Short-term hemodynamic effects of β-blockers influence survival of patients with decompensated cirrhosis

doi:10.1016/j.jhep.2020.03.048

Journal of Hepatology

Volume 73, Issue 4, October 2020, Pages 829-841

https://doi.org/10.1016/j.jhep.2020.03.048 Get rights and content

Highlights

•
Patients with decompensated cirrhosis have different hemodynamic responses to beta blockers than patients with compensated cirrhosis.
•
Patients with decompensated cirrhosis have greater reductions in CO and smaller reductions in portal pressure.
•
The effect of beta blockers on CO may reduce survival times of patients with decompensated cirrhosis.
•
Careful dose titration of beta blockers using non-invasive CO-monitoring may help in patients with decompensated cirrhosis.

Background & Aims

Whether the effect of β-blockers on arterial pressure and/or cardiac function may offset the benefit of reducing portal pressure in advanced cirrhosis is controversial. Herein, we aimed to evaluate the systemic and splanchnic hemodynamic effects of β-blockers in decompensated vs. compensated cirrhosis and to investigate the influence of systemic hemodynamic changes on survival times in decompensated cirrhosis.

Methods

Patients with cirrhosis and high-risk esophageal varices, without previous bleeding, were consecutively included and grouped according to the presence or absence of decompensation (ascites with or without overt encephalopathy). Systemic and hepatic hemodynamic measurements were performed before starting β-blockers and again after 1 to 3 months of treatment (short-term).

Results

Four hundred and three patients were included (190 decompensated and 213 compensated). At baseline, decompensated patients had higher portal pressure than compensated patients and were more hyperdynamic, with higher cardiac output (CO) and lower arterial pressure. Under β-blockers, decompensated patients had lower portal pressure decrease (10 ± 18% vs. 15 ± 12%; p <0.05) and had greater reductions in heart rate (p <0.001) and CO (17 ± 15% vs. 10 ± 21%; p <0.01). Among patients with decompensated cirrhosis, those who died had a greater decrease in CO with β-blockers than survivors (21 ± 14% vs. 15 ± 16%; p <0.05) and CO under β-blockers independently predicted death by competing-risk regression analysis, with good diagnostic accuracy (C-index 0.74; 95% CI 0.66–0.83). Death risk was higher in decompensated patients with CO <5 L/min vs. CO ≥5 L/min (subdistribution hazard ratio 0.44; 95% CI 0.25–0.77; p = 0.004).

Conclusions

In patients with high-risk varices treated to prevent first bleeding, the systemic hemodynamic response to β-blockers is greater and the portal pressure decrease is smaller in those with decompensated cirrhosis. The short-term effect of β-blockers on CO might adversely influence survival in decompensated cirrhosis.

Lay summary

β-blockers are often used to reduce the risk of variceal bleeding in patients with cirrhosis. However, it is not known whether the effect of β-blockers on arterial pressure and/or cardiac function may offset the benefit of reducing portal pressure. Herein, we show that in patients with decompensated cirrhosis the potentially detrimental systemic effects of β-blockers are greater than in compensated patients, while the beneficial pressure lowering effects are reduced. The short-term effect of β-blockers on cardiac output may adversely influence survival in patients with decompensated cirrhosis.

Graphical abstract

Introduction

The decompensation of cirrhosis is characterized by a marked decline in life expectancy.¹^,² Consequently, preventing death can be considered the main therapeutic goal in decompensated cirrhosis.² Non-selective β-blockers (NSBBs) are effective at preventing variceal hemorrhage and improve mortality associated with bleeding.³ Therefore, NSBBs are recommended in patients with high-risk esophageal varices.⁴^,⁵ However, a major controversy has arisen in recent years regarding the efficacy and safety of NSBBs in patients with advanced cirrhosis. Some studies suggest a harmful effect in patients with refractory ascites or spontaneous bacterial peritonitis (SBP).[6], [7], [8] However, these concerns have not been confirmed in other recent studies, which suggest no harmful but rather beneficial effects of NSBBs on patients with advanced cirrhosis.[8], [9], [10], [11], [12]

