT obtained similar good results on sodium retention in rats43 that again were not conrmed in humans.44 A compensatory activation of nitric oxide and prostacyclin production occurs under OCT, and may explain the lack of long-term effects.35

Mechanism of Action
The effects of SMT and OCT on splanchnic circulation have been attributed to their capacity to inhibit glucagon and other gastrointestinal vasodilatory peptides (Fig. 2). In fact, it has been shown that preventing the fall in circulating glucagon levels by a concomitant infusion of glucagon abolishes the hemodynamic effects of SMT infusion.45 This may be the main mechanism underlying the effects of SST analogues on postprandial hyperemia. However, the nearly immediate effects observed after bolus injections resemble those of a direct systemic and splanchnic vasoconstrictor, and can be dissociated from the effects on glucagon release because maximum glucagon suppression occurs when the hemodynamic effects of the bolus have vanished.22 Although initial studies showed a lack of vasoconstrictor effect of SST on isolated splanchnic vasculature from portal hypertensive rats,46 recently, OCT exhibited glucagon-independent direct systemic vasoconstrictive effects in cirrhotic patients.47 A further study showed that OCT lacks direct vasoconstrictor action in vitro, but potentiates the effects of protein kinase C dependent vasoconstrictors,48 which are indeed activated in patients with cirrhosis.49,50 This action may be mediated through SSTR-2.48 Recent in vitro studies have shown that SST blunted endothelin-1induced contraction of activated rat hepatic stellate cells,6 which sug-

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Fig. 2. Mechanism of the effects of SST on portal pressure. SST effects on hepatic resistance are still conjectural. Octreotide shares with SST those effects mediated by SSTR-2. HSC, hepatic stellate cell.

gests that SST may decrease hepatic resistance in cirrhosis (Fig. 2). Because this effect seems to be mediated exclusively through SSTR-1 (not stimulated by OCT),6 it may help to explain the slightly different effects of SST and OCT infusion on portal pressure. However, this hypothesis awaits conrmation in the isolated perfused liver model.

Somatostatin and Its Analogues in the Treatment of Patients With Portal Hypertension
SST in Europe and OCT in America are widely used for the treatment of acute variceal bleeding in patients with cirrhosis. This is based on studies suggesting that these drugs are as effective and may be safer than other alternatives such as vasopressin, terlipressin, or sclerotherapy. However, the available evidence to support that SST or OCT fare better than placebo as single therapy for variceal bleeding is unconvincing. Information from studies in which SST or SST analogues are used in conjunction with endoscopic therapy is more consistent. These will be further claried by the results of ongoing, large-scale, randomized controlled trials (RCTs). OCT has been used in other complications of cirrhosis, but information is scarce. We summarize later the results of RCTs and meta-analysis on the use of these drugs in acute variceal bleeding. Also, brief information on other indications is provided. Acute Variceal Bleeding Somatostatin. The usual scheme for SST administration is an initial bolus of 250 g, followed by a 250-g/h infusion that is maintained until the achievement of a 24-hour bleed-free period. Therapy may be further main-

