Esophageal varices are present in almost 60% of cirrhotic patients at the time of diagnosis ^[1][6]. HVPG ≥10 mmHg is necessary for the development of varices, while the risk of variceal bleeding exists in values of ≥12 mmHg. Variceal bleeding is one of the most serious complications of liver cirrhosis, with an estimated mortality of around 15% [2]. As variceal bleeding mostly depends on variceal size, it is important to avoid variceal enlargement and even better to prevent variceal formation. Although NSBBs are the standard treatment for the prevention of first variceal bleeding, they have failed to impede the development of varices in cirrhotic patients ^[3][9]. Interestingly, Groszmann et al. ^[3][9]. in a randomized, controlled trial (RCT) of 213 cirrhotics with PH but no varices at baseline showed no significant difference in the development of varices between the timolol and placebo groups after a median follow-up of 4.5 years. Furthermore, the two groups had not significantly different rates of liver-related complications ^[3][9]. Regarding the role of NSBBs in inhibiting the enlargement of small varices, an RCT of 206 patients in which 102 were assigned to propranolol and 104 to a placebo showed that 31% of the former and 14% of the latter group had developed large varices after a 2-year follow-up period. However, the limitation of the study was the large number of lost patients during follow-up ^[4][10]. In accordance with the previous findings, Sharin et al. ^[5][11] confirmed in 2013 the inability of NSBBs to prevent variceal growth ^[5][11]. Likewise, a meta-analysis of 6 studies and 784 patients with no or small varices did not demonstrate a significant difference between the NSBBs- and the placebo-treated groups in the degree of small varices’ enlargement. ^[6][12]. In contrast, an RCT by Merkel et al. ^[7][13] including 161 cirrhotic patients with small esophageal varices found a significantly lower cumulative risk of variceal growth in the nadolol group compared to the placebo group (20% vs. 51%; p < 0.001) during a 60-month follow-up period ^[7][13]. Additionally, another study favored carvedilol over the placebo in delaying the progression of small varices, as patients in the carvedilol group were found to have an 18% higher probability of not developing large varices while the progression of small to large varices occurred after 20.8 months in the carvedilol group and 18.7 months in the placebo group, respectively ^[8][14].

Obviously, a discrepancy exists regarding the role of NSBBs in delaying the enlargement of small varices. It is well known that NSBBs reduce the heart rate and the cardiac output by blocking the b1-adrenergic receptors, while they also promote splanchnic vasoconstriction via a b2-adrenergic blockage. These mechanisms result in a reduced portal inflow and, thus, in a decreased portal pressure ^[9][15]. However, as previously mentioned, splanchnic vasodilation occurs in the later phases of PH, when the HVPG is ≥10 mmHg and varices have been already developed. Consequently, treatment with NSBBs in this phase could deteriorate the splanchnic vasodilation, reduce the PH, and prevent variceal growth and bleeding. However, in the initial phases of PH, when HVPG is <10 mmHg and varices are absent or HVPG is close to 10 mmHg and varices have likely developed but are still small, treatment with NSBBs would be ineffective as splanchnic vasodilation has not been activated yet and the PH exclusively depends on intra-hepatic portal obstruction and vasoconstriction. Of note, carvedilol, with its additional vasodilating action via the a1 receptors blockage, could potentially play a role in the initial phases of PH by attenuating the intra-hepatic portal vasoconstriction. Further RCTs are necessary to clarify whether the use of carvedilol in the early stages could effectively delay the development or the progression of varices.

The PREDESCI, a multicenter double-blind RCT, investigated the long-term effect of NSBBs in compensated cirrhotic patients with CSPH without or with small varices. All patients had HVPG measurements and were randomly assigned to be treated with a placebo (101 pts) or b-blockers (100 pts, 67 with propranolol and 33 with carvedilol). The median follow-up period was 37 months, and the primary study end-point was the occurrence of clinical decompensation. The study showed significantly lower decompensating events in the NSBBs arm compared to the placebo arm, (17% vs. 27%, respectively; p = 0.041). The most frequent decompensating event was ascites, which presented less frequently in the NSBBs-treated group (9%) compared to the placebo-treated patients (20%) (HR 0.42, 95% CI 0.19–0.92, p = 0.03). Concerning secondary end-points, the NSBBs arm had a 40% lower probability of developing large varices (HR 0.60, 95% CI 0.30–1.21) and a 46% lower probability of death (HR 0.54, 95% CI 0.20–1.48) ^[10][16]. Based on the above results, the last Baveno VII group recommended the use of carvedilol in compensated cirrhotic patients with CSPH for the prevention of decompensation ^[11][7]. It is questionable whether treatment with NSBBs or carvedilol would have good results in compensated cirrhotic patients without CSPH (HVPG < 10 mmHg) as well. Furthermore, it has to be clarified whether non-invasive methods such as liver or spleen elastography could sufficiently substitute HVPG in detecting patients with CSPH, as they have been found incapable of discriminating a significant proportion of patients ^[11][7].

