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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATHOPHYSIOLOGY OF PORTAL HYPERTENSION
  5. HAEMODYNAMIC STUDIES
  6. CLINICAL APPLICATION OF DRUGS IN PORTAL HYPERTENSION
  7. CONCLUSIONS
  8. Bibliography

The development of varices is a major complication of cirrhosis, and variceal haemorrhage has a high mortality. There have been major advances in the primary and secondary prevention of variceal haemorrhage over the last 20 years involving endoscopic, radiological and pharmacological approaches. This review concentrates principally on drug therapy, particularly on the numerous haemodynamic studies. Many of these drugs have not been studied in clinical trials, but provide data about the underlying pathogenesis of portal hypertension.

Also covered in this review are the randomized controlled trials and meta-analyses that involve a large number of patients. These trials involve relatively few drugs such as non-selective beta-blockers and nitrates. Correlations between haemodynamic and clinical parameters are discussed.

Despite the recent increase in the use of alternative endoscopic therapies, an effective and well tolerated drug remains a clinically important research goal.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATHOPHYSIOLOGY OF PORTAL HYPERTENSION
  5. HAEMODYNAMIC STUDIES
  6. CLINICAL APPLICATION OF DRUGS IN PORTAL HYPERTENSION
  7. CONCLUSIONS
  8. Bibliography

Cirrhosis is the main cause of portal hypertension in North America and Europe. Common causes include alcohol abuse, hepatitis C, primary biliary cirrhosis and autoimmune disease. The major life threatening complication of portal hypertension is the development of gastro-oesophageal varices that have the potential to bleed torrentially. At the time of diagnosis of cirrhosis varices are present in 30% of compensated and 60% of decompensated patients.1 In a third of these patients the varices will bleed, with an inhospital mortality of approximately 50%. Seventy to one-hundred per cent of survivors will re-bleed over 1–2 years, with a 20% mortality for each survivor that re-bleeds.2 These dismal statistics have led to the search for primary prophylaxis against variceal bleeding, and secondary prophylaxis against re-bleeding. Although a variety of strategies including surgical and endoscopic techniques have been proposed, drug therapy has been the strategy most explored. Bearing in mind that the majority of patients will not bleed, pharmacological agents, especially for primary prophylaxis, seem to be the most attractive option. This review aims to present the evidence for the current use of drug therapy in patients with portal hypertension and varices (Table 1). The treatment of an acute variceal haemorrhage will not be covered. Prophylaxis against the formation of varices has been little studied and does not appear to be promising.3

Table 1.  Drugs used in portal hypertension Thumbnail image of

PATHOPHYSIOLOGY OF PORTAL HYPERTENSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATHOPHYSIOLOGY OF PORTAL HYPERTENSION
  5. HAEMODYNAMIC STUDIES
  6. CLINICAL APPLICATION OF DRUGS IN PORTAL HYPERTENSION
  7. CONCLUSIONS
  8. Bibliography

Propranolol was the first drug used to reduce portal pressure in 1981 by Didier Lebrec. Since then an improved understanding of the mechanisms behind portal hypertension has led to the use of a variety of pharmacological agents that act by altering portal haemodynamics favourably.

Normal portal pressure is between 1 and 4 mmHg. The cirrhotic liver leads to an increase in resistance to sinusoidal blood flow, which in turn leads to the development of collaterals that should decompress the portal system and minimize portal hypertension. However increased inflow in the splancnic circulation leads to increased portal inflow, which maintains portal pressure.

Many studies have looked at the hepatic vein pressure gradient (HVPG) as a prognostic marker and as a guide to the efficacy of pharmacological agents. The HVPG is the difference between the wedged hepatic venous pressure (WHVP) and free hepatic venous pressure (FHVP). The HVPG correlates with the true portal pressure in patients with alcoholic cirrhosis,4 hepatitis B5 and hepatitis C,6 but underestimates the true portal pressure in conditions such as primary biliary cirrhosis and chronic active hepatitis.4

The aim of pharmacological therapy is to prevent or reduce the risk of variceal bleeding and because this is unusual if the HVPG is less than 12 mmHg this has been adopted as a haemodynamic target.7 A reduction in the portal pressure of greater than 20% has also been proposed as a therapeutic goal.8 In clinical practice it is also important to combine drug efficacy with tolerability.

HAEMODYNAMIC STUDIES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATHOPHYSIOLOGY OF PORTAL HYPERTENSION
  5. HAEMODYNAMIC STUDIES
  6. CLINICAL APPLICATION OF DRUGS IN PORTAL HYPERTENSION
  7. CONCLUSIONS
  8. Bibliography

β-blockers

A number of β-blockers have been studied in patients with portal hypertension and varices, although only propranolol and nadolol have been studied in large randomized trials.

Propranolol.

In 1982 Lebrec and colleagues investigated the portal hypotensive effect of propranolol in a placebo-controlled haemodynamic study in alcoholic cirrhotic patients.9 Other studies have corroborated these findings reporting reductions in the HVPG of between 10 and 31% (Table 2). The fall in portal pressure is produced by a combination of reduced cardiac output (β1 antagonism) and reduced splancnic blood flow (β2 antagonism). Changes in portal blood flow are probably mainly a result of β1 blockade.10 It was also observed by others that propranolol consistently reduced azygous blood flow, which was elevated in patients with portal hypertension.11 It has been postulated that a reduction in collateral flow, indirectly measured by azygous blood flow, might be an important mechanism of action in reducing variceal bleeding risk.

Table 2.  The effect of propranolol on portal and systemic haemodynamics Thumbnail image of

Others have found that there appeared to be a reciprocal relationship between severity of liver disease and response to propranolol.21 It seemed that although all patients with liver disease responded to propranolol, the response of the collateral circulation to propranolol administration in Child’s C patients was significantly diminished. Child’s C patients had higher baseline azygous blood flow, and despite a fall in the azygous blood flow, a higher fraction of the cardiac output was distributed to the azygous venous bed following propranolol administration. This was described as a pooling of blood in the collateral circulation, and the authors suggest stratification of patients according to the degree of liver disease. This is not universally supported.11 Most of the haemodynamic studies have included predominantly Child’s A and B patients, possibly because Child’s C patients were less tolerant of the drug or were too unwell to be included in such studies.

