It is unclear to what extent systemic arterial blood pressure influences portal pressure. This relationship is clinically important as drugs, which are conventionally used for therapy of portal hypertension, may also influence systemic arterial blood pressure. This study investigated the potential correlation between mean arterial (MAP) and portal venous pressure (PVP) in rats with healthy livers. In a rat model with healthy livers, we investigated the effect of manipulation of MAP on PVP. Interventions consisted of 0.9% NaCl (group 1), 0.1 mg/kg body weight (bw) Sildenafil (low dose), an inhibitor of phosphodiesterase-5 (group 2), and 1.0 mg/kg bw Sildenafil (high dose, group 3) in 600 µL saline injected intravenously. Norepinephrine was used to increase MAP in animals with circulatory failure while PVP was monitored. Injection of the fluids induced a transient drop in MAP and PVP, probably due to a reversible cardiac decompensation. The drop in MAP and drop in PVP are significantly correlated. The time lag between change in MAP and change in PVP by 24 s in all groups suggests a cause-and-effect relationship. Ten minutes after the injection of the fluid, cardiac function was normalized. Thereafter, MAP gradually decreased. In the NaCl group, PVP decreases by 0.485% for a 1% drop of MAP, by 0.550% in the low-dose sildenafil group, and by 0.651% in the high-dose sildenafil group (p < 0.05 for difference group two vs. group one, group three vs. group one, and group three vs. group two). These data suggest that Sildenafil has an inherent effect on portal pressure that exceeds the effect of MAP. Injection of norepinephrine led to a sudden increase in MAP followed by an increase in PVP after a time lag. These data show a close relationship between portal venous pressure and systemic arterial pressure in this animal model with healthy livers. A change in MAP is consequently followed by a change in PVP after a distinct time lag. This study, furthermore, suggests that Sildenafil influences portal pressure. Further studies should be performed in a model with cirrhotic livers, as these may be important in the evaluation of vasoactive drugs (e.g., PDE-5-inhibitors) for therapy of portal hypertension.

Approximately 40% to 95% of people with cirrhosis have oesophageal varices. About 15% to 20% of oesophageal varices bleed in about one to three years of diagnosis. Several different treatments are available, which include endoscopic sclerotherapy, variceal band ligation, beta-blockers, transjugular intrahepatic portosystemic shunt (TIPS), and surgical portocaval shunts, among others. However, there is uncertainty surrounding their individual and relative benefits and harms.

To compare the benefits and harms of different initial treatments for secondary prevention of variceal bleeding in adults with previous oesophageal variceal bleeding due to decompensated liver cirrhosis through a network meta-analysis and to generate rankings of the different treatments for secondary prevention according to their safety and efficacy.

We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until December 2019 to identify randomised clinical trials in people with cirrhosis and a previous history of bleeding from oesophageal varices.

We included only randomised clinical trials (irrespective of language, blinding, or status) in adults with cirrhosis and previous history of bleeding from oesophageal varices. We excluded randomised clinical trials in which participants had no previous history of bleeding from oesophageal varices, previous history of bleeding only from gastric varices, those who failed previous treatment (refractory bleeding), those who had acute bleeding at the time of treatment, and those who had previously undergone liver transplantation.

We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the differences in treatments using hazard ratios (HR), odds ratios (OR) and rate ratios with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance.