Sersté et al. ^[12][17] conducted a study in 2010 that raised concerns about the potential deleterious effect of NSBBs in advanced decompensated cirrhotic patients. Specifically, the authors demonstrated that patients with refractory ascites under treatment with propranolol had worse survival compared to untreated patients (5 vs. 20 months, respectively; p = 0.0001). Furthermore, the 1-year survival was significantly worse in the propranolol compared to the placebo arm (19% vs. 64%, p < 0.0001), while treatment with propranolol was found to be independently associated with poor outcomes in the multivariate analysis. However, as it was observational and not an RCT study, the two groups had no comparative characteristics. Precisely, the propranolol group had more severe underlying liver disease, as defined by a higher Child–Pugh score and a worse biochemical profile. Moreover, the majority of patients in the propranolol group had been treated with unusually high doses of propranolol (≥160 mg per day), which are rarely given in routine clinical practice ^[12][17]. The importance of propranolol dose was identified by Bang et al. ^[13][18] in a retrospective study with 3719 enrolled patients (3075 with mild and 644 with severe decompensated cirrhosis). The authors reported that patients with mild decompensated cirrhosis treated with propranolol had lower mortality rates compared to the untreated patients (HR: 0.7; 95% CI: 0.6–0.9). Likewise, the mortality was lower in patients treated with propranolol and severely decompensated cirrhosis than in non-treated decompensated patients (HR: 0.6; 95% CI: 0.4–0.9). However, lower mortality was found only when the propranolol dose was lower than 160 mg/day ^[13][18]. The potential negative effect of high NSBB doses in advanced decompensated cirrhosis has been attributed to the reduction in blood pressure and cardiac output (via a reduction in heart rate), leading to circulatory incompetence. In the presence of a pre-existed cardiac dysfunction, the risk likely increases. Cirrhosis is often associated with a blunted cardiac function, an entity known as “cirrhotic cardiomyopathy” (CCM), which is characterized by diastolic impairment, reduced systolic reserves during stress, and electrocardiographic alterations, all in the absence of other known causes of cardiac dysfunction ^[14][19]. CCM has been found to negatively affect patients’ prognosis ^[15][20]. Therefore, an evaluation of cardiac function could be justified before receiving NSBBs, particularly in advanced decompensated states ^[15][20]. The interaction between NSBBs and CCM was recently assessed by Giannelli et al. ^[16][21] in a retrospective study of 584 pre-transplanted patients. According to that study, refractory ascites (HR 1.52; 95% CI: 1.01–2.28; p = 0.0083) and treatment with NSBBs in the co-existence of cardiac dysfunction (HR 1.96; 95% CI: 1.32–2.90; p = 0.0009) were associated with an increased waiting list mortality after adjusting for serum sodium and model for end-stage liver disease (MELD) scores ^[16][21]. Later on, Koshy et al. ^[17][22], in a retrospective study of 319 consecutive patients, investigated whether NSBBs could precipitate the development of major adverse cardiac events (MACE) in a 30-day post-transplantation period. Interestingly, a significantly higher proportion of patients in the NSBBs developed perioperative MACE (32.4% vs. 17.2%, p = 0.005). After adjusting for clinical and echocardiographic covariates, NSBBs remained an independent predictor of MACE (OR 2.44; 95% CI: 1.13–5.78), along with pulmonary hypertension, poor functional status, and hepatorenal syndrome ^[17][22].