The first paper to examine the effect of chronic administration of propranolol on portal pressure was published by Vorobioff and colleagues.13 Here the acute and chronic effects on alcoholic cirrhotics with oesophageal varices were studied over an average of 106 days. A portal hypotensive effect of 25% was maintained chronically. However 30% of patients failed to respond after chronic dosing. This paper highlighted the considerable non-response rate of portal pressure to propranolol confirmed by later studies. This may be explained by a portal hypertensive model demonstrating that a rise in the portocollateral resistance accompanies the reduction in portal blood flow thus reducing the overall portal hypotensive response to propranolol.22 It has been shown than in healthy subjects S-propranolol, which is the haemodynamically active component, is present in higher concentrations than R-propranolol on account of reduced first pass metabolism.23 In patients with liver disease the concentration of the S-propranolol is greatly elevated. Stereoisomer concentrations, however, do not appear to predict the haemodynamic response to propranolol, and there is no difference in the relative concentrations of both stereoisomers in propranolol responders and nonresponders.24

Another chronic study with a longer follow-up period of 1 year failed to demonstrate a sustained fall in portal pressure gradient when propranolol was compared with placebo, despite significant reductions in hepatic blood flow, azygous blood flow and cardiac index.18 The investigators suggested that the splancnic hyperdynamic circulation observed in cirrhotics might be partly reversible in some patients, without drug therapy. This may be explained by the fact that patients in the second study were clinically better and had reduced sympathetic tone, but probably more importantly all had stopped drinking alcohol. Patients who were not studied after 1 year due to bleeding episodes or death could introduce selection bias despite the initial haemodynamic parameters being comparable to that of the group who were studied. The findings add weight to the hypothesis that reduction in collateral blood flow and therefore variceal blood flow is the mechanism behind the beneficial effect of propranolol in preventing bleeding. Feu and colleagues investigated the concept of reduced variceal flow using a non-invasive pressure sensitive endoscopic technique.25 Their findings suggested that even in patients in whom the HVPG did not fall significantly there appeared to be a fall in variceal pressure, of similar magnitude to those patients that responded to propranolol.

Groszmann and associates looked at a larger number of patients in a randomized double-blind placebo-controlled trial to investigate whether lowering the HVPG with propranolol protects against a variceal bleed over a 2-year follow-up period.7 They found that a HVPG of less than 12 mmHg protected patients from variceal haemorrhage and improved survival. It is of note that in this study almost all patients bled within the first year and that treatment with propranolol did not result in a greater portal pressure reduction than placebo after 3 months of treatment, suggesting propranolol had a protective effect earlier on. The authors did point out that this might have been due to a greater drop-out rate of patients with the highest pressures in the placebo group from terminating events such as variceal bleed and death. Fifty-one patients were studied in both groups and after 24 months the final number was nine and 12 in the placebo and propranolol groups respectively. It is questionable whether these small numbers allow meaningful analysis. Values for HVPG were higher in the patients who dropped out of the placebo group at 3–12 months. However recent papers by McCormick et al.26 and Stanley et al.27 have supported this observation. The latter study concluded that the HVPG was the only haemodynamic parameter that predicted death or bleeding. Interestingly it has been demonstrated that bleeding may occur at pressures below the threshold level of 12 mmHg,28 although the numbers quoted in this study are quite small.

Nadolol.

Nadolol is also a non-selective β-blocker, which was first studied by Gatta and colleagues.29[30][31]–32 These studies suggested a similar mechanism of action and efficacy to propranolol. Nadolol, unlike propranolol, has low hepatic metabolism and lipid solubility resulting in a longer half life. The main chronic effects at a dose that reduced the heart rate by 25% were of significant reductions in HVPG (19–22%), cardiac output and effective hepatic blood flow. Mean arterial pressure, liver function and renal function were unaffected. Recent studies also suggest that nadolol therapy results in a significant reduction in portal blood flow.33 This paper also suggested that nadolol results in a slight fall in renal blood flow.

Timolol.

This is a non-selective β-blocker that has only been studied in one haemodynamic study.34 The mean reduction in the portal pressure gradient was 20%, which is comparable to the that of propranolol and nadolol. The drug has not been studied in any clinical trials.

Atenolol.

Hillon and colleagues, in a comparative haemodynamic study with propranolol, first investigated atenolol, a selective β1 receptor antagonist in portal hypertensive patients with cirrhosis.35 They found a 16% reduction in HVPG, which significantly correlated with cardiac output. Propranolol produced a greater reduction of portal pressure, although the reduction in cardiac output was similar to that of atenolol. It was postulated that the extra-cardiac effects of propranolol were responsible for the difference.

Another comparative study looked at the effect of atenolol, propranolol and prazosin (α blocker) on portal haemodynamics in a chronic study with an 8-week follow-up period.36 Atenolol resulted in a non-significant 15% reduction in HVPG compared with a significant 25% reduction in HVPG with propranolol. The findings again suggested again suggested a significant correlation between cardiac output and portal pressure with atenolol but not with propranolol. Both β-blockers were well tolerated.

Atenolol therefore appears less effective at reducing portal pressure than propranolol, which suggests that the β2 receptor blockade has a major role to play in the mechanism of action propranolol.

Metoprolol.

Metoprolol is another β1 selective β-blocker. Initial haemodynamic studies suggested that it was of equal efficacy to propranolol in reducing portal pressure.37 The study also demonstrated significant falls in cardiac output in both groups, but a reduced hepatic blood flow only in the propranolol group. The latter finding led the authors to conclude that metoprolol may even be preferable to propranolol in patients with advance liver disease. It has, however, been little studied.

β2 receptor antagonists.

