Systemic Arterial Blood Pressure Determines the Therapeutic Window of Non-selective Beta Blockers in Decompensated Cirrhosis

Tammo L. Tergast; Markus Kimmann; Hans Laser; Svetlana Gerbel; Michael P. Manns; Markus Cornberg; Benjamin Maasoumy

Disclosures

Aliment Pharmacol Ther. 2019;50(6):696-706. 

In This Article

Abstract and Introduction

Abstract

Background: The safety of non-selective β-blockers in patients with advanced cirrhosis has been questioned in recent years. It was hypothesised that there is a particular therapeutic window. However, the specific limits still need to be determined.

Aim: To evaluate potential limits of the therapeutic window of non-selective β-blocker therapy in patients with cirrhosis and ascites

Methods: The impact of non-selective β-blockers on 28-day transplant-free survival was analysed in a cohort of 624 consecutive patients with decompensated cirrhosis and ascites. Three potential limits were investigated: spontaneous bacterial peritonitis, acute-on-chronic liver failure, mean arterial blood pressure ≤ 82 and < 65 mm Hg.

Results: Treatment with non-selective β-blockers was associated with a higher 28-day transplant-free survival in the overall cohort (hazard ratio: 0.621; P = .035) as well as in patients with acute-on-chronic liver failure (hazard ratio: 0.578; P = .031) and those with spontaneous bacterial peritonitis (hazard ratio: 0.594; P = .073). In contrast, survival benefits were markedly attenuated in patients with a mean arterial blood pressure ≤ 82 mm Hg and completely lost in those with mean arterial blood pressure < 65 mm Hg (P = .536). In spontaneous bacterial peritonitis patients with a mean arterial blood pressure < 65 mm Hg non-selective β-blocker treatment was associated with renal impairment. Of note, among those with a mean arterial blood pressure ≥ 65 mm Hg non-selective β-blocker intake was consistently associated with superior transplant-free survival (hazard ratio: 0.582; P = .029) irrespective of the presence of spontaneous bacterial peritonitis (hazard ratio: 0.435; P = .028) or acute-on-chronic liver failure (hazard ratio: 0.480 P = .034).

Conclusions: Ascites, acute-on-chronic liver failure and spontaneous bacterial peritonitis do not limit the safe use of non-selective β-blockers in patients with cirrhosis. Mean arterial blood pressure might represent a better indicator to determine the therapeutic window of non-selective β-blocker treatment.

Introduction

Non-selective β-blockers (NSBB) lower portal pressure[1] and significantly reduce the incidence of variceal bleeding in selected patients with cirrhosis.[2,3] Therefore, they are the cornerstone of primary and secondary prophylaxis of variceal bleeding.[2,4,5] However, some data indicate that NSBB may not always be beneficial in patients with cirrhosis. Especially in those with decompensated liver disease, important safety concerns have been raised. In 2010, Serste et al suggested that NSBB intake is linked to higher mortality among patients with refractory ascites.[6,7]

These data initiated the hypothesis of a certain therapeutic window for NSBB in patients with cirrhosis. The suggested window opens with the development of oesophageal varices (and/or hepatic venous pressure gradient ≥ 10 mm Hg) and closes at advanced stages of cirrhosis indicated by the onset of refractory ascites.[8] However, in particular the upper limit of such a window was challenged in the following years by a couple of studies.[9–11] Leithead et al showed improved survival in patients taking NSBB with decompensated cirrhosis and ascites awaiting liver transplantation.[10] Therefore, refractory ascites alone seems to be inaccurate in defining the therapeutic window for NSBB. Mandorfer et al suggested that the adverse effects of NSBB in patients with ascites might be limited to those with spontaneous bacterial peritonitis (SBP).[12] SBP may cause circulatory dysfunction as a result of the inflammatory response and is associated with a high risk for acute kidney injury (AKI).[13] Mandorfer et al documented that the circulatory dysfunction after paracentesis is further impaired by NSBB intake, which leads to a higher risk for AKI and subsequently also increased overall mortality.[12] Similar to SBP, a hyperinflammatory status can be found in patients with acute-on-chronic liver failure (ACLF), which is also often associated with renal failure and circulatory dysfunction.[14] Moreover, SBP is one of the most frequent triggers for ACLF in Europe.[15,16] However, a sub-analysis of the CANONIC study documented improved survival in ACLF patients using a NSBB.[17]

Currently, it is common consensus in the field of hepatology that there is a certain therapeutic window for the treatment of NSBB in patients with liver cirrhosis, the upper limit of this window remains highly controversial.[18,19] Therefore, we aimed to investigate different potential window limits for the use of NSBB in patients with decompensated cirrhosis in a large, well-defined cohort.

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