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β-Blockers in Decompensated Cirrhosis: More Questions Than Answers
Accepted Manuscript Beta-blockers in decompensated cirrhosis: more questions than answers Anca Trifan, Carol Stanciu
PII: DOI: Reference:
S1542-3565(16)30851-5 10.1016/j.cgh.2016.09.140 YJCGH 54928
To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 19 September 2016 Please cite this article as: Trifan A, Stanciu C, Beta-blockers in decompensated cirrhosis: more questions than answers, Clinical Gastroenterology and Hepatology (2016), doi: 10.1016/ j.cgh.2016.09.140. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Beta-blockers in decompensated cirrhosis: more questions than answers
“Gr. T Popa” University of Medicine and Pharmacy, Iasi, Romania Independentei 1, Iasi, 700111, Romania
Carol Stanciu “St. Spiridon” University Hospital Independentei 1, Iasi, 700111, Romania [email protected]
Coresponding author:
EP
Carol Stanciu
TE D
Tel:+40722306020
M AN U
SC
[email protected]
RI PT
Anca Trifan
“St. Spiridon” University Hospital
AC C
Independentei 1, Iasi, 700111, Romania [email protected] Tel:+40722306020
Conflict of interest: None of the authors have any conflict of interest.
ACCEPTED MANUSCRIPT
Dear Editor: Thirty–five years ago, the first controlled clinical study documented that propranolol significantly reduced the risk of rebleeding from esophageal varices (1), and has been since then
beta-blockers (NSBBs) improve survival in patients with cirrhosis.
RI PT
followed by hundreds of articles (including RCTs and meta-analyses), all showing that non-selective
Five years ago, Sersté et al published an article showing that the use of NSBBs was associated with poor survival in cirrhotic patients with refractory ascites and suggested that beta-blockers should be contraindicated in these patients (2). More recently, Mandorfer et al have demonstrated that in
SC
patients with cirrhosis and spontaneous bacterial peritonitis (SBP), NSBBs reduce transplant-free survival, recommending in the end that such patients should not receive beta-blockers (3). The
M AN U
aforementioned two studies support the “window hypothesis” for beta-blockers by Krag et al (4), who suggested that NSBBs may be effective and improve survival only within a narrow clinical window in the course of liver cirrhosis, and are harmful beyond this window. The presence of refractory ascites or development of SBP closes the window. Both these studies generated significant controversies among clinicians caring cirrhotic patients, many of them deciding to cease the usage NSBBs in patients with decompensated cirrhosis.
TE D
However, in the last two years only, some studies have “re-opened” the window, reporting either no association between the use of NSBBs and increased mortality risk in patients with decompensated cirrhosis or even a beneficial effect of such therapy on survival of these patients (5,6). It is in this context that we expected for the recent meta-analysis published by
EP
Chirapongsathorn et al in Clinical Gastroenterology and Hepatology (7) to bring more light upon the ongoing debate on the use of NSBBs in cirrhotic patients with ascites. The most important conclusion of this meta-analysis is that the use of NSBBs is not associated with a significant increase in all-cause
AC C
mortality in patients with cirrhosis and ascites or refractory ascites. However, the authors underlined that certainty in the available estimates was low and concluded with the well-known refrain - ”further randomised clinical studies are warranted, and adding complications to evaluate the effects of NSBBs therapy on patients with cirrhosis and ascites”, thus complicating a subject of therapy which is already becoming confused, making it more difficult for a disoriented gastroenterologist to find answer to one of the most frequent questions which are being asked about on the safety of NSBBs: to initiate or not the beta-blocker treatment, or to continue/discontinue such therapy in patients with decompensated cirrhosis? Until future randomised controlled trials come with convincing arguments, Baveno VI consensus conference recommendations are a good guide of NSBBs therapy in patients with
ACCEPTED MANUSCRIPT
decompensated cirrhosis: NSBBs can be used in patients with refractory ascites but dose reduction or discontinuation should be considered when systolic blood pressure is <90 mmHg, or serum sodium <130
1. Lebrec D, et al. Lancet 1981;317:920-921. 2. Sersté T, et al. Hepatology 2010;52:1017-1022.
4. Krag A, et al. Gut 2012;61:967-969. 5. Leithead JA, et al. Gut 2015;64:1111-1119. 6. Mookerjee RP, et al. J Hepatol 2016;64:574-582.
SC
3. Mandorfer M, et al. Gastroenterology 2014;146:1680-1690.
RI PT
mEq/L, or in case of renal insufficiency (8).
7. Chirapongsathorn S, et al. Clin Gastroenterol Hepatol 2016;14:1096-1104.
AC C
EP
TE D
M AN U
8. de Franchis R. J Hepatol 2015;63:743-752.