ICI 11855 is a selective β2 antagonist, which was studied by Bihari et al. in 17 patients.38 There was a significant reduction in the portal pressure 60 min following administration of the drug, which was accompanied by significant reductions in the heart rate and cardiac index, both of which were not related to the fall in the portal pressure.

Another selective β2 antagonist mepindolol was compared with intravenous propranolol in patients with cirrhosis and portal hypertension by Brallion and colleagues.39 The effect on the HVPG and systemic circulation was similar to that of propranolol, but at the expense of significantly reduced hepatic blood flow, which was not the case with propranolol. Clearly both these drugs have a significant effect on the systemic circulation, and mepindolol offers no benefit over propranolol in reducing portal pressure. This may explain why they have not been studied further.

Carvedilol.

Carvedilol is a novel vasodilating non-selective β-blocker with weak α1 receptor antagonism and calcium channel antagonism. It has a rapid onset of action with 2–4 times greater β-blocking action than propranolol.

Forrest and colleagues performed the first acute haemodynamic study on cirrhotic patients using 25 mg oral carvedilol.40 A 20% fall in HVPG from 17 to 14 mmHg was achieved mainly due to a fall in wedge hepatic venous pressure. A significant fall in MAP of 10% was noted particularly in ascitic patients. Hepatic blood flow, azygous blood flow and renal blood flow were unaffected. This effect of carvedilol on HVPG was similar to that of propranolol as demonstrated in previous studies (Table 2).

The chronic effect of carvedilol was investigated by Stanley et al.41 A 21% drop in HVPG was maintained chronically. The fall in HVPG was mainly as a result of a significant drop in the wedge hepatic venous pressure. There was no change in renal function or hepatic blood flow. Poor tolerability was noted in three out of the 17 patients who experienced dizziness, breathlessness or hypotension.

A recent study compared carvedilol with intravenous propranolol and placebo.42 Carvedilol at a dose 25 mg was used and resulted in a 21% drop in the HVPG. A lower dose of 12.5 mg carvedilol did not lead to a significant drop in the portal pressure in this series. Propranolol in this study was not as effective in lowering HVPG with only a 13% reduction. Both drugs significantly reduced cardiac output, hepatic blood flow and azygous blood flow. Once again carvedilol caused a significant reduction in the mean arterial pressure of 17% compared with 3.4% with propranolol.

A lower dose of carvedilol has been studied in our center and the findings were published in abstract form.43 The acute and chronic effects of 12.5 mg of carvedilol were studied in six patients. A significant 40% reduction in the HVPG was noted. The drug was very well tolerated.

All these studies seemed to suggest that carvedilol has a portal hypotensive effect greater than propranolol, and that lower doses may avoid significant systemic effects. To date there are no clinical studies looking at the effect of carvedilol in preventing variceal bleeding.

Nitrates

Isosorbide-5-mononitrate is a long acting organic nitrate. The mononitrate, either as native drug or formed from the denitration of isosorbide dinitrate in the lever,44 is the active component, and undergoes minimal first class pass metabolism unlike isosorbide dinitrate,45 thus assisting in appropriate dosing for patients with liver disease and portal shunting. Isosorbide mononitrate reaches peak concentrations within an hour of oral dosing, and has a half-life of approximately 5 h. Only 1–2% of an orally administered dose is excreted unchanged in the urine, with the remainder being eliminated as inactive metabolites. Its pharmacokinetic properties are unchanged in the elderly and in patients with renal failure, or liver cirrhosis.46 It is therefore preferred to isosorbide dinitrate in such patients. To date it is the only nitrate to be used in large randomized controlled trials for preventing variceal bleeding.

The molecular mechanism of action of nitrates is uncertain. It is thought the vasodilatory actions may be a result of enhanced production of intrahepatic nitric oxide or cyclic-GMP.47

There have been a number of haemodynamic studies using isosorbide-5-mononitrate in patients with portal hypertension (Table 3). All the studies with the exception of one, 49 which included predominantly Childs A patients, demonstrated significant reductions in the HVPG. This appears to have been achieved by a fall in the HVWP. Three studies looking at the chronic effects show that the effect of reduced portal pressure is sustained.51[52]–53 Indeed the portal hypotensive effect seemed to be amplified after rechallenge following chronic dosing, confirming lack of tolerance.

Table 3.  The effect of isosorbide-5-mononitrate on portal and systemic haemodynamics Thumbnail image of

Pronounced effects on other parameters may help to explain the mechanism underlying the fall in HVPG, which is comparable to that of propranolol. Early studies48 noted that the hepatic blood flow fell acutely, and this along with an increase in systemic vascular resistance index (SVRI) suggested that a baroreceptor-mediated splancnic vasoconstriction may be responsible for the fall in portal pressure rather than portal venous dilation. However recent work55 demonstrated a significant fall in the portal pressure gradient without affecting the portal blood flow in patients with a transjugular intrahepatic portosystemic stent shunt (TIPSS). It was clear, therefore, that in the study group of patients reflex baroreceptor-mediated vasoconstriction of the splancnic bed could not be the case and that any vasoconstrictive effect to account for the rise in SVRI was limited to the periphery. The observed findings were attributed to reduced intrahepatic vascular resistance rather than a reduction in the liver blood flow (which would be undesirable). Chronic administration resulted in no change or even an increase in the hepatic blood flow50, 51 and may reflect the buffer response of hepatic artery blood flow to a decrease in portal flow.56

Isosorbide-5-mononitrate also reduces the cardiac preload and hence the cardiac output, at least acutely. Significant correlation between the reduction in portal pressure gradient and cardiac output suggests that this may partly be responsible for the reduced portal blood flow observed in this study.48 In all cases the mean arterial pressure fell acutely. It is interesting to note that chronic administration does not appear to have a significant effect on cardiac output or mean arterial pressure.

