β-Blockers in Hepatosplenic Schistosomiasis: A Narrative Review

ABSTRACT.

Hepatosplenic schistosomiasis (HSS) is a serious complication of chronic schistosomiasis that can result in portal hypertension and variceal bleeding. β-blockers, a class of medications commonly used to treat hypertension and other cardiovascular conditions, have been investigated for their potential use in preventing variceal bleeding in HSS. Several studies have shown that β-blockers can reduce portal pressure and prevent variceal bleeding effectively in these patients. However, there are limited data on the long-term efficacy and safety of β-blockers in this setting, and further research is needed to determine the optimal use of these medications. This review summarizes the evidence supporting current recommendations of β-blocker use in patients with HSS.

INTRODUCTION

Schistosomiasis is a neglected tropical infectious disease caused by the trematode Schistosoma ssp. that affects ∼240 million people in more than 74 different countries.^1,2 The socioeconomic implications stemming from schistosomiasis are significant and should not be disregarded, given its adverse effects on the productivity and education of young adults and school-age children, thereby hindering their overall growth and development. In 2019, according to the Global Burden of Disease Study,³ schistosomiasis resulted in the loss of 11,500 lives and caused 1.64 million disability-adjusted life years, concentrated predominantly in sub-Saharan Africa. Human infection occurs through contact with water (bathing, swimming, washing clothes) infested with larval forms (Cercariae) that develop in freshwater snails (Biomphalaria ssp. and Bulinus ssp.) and the intermediate hosts.^1,4 Approximately 5% to 10% of infected individuals develop the hepatosplenic form—hepatosplenic schistosomiasis (HSS), which is characterized by periportal fibrosis and noncirrhotic portal hypertension (PH).^5–7 Six different species of Schistosoma spp. can infect humans. However, HSS is caused most commonly by Schistosoma mansoni distributed in sub-Saharan Africa and Latin America, and Schistosoma japonicum in East Asia, mainly in China and the Philippines.¹ Praziquantel is the treatment of choice for schistosomiasis and has been shown to improve periportal fibrosis and splenomegaly, especially in young patients with early-grade fibrosis.^8,9 However, upper gastrointestinal bleeding (UGB) still occurs in ∼80% of patients with HSS as a result of sequelae of presinusoidal PH, leading to a mortality rate per episode of up to 29%.⁵ Given the serious nature of UGB in HSS, multiple approaches have been tested to prevent bleeding, such as β-blockers, variceal sclerotherapy or banding, esophagogastric devascularization with splenectomy, transjugular intrahepatic portosystemic shunt (TIPS) and splenorenal shunting.

Although β-blockers are the standard of care for upper variceal bleeding (UVB) and liver decompensation prophylaxis in patients with liver cirrhosis, specific data on schistosomiasis-related presinusoidal PH are scarce and still controversial. Although nonselective β-blockers (NSBBs) are classically used as primary and secondary prophylaxis of UVB in patients with HSS, evidence is largely extrapolated from cirrhosis, which has a completely different pathophysiology.^10,11 This review aims to provide a comprehensive summary of the existing evidence on the effectiveness of β-blockers in the clinical management of PH in HSS.

MATERIALS AND METHODS

This narrative review used certified databases such as PubMed, Scielo, LILACS, and Medline, and included original and review articles published between 1987 and 2022. Articles involving human and animal in vivo experiments; clinical trials; and cross-sectional, cohort, and case–control studies were included to summarize the existing evidence on the clinical management of HSS PH with β-blockers. No formal review protocol was registered. Search results were merged and duplicates removed before screening for relevance. To find these articles, a search was performed using English and Portuguese language descriptors, including “hepatosplenic schistosomiasis” (n = 576), “schistosomiasis” AND “variceal bleeding” (n = 218), “schistosomiasis” AND “propranolol” (n = 30), “schistosomiasis” AND “carvedilol” (n = 3), “schistosomiasis” AND “beta blocker” (n = 25), and “esquistossomose” AND “hemorragia digestiva alta” (n = 17). Studies were included if both full text and abstract were available. Two authors (F. A. G. and G. G. L. C.) reviewed titles and abstracts of publications retrieved by the search to identify those potentially eligible. In case of doubt, a third author (C. A. C) assessed the publication content to reach a unanimous decision. A search in PubMed yielded 852 articles, and additional reports were identified in the LILACS (n = 12) and Scielo (n = 7) databases. Sixty-two articles were fully screened after removal of irrelevant titles, abstracts, and duplicates. After individual review by two independent reviewers and resolution of discrepancies, nine articles were finally identified for inclusion in a qualitative synthesis.

