Table 1.
The effect of NSBBs on cirrhotic patients, beyond the primary and secondary prophylaxis of variceal bleeding.
| Authors/Year/Ref | Study | Effect of NSBBs | Results |
|---|---|---|---|
| Preprimary prophylaxis of variceal formation (HVPG < 10 mmHg) | |||
| Groszmann RZ, et al. (2005) [9] |
RCT | Negative | Timolol vs. placebo in patients without varices Median follow-up 4.5 years No significant difference in variceal formation |
| Prevention of small varices enlargement (HVPG > 10 but <12 mmHg) | |||
| Cales P, et al. (1999) [10] |
RCT | Negative | Propranolol vs. placebo in patients with small varices 2-year follow-up period Propranolol did not prevent variceal enlargement |
| Sharin SK, et al. (2013) [11] |
RCT | Negative | Propranolol vs. placebo in patients with small varices 2-year risk of variceal growth: 11% in the propranolol vs. 16% in the placebo group (p = 0.786). Variceal bleeding and mortality were comparable between the two groups. |
| Qi X-S, et al. (2015) [12] |
Meta-analysis | Negative | 6 studies and 784 patients with no or, small varices. No benefit from the NSBBs, regarding the deceleration of variceal enlargement |
| Merkel C, et al. (2004) [13] |
RCT | Positive | Nadolol vs. placebo 60-month follow-up period Lower risk of variceal growth in the nadolol compared to the placebo group, (20% vs. 51%; p < 0.001) |
| Bhardwaj A, et al. (2017) [14] |
RCT | Positive | Carvedilol vs. placebo The carvedilol group had an 18% higher probability of not developing large varices. The mean time of non-progression to large varices: 20.8 months in the carvedilol vs. 18.7 months in the placebo. |
| Prevention from liver decompensation; Effect on survival of decompensated patients | |||
| Villanueva C, et al. (2019) [16] |
RCT | Positive | NSBBs vs. placebo Significantly lower decompensating events in NSBBs, compared to the placebo (17% vs. 27%; HR 0.51, 95% CI 0.26–0.97, p = 0.041). Ascites development: 9% in NSBBs vs. 20% in the placebo (HR 0.42, 95% CI 0.19–0.92, p = 0.03). 46% lower probability of death in NSBBs (HR 0.54, 95% CI 0.20–1.48). |
| Sersté T, et al. (2010) [17] |
Observational Not RCT |
Negative | Median survival time: 20 months in non-treated vs. 5 months in propranolol-treated pts (p = 0.0001). 1-year probability of survival: 19% in NSBBs treated vs. 64% in untreated patients (p < 0.0001). |
| Bang UC, et al. (2016) [18] |
Retrospective | Positive (Only in low doses) |
Lower mortality rates in patients with mild decompensated cirrhosis treated with propranolol (HR:0.7; 95% CI: 0.6–0.9). Lower mortality rates in patients with severe decompensated cirrhosis, treated with propranolol (HR:0.6; 95% CI: 0.4–0.9). Reduced mortality, only in doses < 160 mg/day |
| Gianelli V, et al. (2020) [21] |
Retrospective | Negative | Increased waiting list mortality in NSBBs treated, in the co-existence of cardiac dysfunction (HR 1.96; 95% CI: 1.32–2.90; p = 0.0009) |
| Koshy AN, et al. (2020) [22] |
Retrospective | Negative | MACE in the 30-day post-transplantation period: 32.4% in NSBBs vs. 17.2% in controls, p = 0.005. NSBBs were independently associated with MACE (OR 2.44; 95% CI: 1.13–5.78) |
| Leithead JA, et al. (2015) [26] |
Retrospective | Positive | Patients with ascites awaiting liver transplantation Median time to death: 150 days in NSBBs vs. 54 days in controls. Reduced mortality in NSBBs patients vs. propensity-matched non-NSBBs patients (HR 0.55; 95% CI: 0.32–0.95, p = 0.032), In refractory ascites: NSBBs were independently associated with fewer waitlist deaths (adj HR 0.35; 95% CI: 0.14–0.86, p = 0.022) |