Different pathophysiological mechanisms are involved in compensated and decompensated cirrhosis. Splanchnic arterial vasodilation and hyperdynamic circulation, which mainly develop in patients with clinically significant portal hypertension (CSPH), markedly worsen portal hypertension and increase the risk of decompensation.¹³ NSBBs are mainly effective once hyperdynamic circulation develops.¹³ Hyperdynamic circulation is more pronounced in decompensated than in compensated cirrhosis.¹⁴ However, whether the systemic and hepatic hemodynamic changes induced by NSBBs differ with the development of decompensation has not been clarified. In advanced stages of decompensated cirrhosis, organ perfusion is highly dependent on cardiac output (CO) and maintenance of blood pressure.¹⁵ NSBBs can worsen the arterial hypotension associated with decompensated cirrhosis and can impair the β-adrenergic-mediated increase in CO. These changes may in turn be detrimental to maintain organ perfusion in advanced cirrhosis.⁶^,¹⁵ Whether the effect of NSBBs on these circulatory disturbances may influence survival in patients with advanced decompensated cirrhosis has not been fully clarified. This is a relevant issue given the marked decline in survival expectancy observed in decompensated cirrhosis.²

We aimed to evaluate whether the effect of NSBBs on systemic and hepatic hemodynamics in patients with decompensated cirrhosis is different than that observed in patients with compensated cirrhosis. We also aimed to evaluate the influence of the systemic hemodynamic changes induced by NSBBs on the survival of patients with decompensated cirrhosis.

Section snippets

Patients and methods

All patients referred to our Hepatic Hemodynamic Laboratory for prevention of variceal bleeding were successively included in a prospective register and were consecutively considered for inclusion in this study. Patients were enrolled between January 2001 and June 2016 and were followed-up until January 2017. Informed consent was obtained from all patients and the hospital ethics committee approved the study protocol. The study was conducted according to the guidelines of the Declaration of

Results

During the study period 508 patients were eligible and 88 had one or more exclusion criteria (Fig. S1). The baseline hemodynamic study was performed in 420 patients, 17 of whom had an HVPG <10 mmHg and were also excluded. Finally, 403 were included, 190 with decompensated cirrhosis and 213 with compensated cirrhosis. A small proportion had been included in previous studies.¹⁶^,¹⁹ All decompensated patients had ascites and 35 also had previous episodes of encephalopathy.

Two-hundred and

Discussion

This study shows that patients with decompensated cirrhosis, in addition to higher portal hypertension, have a much more developed hyperdynamic circulation than compensated patients. This is indicated by higher heart rate and CO, as well as lower SVR and MAP in decompensated patients. Our results are in keeping with experimental and clinical studies showing that development of hyperdynamic circulation is progressive over the course of different stages of cirrhosis.¹⁴ In early compensated

Financial support

This study has been supported in part by grants from the Instituto de Salud Carlos III (PI10/01552, PI13/02535, PI16/01992) and Fondos Feder.

The CIBERehd is funded by the Instituto de Salud Carlos III (ISCiii).

Edilmar Alvarado-Tapias is a recipient of a “Río Hortega” fellowship grant from the Instituto de Salud Carlos III (CM16/00133).

Authors' contributions

Study concept and design: EA, CV; acquisition of data: EA, AA, OP, IG, AB, BC; analysis and interpretation of data: EA, CV, drafting of the manuscript: EA, CV; critical revision of the manuscript for important intellectual content: CV, statistical analysis: EA, CV, FT; study supervision: CV.

Conflict of interest

The authors declare no conflicts of interest that pertain to this work.

Please refer to the accompanying ICMJE disclosure forms for further details.