Azygous blood flow has already been demonstrated as a useful indicator of variceal blood flow in patients with cirrhosis.57 Azygous blood flow responds in a variable fashion to isosorbide-5-mononitrate. Jones and colleagues53 demonstrated no significant change in the azygous blood flow in response to varying doses of nitrates, both acutely and following chronic dosing. However, a relationship was noted between baseline azygous blood flow and the response to nitrates, with those patients with a high azygous blood flow responding by reducing their flow and vice versa. The dose did not seem to influence the azygous blood flow.

Nitrate tolerance is clearly documented in cardiovascular medicine.58, 59 However, of the studies looking at the chronic effects of isosorbide-5-mononitrate therapy only one has reported partial tolerance in five out of 11 patients,51 with others reporting no tolerance.52, 53 The exact mechanism behind why patients with cirrhosis do not develop nitrate tolerance is unknown. It has been suggested that patients with cirrhosis may not be able to develop compensatory mechanisms that are necessary to bring about nitrate tolerance.53

An important observation with nitrate monotherapy has been the deleterious effect on renal function.60 Activation of the renin-angiotensin system was felt to be a major factor. In particular, patients with ascites suffered from a reduced glomerular filtration rate, sodium excretion and renal plasma flow. It is interesting that combination therapy with other portal hypotensive agents abolished these undesirable renal effects. The combination therapies will be covered later.

Drugs acting on alpha adrenergic receptors

Prazosin.

Prazosin is an α1 receptor blocker, which was initially studied by Mills and colleagues36 in a comparative haemodynamic study with propranolol and atenolol over an 8-week follow-up period. An 18% reduction of the hepatic venous pressure gradient was obtained with prazosin compared with 25% with propranolol. Prazosin did not affect the cardiac index or hepatic blood flow, and had no effects on renal function or sodium handling. It acts by reducing intra-hepatic resistance. In a recent study61 impressive results were obtained with acute and chronic reductions in the HVPG of 25.7% and 19.1% respectively, which are comparable to propranolol. However this was accompained by a significant fall in the MAP and systemic vascular resistance. An important finding in this study was the tendency to increased ascites and oedema as a result of a reduction in sodium excretion and expansion of the plasma volume. Tolerance was also felt likely to have occurred following chronic administration. Hepatic blood flow and liver function, as quantified by indocyanide green clearance and galactose elimination, were noted to have improved. These findings were mirrored in a subsequent study62 and thus the use of prazosin in clinical practice was not an attractive proposition. There are at present no clinical trials using prazosin in primary or secondary prophylaxis of variceal haemorrhage.

Clonidine.

Clonidine is a centrally acting α2 agonist that acts by reducing peripheral noradrenaline outflow and thus the sympathetic tone in patients with cirrhosis.63[64]–65 A fall in the hepatic venous wedge pressure was believed to occur secondary to reduced post sinusoidal hepatic vascular resistance. Azygous blood flow was reduced, but hepatic blood flow remained unaffected. The change in hepatic haemodynamic parameters was unrelated to changes in the systemic haemodynamics, where there was a reduction in the cardiac output and mean arterial pressure. The hepatomesenteric circulation was more sensitive to the actions of clonidine in cirrhotic patients compared with healthy controls. Clonidine resulted in a greater fall in the portal pressure compared with propranolol66 and a recent study looking at the effects of clonidine and propranolol in cirrhotic patients found that only propranolol or a combination of propranolol and clonidine resulted in a fall in the portal blood flow.67 Despite these results, there are no randomized clinical trials using clonidine for primary or secondary prophylaxis in patients with varices. The effect on systemic haemodynamics may limit its use.

Drugs acting on the renin-angiotensin system

Losartan.

This is an angiotensin II receptor antagonist that is used in the treatment of systemic hypertension. In cirrhotic patients it is known that the levels of angiotensin II are elevated68 and in vitro studies have shown that angiotensin II can cause a rise in the portal pressure.69 The only published human study demonstrated impressive reductions in the portal pressure of over 20% in response to Losartan70 with minimal effects on the systemic circulation.

Irbesartan.

This is another angotensin II receptor antagonist that has been studied by Debernardi-Venon and colleagues with the results published in abstract form.71 A mean reduction in portal pressure of 20.7% after 2 months in 10 patients is similar to that demonstrated with Losartan. One patient experienced symptomatic hypotension. There was no adverse effect on renal function.

If other studies corroborate these findings, and they were proved not to have deleterious effects on renal function, sodium handling and systemic haemodynamics, angiotensin II receptor antagonists could be ideal agents for use in large randomized clinical trials. Caution is necessary however, because of the deleterious effect on renal function demonstrated in the past with captopril.72

Drugs acting on the seretonin S2 receptors

It has been shown in an experimental model that portal hypertensive animals are more sensitive to the vasoconstrictor effects of seretonin on mesenteric veins, and that administration of ketanserin, a 5HT2 receptor blocker with α adrenergic antagonist activity, resulted in significant reductions in the portal venous inflow and portal pressure.73 The reduction in portal pressure caused by ketanserin was due mainly to a decrease in portal venous inflow secondary to a decreased cardiac output, which was only seen in portal hypertensive rats. This would be consistent with venous dilatation and pooling of blood in the portal venous system secondary to 5HT2 receptor blockade. These finding led to human studies investigating the effect of 5HT2 receptor blockade on portal pressure.

Early trials in cirrhotic patients demonstrated a significant reduction of 23% in the HVPG following ketanserin administration, which was accompanied by reductions in the azygous blood flow and mean arterial pressure with the hepatic blood flow remaining unaffected.74 Subsequent studies corroborated these findings.75, 76 The chronic administration of ketanserin was associated with a sustained drop in the portal pressure of 14.6%, a reduction in the cardiac index, and a drop in the mean arterial pressure.76 This study also demonstrated that 50% of patients developed reversible portosystemic encepahlopathy. Hypotension probably results from α receptor blockade.

Combination treatments have also been studied. Ketanserin in combination with propranolol, both administrated intravenously, has been shown to reduce the HVPG in patients who did not initially respond to propranolol.77 Ritanserin, a more selective serotonin S2 blocker, was combined with propranolol in a study investigating the haemodynamic effects of the chronic dosing of these agents.78 An initial reduction in the portal pressure was noted, but this effect was not sustained during follow up.