RESULTS

Pharmacology of β-blockers.

There are three generations of β-blockers, classified according to their pharmacological properties. First-generation β-blockers are nonselective, blocking both β1- and β2-receptors; second-generation β-blockers exhibit greater cardioselectivity by preferentially targeting β1-receptors; and third-generation β-blockers are highly selective for β1-receptors.¹² Propranolol, the inaugural β-blocker used in clinical settings, belongs to the first generation and has high lipophilicity, allowing it to cross the blood–brain barrier. When administered orally, it demonstrates favorable absorption, but undergoes significant first-pass metabolism, with only 25% of the drug entering systemic circulation. Propranolol clearance depends on hepatic blood flow and is, consequently, influenced by hepatic physiological factors such as liver pathologies or concurrent administration of other drugs that affect hepatic biotransformation. Moreover, propranolol exhibits a relatively short half-life (3–6 hours).¹³ Metoprolol, a second-generation β- blocker, displays notable pharmacokinetic properties, including a high absorption rate, extensive first-pass metabolism, and an elimination half-life of 3 to 4 hours. Carvedilol, a third-generation NSBB, presents a high absorption rate, undergoes substantial first-pass biotransformation, and features an elimination half-life of 7 to 10 hours.¹³

Approximately six decades ago, β-blockers were introduced as a means of managing systemic hypertension.¹⁴ Although all β-blockers have antihypertensive properties, their pharmacokinetics and pharmacodynamics vary based on their molecular configuration. These agents can be categorized into water-soluble and lipid-soluble groups.^15,16 β-Adrenergic antagonists can be broadly classified into cardioselective agents with a particular affinity for β1-receptors in cardiac muscles and nonselective compounds such as propranolol or nadolol, which demonstrate similar affinities for both β1- and β2-receptors in splanchnic vessels. Inhibition of β1-receptors leads to reduced cardiac output, whereas inhibition of β2-receptors induces splanchnic vasoconstriction; both actions contribute to portal pressure (PP) reduction.^17–21 Nonselective β-blockers also affect β3-receptors, although minimally.²²

Several trials have studied the effects of NSBBs on PH, especially among patients with cirrhosis. In 1980, Lebrec et al.²³ conducted a controlled prospective trial demonstrating that propranolol administration, which reduced resting heart rate by 25%, could protect patients with liver cirrhosis from recurrent UGB. There is substantial literature available that provides in-depth analyses of the pharmacological effects of NSBBs in patients with cirrhosis and PH.¹¹ Despite this, it has been observed that not all patients exhibit a favorable response to such treatment options (50% with propranolol and 25% with carvedilol). This discrepancy warrants further investigation and exploration to acquire a better understanding and potential development of more effective therapies. Several studies have suggested that the benefits of NSBBs are mainly observed in hemodynamic responders, which are defined as patients with a significant reduction in their hepatic venous pressure gradient (HVPG) of more than 20% or with an HVPG < 12 mmHg.^24–29 These patients tend to have a better prognosis and a lower risk of developing complications related to PH, such as variceal bleeding or hepatic encephalopathy.²⁹