| Ngwa T, et al. (2020) [27] |
Observational Not RCT |
Positive for mortality Negative for AKI |
90-day post-transplantation mortality: 6% in NSBBs vs. 15% in non-NSBBs patients; HR 0.27, 95% CI: 0.09–0.88, p = 0.03). More AKI in NSBBs (22% vs. 11%, p = 0.048). |
| Sinha R, et al. (2017) [28] |
Retrospective | Positive only for patients with mild ascites | Patients with ascites followed for a median time of 2.3 years, Survival: 24% in the carvedilol vs. 2% in the non-carvedilol group (log-rank p < 0.0001). A 53% lower risk of death in patients with mild ascites treated with carvedilol. No differences in moderate or, severe ascites |
| Tergast TL, et al. (2019) [29] |
Retrospective | Positive only for hemodynamically competent patients | NSBBs or carvedilol vs. non-treated patients Carvedilol and NSBBs increased the survival, but only in cases of MAP > 82 mmHg |
| Effect on patients’ survival in cases of further decompensation (development of SBP, AKI or, ACLF) | |||
| Mandorfer M, et al. (2014) [31] |
Retrospective | Negative | Patients in NSBBs had a worse outcome than the non-treated patients. NSBBs were associated with HRS, AKI, and decreased transplant-free survival. |
| Lutz P, et al. (2015) [33] |
Retrospective | Positive | In 55 patients with SBP 30-day post-episode survival: 76% in NSBBs and 41% in non-NSBBs patients (p = 0.049) |
| Kalambokis GN, et al. (2016) [35] |
Retrospective | Negative | HRS more frequently developed in the Child-Pugh C, treated with NSBBs patients than in the untreated patients (In 12 months: 36% vs. 0%; p = 0.01) |
| Kim SG, et al. (2017) [36] |
Nested case-control study | Negative | AKI: More frequently in ascites (79% vs. 51.7%) and NSBBs use (45.9% vs. 37.1%; p = 0.08) AKI was dependent on the presence of ascites (NSBBs plus ascites: HR 3.31; 95% CI: 1.57–6.95) In patients without ascites, the NSBBs reduced the AKI risk (NSBBs without ascites: HR 0.19; 95% CI: 0.06–0.60) |
| Sasso R, et al. (2021) [37] |
Retrospective | Positive for HRS Negative for cardiorenal AKI |
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). |
| Mookerjee RP, et al. (2016) [39] |
Observational | Positive | Sub-analysis of the CANONIC study, with 349 hospitalized ACLF patients Abetter 28-day survival in treated, compared to untreated with NSBBs patients |
| Tergast TL, et al. (2019) [29] |
Retrospective | Positive only for hemodynamically competent patients | 624 consecutive patients with decompensated cirrhosis and ascites. The NSBBs improved the survival in patients with ACLF (HR: 0.578; p = 0.031), only when MAP was >82 mmHg |
| Kumar M, et al. (2019) [40] |
RCT | Positive | Carvedilol presented lower 28-day mortality and lower rates of AKI and SBP vs. the placebo. After 2 weeks of treatment: An aggravation of ACLF grading in 22.9% of the controls vs. 6.1% of the carvedilol patients (p = 0.007) |
| Tittanegro T, et al. (2023) [41] |
RCT | Neither positive nor negative | No a beneficial impact on the mortality at 28 days, 3, and 6 months from the use of NSBBs |
RCT: Randomized controlled trial; NSBBs; Non-selective b-blockers; HR: Hazard ratio; CI: Confidence interval; OR Odds ratio; MACE: Major adverse cardiac events; AKI: Acute kidney injury; MAP: Mean arterial pressure; HRS: Hepatorenal syndrome; SBP: Spontaneous bacterial peritonitis; ACLF: Acute on chronic liver failure.