In addition to these previous studies, there are many others that have investigated the effect of NSBBs on the prognosis of patients with decompensated cirrhosis, and the majority of them favored the use of NSBBs ^[18][19][20][23,24,25]. Similarly, in patients with decompensated cirrhosis, Leithead et al. ^[21][26] demonstrated a longer median time to death in the NSBBs compared to the non-NSBBs group (150 vs. 54 days, respectively). Moreover, in the multivariate Cox analysis, patients in the NSBBs group had a decreased mortality compared to the propensity-matched non-NSBBs patients (HR 0.55; 95% CI: 0.32–0.95, p = 0.032), whereas in cases of refractory ascites, NSBBs were found to be associated with lower mortality (adj HR 0.35; p = 0.022) ^[21][26]. Subsequently, Ngwa, et al. ^[22][27] assessed the role of NSBBs in 90-day post-transplantation prognosis and found a lower 90-day mortality in NSBBs patients (6% vs. 15%; HR 0.27, 95% CI: 0.09–0.88, p = 0.03), though these patients had more advanced MELD scores and Child–Pugh scores. However, NSBB use was related to a higher probability of acute kidney injury (AKI) within 90 days (22% vs. 11%, p = 0.048). Moreover, 12 of 45 patients (27%) discontinued NSBBs during the follow-up period due to severe hypotension and AKI ^[22][27].

Considering a whole number of studies, universal use of NSBBs in advanced decompensated cirrhotic patients, irrespective of cardiac and hemodynamic reserves, cannot be recommended. Nonetheless, in selected cases, with competent cardiac and hemodynamic function, NSBBs in low or moderate doses could potentially improve the outcome.

In a retrospective study of 607 patients treated with paracentesis for ascites, Mandorfer et al. ^[23][31] first identified worse outcomes in patients with SBP taking NSBBs. Specifically, they had significantly more episodes of hepatorenal syndrome (HRS) and AKI and decreased transplant-free survival compared to patients not treated with NSBBs. However, more patients with Child–Pugh stage C and lower arterial blood pressure had been enrolled in the NSBBs group, featuring, once again, the significance of the hemodynamic parameters in advanced decompensated individuals ^[23][31]. Bacterial endotoxin has been associated with more severe left diastolic cardiac dysfunction ^[24][32] and, consequently, with an increased risk of hemodynamic incompetence. Thus, SBP in patients with low blood pressure and limited hemodynamic consistency predisposes them to the development of HRS and negatively impacts their prognosis. In contrast, in a population of 55 patients with SBP, Lutz et al. ^[25][33] found a 30-day post-episode survival of 76% and 41%, respectively, between NSBBs-treated and untreated patients (p = 0.049). In addition, during SBP, NSBBs patients had significantly higher fractions of mononuclear cells in ascitic fluid compared to non-NSBB patients (31% vs. 19%, p = 0.036), as well as lower IL-8 ascitic concentrations (470 pg/mL vs. 1289 pg/mL, respectively, p = 0.29). The authors inferred that NSBBs may attenuate the stimulation of IL-8, leading to more balanced intra-peritoneal inflammation ^[25][33]. Similarly, in a subsequent study of 361 patients, NSBBs were found to correlate with improved survival and a lower risk of SBP ^[13][18]. The above results are in agreement with those published in 2009 by Senzolo et al. ^[26][34] who showed lower SBP rates due to the ability of NSBBs to enhance bowel motility and reduce intestinal permeability ^[26][34].

Apart from the aforementioned study of Mandorfer et al. ^[23][31], which showed an increased risk of HRS and AKI in advanced cirrhotics treated with NSBBs in the setting of SBP, some other studies reported an increased risk of renal injury in patients taking NSBBs, even in the absence of any infection. Hence, Kalambokis et al. ^[27][35] found HRS more frequently in Child–Pugh C subjects treated with NSBBs than in untreated subjects (HRS in 12 months of follow-up: 36% vs. 0%, respectively; p = 0.01) ^[27][35]. Similarly, in a cohort of 2361 patients waiting for liver transplantation, those who developed AKI (205 pts; median follow-up period: 18.2 months) had ascites more frequently, (79% vs. 51.7%) and more frequent use of NSBBs (45.9% vs. 37.1%; p = 0.08) compared to those who had not. Interestingly, NSBBs predisposed them to AKI development when ascites was present (NSBBs plus ascites: HR 3.31; 95% CI: 1.57–6.95), whereas in patients without ascites, the use of NSBBs reduced the risk of AKI (NSBBs without ascites: HR 0.19; 95% CI: 0.06–0.60) ^[28][36]. Consequently, the risk from NSBBs is higher in patients with more severe liver disease and more aggravated PH, splanchnic vasodilation, and hyperdynamic circulation. On the other hand, Sasso et al. ^[29][37] recently provided results from a retrospective analysis of 529 cirrhotic patients admitted to hospital with AKI between 2015 and 2018. Two hundred and seven patients had been treated with NSBBs and 322 had not. The patients’ characteristics did not differ regarding the MELD score, age, serum sodium, bilirubin, INR, creatinine, blood pressure, history of ascites, or hepatic encephalopathy. However, the former group had a significantly lower platelet count. Patients with NSBBs had less frequent HRS compared to those without (6.3% vs. 12%, p < 0.05), but they had pre-renal and cardiorenal AKI more frequently (74.4% vs. 61.5%, respectively p < 0.05). Furthermore, patients in NSBBs were less likely to develop SBP or die ^[29][37].