These agents have not been studied in randomized controlled trials for the prevention of variceal bleeding or for the treatment of variceal bleeding. The high incidence of encepahlopathy observed with monotherapy, and the potential for systemic hypotension may limit their clinical use. Combination therapy with non-selective β-blockers seems more promising.

Drugs affecting plasma volume

The expansion of plasma volume leading to increased cardiac index is believed to play a major role in sustaining portal hypertension.79 Thus diuretics or a low sodium diet may in theory help to reduce portal pressure. Early studies suggested that spironolactone had the potential to be as potent a portal hypotensive agent as propranolol.80 A significant reduction in the portal pressure of between 10 and 15% was shown to be accompanied by reductions in plasma volume, cardiac output, mean arterial pressure and azygous blood flow.81[82]–83 Hepatic blood flow was unaffected. Although there was no significant correlation between the plasma volume and HVPG, a significant inverse relationship between post treatment serum aldosterone levels and the HVPG was noted, thus confirming the mode of action of aldosterone.81 The reductions in the HVPG following spironolactone administration were not affected by dietary sodium content suggesting that a low sodium diet alone is not sufficient to reduce the portal pressure.82, 83 In clinical practice the use of spironolactone, like propranolol, may be limited by its side effects, particularly painful gynaecomastia which was present in 55% of male patients in one series.84 There are no published clinical trials assessing the efficacy of spironolactone in preventing variceal bleeding, although an ongoing study is comparing nadolol monotherapy with nadolol and spironolactone combination therapy in the primary prevention of variceal bleeding.85 Initial results show no differences in the bleeding rate in the two groups.

Combination therapy

Combination therapy was first used for the treatment of portal hypertension using nitrates and vasopression.86, 87 Enhancement of the portal hypotensive effect was observed. Studies using propranolol, as already discussed, have revealed that 30% of patients failed to reduce portal pressure.13 This observation and the fact that nitrate monotherapy consistently reduced portal pressure led to studies to investigate the effect of combined nitrate and β-blocker therapy (Table 4), a combination that was first investigated in vitro by Kroeger and Groszmann.88 In general there is an enhanced portal hypotensive effect of the combination therapy using isosorbide-5-mononitrate leading to a further 13–16% fall in the HVPG. This effect is particularly striking in those patients who did not respond to a β-blocker alone.16 The mechanism proposed has been that of a decrease in the outflow resistance.91 It is of note that 1 year after combination therapy with nadolol there did not seem to be any additional effect of the nitrate either in the hepatic or systemic haemodynamics93 despite there being a sustained effect after 3 months of therapy. This may be partly explained by a study by Bendsten and associates who demonstrated that placebo treatment had an equal effect to propranolol after 1 year suggesting that portal hypertension improves spontaneously in some patients.18 Although studies looking at the short term effect of nitrates failed to demonstrate tolerance,52, 53 nitrate tolerance could still be an explanation for the lack of effect due to a longer follow-up period in this study.93

Table 4.  The effect of combination therapy on portal and systemic haemodynamics Thumbnail image of

The hepatic blood flow and liver metabolic activity are unaffected, but the azygous blood flow decreased in most cases with the effect being less pronounced with longer duration of treatment. Mean arterial blood pressure and cardiac output both fell, again with the effect most pronounced following acute administration.

Renal function and ascites formation have been the focus of some of the studies,89, 90, 92 particularly as isosorbide-5-mononitrate has been associated with deteriorating renal function.60 The findings suggest that the combination of isosorbide-5-mononitrate with either propranolol or nadolol had no detrimental effect on renal function in patients with or without ascites, despite significant effects on hepatic haemodynamics. These encouraging findings have led to a number of clinical trials using such combinations.

Other combination therapies have also been studied, but none of them have been studied in large clinical trials. One combination therapy worth noting is that of prazosin and propranolol.92 This study showed a greater portal hypotensive effect of prazosin and propranolol than isosorbide-5-mononitrate and prazosin, with no effect on hepatic or renal function. Undesirable systemic effects unfortunately offset the impressive hepatic haemodynamic results with more patients experiencing symptomatic hypotension in the prazosin arm of the study, thus limiting its use in clinical practice.

CLINICAL APPLICATION OF DRUGS IN PORTAL HYPERTENSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATHOPHYSIOLOGY OF PORTAL HYPERTENSION
  5. HAEMODYNAMIC STUDIES
  6. CLINICAL APPLICATION OF DRUGS IN PORTAL HYPERTENSION
  7. CONCLUSIONS
  8. Bibliography

Primary prophylaxis

β-blockers versus placebo.

Propranolol and nadolol have been compared with placebo in nine randomized controlled trials in patients with varices (Table 5), although two of these were published in abstract form.99, 100 Another large trial involving 319 patients treated with either placebo or propranolol is not comparable with the other trials.103 Here patients were unselected with regard to the presence of cirrhosis and varices. This accounts for the low event rate with just 11 patients bleeding and probably explains why no difference was found in the two groups.

Table 5.  Beta-blocker therapy in the primary prophylaxis of variceal haemorrhage Thumbnail image of

The results of meta-analyses of these trials 104[105]–106 are very favourable for the treatment group, with reductions in the number of bleeding episodes approaching 50%. Overall deaths due to bleeding were significantly reduced by 45% in one of these studies and overall deaths by 22% (P = 0.052).104 The other two analyses did not show any benefit on overall survival, although in one mortality from bleeding episodes was reduced by 50%.105 This analysis also demonstrated that the presence of ascites was associated with greater mortality and bleeding risk. One of the main problems with many of the trials is the low number of patients, resulting in insufficient power to detect a reduction in bleeding risk and especially mortality. The study by Colman et al.100 is unique in showing an increase in bleeding rate in the treatment group. However the sample size of this study is low and the very low event rate in the control group suggests that patient selection may have been responsible.

