Current and future pharmacological therapies for managing cirrhosis and its complications

Table 1 Observational studies investigating the effects of non-selective beta-blockers in advanced cirrhosis

Study	Study type	Study population	Type of NSBB	Outcomes
Sersté et al[12]	Single-centre, prospective cohort study	Cirrhotic inpatients with refractory ascites (n = 151; mean MELD 18.8 ± 4.1; 69% diuretic-intractable, 31% diuretic-resistant), all treated with large-volume paracentesis + IV albumin Median follow-up: 8 mo (range 1-47)	Propranolol (40-160 mg per day)	Median survival was 5.0 mo (95% CI 3.5-6.5 mo) for patients on propranolol compared to 20.0 mo (95% CI 4.8-35.2 mo) for patients not on propranolol (P < 0.0001)
Sersté et al[13]	Single centre, retrospective cohort study	Cirrhotic inpatients with alcoholic hepatitis (n = 139; mean MELD score 27.3 ± 7.6; mean Maddrey score 71.0 ± 34.4), all treated with methylprednisolone	Propranolol (40-160 mg per day)	At 168-d follow-up: AKI incidence was 89.6% (95% CI 74.9%-95.9%) for patients on propranolol compared to 50.4% (95% CI 39.0%-60.7%) for patients not on propranolol (P < 0.0001) Transplant-free mortality was 56.8% (95% CI 41.3%-69.7%) in NSBB users compared to 46.7% (95% CI 35.0%-57.6%) in non-users (P = 0.25)
Mandorfer et al[14]	Single-centre retrospective observational study	Cirrhotic outpatients with ascites (n = 607; mean MELD 17.5 ± 10.6), all treated with large-volume paracentesis + IV albumin Follow-up: 660 person-years	Propranolol (20-120 mg per day); Carvedilol (6.25-25 mg per day)	In patients without SBP: NSBB use was associated with higher transplant-free survival (HR 0.75, 95% CI 0.581-0.968) and with reduced length of hospitalisation In patients with SBP: NSBB use was associated with reduced transplant free survival (HR 1.58, 95% CI 1.098-2.274), development of HRS (24% vs 11%, P = 0.03), and increased length of hospitalisation
Bang et al[15]	Multicentre, retrospective, propensity-adjusted, longitudinal study of Danish databases	Decompensated cirrhotic in- and outpatients (n = 702 propranolol-users matched to n = 702 non-users). Stratified into mild decompensation (1-4 previous paracenteses) and severe decompensation (> 4 paracenteses)	Propranolol (< 80 mg, 80-160 or > 160 mg per day)	At 2-year follow-up: Propranolol use was associated with lower mortality in patients with mildly decompensated cirrhosis (HR 0.7, 95% CI 0.6-0.9) and severely decompensated cirrhosis (HR 0.6, 95% CI 0.4-0.9). Survival benefit was only found for propranolol doses < 160 mg/d.
Kim et al[22]	Single-centre, retrospective, nested case-control study	Cirrhotic patients listed for liver transplantation who developed AKI (n = 205 patients with AKI matched to n = 205 patients without AKI) Median follow-up: 18.2 mo (range 1-198 mo)	Propranolol and nadolol (propranolol equivalent 40 mg per day, IQR 30.0–60.0 mg)	In patients with ascites: NSBB use was associated with an increased risk of AKI (HR 3.31, 95% CI 1.57-6.95) In patients without ascites: NSBB use was associated with a reduced risk of AKI (HR 0.19, 95% CI 0.06-0.60)
Bossen et al[23]	Post-hoc observational analysis of three multicentre RCTs (satavaptan vs placebo)	Cirrhotic patients with diuretic-responsive (n = 600) and refractory (n = 588) ascites (n = 559 NSBB users, n = 629 non-users)	Propranolol and carvedilol (doses not specified)	At 52-wk follow-up: In patients with refractory ascites, the cumulative mortality in NSBB users was 30.5% compared to 30.9% in non-users (HR 1.02, 95% CI 0.74-1.39). In patients with diuretic-responsive ascites, the cumulative mortality in NSBB users was 17.0% compared to 19.5% in non-users (HR 0.78, 95% CI 0.53-1.16)
Leithead et al[24]	Single-centre, retrospective, propensity-adjusted, observational study	Consecutive cirrhotic patients with ascites listed for liver transplantation (n = 105 NSBB users matched to n = 105 non-users) Median follow-up: 72 d (IQR 27-162 d)	Propranolol (median dose 80mg per day, range 10-240 mg); Carvedilol (median dose 6.25 mg per day, range 3.125-12.5)	In patients with diuretic-responsive ascites: NSBB users showed lower waitlist mortality compared to non-users (HR 0.55, 95% CI 0.32-0.95) In patients with refractory ascites: NSBB users showed lower waitlist mortality compared to non-users (HR 0.35, 95% CI 0.14-0.85)
Onali et al[25]	Single-centre, retrospective audit	Consecutive cirrhotic patients with ascites assessed for liver transplant suitability (n = 316, median MELD score 15, range 6-40) Median follow-up: 7 mo (± 12)	Propranolol (median dose 80 mg per day, IQR 40); Carvedilol (median dose 6.25 mg per day, IQR not specified)	In the whole population, NSBB use was associated with lower mortality (HR 0.55, 95% CI 0.33-0.94). In patients with refractory ascites, there was no difference in survival in NSBB users compared to non-users (HR 0.43, 95% CI 0.20-1.11)

AKI: Acute kidney injury; CI: Confidence interval; HR: Hazard ratio; HRS: Hepatorenal syndrome; IQR: Interquartile range; IV: Intravenous; MELD: Model for end stage liver disease; NSBB: Non-selective beta-blocker; RCT: Randomised controlled trial; SBP: Spontaneous bacterial peritonitis.