A more recent NSBB, carvedilol, offers the added advantage of blocking α1-adrenergic receptors, leading to a decrease in intrahepatic resistance and a further reduction in PP.¹⁹ Although these characteristics are not unique, they often necessitate unphysiologically high concentrations.³⁰ Carvedilol binding to β- and α1-adrenergic receptors occurs at similar affinities and within plasma concentration ranges.³¹ In healthy individuals, the administration of 12.5- and 25-mg doses on a daily basis yields plasma concentrations that fall within the range of 115 to 131 nmol. For patients with chronic renal insufficiency, the corresponding values are between 256 and 315 nmol.³² In addition, carvedilol exhibits a longer half-life and increased bioavailability in individuals with cirrhosis. However, its vasodilatory properties result in a more pronounced decrease in blood pressure, potentially limiting its use in certain patients, especially those with advanced decompensated cirrhosis, in whom an upregulated sympathetic nervous system helps to maintain arterial pressure.^33,34

Unlike the majority of other NSBBs, carvedilol demonstrates biased signaling, influencing both the G protein–dependent pathway and recruiting β-arrestin 2.³⁵ Biased signaling has been linked to cardioprotective effects. Nonetheless, the functional implications of carvedilol-induced biased signaling in patients with liver cirrhosis are yet to be elucidated.^36,37 β-arrestin 1 and 2 are proteins that modulate G protein–coupled receptor (GPCR) responses.³⁸ They attenuate G protein–mediated signaling by binding to phosphorylated GPCRs, partially through receptor endocytosis.³⁹ Researches are increasingly concentrating on the role of β-arrestin as a scaffold protein that initiates additional signaling pathways within a cell.^36,38,40 This phenomenon has been observed in the activation of the angiotensin II receptor and is likely relevant to other adrenergic receptors. Elevated β-arrestin signaling has been associated with profibrotic diseases, and, in liver cirrhosis, an upregulation of β-arrestin 2 has been detected in various tissues.^41,42 The functional consequences of β-arrestin signaling remain uncertain in cirrhosis, PH, splanchnic vascular cells, or cardiac function amid liver dysfunction.^43,44 Recently, a prospective Egyptian study⁴⁵ investigated the relationship between the expression of β-arrestin 2 and the response to NSBB therapy in patients with PH and varices. The authors found that greater serum levels and gastric antral expression of β-arrestin 2 were associated with improved outcomes, including longer bleeding-free intervals, a greater reduction in the portal vein congestion index, and improved grade of varices. Patients with a high expression of β-arrestin 2 were more likely to respond NSBB therapy than those with a low expression, and a serum β-arrestin 2 value ≥ 2.23 ng/mL was associated with a lower likelihood of variceal bleeding, with a sensitivity of 90% and a specificity of 71%.⁴⁵

In addition, the efficacy of NSBBs in the prevention of cirrhosis decompensation has been a topic of interest in scientific studies.^33,46 A controlled trial conducted by Groszman et al.⁴⁶ examined whether administering NSBBs during the early stages of liver cirrhosis could prevent the development of varices, bleeding, or ascites, and thus prevent further decompensation. Timolol, a β-blocker, was used in their study, which found no significant difference between the NSBB and placebo groups.⁴⁶ In 2019, a randomized, double-blind, placebo-controlled, multicenter trial³³ referred as PREDESCI carried out by Spanish working groups, focused on patients with an HVPG ≥ 10 mmHg, and used propranolol and carvedilol as NSBBs. The response to standardized intravenous propranolol was assessed during the inclusion process, and patients who did not demonstrate a decrease in their HVPG of ≥ 10% received carvedilol. The decrease in the HVPG from the baseline at 1 year was more pronounced with carvedilol (16%) than with propranolol (10%), although carvedilol was only administered to intravenous propranolol nonresponders. After a median follow-up of 37 months, the composite end point (death, ascites, bleeding, or overt encephalopathy) occurred less frequently in the NSBB group compared with the placebo group, primarily as a result of a reduction in ascites formation. Based on these findings, a new approach was suggested, including the use of NSBBs to prevent any type of decompensation, not just variceal hemorrhage for any patient with compensated cirrhosis and clinically significant PH.³³

