When Should the β-Blocker Window in Cirrhosis Close?
2014; Elsevier BV; Volume: 146; Issue: 7 Linguagem: Inglês
10.1053/j.gastro.2014.04.028
ISSN1528-0012
AutoresPhillip S. Ge, Bruce A. Runyon,
Tópico(s)Organ Transplantation Techniques and Outcomes
ResumoSee "Nonselective β blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis," by Mandorfer M, Bota S, Schwabl P, et al, on page 1680. See "Nonselective β blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis," by Mandorfer M, Bota S, Schwabl P, et al, on page 1680. The β-blocker controversy continues.1Mandorfer M. Bota S. Schwabl P. et al.Nonselective β blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis.Gastroenterology. 2014; 146: 1680-1690Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar β Blockers are well-established in the primary and secondary prevention of variceal hemorrhage in patients with cirrhosis.2Lebrec D. Poynard T. Hillon P. et al.Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a controlled study.N Engl J Med. 1981; 305: 1371-1374Crossref PubMed Scopus (406) Google Scholar, 3Pascal J.P. Cales P. Propranolol in the prevention of first upper gastrointestinal tract hemorrhage in patients with cirrhosis of the liver and esophageal varices.N Engl J Med. 1987; 317: 856-861Crossref PubMed Scopus (269) Google Scholar Nonselective β blockers such as propranolol exert their influence via splanchnic vasoconstriction and the reduction of cardiac output, thereby reducing the hepatic venous pressure gradient. However, a series of recent studies from Sersté et al4Sersté T. Melot C. Francoz C. et al.Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites.Hepatology. 2010; 52: 1017-1022Crossref PubMed Scopus (392) Google Scholar, 5Sersté T. Francoz C. Durand F. et al.Beta-blockers cause paracentesis-induced circulatory dysfunction in patients with cirrhosis and refractory ascites: a cross-over study.J Hepatol. 2011; 55: 794-799Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar demonstrated reduced survival in patients with decompensated cirrhosis and refractory ascites who were treated with β blockers. Not surprisingly, these findings have ignited significant controversy among hepatologists, ranging from outright disbelief to calls for additional studies in the hopes that "better-designed" studies would refute these findings.6Wong F. Salerno F. Beta-blockers in cirrhosis: friend and foe?.Hepatology. 2010; 52: 811-813Crossref PubMed Scopus (41) Google Scholar In this issue of Gastroenterology, Mandorfer et al1Mandorfer M. Bota S. Schwabl P. et al.Nonselective β blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis.Gastroenterology. 2014; 146: 1680-1690Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar provide important new evidence demonstrating the detrimental effect of β blocker treatment after the development of spontaneous bacterial peritonitis (SBP). In this retrospective cohort study of 607 patients with cirrhosis, nonselective β blockers were shown to increase transplant-free survival in patients without SBP, with reduced hospitalization rates. However, with the first diagnosis of SBP, nonselective β blockers were associated with hemodynamic compromise and decreased blood pressures, reduced transplant-free survival, increased hospitalization rates, and increased incidence of the hepatorenal syndrome and acute kidney injury. Although the study was retrospective, it was well-designed and thorough; statistical models were adjusted for Child–Pugh stage and presence of varices in an attempt to avoid the limitations of the Sersté et al studies.6Wong F. Salerno F. Beta-blockers in cirrhosis: friend and foe?.Hepatology. 2010; 52: 811-813Crossref PubMed Scopus (41) Google Scholar Aside from a higher proportion of female patients in the β-blocker group at first paracentesis, and a higher bilirubin level in the β-blocker group at first SBP diagnosis, no other differences were noted between the study populations. Mandorfer et al1Mandorfer M. Bota S. Schwabl P. et al.Nonselective β blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis.Gastroenterology. 