We included a total of 48 randomised clinical trials (3526 participants) in the review. Forty-six trials (3442 participants) were included in one or more comparisons. The trials that provided the information included people with cirrhosis due to varied aetiologies. The follow-up ranged from two months to 61 months. All the trials were at high risk of bias. A total of 12 interventions were compared in these trials (sclerotherapy, beta-blockers, variceal band ligation, beta-blockers plus sclerotherapy, no active intervention, TIPS (transjugular intrahepatic portosystemic shunt), beta-blockers plus nitrates, portocaval shunt, sclerotherapy plus variceal band ligation, beta-blockers plus nitrates plus variceal band ligation, beta-blockers plus variceal band ligation, sclerotherapy plus nitrates). Overall, 22.5% of the trial participants who received the reference treatment (chosen because this was the commonest treatment compared in the trials) of sclerotherapy died during the follow-up period ranging from two months to 61 months. There was considerable uncertainty in the effects of interventions on mortality. Accordingly, none of the interventions showed superiority over another. None of the trials reported health-related quality of life. Based on low-certainty evidence, variceal band ligation may result in fewer serious adverse events (number of people) than sclerotherapy (OR 0.19; 95% CrI 0.06 to 0.54; 1 trial; 100 participants). Based on low or very low-certainty evidence, the adverse events (number of participants) and adverse events (number of events) may be different across many comparisons; however, these differences are due to very small trials at high risk of bias showing large differences in some comparisons leading to many differences despite absence of direct evidence. Based on low-certainty evidence, TIPS may result in large decrease in symptomatic rebleed than variceal band ligation (HR 0.12; 95% CrI 0.03 to 0.41; 1 trial; 58 participants). Based on moderate-certainty evidence, any variceal rebleed was probably lower in sclerotherapy than in no active intervention (HR 0.62; 95% CrI 0.35 to 0.99, direct comparison HR 0.66; 95% CrI 0.11 to 3.13; 3 trials; 296 participants), beta-blockers plus sclerotherapy than sclerotherapy alone (HR 0.60; 95% CrI 0.37 to 0.95; direct comparison HR 0.50; 95% CrI 0.07 to 2.96; 4 trials; 231 participants); TIPS than sclerotherapy (HR 0.18; 95% CrI 0.08 to 0.38; direct comparison HR 0.22; 95% CrI 0.01 to 7.51; 2 trials; 109 participants), and in portocaval shunt than sclerotherapy (HR 0.21; 95% CrI 0.05 to 0.77; no direct comparison) groups. Based on low-certainty evidence, beta-blockers alone and TIPS might result in more, other compensation, events than sclerotherapy (rate ratio 2.37; 95% CrI 1.35 to 4.67; 1 trial; 65 participants and rate ratio 2.30; 95% CrI 1.20 to 4.65; 2 trials; 109 participants; low-certainty evidence). The evidence indicates considerable uncertainty about the effect of the interventions including those related to beta-blockers plus variceal band ligation in the remaining comparisons.

The evidence indicates considerable uncertainty about the effect of the interventions on mortality. Variceal band ligation might result in fewer serious adverse events than sclerotherapy. TIPS might result in a large decrease in symptomatic rebleed than variceal band ligation. Sclerotherapy probably results in fewer 'any' variceal rebleeding than no active intervention. Beta-blockers plus sclerotherapy and TIPS probably result in fewer 'any' variceal rebleeding than sclerotherapy. Beta-blockers alone and TIPS might result in more other compensation events than sclerotherapy. The evidence indicates considerable uncertainty about the effect of the interventions in the remaining comparisons. Accordingly, high-quality randomised comparative clinical trials are needed.

Background It is not clear whether β₁-selective or nonselective β-blockers should be used in patients with cirrhosis and acute myocardial infarction. Methods and Results Medical records were retrieved from Taiwan NHIRD (National Health Insurance Research Database) during 2001-2013. Patients were excluded for age <20, previous acute myocardial infarction, contraindication to β-blockers, chronic obstructive pulmonary disease, asthma, or atrioventricular conduction disease. Patients who died during index admission, had a follow-up <6 months, had a medication ratio of either β₁-selective or nonselective β-blocker <80%, or who switched between β-blockers were also excluded. Patients on β₁-selective blockers and nonselective β-blockers were propensity score matched and compared for outcome. Primary outcomes were 1- and 2-year cardiovascular events, liver adverse outcomes, and all-cause mortality. A total of 203 595 patients with acute myocardial infarction were enrolled, of whom 6355 had cirrhosis. After screening for exclusion criteria, 1769 patients (655 patients on β-blockers and 1114 patients not on β-blockers) were eligible for analysis. Among patients on β-blockers, propensity score matching was performed, and 218 patients on β₁-selective blockers and 218 patients on nonselective β-blockers were studied. During a 2-year follow-up, patients on β₁-selective blockers had significantly fewer major cardiac and cerebrovascular events (hazard ratio=0.62; 95% confidence interval=0.42-0.91; P=0.014), a trend toward lower all-cause mortality (hazard ratio=0.66; 95% confidence interval=0.38-1.14; P=0.135), and nonworsening liver outcome (hazard ratio=0.66; 95% confidence interval=0.38-1.14; P=0.354). Conclusions In patients with cirrhosis and acute myocardial infarction, selecting a β-blocker is a clinical dilemma. Our study showed that the use of β₁-selective blockers is associated with lower risks of major cardiac and cerebrovascular events.