Acute on-chronic-liver failure (ACLF) is an excessive inflammatory condition acutely present in patients with an already established liver disease. Acute alcoholic hepatitis, infections, reactivation of chronic hepatitis B, and variceal bleeding are the most common precipitating factors ^[30][38]. Patients with ACLF present circulatory incompetence due to extensive vasodilation and poly-organic dysfunction. Regarding NSBBs and their potentially hazardous effect in further deteriorating the hemodynamic status of patients, a sub-analysis of the CANONIC study with 349 hospitalized ACLF patients showed a better 28-day survival in treated- compared to untreated NSBB subjects. In addition, there was a significant difference in the ACLF severity between the two groups. Specifically, the prevalence of ACLF-1 was higher in patients receiving NSBBs, whereas the prevalence of more severe ACLF-2 and ACLF-3 was higher in patients not receiving NSBBs. Moreover, significantly more NSBB patients developed a 1-grade reduction in the ACLF classification (43.2% vs. 27.5%, p = 0.0032), while 1-grade worsening was significantly higher in patients not treated with NSBBs (18.1% vs. 10.1%, p = 0.0427). ^[31][39]. Subsequently, a study of 624 decompensated patients demonstrated that 28-day transplant-free survival was higher in patients treated with NSBBs in general (HR: 0.621; p = 0.035), but also in those treated with NSBBs having ACLF in particular (HR: 0.578; p = 0.031). Importantly, the survival benefits were markedly attenuated in patients with MAP ≤ 82 mmHg and completely lost in MAP < 65 mmHg. Of note, among patients with MAP ≥ 65 mmHg, NSBBs were consistently associated with improved transplant-free survival, regardless of ACLF presence (HR: 0.480, p = 0.034) ^[32][29]. Simultaneously, in 2019, another group investigated the role of carvedilol in patients with ACLF. One hundred and thirty-six ACLF patients with HPVG ≥ 12 mmHg were randomized to receive either carvedilol or a placebo. The carvedilol group presented a lower 28-day mortality and lower rates of AKI, SBP, and variceal growth compared to the placebo group (0.6% vs. 24.3%, p = 0.044; 3.6% vs. 35.7%, p = 0.012; 6.1% vs. 21.4%, p = 0.013; 11.1% vs. 32.6%, p = 0.021, respectively). Moreover, 2 weeks after the initiation of treatment, a further aggravation of ACLF grading in 22.9% of the controls and 6.1% of the carvedilol-treated patients (p = 0.007) was reported, but the benefit was lost at 90 days ^[33][40]. The beneficial effect of NSBBs on ACLF has been attributed to their pleiotropic actions, beyond the reduction in portal pressure. In a sub-analysis of the ATTIRE study (Albumin infusion to prevent infection in chronic liver failure), NSBB-treated patients and controls were investigated to find out whether the use of NSBBs was associated with higher hospitalization rates due to infection, more frequent nosocomial infections, higher rates of liver-related complications, or a worse prognosis. Using propensity matching, the two groups had been matched to account for differences in the severity of the disease. According to the results, no differences in renal or cardiovascular dysfunction during days 3–15 of hospitalization were found between the two groups, despite the higher serum creatinine of NSBB patients at baseline. Interestingly, the group of patients under treatment with NSBBs had a significantly lower infection rate and lower serum levels of inflammatory factors, but no significant differences were found between the two groups regarding the rate of nosocomial infections and 6-month mortality. Based on these findings, it could be hypothesized that NSBBs do not prevent nosocomial infections but might downregulate the inflammatory response, preventing ACLF development ^[34][41].