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.

Table 2 Summary of further pharmacological agents with potentially therapeutic effects

Treatment	Potential mechanism of action	Indications and Evidence
Human Serum Albumin (HAS)	Oncotic properties: Acts as a plasma expander to counteract splanchnic arterial vasodilatation in cirrhosis; Non-oncotic properties: Modulation of the inflammatory response through binding of reactive oxygen species and NO. Also affects capillary integrity. Furthermore, cirrhosis affects the capacity of albumin to bind endogenous and exogenous substances, which may be compensated for by albumin infusion.	A recent meta-analysis found that HAS infusion in combination with antibiotics decreases the incidence of renal failure and mortality in patients with SBP; Several studies demonstrate that HAS infusion together with vasoconstrictors reduces mortality in patients with type 1 HRS; A meta-analysis by Bernardi et al showed that HAS infusion was effective in preventing paracentesis-induced circulatory dysfunction; A multicentre RCT by Caraceni et al[148] (n = 440) in cirrhotic patients with uncomplicated ascites showed that long-term HAS plus diuretics prolonged survival compared to diuretics alone[142-148].
Faecal microbiota transplant (FMT)	As described previously, cirrhosis and its progression have been closely linked to gut dysbiosis with a predominance of pathogenic bacterial taxa and SIBO. Amelioration or even reversion of dysbiosis may be achieved through direct manipulation of the intestinal microbiome using FMT.	Although FMT has been extremely successful in repopulating the healthy intestinal microbiome of patients with C. difficile diarrhoea and has even been endorsed in guidelines for the treatment of recurrent C. difficile diarrhoea, studies of FMT in patients with liver disease are smaller and more limited. A pilot study suggested a reduced burden of HE in patients given a single FMT enema compared to standard-of-care therapy. Currently, Woodhouse et al[126] are in the process of conducting a randomised, single-blinded, placebo-controlled trial in 32 cirrhotic patients in order to assess the safety and tolerability of FMT delivered by upper GI endoscopy[126,149-151].
Caffeine/ Coffee	Caffeine antagonizes the A2a adenosine receptor on hepatic stellate cells, the effector cells of fibrogenesis. Activation of the A2a adenosine receptor has been directly associated with matrix production in rodent models. However, decaffeinated coffee has also been shown to lower transaminases. Hence there may be additional anti-fibrotic constituents of coffee such as polyphenols which are potent anti-inflammatories and anti-oxidants.	Both retrospective and prospective observational studies have indicated that an inverse dose-response relationship exists between coffee consumption and cirrhosis risk as well as cirrhosis-related complications. Corrao et al[155] retrospectively analysed 274 decompensated cirrhotic patients and 458 matched controls with chronic liver disease, finding that daily consumption of one cup of coffee conferred an odds ratio of 0.47, while daily consumption of four cups of coffee even conferred an odds ratio of 0.16 for cirrhosis risk. Similarly, a prospective cohort study of patients with advanced hepatitis C induced liver disease found that liver-related mortality and complication rates declined with increasing coffee consumption (12.1/100 person years for > 1 cup/d; 8.2/100 for 1-3 cups/d; 6.3/100 for > 3 cups/d; p-trend = 0.001). A recent prospective cohort study analysed non-invasive liver stiffness measurements in the general Dutch population (n = 2424), observing that coffee consumption was inversely correlated with liver stiffness. Similarly, recent data from a meta-analysis showed a favourable effect of coffee consumption on risk of HCC development (RR 0.55, 95% CI 0.44-0.67). At present, no guidelines exist regarding the prescription of coffee to patients with cirrhosis or chronic liver disease[152-158].

CI: Confidence interval; FMT: Faecal microbiota transplant; GI: Gastrointestinal; HAS: Human Serum Albumin; HCC: Hepatocellular carcinoma; HE: Hepatic encephalopathy; HRS: Hepatorenal syndrome; NO: Nitric oxide; RCT: Randomised controlled trial; RR: Relative risk; SBP: Spontaneous bacterial peritonitis; SIBO: Small intestinal bacterial overgrowth.