tained for up to 5 days to prevent early rebleeding. As discussed previously, this infusion dose is suboptimal in terms of reduction of portal pressure and gastroesophageal collateral blood ow.14 Very recently, the use of higher doses (500 g/h) has been shown to translate into increased clinical efcacy in the subset of patients with more severe hemorrhage, pointed out by the nding of active bleeding at emergency endoscopy.16 Therefore, it seems that there is space for further renement in the use of SST in acute variceal bleeding. Three double-blind trials have compared SST with placebo51-53 with conicting results. One showed benet,52 whereas the other 2 did not.51,53 In addition, 4 unblinded RCTs compared SST with a nonactive treatment with a trend toward benet for the drug.54 In a recent, double-blind, placebo-controlled study, SST administered before emergency sclerotherapy reduced the number of patients actively bleeding at endoscopy, facilitating the procedure, and reduced the rate of treatment failures.55 Six-week mortality, however, was similar in both groups. A meta-analysis of 7 of these studies (excluding the study by Valenzuela et al.51 because of an excessive rate of bleeding control in placebo group) showed a signicant reduction of failure to control bleeding with SST.54 However, because only 4 of these studies were placebo controlled, this evidence is not as denite as that available for other agents such as terlipressin. Additional data from studies comparing somatostatin with other treatments support the efcacy of this drug. Seven RCTs compared SST with vasopressin. These studies showed that somatostatin is equivalent in efcacy to vasopressin, but much safer: major side effects requiring drug-dosage reduction or withdrawal were more frequent (20%) with vasopressin (only 2 studies used concomitant nitroglycerin) than with SST (2%).54 Three RCTs compared SST with terlipressin, showing equivalence between both treatments either in controlling bleeding, early rebleeding, transfusion requirements, mortality, and adverse events.54 In addition, 4 RCTs compared SST with sclerotherapy (Fig. 3). No differences either in failure to control bleeding or mortality were observed. However, adverse events were signicantly more frequent with sclerotherapy, and severe ones were only observed in the sclerotherapy group.54,56 A large RCT showed that maintaining SST treatment for 5 days prevents early rebleeding as effectively as sclerotherapy.57 Therefore, RCTs comparing somatostatin with other active treatments strongly support that somatostatin is effective in the treatment of acute variceal bleeding.54 Overall, the efcacy of SST as a single treatment in controlling acute variceal bleeding

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Fig. 3. Meta-analysis (random-effects model) of randomized clinical trials of SST-OCT compared with sclerotherapy for acute variceal bleeding. (A) Treatment effect on failure to control bleeding. (B) Treatment effect on mortality. SST and OCT are not different from sclerotherapy in terms of failure to control bleeding and mortality. EVS, sclerotherapy; RD, risk difference. Adapted from DAmico et al.56

across these trials is 60% to 80%. No study has assessed so far the combination of SST and esophageal band ligation. Octreotide. OCT treatment schemes differ widely across clinical trials. The optimal schedule remains to be determined, but hemodynamic data show that, when used as a bolus, 50 g achieve the maximum hemodynamic effects. Infusion doses used have been 25 or 50 g/h. Additionally, in some studies, OCT was given subcutaneously 100 g 3 times a day after control of bleeding. As with SST, therapy can be maintained for 5 days to prevent early rebleeding. In 4 of the 5 studies comparing OCT with placebo or no treatment, drug therapy was initiated after performing sclerotherapy58-60 or band ligation.61 Only in the study by Burroughs et al.,62 reported just in abstract form, was

OCT-placebo used as the initial treatment and sclerotherapy performed in treatment failures. A recent meta-analysis, which did not include the more recent report,60 showed that OCT signicantly reduced failure to control bleeding, but rebleeding or mortality was not changed.54 However, when sclerotherapy was used only in OCTplacebo failures,62 no benet for the drug was found. Therefore, these data suggest that OCT improves the efcacy of endoscopic therapy but there is little evidence supporting its efcacy when used alone. A recent study further reinforces the concept that SST analogues improve the efcacy of sclerotherapy. In this study, patients were randomized at admission to receive vapreotide (a 50-g bolus followed by a 5-day 50-g/h infusion) or placebo. An average of 2.6 hours later, therapeutic endoscopy (sclerotherapy or band ligation) was performed. The frequency of active bleeding at endoscopy, transfusion requirements, and the proportion of patients in whom bleeding was controlled and who survived for 5 days (evaluated as a combined outcome) were signicantly lower with vapreotide. However, the mortality of the bleeding episode (6-wk) was not different in vapreotide- or placebo-treated patients.63 These results are fairly similar to those obtained by Avgerinos et al.55 with SST. The efcacy of OCT has also been compared with that of other treatments. Three RCTs have compared octreotide with vasopressin, showing that octreotide is significantly more effective in achieving control of bleeding, but not in improving survival.54 Two RCTs have shown OCT to be equivalent to terlipressin.54 Side effects were less frequent and severe with OCT than with vasopressin, and there were no signicant differences versus terlipressin. OCT also has been compared with sclerotherapy in 6 RCTs (Fig. 3). A recent meta-analysis of these trials showed that the 2 treatments are equivalent in control of bleeding, early rebleeding, and mortality.56 However, side effects were not different between the 2 groups. A recently published meta-analysis comparing OCT with all other therapies showed that OCT increased the rate of sustained control of variceal bleeding, but without effects on mortality.64 This meta-analysis did not include the largest trial comparing OCT with placebo.62 Another meta-analysis (again not including the earlier-mentioned trial) concluded that OCT or SST treatment has no benet when compared with placebo or no treatment in terms of initial control of bleeding, rebleeding, need for balloon tamponade, or survival.65 Adverse Effects Major complications associated with SST are very uncommon. Minor adverse effects, such as nausea and