A recent trial by Calès and colleagues involving 206 patients with no or only small (< 5 mm) varices was performed to investigate whether propranolol prevents the development of varices.3 One-hundred and four patients were randomized to receive placebo and 102 to receive long acting propranolol (160 mg/day). After a 2-year follow-up period 31% of patients in the propranolol arm and 14% of patients taking placebo developed large varices (P < 0.05). There was no difference in the rate of bleeding or mortality in the two groups. The low bleeding rate in the placebo group may reflect the small numbers of patients in Child’s C class (13%). However the high incidence of the development of varices in the propranolol group is striking. The authors postulated that above a certain portal pressure the development of varices is not directly related to portal pressure and other ‘non-haemodynamics’ play a part. Another mechanism proposed was that of increased vascular resistance in the collateral circulation following propranolol administration, although it is not clear what the relationship between collateral resistance and the development of varices is. Clearly further studies would assist in elucidating the exact mechanisms. This may involve the measurement of portal pressure in the two groups. Until further studies are performed it is not recommended that propranolol be prescribed for the prevention of the development of varices and bleeding in cirrhotic patients with small or no varices.

Studies have shown propranolol to be safe in long term use in patients with cirrhosis, but up to a third of patients are intolerant of the side effects resulting in discontinuation of the drug.23 The dosage in most of the studies is that required to reduce the resting heart rate by 25%. This usually means starting therapy with a dose 40 mg twice daily and working up to an average maintenance dose of 160 mg/day. Nadolol is typically administered at a dose of 80 mg/day. Fatigue is the most important side effect. Compliance can be a major problem, especially in patients with alcoholic liver disease.

Isosorbide-5-mononitrate.

There is only one published randomized controlled trial comparing ISMN with placebo.107 Forty-two cirrhotic patients were randomized to either ISMN (n= 23) or placebo (n= 19). Both groups were followed up for an average of 43–49 weeks. There was a tendency towards reduced bleeding and death in the ISMN group, although the results did not reach statistical significance. It is also of note ISMN was well tolerated.

A recent randomized double-blinded study published in abstract form comparing ISMN (in patients intolerant of β-blockers) with placebo in 133 consecutive cirrhotic patients with gastro-oesophageal varices, reported a higher first bleeding rate in the treatment group (29%) than in the placebo group (14%) following a 2-year follow-up period.108 There was no significant difference in survival. The presence of ascites, larger variceal size and red signs were associated with a greater incidence of the first bleed. A greater withdrawal from the study because of side effects was noted in the ISMN group.

There was no effect on the development of new ascites or worsening of existing ascites in the treatment arm. The incidence of bleeding in the placebo group was lower than in most other studies. The full paper will need to be published before conclusions can be made from this study.

Others have compared ISMN with propranolol.109 This was a large randomized trial over a 7-year follow-up period involving 118 patients. The probability of bleeding was identical in both the groups. Mortality was significantly greater in the nitrate group, but this was only in patients above 50 years of age.

A smaller study demonstrated that ISMN was less effective than nadalol in preventing bleeding in 30 patients with ascites.110 Mortality was unaffected, but sodium excretion was reduced by almost 50% in the nitrate group. The small size of this study makes it difficult to draw conclusions from the findings.

It appears that ISMN is at least as effective as propranolol in the prevention of gastrointestinal haemorrhage. However the reduced mortality seen with propranolol is not present in the nitrate group. Caution is needed in prescribing nitrate monotherapy on account of the potential for deterioration in renal function and the increased mortality seen in the older age group.109 This may explain why there are not so many trials using nitrate monotherapy and many more looking at combination therapy.

Combination therapy.

As discussed earlier, combination therapy has been shown to be effective in producing a sustained portal hypotensive response. The only combination that has been studied in large randomized trials is that of nitrates and β-blockers.

Nadolol monotherapy has been compared with nadalol and ISMN dual therapy by Merkel and colleagues with the results of long-term follow-up published recently.111, 112 Initial results following a 30-month follow-up period in 146 patients demonstrated a significant reduction of greater than 50% in the cumulative risk of variceal bleeding in the combination treatment group compared with nadolol alone. There was a non-significant trend towards reduced mortality in the combination therapy group. However there was a high incidence of side effects in the combination group (51%), which were severe enough to cause withdrawal from the study in 11% of patients. This compares with 4% in the nadalol only group.

Long-term follow-up of these patients over 7 years has revealed a sustained effect of combination therapy in preventing variceal haemorrhage.112 Survival was unaffected. A larger sample size would be required to show up any survival differences. Two significant findings are of note. First, long-term administration did not result in further side-effects leading to withdrawal from the study. Thus side-effects usually occur early, after the initial doses for nitrates, and in the first few months in the case of β-blockers. Second, there was no significant effect on the occurrence of de novo ascites in the two groups. Previous studies have shown a deleterious effect on renal function and sodium handling when using nitrate monotherapy.60

Another two double-blind placebo-controlled randomized studies have been published in abstract form.113, 114 The first of these compared propranolol and placebo with propranolol and ISMN in 349 patients of whom 57% had > 5 mm size varices.113 Low bleeding rates at 2 years in both the groups were 13% and 10% respectively. The bleeding rates were similar in patients with only large varices. Mortality was similar in both groups, but there were significantly more side-effects in the combination group (36.5% vs. 24.7%, P < 0.05). Development of ascites and renal function were unaffected.

The second study114 involved fewer patients. Patients with large oesophageal varices and red colour signs were randomized to either nadolol and placebo (n=27) or nadolol and ISMN (n=30). There was no significant difference in the bleeding rate or mortality following a 2-year follow-up. Side-effects were significantly more common in the combination group (53% vs. 26%, P=0.03) with 40% in the combination group withdrawing as a result, compared with 15% in the nadalol monotherapy group (P=0.034). However the study was terminated early on account of excess mortality in patients treated with nadolol and ISMN in a parallel trial for the prevention of rebleeding.115 Thus it is not appropriate to make valid conclusions based on this trial.