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Cirrhotic cardiomyopathy (CCM) is defined as systolic or diastolic dysfunction in the absence of prior heart disease or another identifiable cause in patients with cirrhosis, in whom it is an important determinant of outcome. Its underlying pathogenic/pathophysiological mechanisms are rooted in two distinct pathways: 1) factors associated with portal hypertension, hyperdynamic circulation, gut bacterial/endotoxin translocation and the resultant inflammatory phenotype; 2) hepatocellular insufficiency with altered synthesis or metabolism of substances such as proteins, lipids, carbohydrates, bile acids and hormones. Different criteria have been proposed to diagnose CCM; the first in 2005 by the World Congress of Gastroenterology, and more recently in 2019 by the Cirrhotic Cardiomyopathy Consortium. These criteria mainly utilised echocardiographic evaluation, with the latter refining the evaluation of diastolic function and integrating global longitudinal strain into the evaluation of systolic function, an important addition since the haemodynamic changes that occur in advanced cirrhosis may lead to overestimation of systolic function by left ventricular ejection fraction. Advances in cardiac imaging, such as cardiac magnetic resonance imaging and the incorporation of an exercise challenge, may help further refine the diagnosis of CCM. Over recent years, CCM has been shown to contribute to increased mortality and morbidity after major interventions, such as liver transplantation and transjugular intrahepatic portosystemic shunt insertion, and to play a pathophysiologic role in the genesis of hepatorenal syndrome. In this review, we discuss the pathogenesis/pathophysiology of CCM, its clinical implications, and the role of cardiac imaging modalities including MRI. We also compare diagnostic criteria and review the potential diagnostic role of electrocardiographic QT prolongation. At present, no definitive medical therapy exists, but some promising potential treatment strategies for CCM are reviewed.
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The portal pressure decreasing effect of NSBBs is particularly pronounced in such patients.4 It is much less marked before developing CSPH, when hyperdynamic circulation is poorly developed,4 and is also less pronounced once decompensation occurs.33 Moreover, due to its anti-α-adrenergic activity and to an enhanced intrahepatic release of nitric oxide, carvedilol decreases intrahepatic vascular resistance,11,12 which is a key factor leading to PH in compensated cirrhosis.7,13
Whether non-selective β-blockers can prevent decompensation of cirrhosis warrants clarification. Carvedilol might be particularly effective since its intrinsic vasodilatory activity may ameliorate hepatic vascular resistance, a major mechanism of portal hypertension in early cirrhosis. We assessed whether carvedilol may prevent decompensation and improve survival in patients with compensated cirrhosis and clinically significant portal hypertension (CSPH).
By systematic review we identified randomized-controlled trials (RCTs) comparing carvedilol vs. control therapy (no-active treatment or endoscopic variceal ligation [EVL]) in patients with cirrhosis and CSPH without previous bleeding. We performed a competing-risk time-to-event meta-analysis using individual patient data (IPD) obtained from principal investigators of RCTs. Only compensated patients were included. Primary outcomes were prevention of decompensation (liver transplantation and death were competing events) and death (liver transplantation was a competing event). Models were adjusted using propensity scores for baseline covariates with the inverse probability of treatment weighting (IPTW) approach.
Among 125 full-text studies evaluated, 4 RCTs were eligible. The 4 provided IPD and were included, comprising 352 patients with compensated cirrhosis, 181 treated with carvedilol and 171 controls (79 received EVL and 92 placebo). Baseline characteristics were similar between groups. Standardized differences were <10% by IPTW. The risk of developing decompensation of cirrhosis was lower with carvedilol than in controls (subdistribution hazard ratio [SHR] 0.506; 95% CI 0.289-0.887; p = 0.017; I² = 0.0%, Q-statistic-p = 0.880), mainly due to a reduced risk of ascites (SHR 0.491; 95% CI 0.247-0.974; p = 0.042; I² = 0.0%, Q-statistic-p = 0.384). The risk of death was also lower with carvedilol (SHR 0.417; 95% CI 0.194-0.896; p = 0.025; I² = 0.0%, Q-statistic-p = 0.989).