The hemodynamic effect of β-blockers in patients without cirrhosis but with presinusoidal PH is much less studied. The Baveno VII Consensus⁴⁷ recommends the pragmatic use of β-blockers and band ligation as secondary prophylaxis for patients with prehepatic PH, although they acknowledge the absence of supporting evidence for this recommendation, especially in primary prophylaxis. In a prospective on- and off-treatment case series of 12 patients without cirrhosis but with presinusoidal PH, Sørensen et al.⁴⁸ showed that propranolol caused a clinically significant reduction in the pressure gradient from spleen pulp to the free hepatic vein from a mean off-treatment value of 32 mmHg to an on-treatment value of 26 mmHg (P < 0.05), with a reduction of at least 20% in 42% of the patients.

Brief overview of the pathophysiological basis for using β-blockers in cirrhosis and schistosomiasis.

Portal hypertension is a common and lethal complication shared by cirrhosis and HSS. It is defined as a pathological increase in PP, in which the portal pressure gradient (PPG)—the pressure gradient between the portal vein and the inferior vena cava—is more than the upper normal limit of 5 mmHg. Varices develop when the PPG increases to more than 10 mmHg, and variceal bleeding occurs when the value exceeds 12 mmHg.^49,50 The PPG is determined by the product of blood flow and vascular resistance within the portal system. Portal hypertension is initiated by an increased resistance to portal blood flow and is aggravated by an increased portal venous inflow. The site of increased resistance to portal blood flow is the basis for the classification of PH: prehepatic (schistosomiasis), intrahepatic (cirrhosis), and posthepatic (congestive heart failure).⁵⁰

Liver cirrhosis is one of the leading causes of death globally, with alcoholic and nonalcoholic fatty liver disease, and chronic hepatitis B or C infections as major causes.^51,52 Cirrhosis is established by the process of necrosis, sinusoidal fibrosis, regenerative nodules involving the entire parenchyma that promote subversion of liver architecture, and PH. Mortality is mainly related to complications of PH, systemic inflammation, and progression of liver failure. Ascites, hepatic encephalopathy, and UGB are frequent causes of hospitalization and death.^10,53 The augmentation of intrahepatic resistance arises as a result of a combination of structural modifications (accounting for ∼70% of the increased resistance) in the hepatic sinusoids and functional vasoconstriction within the intrahepatic circulation that results from a reduced production of vasodilators, such as nitric oxide, and an increased release of vasoconstrictors, such as endothelins. In addition, splanchnic arterial vasodilation is a core factor in the progression and worsening of PH, leading to a decrease in mean arterial pressure and a decrease in effective arterial blood volume, which activates neurohumoral systems, promotes sodium and water retention, and increases cardiac output—a hyperdynamic circulatory state that increases PP further and leads to clinically significant PH.^20,49

Unlike cirrhosis, the main lesion in HSS is fibrosis around portal vessels of the liver (periportal fibrosis) without bridging, nodular formation, or significant hepatocellular destruction, known as Symmers’ pipestem fibrosis.^20,54 The fibrosis results from granulomatous inflammation around eggs embolized to presinusoidal periportal spaces of the liver that occur in the early stages of the chronic phase of the disease. Prolonged inflammation, along with periportal collagen deposition and fibrosis, causes gradual blockage of the portal vein’s terminal branches, ultimately leading to the development of PH, splenomegaly, collateral venous circulation, portocaval shunting, and gastroesophageal varices, which are typical features of the clinical presentation of HSS. Therefore, liver failure is not typically present in patients with this condition, unless there is an additional underlying cause of liver disease or a complication such as portal vein thrombosis.⁵⁵ A hyperkinetic circulation, characterized by high cardiac outflow and low peripheral resistance, is usually observed, but with a normal cardiac rate and mean arterial pressure. With regard to hepatic hemodynamics, transhepatic measurements show very high PP, whereas free and wedged venous pressures are typically normal. Portal flow remains within the normal range, despite extremely high splenic flow and lower than normal mesenteric flow. Azygos blood flow is also high, but it is not as elevated as the values found in cirrhosis.⁵⁶ Last, patients with HSS exhibit a greater than normal hepatic perfusion index, as determined by angioscintigraphy using colloidal sulfur, indicating they have increased hepatic artery perfusion, which can change circulatory dynamics (liver “arterialization”).⁵⁷

β-Blockers in schistosomiasis-related PH.