Research and development of new drugs requires both long time and high costs, whereas safety and tolerability profiles make the success rate of approval very low. Drug repurposing, applying known drugs and compounds to new indications, has been noted recently as a cost-effective and time-unconsuming way in developing new drugs, because they have already been proven safe in humans. In this review, we discuss drug repurposing of approved cardiovascular drugs, such as aspirin, beta-blockers, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, cardiac glycosides and statins. Regarding anti-tumor activities of these agents, a number of experimental studies have demonstrated promising pleiotropic properties, whereas all clinical trials have not shown expected results. In pathological conditions other than cancer, repurposing of cardiovascular drugs is also expanding. Numerous experimental studies have reported possibilities of drug repurposing in this field and some of them have been tried for new indications ('bench to bedside'), while unexpected results of clinical studies have given hints for drug repurposing and some unknown mechanisms of action have been demonstrated by experimental studies ('bedside to bench'). The future perspective of experimental and clinical studies using cardiovascular drugs are also discussed.

There are many studies investigating the role of non-selective beta-blockers in portal hypertension. Satisfactory reduction in portal pressure is possible in a third to half of patients with propranolol and nadolol, although combining these drugs with nitrates may be more effective. Carvedilol is a more potent agent than propranolol in reducing portal pressure, particularly in non-responders, and is better tolerated. All these drugs have been studied in primary and secondary prophylaxis, sometimes in combination with band ligation and/or nitrates. There is some evidence to support combining these agents with band ligation, despite a lack of survival benefit and increased adverse events. Hemodynamic monitoring can help select non-responders who may benefit from additional therapies such as band ligation, as lack of response is associated with worse outcomes. Propranolol should be used with caution in patients with refractory ascites, although the current evidence is not of sufficient quality to justify not using these drugs in such situations. Beta-blockers have been shown to reduce bacterial translocation and spontaneous bacterial peritonitis in cirrhosis.

Cirrhosis is a leading cause of death in the United States and worldwide. Beta-blockers have been established in numerous studies as part of the cornerstone of the medical management of cirrhosis, particularly in the primary and secondary prevention of variceal hemorrhage. However, new evidence has cautioned the use of beta-blockers in patients with end-stage cirrhosis and refractory ascites. In this article, we review the beneficial effects of beta-blocker therapy, the potential harms of aggressive beta-blocker therapy, and provide suggestions regarding the appropriate use of this class of medications in patients with cirrhosis.

In the past 10 years, it has been clearly shown that vasoactive substances reduce portal pressure in patients or animals with portal hypertension. Some of these substances act by inducing splanchnic vasoconstriction, while others reduce hepatic and porto-systemic collateral vascular resistance and, thus, induce a portal hypotensive effect. Still others induce arterial hypotension, which causes a vasoconstrictive effect in the splanchnic territory. Since these drugs act on different vascular receptors, their combination should have a more marked effect on portal hypertension. Up to now, only nonselective beta-blockers have been used in the prevention of first gastrointestinal bleeding in patients with portal hypertension and esophageal varices and in the prevention of recurrent gastrointestinal bleeding. These trials have shown that propranolol or nadolol significantly reduce either a first episode of bleeding or recurrent bleeding. This pharmacological treatment also improves the survival rate in these patients. All of these studies have helped us to understand, in part, why gastrointestinal hemorrhage occurs in certain patients. Additional studies of beta-blockers or other substances are, nevertheless, necessary to select patients who will respond to this type of treatment. Finally, it is possible that the pharmacological treatment of portal hypertension may also be used before esophageal varices occur.