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vomiting, occur in up to 25% of patients51 and hyperglycemia in 2% to 4%.16,57,66 Less common side effects are hypoglycemia, abdominal cramps, diarrhea, supraventricular tachycardia, and bradycardia. OCT shares this adverse-effects prole.64 However, contrary to SST, serious adverse events such as pulmonary edema, paralytic ileus,67 and liver toxicity68 have been reported with this drug. Development of gallstones in 20% to 30% of the patients is a concern when considering long-term administration of OCT, but only 1% of the patients per year of treatment develop related symptoms.9 Acute withdrawal of long-term OCT has been associated with biliary colic, presumably caused by rebound gallbladder hypermotility.69

SST and Its Analogues in Other Complications of Portal Hypertension

One study has evaluated subcutaneous OCT as an adjuvant to sclerotherapy in the secondary prevention of variceal bleeding.32 Combined treatment reduced rebleeding and improved survival. However, these results have been questioned because of the small sample, lack of placebo and blinding, and possible confounding factors such as alcohol withdrawal.33 A randomized, doubleblind, placebo-controlled trial is now ongoing comparing the combination of esophageal band ligation and slowrelease formulation of lanreotide versus band ligation alone in secondary prophylaxis. SST and OCT have been proposed for the treatment of portal hypertensive gastropathy based on the ability of SST to decrease gastric perfusion in patients with this condition.72 Only 1 uncontrolled study so far has evaluated these drugs in the treatment of acute bleeding from portal hypertensive gastropathy,73 achieving hemostasis in all patients. However, the uctuating nature of portal hypertensive gastropathy makes it impossible to draw conclusions. OCT, in combination with the oral -adrenergic agonist midodrine and albumin infusion, has been tested in the treatment of hepatorenal syndrome. In a pilot study, this treatment achieved a marked improvement in renal function with no side effects.74 Finally, OCT has been evaluated in a single investigation for the palliative treatment of hepatocellular carcinoma75 with positive but unreliable results.76

Recommendations
There are insufcient studies to provide direct evidence that SST or OCT fare better than placebo or no treatment in acute variceal bleeding. However, there is a large corpus of indirect evidence supporting this view. This is based on RCTs pointing out that SST or OCT are equivalent to sclerotherapy and terlipressin in the control of acute bleeding. Two large, randomized studies have shown that early administration of SST or an analogue facilitates endoscopic treatment and improves control of bleeding. Whether some patients could be treated with SST or an analogue alone, sparing morbidity and cost derived from endoscopic therapy are still unknown. A recent study compared the combination of sclerotherapy plus SST with SST alone.66 Combination therapy improved the efcacy of SST, but the rate of complications in the combination group was signicantly greater. The current recommended treatment schedule is to start on a vasoactive drug (terlipressin, SST, OCT, or vapreotide) from admission, and to associate endoscopic therapy at time of diagnostic endoscopy.70 However, the objective benet afforded by this combined treatment approach has not been evaluated adequately. A very recent meta-analysis shows that this approach improves the control of bleeding and reduces early rebleeding, but has no signicant effect on mortality.71 Also, whether endoscopic therapy shall be performed as an emergency procedure or may be delayed until nearest working hours remains unknown, and is a question that is worth a trial because of its important practical implications. These recommendations do not consider cost-benet analysis, which are still lacking in this eld.

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