REVIEW CON ( The Window Is Closed ): In Patients With Cirrhosis With Ascites, the Clinical Risks of Nonselective beta-blocker Outweigh the Benefits and Should NOT Be Prescribed Ariel W. Aday, M.D.,* Nicole E. Rich, M.D.,* Arjmand R. Mufti, M.D., and Shannan R. Tujios, M.D. KEY POINTS Even though nonselective beta-blockers (NSBBs) have proven benefits in cirrhosis, some evidence suggests they may be harmful in a subset of patients with decompensated cirrhosis, in particular those with refractory ascites, baseline hypotension, or at high risk for infection. The decision to initiate a NSBB should be individualized; continuation of NSBB should be continually reassessed in decompensated patients with ascites. Consider decreasing or stopping the NSBB in patients with low mean arterial pressure (<80 mm Hg), hyponatremia, renal insufficiency, ongoing infection, or refractory ascites requiring frequent paracentesis. Nonselective beta-blockers (NSBBs) have proven benefits in patients with cirrhosis with portal hypertension, particularly for secondary prophylaxis of variceal hemorrhage. 1 However, growing evidence suggests NSBB may be harmful in a subset of patients with decompensated cirrhosis, particularly those Abbreviations: ADH, antidiuretic hormone; EABV, effective arterial blood volume; HRS, hepatorenal syndrome; HVPG, hepatic venous pressure gradient; LVP, large-volume paracenteses; MAP, mean arterial pressure; NSBB, nonselective beta-blocker; PICD, paracentesis-induced circulatory dysfunction; RAAS, renin-angiotensin-aldosterone system; RCT, randomized controlled trial; SBP, spontaneous bacterial peritonitis; SNS, sympathetic nervous system. From the Department of Internal Medicine, Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, TX. *These authors contributed equally to this work. Potential conflict of interest: Nothing to report. Received 17 December 2017; accepted 2 February 2018 View this article online at wileyonlinelibrary.com VC 2018 by the American Association for the Study of Liver Diseases 123 CLINICAL LIVER DISEASE, VOL 11, NO 5, MAY 2018 An Official Learning Resource of AASLD
FIG 1 The various effects of beta-blockers in cirrhosis. 3 Studies suggest that beta-blockers may be effective only within a particular clinical window of advanced liver disease and, outside of this window, may be ineffective and potentially harmful in advanced decompensated disease. Abbreviations: RAAS, renin--angiotensin--aldosterone system; SNS, sympathetic nervous system. with refractory ascites, spontaneous bacterial peritonitis (SBP), or low mean arterial pressure (MAP). This has led to the proposal of the window hypothesis, suggesting a physiological window within which patients with cirrhosis benefit from NSBB and outside of which they may experience deleterious effects (Fig. 1). 2,3 This article will discuss key points for the clinician to consider prior to starting the aforementioned patient on a NSBB. NSBBs MAY INCREASE MORTALITY In an observational study of 151 patients with decompensated cirrhosis and refractory ascites, Serste andcolleagues 4 found that patients taking NSBBs had significantly higher mortality than patients not taking NSBBs (median survival 5 versus 20 months; p < 0.0001). In addition, on multivariate analysis, NSBBs were independently associated with a 2.6- fold increased risk for death. 4 The authors advocate that caution should be used when starting NSBBs in patients with refractory ascites, prompting significant debate and further studies. NSBBs MAY CAUSE HARM AND FURTHER HEMODYNAMIC COMPROMISE Systemic vasodilation, leading to low MAP and decreased effective arterial blood volume (EABV), is a hallmark of late decompensated cirrhosis (Fig. 2). 5 Prior data suggest that 124 CLINICAL LIVER DISEASE, VOL 11, NO 5, MAY 2018 An Official Learning Resource of AASLD
FIG 2 Mechanisms leading to circulatory and renal dysfunction in cirrhosis. 5 The main mechanism is a progressive splanchnic arterial vasodilatation caused by the overproduction of vasodilator molecules. During the initial phases of decompensated cirrhosis, when the activation of vasoconstrictor systems is moderate, patients experience sodium retention and ascites. In subsequent stages, activation of ADH leads to dilutional hyponatremia. Finally, in the most advanced phase, when circulatory dysfunction is extreme, the renal vasodilatory systems are overcome and patients experience severe renal vasoconstriction and type 2 HRS. Abbreviations: ADH, antidiuretic hormone; RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system. Reproduced with permission from Annals of Hepatology. 6 Copyright 2011, Mexican Association of Hepatology, the Latin-American Association for the Study of the Liver and the Canadian Association for the Study of the Liver. patients with cirrhosis with ascites and mean MAP <80 mm Hg have worse 1-year survival compared with those with MAP >80 mm Hg (P < 0.05). 6 In addition, prior studies showing a higher mortality with NSBB also noted lower MAP in the NSBB group. 