Beta-blockers modify splanchnic hemodynamics in cirrhotic patients. Nonselective beta-blockers are more effective than selective beta-blockers. Azygos blood flow, as a measure of collateral circulation, including that through varices, is always reduced, but the effects on portal pressure, whether measured directly or by the wedged hepatic venous pressure, are variable. The initial reported correlation between a 25% reduction of resting pulse rate and similar percentage reduction in the wedged free hepatic venous gradient has not been reproduced in subsequent studies. Therefore, to study the effect of changes in hemodynamic indices and the likelihood of variceal bleeding, direct measurements of such indices need to be made in clinical trials. At present, only one primary-prevention trial of propranolol suggests that a hemodynamic index can be used to identify patients given propranolol who will not bleed. Some clinical factors may be important in identifying nonresponders in trials of secondary prevention, but these are not universally recognized. The results of secondary-prevention studies are very heterogeneous, and it is difficult to understand why this is so. However, comparative studies versus sclerotherapy suggest that reductions in rebleeding and mortality are similar. Pharmacologic treatment, including beta-blockade, is ideal for primary prevention of variceal bleeding. The initial results from randomized studies are more homogeneous regarding the benefit of beta-blockers than in the secondary-prevention studies, although there is still doubt about the response in cirrhotics with ascites. No fatal complications due to propranolol administration have been reported in cirrhotic patients, and the complications are reversible. The future of pharmacologic therapy for portal hypertension lies in combination therapy. The addition of vasodilators to beta-blockers appears to potentiate their effect on portal pressure reduction. The results of clinical trials are awaited with great interest.

The effect of chronic beta adrenergic blockade on potassium homeostasis during moderate intensity exercise (40% of VO2 max) was examined in seven end-stage renal patients who were being maintained on chronic dialysis treatment. Subjects participated in three study protocols: 1) exercise alone, 2) exercise plus propranolol (a nonselective beta-1, beta-2 antagonist), and 3) exercise plus metoprolol (a specific beta-1 antagonist). The basal potassium concentration was similar in all three studies and averaged 4.95 +/- 0.12 mEq/liter. During Study 1 (exercise alone), plasma potassium rose by 0.26 +/- 0.09 mEq/liter. During exercise with propranolol, plasma K concentration rose significantly higher (delta plasma K = 0.44 +/- 0.26 mEq/liter; P less than 0.05 vs. exercise alone). In contrast, the rise in plasma K during exercise with metoprolol (delta plasma K = 0.20 +/- 0.08 mEq/liter) was similar to that observed with exercise alone. Differences in potassium homeostasis between metoprolol and propranolol could not be explained by differences in hemodynamic parameters, levels of potassium regulatory hormones, or acid base status. Thus, the higher rise in potassium concentration during exercise with propranolol could only be explained by adrenergic blockade at the beta-2 receptor site. These results support the concept that adrenergic control of extrarenal potassium homeostasis in dialysis patients is mediated at the beta-2 receptor. Since a deterioration in potassium homeostasis during exercise is observed with beta-2, but not beta-1 blockade, selective beta-1 adrenergic blocking agents may be safer in dialysis patients.

Fifty patients with non-cirrhotic portal fibrosis who were admitted to hospital because of upper gastrointestinal bleeding were randomly assigned to treatment with either oral propranolol given in doses that reduced the resting pulse rate by 25% (25 patients) or with a placebo (25 patients). One year after the start of the study 20 patients in the propranolol group and five patients in the placebo group were free from recurrent gastrointestinal bleeding (p less than 0.0001). Giving continuous oral propranolol treatment is therefore effective in preventing recurrent upper gastrointestinal bleeding in patients with non-cirrhotic portal fibrosis.

The haemodynamic effects and clinical uses of drugs used in the management of patients with oesophageal variceal bleeding are reviewed. Vasoconstrictor agents (vasopressin, teripressin) alone or in combination with nitrates continue to be used for acute bleeding episodes, while somatostatin is an alternative. Alpha- and beta-adrenergic blocking drugs and vasodilators which lead to a sustained decrease in portal pressure can be used for the prevention of bleeding episodes, but despite numerous studies the pharmacological treatment of variceal bleeding remains controversial.