PII: DOI: Reference:
S1542-3565(16)30851-5 10.1016/j.cgh.2016.09.140 YJCGH 54928
To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 19 September 2016 Please cite this article as: Trifan A, Stanciu C, Beta-blockers in decompensated cirrhosis: more questions than answers, Clinical Gastroenterology and Hepatology (2016), doi: 10.1016/ j.cgh.2016.09.140. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Beta-blockers in decompensated cirrhosis: more questions than answers
“Gr. T Popa” University of Medicine and Pharmacy, Iasi, Romania Independentei 1, Iasi, 700111, Romania
Carol Stanciu “St. Spiridon” University Hospital Independentei 1, Iasi, 700111, Romania [email protected]
Coresponding author:
EP
Carol Stanciu
TE D
Tel:+40722306020
M AN U
SC
[email protected]
RI PT
Anca Trifan
“St. Spiridon” University Hospital
AC C
Independentei 1, Iasi, 700111, Romania [email protected] Tel:+40722306020
Conflict of interest: None of the authors have any conflict of interest.
ACCEPTED MANUSCRIPT
Dear Editor: Thirty–five years ago, the first controlled clinical study documented that propranolol significantly reduced the risk of rebleeding from esophageal varices (1), and has been since then
beta-blockers (NSBBs) improve survival in patients with cirrhosis.
RI PT
followed by hundreds of articles (including RCTs and meta-analyses), all showing that non-selective
Five years ago, Sersté et al published an article showing that the use of NSBBs was associated with poor survival in cirrhotic patients with refractory ascites and suggested that beta-blockers should be contraindicated in these patients (2). More recently, Mandorfer et al have demonstrated that in
SC
patients with cirrhosis and spontaneous bacterial peritonitis (SBP), NSBBs reduce transplant-free survival, recommending in the end that such patients should not receive beta-blockers (3). The
M AN U
aforementioned two studies support the “window hypothesis” for beta-blockers by Krag et al (4), who suggested that NSBBs may be effective and improve survival only within a narrow clinical window in the course of liver cirrhosis, and are harmful beyond this window. The presence of refractory ascites or development of SBP closes the window. Both these studies generated significant controversies among clinicians caring cirrhotic patients, many of them deciding to cease the usage NSBBs in patients with decompensated cirrhosis.
TE D
However, in the last two years only, some studies have “re-opened” the window, reporting either no association between the use of NSBBs and increased mortality risk in patients with decompensated cirrhosis or even a beneficial effect of such therapy on survival of these patients (5,6). It is in this context that we expected for the recent meta-analysis published by
EP
Chirapongsathorn et al in Clinical Gastroenterology and Hepatology (7) to bring more light upon the ongoing debate on the use of NSBBs in cirrhotic patients with ascites. The most important conclusion of this meta-analysis is that the use of NSBBs is not associated with a significant increase in all-cause
AC C
mortality in patients with cirrhosis and ascites or refractory ascites. However, the authors underlined that certainty in the available estimates was low and concluded with the well-known refrain - ”further randomised clinical studies are warranted, and adding complications to evaluate the effects of NSBBs therapy on patients with cirrhosis and ascites”, thus complicating a subject of therapy which is already becoming confused, making it more difficult for a disoriented gastroenterologist to find answer to one of the most frequent questions which are being asked about on the safety of NSBBs: to initiate or not the beta-blocker treatment, or to continue/discontinue such therapy in patients with decompensated cirrhosis? Until future randomised controlled trials come with convincing arguments, Baveno VI consensus conference recommendations are a good guide of NSBBs therapy in patients with
ACCEPTED MANUSCRIPT
decompensated cirrhosis: NSBBs can be used in patients with refractory ascites but dose reduction or discontinuation should be considered when systolic blood pressure is <90 mmHg, or serum sodium <130
1. Lebrec D, et al. Lancet 1981;317:920-921. 2. Sersté T, et al. Hepatology 2010;52:1017-1022.
4. Krag A, et al. Gut 2012;61:967-969. 5. Leithead JA, et al. Gut 2015;64:1111-1119. 6. Mookerjee RP, et al. J Hepatol 2016;64:574-582.
SC
3. Mandorfer M, et al. Gastroenterology 2014;146:1680-1690.
RI PT
mEq/L, or in case of renal insufficiency (8).
7. Chirapongsathorn S, et al. Clin Gastroenterol Hepatol 2016;14:1096-1104.
AC C
EP
TE D
M AN U
8. de Franchis R. J Hepatol 2015;63:743-752.