4,7 In the case presented earlier, the patient s baseline MAP is already low (70 mm Hg), and addingannsbbwouldonlyleadtofurtherdeclineinmap. Although it may be possible to use lower doses of NSBB in some patients with decompensated cirrhosis, it is unlikely to be tolerated in this case. In addition, a patient with refractory ascites requiring frequent large-volume paracenteses (LVP) is at increased risk for paracentesis-induced circulatory dysfunction (PICD), which can precipitate impaired renal perfusion and hepatorenal syndrome (HRS). NSBB may exacerbate this risk by reducing the patient s ability to mount a compensatory increase in cardiac output. This was demonstrated in a crossover study by Serste andcolleagues 8 in which they found 9/10 patients taking NSBBs experienced PICD following LVP. Once the NSBB was discontinued, only 1/10 experienced PICD. Crucially, to date, there are no randomized controlled trials (RCTs) that show a mortality benefit of NSBBs in patients with refractory ascites. Several studies have also shown an increased risk for renal injury in patients with decompensated cirrhosis who are taking NSBBs. Kalambokis et al. 9 found that NSBBs increased risk for HRS in patients with Child C cirrhosis (36% versus 0% in the non-nsbb group; P 5 0.01). Similarly, in a cohort of patients on the liver transplant wait list, those with ascites who were taking NSBBs had a 3-fold increased risk (hazard ratio 3.31, 95% confidence interval 1.57-6.95) of experiencing development 125 CLINICAL LIVER DISEASE, VOL 11, NO 5, MAY 2018 An Official Learning Resource of AASLD
TABLE 1. LIMITATIONS OF AVAILABLE DATA ON USE OF NSBBS Observational/retrospective cohorts; no RCT to date Populations include a small proportion of patients with refractory ascites Variation in type and dose of NSBB prescribed Highly selected populations (e.g. patients listed for liver transplantation) Short durations of follow-up Use of administrative datasets lacking granular data of acute kidney injury compared with those without ascites. 10 The aforementioned patient already shows evidence of renal dysfunction, and addition of a NSBB will decrease EABV and risk worsening renal function. Furthermore, patients with decompensated cirrhosis, especially those with refractory ascites, are at increased risk for infections including SBP. Mandorfer and colleagues 7 found exaggerated hemodynamic compromise and hypotension in patients with cirrhosis with SBP while taking NSBBs, as well as reduced transplant-free survival, increased duration of hospitalization, and increased rates of HRS and acute kidney injury. NSBBs HAVE UNCLEAR EFFICACY Although there is abundant evidence supporting the use of NSBBs as both primary and secondary prophylaxis for variceal hemorrhage, prior RCTs largely excluded patients such as the earlier case with Child C cirrhosis, refractory ascites, and renal failure. 1,11 A meta-analysis by D Amico and colleagues 12 found risk for variceal hemorrhage and death were both significantly lower in patients taking NSBBs who were hepatic venous pressure gradient (HVPG) responders (defined as decrease in HVPG to <12 mm Hg or >20% from baseline). However, measurement of HVPG is invasive, not all patients are hemodynamic responders to NSBB, and it remains unclear whether the same benefit would be seen in the late decompensated patient. Although combination endoscopic ligation and NSBB remain optimal therapy for variceal management, risk for bleeding is directly related to variceal size. 13 The risk for bleeding from small varices, such as in this patient who has undergone successful ligation protocol, is low and likely lower than the potential hemodynamic consequences of NSBBs in a patient with refractory ascites, decreased estimated glomerular filtration rate, and already low MAP at baseline. TABLE 2. SITUATIONS IN WHICH TO CONSIDER REDUCING NSBB DOSE OR DISCONTINUING NSBB THERAPY IN THE PATIENT WITH DECOMPENSATED CIRRHOSIS AND ASCITES Systolic blood pressure < 90 mm Hg or MAP < 80 mm Hg Renal insufficiency (acute kidney injury or HRS) Hyponatremia Refractory ascites requiring frequent LVP Concern for spontaneous bacterial peritonitis or other active infection EVIDENCE SUPPORTING USE OF NSBBs IN DECOMPENSATED CIRRHOSIS IS LACKING Although some data suggest a benefit of NSBBs in decompensated cirrhosis, 14-16 none of these studies would have included the patient described in the earlier case. For instance, although Mookerjee and colleagues 14 suggested a beneficial effect of NSBBs in hospitalized patients with acute-on-chronic liver failure and high Model for End- Stage Liver Disease-Na scores, the mean MAP was significantly higher (78 mm Hg) than our patient s MAP of 70 mm Hg. Additional limitations of these studies, outlined in Table 1, include: (1) short duration of follow-up 15 ; (2) lack of granular data on underlying liver function 16 ; and (3) a low proportion of patients with refractory ascites (36% in Leithead et al. 15 and 17% in Bang et al. 16 ). In summary, although NSBBs have proven beneficial effects in cirrhosis, the available data suggest they may be harmful in a subset of patients with late decompensated cirrhosis, particularly those with refractory ascites. Given the lack of level I evidence, clinicians should carefully weigh the risks and benefits of starting an NSBB in each individual patient. In patients currently taking NSBB, it is important to periodically reassess the patient s underlying liver function and hemodynamic status to recognize when previously tolerated NSBBs should be discontinued to optimize survival (Table 2). CORRESPONDENCE Shannan R. Tujios, M.D., Division of Digestive and Liver Diseases, University of Texas Southwestern, 5959 Harry Hines Boulevard, POB 1, Suite 520, Dallas, TX 75390-8887. E-mail: shannan.tujios@utsouthwestern.edu REFERENCES 1) Albillos A, Zamora J, Martinez J, et al. Stratifying risk in the prevention of recurrent variceal hemorrhage: results of an individual patient meta-analysis. Hepatology 2017;66:1219-1231. 126 CLINICAL LIVER DISEASE, VOL 11, NO 5, MAY 2018 An Official Learning Resource of AASLD
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