Survival after variceal bleeding depends greatly on the outcome of the immediate posthaemorrhagic period. This may in turn depend on the recurrence of bleeding. We therefore prospectively evaluated the influence of propranolol on the recurrence of variceal haemorrhage during the early period after the acute bleeding episode. Twenty consecutive patients with acute variceal haemorrhage and liver disease were randomly assigned to treatment either with propranolol or placebo orally for 14 days. Propranolol significantly decreased the rate of recurrence of variceal haemorrhage during this early period (p = 0.0028; 95% confidence interval in the placebo group, 90 +/- 20%; in the beta blocker group, 20 +/- 26%). Whereas a recurrence of variceal bleeding occurred in 9 of 10 patients in the placebo group, only 2 of 10 rebled during treatment with propranolol. These results suggest that propranolol may prevent rebleeding in the crucial early period after acute haemorrhage from oesophageal varices.

An experimental model of cirrhosis was developed in the rat to assess the effect of disease and pharmacological manipulation on blood flow, shunting and portal pressure. With progression in the severity of histological cirrhosis there was a steady fall in effective liver blood flow as measured with radioisotope labelled colloid. This corresponded to a rise in portal pressure and shunting with a close correlation between the two (r = 0.7, p less than 0.01). In control animals and when portal hypertension was caused by extrahepatic obstruction, beta-blockade with propranolol, but not selective beta 2 blockade, significantly decreased liver blood flow. With cirrhosis there was a variable response to propranolol depending on the histological severity of disease, the height of portal pressure and degree of shunting. There is a possibility therefore that a potential may exist for lowering portal pressure by manipulating intrahepatic shunting.

One hundred and twelve consecutive Child Class A and B cirrhotic patients were included in a prospective controlled trial aimed at investigating the efficacy and safety of endoscopic sclerotherapy vs. distal splenorenal shunt in the elective treatment of hemorrhage from esophagogastric varices. Fifty-seven patients were randomly allocated to splenorenal shunt and 55 to endoscopic sclerotherapy. Since only 4 of the 55 patients assigned to endoscopic sclerotherapy had to be excluded after randomization and before treatment as compared to 14 of the 57 patients assigned to splenorenal shunt, it is suggested that the applicability of endoscopic sclerotherapy is greater than that of splenorenal shunt. One patient in each group died within 30 days of the procedure and two in the endoscopic sclerotherapy group were lost to follow-up just after discharge. Variceal rebleeding during follow-up occurred in 37.5% (18/48) of patients in the endoscopic sclerotherapy group and in 14.3% of those in the splenorenal shunt group (6/42) (p less than 0.02), whereas hepatic encephalopathy was more frequent in patients submitted to splenorenal shunt (10/42, 24%) than in those treated by endoscopic sclerotherapy (4/48, 8%) (p less than 0.05). The therapeutic modality was the only variable with independent predictive value for rebleeding during follow-up, whereas for hepatic encephalopathy, the therapeutic modality, and the presence of encephalopathy related to the bleeding episode each showed independent predictive value. Early and long-term mortality, did not differ between the two therapeutic groups, being the 2-year survival was 71% for splenorenal shunt and 68% for endoscopic sclerotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)

beta-Adrenoceptor blockers always change splanchnic haemodynamics in cirrhotic patients. Azygous blood flow, as a measure of collateral circulation including that through varices, is always reduced, but the effects on portal pressure, whether measured directly or by the wedged hepatic venous pressure, are variable. The initial correlations between a 25% reduction of resting pulse rate and similar percentage reduction in the wedge-free hepatic venous gradient, has not been reproduced in subsequent studies. Therefore, to study the effect of changes in haemodynamic indices and the likelihood of variceal bleeding, direct measurements of such indices need to be made in clinical trials. At present there are no haemodynamic or clinical factors which can be used to select patients who will have a good therapeutic response to propranolol other than those documented in the first clinical trial of propranolol for the prevention of variceal re-bleeding from Paris. Thus the hypothesis that beta-adrenoceptor blockers may lessen the incidence of bleeding in cirrhotics, by partially reducing portal pressure or flow or both, needs testing in further clinical studies. The selection criteria of the first clinical trial of propranolol in Paris need to be confirmed. Two subsequent trials, in which patients were not selected but in which many patients had similar clinical characteristics to the Paris patients, could not confirm a therapeutic effect of propranolol. No fatal complications due to propranolol administration have been reported in cirrhotic patients. Complications are reversible. Pharmacological treatment including beta-adrenoceptor blockade appears ideal for trials of primary prevention of variceal bleeding. Some preliminary results including use in decompensated cirrhotics are encouraging. However, as for trials for prevention of re-bleeding, the design and analysis of such trials needs careful evaluation to take into account the outcome of patients who discontinue medication, whether due to simple noncompliance or due to side-effects, and also the influence of abstinence from alcohol on bleeding from varices.