Beta-blocker and ISMN combination therapy, in particular nadolol and ISMN, appears to be more effective than nadolol monotherapy in preventing the first variceal bleed. Until further studies are performed there does not appear to be any advantage in adding ISMN to propranolol. The side-effect profile of combination therapy is considerably worse, and this is likely to limit its clinical application. Outside of clinical trials patients and clinicians may not be so vigilant in continuing therapy that leads to so many side-effects when alternatives such as endoscopic treatments are available.

Pharmacological agents compared with endoscopic treatments.

Sclerotherapy has been compared with placebo and propranolol in two studies97, 98 and the efficacy of sclerotherapy and propranolol combination therapy assessed in one of these and a further study.97, 116 One study revealed that bleeding from a portal hypertensive source was significantly less in the propranolol group than the sclerotherapy group (4.7% vs. 21.4%, P < 0.003).98 None of the studies showed differences in variceal bleeding or mortality when propranolol was compared with sclerotherapy.

A recent trial, which selected patients with high intra-oesophageal variceal pressures, randomized patients to propranolol (42 patients) or to propranolol plus sclerotherapy (44 patients).116 After a 2-year follow-up period, 23% of the patients in the combination group bled due to varices or congestive gastropathy as compared with 14% in the propranolol group (not significant). Fifty-two per cent in the combination group developed complications as compared with 19% in the propranolol group (P=0.002). The mortality rate was similar in both groups. The findings are similar to those in an earlier study where patients were unselected with regard to the characteristics of varices.97

Endoscopic band ligation is a recent technique that has been compared with sclerotherapy in a meta-analysis,117 and was found to be superior to sclerotherapy in the secondary prophylaxis against variceal rebleeding with fewer complications and quicker eradication of varices. Band ligation has been compared with propranolol for the primary prophylaxis of variceal bleeding in two published trials118, 119 and also a recent abstract from our center.120 In the first study,118 30 patients with grade III or higher varices were studied over a 17-month follow-up period. There was no difference in the bleeding rate in the two groups. Sarin and colleagues119 studied 89 patients with greater than 5 mm varices and observed that over a 17-month period the probability of bleeding was 43% in the propranolol group and 15% in the ligation group (P=0.04). There was no difference in mortality. The very high bleeding rate in the propranolol group contrasts with that observed in other trials. The dose of propranolol was also lower than in other trials. A recent multicenter trial involving 172 patients compared propranolol, ISMN and band ligation over a mean follow up of 20 months.120 Banding was superior to ISMN but similar to propranolol in preventing the first bleed. There was no difference in the overall mortality in the three groups. A very significant proportion of patients had to withdraw from drug therapy as result of side-effects.

Clearly, of the two modes of endoscopic treatments, banding is preferable to scelotherapy because there are fewer iatrogenic complications and it has been shown to be at least as good as if not better than propranolol. Banding is particularly useful where patients are intolerant of drug therapy. Sclerotherapy combined with propranolol does not offer any further benefit over propranolol monotherapy. It remains to be seen whether this is also the case with banding. It therefore appears that banding is at least as good as propranolol in the primary prevention of variceal bleeding and will probably be widely employed, because of its lack of dependence on compliance and the attraction of eradicating oesophageal varices.

Secondary prophylaxis

It is clear that secondary prevention following a variceal bleed is essential in view of the high rate of rebleeding without intervention.2 There is a greater choice of endoscopic, pharmacological, radiological and surgical therapies for secondary prophylaxis than for primary prophylaxis.

β-blockers versus placebo.

There were several trials in the 1980s, and a meta-analysis of these performed in our center revealed significant benefits of propranolol therapy.104 In a population of 1080 patients there was a 39% reduction in rebleeding episodes, a 40% reduction in deaths from bleeding and a 25% reduction in total mortality in the propranolol groups. Heterogeneity was significant for rebleeding episodes, but not when deaths from bleeding or overall mortality were assessed. Although not all of these trials were randomized or placebo controlled, further analysis of selected trials that met more strict criteria, and in those where there was no significant heterogeneity, demonstrated significant benefits from propranolol therapy in the reduction of bleeding and improved mortality rates.

There are 12 published randomized controlled trials comparing β-blockers with placebo against variceal rebleeding (Table 6). Propranolol was assessed in 11, nadalol in one and atenolol in one study which also included propranolol.128 The latter study found atenolol to be less effective than propranolol at reducing rebleeding and improving patient survival. A meta-analysis of these trials106 demonstrated a significant reduction in the rebleeding rate from 66% in the placebo group to 44% in the treatment group (pooled odds ratio of 0.4). There was no significant effect of drug therapy on survival, which may reflect the heterogeneity of the study populations, particularly with respect to aetiology, severity of the liver disease and the time to treatment from the index bleed. Only two of these studies included a significant proportion of Child’s C patients,123, 131 and benefit for the Child’s C patients was seen in one.131

Table 6.  β-blocker therapy in the secondary prophylaxis against variceal rebleeding Thumbnail image of

A recent meta-analysis also revealed that there was a significantly greater reduction in the variceal rebleeding rate in the β-blocker treated patients than in the placebo group (20% mean improvement rate, P < 0.001).134 However this study also demonstrated that there was a significant improvement in the survival rate in the treatment group with a mean improvement of 5.5% (P=0.05), with this being more marked in patients with more advanced liver disease. The methods of analysis did not reveal any significant heterogeneity amongst the trials. It would therefore seem appropriate that β-blocker therapy for secondary prophylaxis can be recommended for patients regardless of the degree of liver disease. Although the prevalence of adverse events was significantly higher in the treatment group, because adverse events were only mentioned in some of the studies it remains somewhat unclear of the impact of this on practice.

Combination therapy.

There is only one published trial assessing the effect of combination drug therapy in preventing variceal rebleeding.135 In this randomized study involving 95 patients, after a 2-year follow-up period, overall rebleeding and survival was not improved by the addition of ISMN to propranolol compared with propranolol alone. However there was a significant reduction in the risk of rebleeding when patients were stratified according to age, i.e. less than 50 years old versus over 50 year olds or by adding an extra year of follow up. It is also of note that more patients experienced side-effects leading to discontinuation of medication with the combination therapy. However no adverse events concerning renal function or effect on ascites was observed with the combination therapy.