Nonselective beta blockers are widely recognized as effective in preventing variceal bleeding in patients with cirrhosis, both for primary and secondary prevention.^10,16 However, data regarding the impact of NSBB therapy on the management of UVB in HSS are limited.^18,58–62 Propranolol is the most commonly used nonselective β-adrenergic blocker to treat PH in HSS. Blocking β1-adrenergic receptors and causing splanchnic arterial vasoconstriction through a β2-adrenergic blockade result in a decrease in portal flow and pressure. On the other hand, carvedilol, besides being a much more potent NSBB, has an additional intrinsic anti-α1-adrenergic effect that causes intrahepatic vasodilatation and decreases PP further in patients with cirrhosis—an effect that is not anticipated in HSS as a result of presinusoidal obstruction.

In animal models, propranolol has decreased the development of portal–systemic shunting by reducing the flow and pressure in the portal system by 38%.⁶³ Furthermore, a striking regression of gastrovascular and microvascular changes has been observed in a chronic murine schistosomiasis mansoni model after propranolol therapy.⁶⁴ Few studies have addressed β-blockers in human HSS (Table 1⁶⁵). Bioavailability of propranolol in human patients with HSS was initially measured by a Sudanese group in 1987.⁶⁶ Blood concentrations of propranolol in patients with HSS were nearly 3-fold greater than in control subjects after a single oral dose, possibly as a result of reduced presystemic extraction, whereas the time of maximum blood concentration was not significantly different.⁶⁶ In 1988, Mies et al.⁶⁷ investigated the effect of propranolol on patients with a history of UGB related to HSS. Their study included 94 participants who were assigned randomly to receive either propranolol or a placebo in a controlled trial. Of the 94 participants, 42 received propranolol doses compatible with a 25% reduction in heart frequency; 52 subjects did not receive the medication. The duration of medication use varied and corresponded to approximately 30 days. Propranolol reduced UVB recurrence significantly from 17.3% to 2.4%.⁶⁷ In 1997, the same group of authors showed that the administration of propranolol corrects hyperdynamic circulation, does not alter PP, and reduces sectorial portal blood flows, especially of the azygos vein, with maintenance of total hepatic blood flow.⁶⁸

Table 1.

Summary of studies investigating the use of beta blockers for the clinical management of hepatosplenic schistosomiasis