Endoscopic sclerotherapy remains an uncertain therapy for bleeding esophageal varices. Several recently reported randomized trials address the efficacy of immediate, long-term and prophylactic sclerotherapy. Analysis of these studies suggests that sclerotherapy may stop acute bleeding but has little impact on survival of an acute bleeding episode. Ongoing sclerosis reduces the incidence of rebleeding episodes and improves survival for those patients fortunate enough to survive the acute bleeding episode. Prophylactic therapy is an exciting concept limited by difficulty in identifying "high-risk" patients and by the high rate of complications associated with sclerotherapy.

In a prospective, randomized controlled trial, 53 patients with variceal hemorrhage from portal hypertension, including 44 with cirrhosis, were allocated, after initial control of the bleeding, to treatment by sclerotherapy alone, or by this together with oral propranolol in a dose sufficient to reduce resting pulse rate by 25% during the period up to the time when varices were obliterated. Eight of the 27 patients undergoing sclerotherapy alone rebled during this period as compared to 7 of the 26 patients in the additional propranolol group (p greater than 0.80), two patients from each group dying from uncontrollable variceal hemorrhage. Propranolol precipitated encephalopathy in one patient and complicated resuscitation following bleeding in a second, and as there was no evidence in this study that use of the drug reduced the frequency or severity of the variceal bleeding, its administration cannot be recommended during the period prior to obliteration of varices by sclerotherapy.

During the intervening years since metoprolol was first reviewed in the Journal (1977), it has become widely used in the treatment of mild to moderate hypertension and angina pectoris. Although much data have accumulated, its precise mechanisms of action in these diseases remain largely uncertain. Optimum treatment of hypertension and angina pectoris with metoprolol is achieved through dose titration within the therapeutic range. It has been clearly demonstrated that metoprolol is at least as effective as other beta-blockers, diuretics and certain calcium antagonists in the majority of patients. Although a twice daily dosage regimen is normally used, satisfactory control can be maintained in many patients with single daily doses of conventional or, more frequently, slow release formulations. Addition of a diuretic may improve the overall response rate in hypertension. Several controlled trials have studied the effects of metoprolol administered during the acute phase and after myocardial infarction. In early intervention trials a reduction in total mortality was achieved in one moderately large trial of prolonged treatment, but in another, which excluded patients already being treated with beta-blockers or certain calcium antagonists and where treatment was only short term, mortality was significantly reduced only in 'high risk' patients. Overall results with metoprolol have not demonstrated that early intervention treatment in all patients produces clinically important improvement in short term mortality. Thus, the use of metoprolol during the early stages of myocardial infarction is controversial, largely because of the requirement to treat all patients to save a small number at 'high risk'. This blanket coverage approach to treatment may be more justified during the post-infarction follow-up phase since it has been shown that metoprolol slightly, but significantly, reduces the mortality rate for periods of up to 3 years. Metoprolol is generally well tolerated and its beta 1-selectivity may facilitate its administration to certain patients (e.g. asthmatics and diabetics) in whom non-selective beta-blockers are contraindicated. Temporary fatigue, dizziness and headache are among the most frequently reported side effects. After a decade of use, metoprolol is well established as a first choice drug in mild to moderate hypertension and stable angina, and is beneficial in post-infarction patients. Further study is needed in less well established areas of treatment such as cardiac arrhythmias, idiopathic dilated cardiomyopathy and hypertensive cardiomegaly.