Long-term carvedilol therapy reduced decompensation of cirrhosis and significantly improved survival in compensated patients with CSPH. This suggests that screening patients with compensated cirrhosis for CSPH to enable the prompt initiation of carvedilol could improve outcomes.
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The transition from compensated cirrhosis to decompensated cirrhosis is associated with markedly reduced life expectancy. Therefore, preventing decompensation in patients with compensated cirrhosis would be associated with greatly improved patient outcomes. There has been controversy regarding the use of non-selective β-blockers (portal pressure-lowering medications) in patients with cirrhosis and elevated portal blood pressure (portal hypertension). Herein, using a competing-risk meta-analysis to optimize sample size and properly investigate cirrhosis as a multistate disease and outcomes as time-dependent events, we show that carvedilol (a non-selective β-blocker) is associated with a reduced risk of decompensating events and improved survival in patients with cirrhosis and portal hypertension.
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Nonselective beta blockers (NSBBs) exert beneficial effects beyond lowering hepatic venous pressure gradient (HVPG), which may be particularly relevant in patients with decompensated cirrhosis (DC), in whom bacterial translocation and bacterial-induced systemic inflammation drive the development of complications such as acute-on-chronic liver failure (ACLF). We evaluated whether NSBB-related changes in von Willebrand factor (VWF) may serve as a biomarker for these effects.
In this retrospective analysis, 159 prospectively characterized patients with clinically stable DC (ie, without acute decompensation) who underwent paired HVPG/VWF assessments before/on NSBB therapy were classified as ‘VWF-responders’ (as defined by a ≥5% decrease in VWF) versus ‘VWF-non-responders.’
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Decreases in VWF upon NSBB therapy reflect their anti-inflammatory activity, are accompanied by less pronounced adverse effects on systemic hemodynamics, and are independently associated with a decreased risk of further decompensation, ACLF, and death. VWF-response may discriminate between decompensated patients who benefit from NSBB treatment and have a favorable prognosis versus patients with poor outcomes.
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Reasons attributed to the failure of these trials were small sample size and lack of achieving and/or inability to safely achieve a low/the low target heart rate in cirrhotic patients [145]. In reverse, a recent study published in 2020 by Tapias et al. [146] showed a deleterious effect of beta blockers in decompensated cirrhosis, with higher wait list mortality. This finding was in line with a similar result published by Serste et al. in 2010 [147], where use of propranolol was shown to have increased mortality in decompensated cirrhosis.
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Non-selective beta blockers and mortality in decompensated cirrhosis: Is cirrhotic cardiomyopathy the missing link?
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^†: Authors share co-first authorship.

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Research ArticleShort-term hemodynamic effects of β-blockers influence survival of patients with decompensated cirrhosis

Highlights

Background & Aims

Methods

Results

Conclusions

Lay summary

Graphical abstract

Introduction

Section snippets

Patients and methods

Results

Discussion

Financial support

Authors' contributions

Conflict of interest

J Hepatol

J Hepatol

J Hepatol

J Hepatol

J Hepatol

Hepatology

J Hepatol

J Hepatol

J Hepatol

J Hepatol

J Hepatol

Clin Liver Dis

Now there are many (stages) where before there was one: in search of a pathophysiological classification of cirrhosis

Hepatology

Beta-adrenergic-antagonist drugs in the prevention of gastrointestinal bleeding in patients with cirrhosis and esophageal varices. An analysis of data and prognostic factors in 589 patients from four randomized clinical trials

N Engl J Med

Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the Study of Liver Diseases

Hepatology

Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites

Hepatology

Nonselective β-blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis

Gastroenterology

Research Article
Short-term hemodynamic effects of β-blockers influence survival of patients with decompensated cirrhosis