Author, year, country	Type of prophylaxis	Study design and no. of subjects	Inclusion criteria	Intervention	Follow-up	End point	Notes/other
Farias et al.,58 2009, Brazil	Primary	C, n = 13	High-risk EV at endoscopy	Propranolol: mean dose, 105.38 mg; reduction in heart rate by 20%	N/S (until effect reached)	Reduction in variceal pressure (35.7% ± 18.4%, P < 0.0001)* and wall tension (35.9% ± 26.7%, P = 0.9993)†	Limitation: lack of placebo arm
Kong,60 2013, China	Primary	RCT, n = 48	Schistosome eggs in stool specimens, ultrasound criteria for HSS, and endoscopic evidence of EVs	Propranolol (n = 20) vs. propranolol + isosorbide (n = 20)	6 months	Reduction in variceal pressure (both groups) along with percentage decrease in variceal pressure significant after propranolol + isosorbide compared with propranolol alone (15.93% ± 8.37% vs. 6.05% ± 3.67%)*	Limitation: lack of placebo arm; no difference in variceal bleeding and mortality
el Tourabi et al.,61 1994, Sudan	Secondary	RCT, n = 82	Endoscopically proven varices and ultrasound-confirmed hepatic fibrosis secondary to schistosomiasis	Propranolol, 80–160 mg (n = 42) vs. placebo (n = 40); reduction in the heart rate by 13% both supine and standing	24 months	Reduction in incidence of rebleeding (median time to rebleeding, 589 days for propranolol vs. 252 days for placebo; P < 0.02) and mortality using propranolol (three deaths vs. seven deaths in placebo; P < 0.02)*	Positive indicator: large portal vein diameter; negative outcome indicatory, small liver size; limitation: withdrawal of 15 patients from the propranolol group and 18 from the placebo group
Dowidar et al.,65 2005, Egypt	Secondary	RCT, n = 40	Bleeding EVs	Variceal sclerotherapy (n = 20) vs. sclerotherapy + propranolol 40 mg three times a day until variceal eradication (n = 20)	24 months	Fewer injection sessions for variceal eradication were required in propranolol + sclerotherapy group (8 vs. 11: P > 0.05); sclerotherapy associated with propranolol had more variceal recurrences than the group undergoing injection sclerotherapy alone (25% vs. 13.3%, P > 0.05); 5 of 20 patients undergoing sclerotherapy + propranolol experienced rebleeding compared with 6 of 20 patients undergoing injection sclerotherapy only (P > 0.05); the probability of rebleeding and survival was similar in both groups (P > 0.05)†	Limitation: reduced number of sessions until varices eradication and of varices recurrences
Sinkala et al.,59 2020, Zambia	Primary and secondary	C, n = 66	Hematemesis and/or splenomegaly, varices on endoscopy, periportal fibrosis on ultrasound, positive serology for schistosomiasis, and older than 18 years	Propranolol at a dosage to reduce heart rate to < 60 beats/min (n = 66)	6 months	Reduction in portal vein diameter from a median of 12 mm to a median of 10 mm (P < 0.001)*	–
de Abreu et al.,62 2022, Brazil	Secondary	C, n = 57	Previous UGB episode treated subsequently with NSBBs (carvedilol or propranolol) as well as endoscopic band ligation	Propranolol: median, 80 mg (n = 43) vs. carvedilol: maximum, 12.5 mg (n = 14)	12 months	Bleeding recurrence with propranolol (20.9%) vs. carvedilol (28.6%)†	Retrospective study with results suggesting carvedilol may be equally effective as propranolol in preventing secondary UGB in HSS
Razafindrazoto et al.,18 2022, Australia	Secondary	RCT, n = 61	Patients with PH resulting from HSS with at least one episode of variceal bleeding	Propranolol: median, 80–160 mg (n = 30) vs. carvedilol, 12.5–25 mg (n = 31)	14 months	Difference in hemorrhagic recurrence between carvedilol (3.33%) and propranolol (10%, P = 0.30)†	Carvedilol a possible alternative to propranolol for secondary prophylaxis of variceal rebleeding in HSS

C = cohort study; EVs = esophageal varices; HSS = hepatosplenic schistosomiasis; N/S = not specified; NSBB = nonselective beta blockers; PH = portal hypertension; RCT = randomized clinical trial; UGB = upper gastrointestinal bleeding.

^*Statistically significant.

^†Not significant.