Another two studies published in abstract form reinforce the findings of the above study that combining β-blockers with ISMN offers no additional benefit in reducing the overall rebleeding rate and mortality.136, 137 In fact one of these studies reported greater mortality in patients treated with nadolol and ISMN than nadolol alone (32% vs. 14%, P = 0.02).136 Clearly the full paper would need to be published and analysed before firm conclusions can be made.

It seems, therefore, that combination therapy may have a role in secondary prophylaxis, but adverse side-effects may limit its clinical use. Further studies are necessary before confident recommendations can be made.

Pharmacological agents compared with endoscopic treatments.

There have been several trials comparing sclerotherapy with β-blockers alone or β-blockers combined with sclerotherapy. Meta-analysis of these studies104 demonstrated a small benefit of sclerotherapy over propranolol on the rebleeding rate but no effect on survival. Sclerotherapy was associated with a greater number and severity of complications. Propranolol combined with sclerotherapy was found to be better than sclerotherapy in reducing the rebleeding rate, but there was no difference in survival. The rationale being that the addition of propranolol reduces the risk of rebleeding in the first few months before the varices are completely eradicated. However the meta-analysis revealed significant heterogeneity in all these trials, which makes firm conclusions difficult. A recent abstract found that propranolol and sclerotherapy were significantly more effective at reducing the rebleeding rate than sclerotherapy alone (11/35 vs. 16/30 patients, P < 0.001).138 It is interesting that most of the difference was accounted for by a greater incidence of bleeding from gastric varices and congestive gastropathy in the sclerotherapy only group.

Propranolol in combination with sclerotherapy was found to be superior, in terms of rebleeding rate and survival, to propranolol alone based on the results of two studies. In the meta-analysis the odds ratios for rebleeding in the above trial comparisons were not as low as that when comparing propranolol with placebo. The trials comparing the latter were also of a higher quality with a longer follow-up period. Another meta-analysis comparing propranolol with sclerotherapy mirrors these findings in that sclerotherapy was more effective at reducing variceal rebleeding, but was associated with more iatrogenic adverse events.139 Survival was similar in the two groups.

The combination of nadolol and ISMN was found to be superior to sclerotherapy in a recent trial.140 Rebleeding rate and treatment related complications were significantly lower than in sclerotherapy. Overall survival was, however, identical in the two groups. It is interesting that patients in whom the hepatic venous wedge pressure fell by 20% or more had far fewer episodes of rebleeding.

Banding has been compared with β-blocker and ISMN combination therapy in preventing recurrent variceal bleeding in three studies all published in abstract form.141[142]–143 The results suggest that drug therapy is better than band ligation in reducing the risk of rebleeding, although there was no effect on mortality. The full report of these trials is awaited.

It seems, therefore, that further trials with a longer follow-up and including banding combined with propranolol are necessary before combination drug or endoscopic therapy can be recommended for the secondary prophylaxis against variceal rebleeding.

Pharmacological agents compared with transjugular intrahepatic portosystemic stent shunt (TIPSS).

The only publication is a study published in abstract form that randomized patients to either TIPSS only (n=47) or propranolol and isosorbide-5-mononitrate combination therapy (n=44).144 The TIPSS arm had significantly fewer episodes of rebleeding (11% vs. 32%, P=0.02), but encepahlopathy was significantly higher in the shunted group (38% vs. 11%, P=0.004). Mortality was similar for both groups. The cost of TIPSS was more than twice that of drug therapy. Full publication of the report is awaited.

There is no doubt that TIPSS is very effective at reducing rebleeding and has been demonstrated in a recent meta-analysis to be more effective than endoscopic therapy, although overall survival is similar.145 Encephalopathy often responds to simple measures and in most cases improves or resolves over time.146 There is now more of a case for TIPSS to be used early in the secondary prevention of variceal bleeding in patients with more advanced disease. Further studies with drug therapy are needed before conclusions can be made about its efficacy compared with TIPSS in the prevention of variceal rebleeding.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATHOPHYSIOLOGY OF PORTAL HYPERTENSION
  5. HAEMODYNAMIC STUDIES
  6. CLINICAL APPLICATION OF DRUGS IN PORTAL HYPERTENSION
  7. CONCLUSIONS
  8. Bibliography

There have been many studies investigating the effect of pharmcological agents on portal hypertension with varying results. Of these agents non-selective β-blockers and isosorbide-5-mononitrate alone and in combination seem to be the most promising. The haemodynamic response to drug therapy also has been shown to correlate with the risk of bleeding, and monitoring the haemodynamic response to medical therapy may assist in appropriate dosing and choice of agent. Newer preparations such as carvedilol and losartan deserve further study following very encouraging initial results.

Large randomized clinical trails remain the gold standard for testing the efficacy of these agents in preventing the initial variceal bleed and rebleeding. The first choice for primary prevention are non-selective β-blockers, although recent evidence suggests a role for β-blockers in combination with isosorbide-5-mononitrate. Endoscopic variceal ligation also compares favourably with drug therapy especially where drugs are not tolerated.

For secondary prevention non-selective β-blockers are also effective and similar to sclerotherapy. As band ligation replaces sclerotherapy the relative efficacy of drug therapy versus band therapy should be studied. Following initial encouraging results further studies looking at combination therapy for secondary prevention are needed. TIPSS is also very effective at reducing the rebeleeding rate compared with endoscopic therapy, and has a place in the management of patients with more advanced liver disease. It is currently unclear how TIPSS compares with pharmacological agents.

Bibliography

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATHOPHYSIOLOGY OF PORTAL HYPERTENSION
  5. HAEMODYNAMIC STUDIES
  6. CLINICAL APPLICATION OF DRUGS IN PORTAL HYPERTENSION
  7. CONCLUSIONS
  8. Bibliography
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