Later, el Tourabi et al.⁶¹ conducted a randomized clinical trial comparing placebo versus propranolol at a dose of 80 to 160 mg/d to obtain a heart rate reduction of 14%. The study included 42 patients in the propranolol group and 40 patients in the control group. After a follow-up of 24 months, there was a significant reduction in the incidence of rebleeding (20% to 2.4%) and mortality (17.5% to 7%). In 2005, Dowidar et al.⁶⁵ found an indirect benefit of adding propranolol to sclerotherapy for preventing variceal rebleeding. In a single-blinded randomized controlled trial, 40 consecutive patients with UGB underwent either injection sclerotherapy or injection sclerotherapy with an adjuvant fixed daily dose of 40 mg propranolol. Although not statistically different, the group that received the combination therapy required fewer injection sessions for variceal eradication after a follow-up of 2 years (8 versus 11; P > 0.05). However, patients who underwent injection sclerotherapy with adjuvant propranolol experienced more variceal recurrences than those undergoing injection sclerotherapy alone (25% versus 13.3%; P > 0.05).⁶⁵ Sinkala et al.⁵⁹ conducted a prospective observational study of patients with HSS as an extension of a 42-day rifaximin clinical trial to test the hypothesis that rifaximin could reduce markers of bacterial translocation in HSS. Forty-four patients received rifaximin and propranolol; 41 received propranolol only. The propranolol dosage was initially 40 mg three times daily, titrated upward, aiming for a resting radial pulse of less than 60 beats/min. All patients also received praziquantel, 40 mg/kg body weight. The diameter of the portal vein evaluated by ultrasound reduced significantly from a median of 12 mm to 10 mm after a follow-up of 180 days, suggesting a benefit of propranolol treatment. The median baseline hemoglobin levels of 8 g/dL improved significantly to 12 g/dL (P < 0.001), although there was no significant change in the size of the spleen.⁵⁹

Recently, the use of NSBBs for primary prophylaxis of UGB in patients with high-risk esophageal varices resulting from HSS has been investigated. Farias et al.⁵⁸ reported a reduction in variceal pressure and wall tension of 35.7 ± 18.4% and 35.9 ± 26.7%, respectively, compared with baseline values using Varipress system (Labotron, Barcelona) measurements in a cohort of 13 patients with HSS with large varices with red signs at endoscopy or fundal varices. They showed that a mean dose of 60 to 120 mg/d, titrated to reduce pulse frequency by 20%, was sufficient to achieve this effect, which is in contrast to the findings of Mies et al.,⁶⁸ where extremely high doses of propranolol were required to achieve clinical targets. In a randomized controlled trial,⁶⁰ the role of propranolol or propranolol + isosorbide-5-mononitrate (ISMN) in preventing first UGB was assessed in 40 patients with HHS. The dose was adjusted until the resting heart frequency reduced by 25% or was less than 55 beats/min. The ISMN dosage was increased up to 20 mg orally twice a day. Variceal pressure was measured by the balloon technique. A significant reduction in variceal pressure was observed in both groups after a follow-up of 6 months (P<0.001), but no difference between groups was found.⁶⁰

Studies addressing carvedilol, an NSBB with additional anti-α-adrenergic activity (two to four times more potent than propranolol), have also been published. de Abreu et al.⁶² conducted a retrospective exploratory study of 57 patients with HSS and UGB treated with endoscopy variceal ligation and either propranolol (median dose, 80 mg) or carvedilol (median dose, 12.5 mg). Forty-three patients received propranolol as secondary prophylaxis; 14 received carvedilol. After a follow-up of 12 months, rebleeding was not significantly different between groups (20.9% in patients receiving propranolol and 28.6% in patients receiving carvedilol).⁶² Razafindrazoto et al.¹⁸ conducted a prospective randomized study for 14 months in which patients with HSS with previous UGB were divided into two groups, receiving either carvedilol (n = 31) or propranolol (n = 30). Again, no significant difference in hemorrhagic recurrence between groups was observed (3.33% versus 10%, P = 0.3). The two groups did not show any meaningful distinction regarding adverse effects and the medications were well tolerated.¹⁸

CONCLUSION

In summary, β-blockers seem to be beneficial in HSS by reducing PH and preventing variceal bleeding, which can improve patient outcomes and quality of life. Propranolol has been shown to be effective in primary and secondary prophylaxis of UVB, whereas carvedilol was studied only in secondary prevention. Although cirrhosis and HSS may present with PH, the underlying causes and mechanisms of the hypertension are different, and the treatments must be tailored accordingly. There is an unmet need for well-designed randomized controlled trials with larger sample sizes to confirm the effectiveness and optimal dose of β-blockers in reducing PH and preventing variceal bleeding in HSS.

Financial Disclosure

We acknowledge the financial support of the Pró-Reitoria de Pesquisa da Universidade Federal de Minas Gerais.