2014; 146: 1680-1690Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar conclude in this study that patients with cirrhosis and SBP should not receive nonselective β-blocker therapy. However, the impact and clinical implications of this study are far-reaching—it adds to the growing body of recent evidence documenting the harms of β-blocker therapy in patients with advanced cirrhosis.7Ge P.S. Runyon B.A. The changing role of beta-blocker therapy in patients with cirrhosis.J Hepatol. 2014; 60: 643-653Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar, 8Runyon B.A. Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline management of adult patients with ascites due to cirrhosis 2012.Hepatology. 2013; 57: 1651-1653Crossref PubMed Scopus (485) Google Scholar Together with the studies from Sersté et al,4Sersté T. Melot C. Francoz C. et al.Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites.Hepatology. 2010; 52: 1017-1022Crossref PubMed Scopus (392) Google Scholar, 5Sersté T. Francoz C. Durand F. et al.Beta-blockers cause paracentesis-induced circulatory dysfunction in patients with cirrhosis and refractory ascites: a cross-over study.J Hepatol. 2011; 55: 794-799Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar these studies directly support the recently described "window hypothesis" for β-blocker therapy, in which Krag et al9Krag A. Wiest R. Albillos A. et al.The window hypothesis: haemodynamic and non-haemodynamic effects of beta-blockers improve survival of patients with cirrhosis during a window in the disease.Gut. 2012; 61: 967-969Crossref PubMed Scopus (135) Google Scholar propose that β blockers improve survival within only a narrow window in the natural history of cirrhosis. According to this hypothesis, β blockers are beneficial only during a certain "window" of clinical opportunity, and are either ineffective or harmful outside of this window. In early cirrhosis, β blockers have no effect on survival, increase adverse events and do not prevent the formation of varices.10Groszmann R.J. Garcia-Tsao G. Bosch J. et al.Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis.N Engl J Med. 2005; 353: 2254-2261Crossref PubMed Scopus (699) Google Scholar As cirrhosis progresses, portal pressures increase and the sympathetic nervous system becomes increasingly activated. Ascites and esophageal varices develop, and there is increased risk of variceal bleeding and bacterial translocation. Systemic hemodynamics remains relatively preserved, and blood pressure and cardiac output are maintained to deliver adequate end-organ perfusion. In this middle stage of cirrhosis, the β-blocker "window" opens for the primary and secondary prevention of gastrointestinal bleeding.2Lebrec D. Poynard T. Hillon P. et al.Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a controlled study.N Engl J Med. 1981; 305: 1371-1374Crossref PubMed Scopus (406) Google Scholar, 3Pascal J.P. Cales P. Propranolol in the prevention of first upper gastrointestinal tract hemorrhage in patients with cirrhosis of the liver and esophageal varices.N Engl J Med. 1987; 317: 856-861Crossref PubMed Scopus (269) Google Scholar However, in advanced cirrhosis with refractory ascites, the inability of the circulatory system to increase cardiac output via the β-adrenergic system during situations of increased physiologic stress results in decreased mean arterial pressures, decreased perfusion to vital organs, azotemia, and subsequently increased risk for the hepatorenal syndrome and end-organ damage.9Krag A. Wiest R. Albillos A. et al.The window hypothesis: haemodynamic and non-haemodynamic effects of beta-blockers improve survival of patients with cirrhosis during a window in the disease.Gut. 2012; 61: 967-969Crossref PubMed Scopus (135) Google Scholar, 11Krag A. Bendtsen F. Henriksen J.H. et al.Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites.Gut. 2010; 59: 105-110Crossref PubMed Scopus (255) Google Scholar, 12Ruiz-del-Arbol L. Monescillo A. Arocena C. et al.Circulatory function and hepatorenal syndrome in cirrhosis.Hepatology. 2005; 42: 439-447Crossref PubMed Scopus (446) Google Scholar Exactly when the "window" closes is up for debate. Part of the reason why it is unclear when the "window" closes is that, until recently, the effects of β blockers in patients with cirrhosis and refractory ascites had never been studied.4Sersté T. Melot C. Francoz C. et al.Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites.Hepatology. 2010; 52: 1017-1022Crossref PubMed Scopus (392) Google Scholar In the original study from Lebrec et al in 1981,2Lebrec D. Poynard T. Hillon P. et al.Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a controlled study.N Engl J Med. 1981; 305: 1371-1374Crossref PubMed Scopus (406) Google Scholar which established the role of β blockers in prevention of variceal bleeding, patients with ascites were purposely excluded. Given that cirrhosis is a dynamic process, it makes sense that early studies only included the middle stages of cirrhosis, because the entire disease course is too heterogeneous. The recommendation to start and indefinitely continue β blockers, in essentially all patients with cirrhosis and medium-to-large varices regardless of blood pressure or ascites, was largely extrapolated rather than specifically studied. The role of cardiac output and blood pressure is central to understanding why β blockers are harmful in patients with advanced cirrhosis. As cirrhosis progresses, circulatory changes occur including the maximal up-regulation of the sympathetic nervous system13Murray J.F. Dawson A.M. Sherlock S. Circulatory changes in chronic liver disease.Am J Med. 1958; 24: 358-367Abstract Full Text PDF PubMed Scopus (341) Google Scholar and of the renin–angiotensin–aldosterone system.14Rosoff Jr., L. Zia P. Reynolds T. et al.Studies of renin and aldosterone in cirrhotic patients with ascites.Gastroenterology. 1975; 69: 698-705PubMed Google Scholar These changes, along with sodium and water retention and the formation of ascites, are aimed at maintaining adequate cardiac output and organ perfusion. Together, they reflect an adaptive response to the peripheral vasodilation, effective hypovolemia, and arterial hypotension that accompanies advanced cirrhosis. However, the cardiovascular system eventually loses its compensatory ability. It is at this stage that the maintenance of blood pressure and cardiac output is paramount, and the hemodynamic effects of β blockers in reducing blood pressure and cardiac output results in decreased survival.4Sersté T. Melot C. Francoz C. et al.Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites.Hepatology. 2010; 52: 1017-1022Crossref PubMed Scopus (392) Google Scholar, 9Krag A. Wiest R. Albillos A. et al.The window hypothesis: haemodynamic and non-haemodynamic effects of beta-blockers improve survival of patients with cirrhosis during a window in the disease.Gut. 2012; 61: 967-969Crossref PubMed Scopus (135) Google Scholar, 11Krag A. Bendtsen F. Henriksen J.H. et al.Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites.Gut. 2010; 59: 105-110Crossref PubMed Scopus (255) Google Scholar The correlation between blood pressure and survival in patients with cirrhosis was suggested by Llach et al in 1988.15Llach J. Gines P. Arroyo V. et al.Prognostic value of arterial pressure, endogenous vasoactive systems, and renal function in cirrhotic patients admitted to the hospital for the treatment of ascites.Gastroenterology. 1988; 94: 482-487Abstract Full Text PDF PubMed Google Scholar In their study, a mean arterial pressure of ≤82 mmHg was the single variable most strongly correlated with shortened survival; the survival probability rate of patients with mean arterial pressure ≤82 mmHg was 20% at 24 months and 0% at 48 months, in contrast with 70% at 24 months and 50% at 48 months among patients with a mean arterial pressure of >82 mmHg.15Llach J. Gines P. Arroyo V. et al.Prognostic value of arterial pressure, endogenous vasoactive systems, and renal function in cirrhotic patients admitted to the hospital for the treatment of ascites.Gastroenterology. 1988; 94: 482-487Abstract Full Text PDF PubMed Google Scholar A similar study by Krag et al11Krag A. Bendtsen F. Henriksen J.H. et al.Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites.Gut. 2010; 59: 105-110Crossref PubMed Scopus (255) Google Scholar demonstrated that a cardiac index od <1.5 L/min/m2 predicted the development of hepatorenal syndrome and subsequent mortality in patients with cirrhosis and ascites. They suggested that, in patients with low cardiac indices and ascites, β blockers and/or other antihypertensives may further worsen hemodynamics, resulting in the hepatorenal syndrome and subsequent mortality.11Krag A. Bendtsen F. Henriksen J.H. et al.Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites.Gut. 2010; 59: 105-110Crossref PubMed Scopus (255) Google Scholar The use of newer generation β blockers such as carvedilol and β-1–selective β blockers such as metoprolol are similarly limited by systemic hypotension and merits further investigation.16Banares R. Moitinho E. Matilla A. et al.Randomized comparison of long-term carvedilol and propranolol administration in the treatment of portal hypertension in cirrhosis.Hepatology. 2002; 36: 1367-1373Crossref PubMed Scopus (163) Google Scholar Blood pressure decreases silently and incrementally as decompensation occurs. If antihypertensives including β blockers are not discontinued, azotemia develops and progresses.11Krag A. Bendtsen F. Henriksen J.H. et al.Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites.Gut. 2010; 59: 105-110Crossref PubMed Scopus (255) Google Scholar In our experience, we increasingly encounter patients with cirrhosis on β blockers and/or other antihypertensives who develop azotemia, hypotension, and acute kidney injury as their cirrhosis progresses. If these drugs are discontinued early enough after harm is detected, azotemia can resolve. Because cirrhosis is a dynamic process which can rapidly decompensate, the "window" as proposed by Krag et al may actually be smaller than it seems. It seems reasonable that, at a minimum, the "window" should close (Figure 1) when patients (1) develop refractory ascites, (2) develop systolic blood pressures <100 mmHg or mean arterial pressures <82 mmHg, (3) develop acute kidney injury or hepatorenal syndrome, (4) develop sepsis, or (5) have poor medical follow-up and/or have issues with medication noncompliance.7Ge P.S. Runyon B.A. The changing role of beta-blocker therapy in patients with cirrhosis.J Hepatol. 2014; 60: 643-653Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar Based on this study from Mandorfer et al,1Mandorfer M. Bota S. Schwabl P. et al.Nonselective β blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis.Gastroenterology. 2014; 146: 1680-1690Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar it seems that the "window" should also close (6) at the first onset of SBP. Furthermore, β blockers should not be restarted once stopped for these reasons. Arvaniti et al demonstrated that, after the occurrence of bacterial infections in patients with cirrhosis, mortality is increased 4-fold, with 30% mortality within 1 month, and an additional 30% mortality within 1 year.17Arvaniti V. D'Amico G. Fede G. et al.Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis.Gastroenterology. 2010; 139 (1256 e1–5): 1246-1256Abstract Full Text Full Text PDF PubMed Scopus (733) Google Scholar This suggests that, in the natural history of cirrhosis, patients eventually progress past a certain "point of no return," after which their circulatory system's compensatory ability is permanently and irreversibly impaired.18Ruiz-del-Arbol L. Urman J. Fernandez J. et al.Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis.Hepatology. 2003; 38: 1210-1218Crossref PubMed Scopus (386) Google Scholar This is the point at which the "window" closes, and where the hemodynamic effects of β blockers become significant and harmful if restarted or continued. It goes without saying that additional prospective studies on the use of β blockers in patients with advanced cirrhosis are warranted. In particular, the addition of midodrine to support blood pressure in patients taking β blockers should be studied. Midodrine has been shown to improve survival in patients with cirrhosis and refractory ascites.19Singh V. Dhungana S.P. Singh B. et al.Midodrine in patients with cirrhosis and refractory or recurrent ascites: a randomized pilot study.J Hepatol. 2012; 56: 348-354Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar An increasing amount of evidence is demonstrating decreased survival and increased risk of harm when β blockers are used too liberally in patients with advanced cirrhosis. The next iteration of the American Association for the Study of Liver Diseases and European Association for the Study of the Liver practice guidelines on the prevention and management of variceal hemorrhage will need to incorporate these recent studies and their clinical implications. Recent studies are increasingly suggesting that the use of β blockers is beneficial only within a small "window" of clinical opportunity, one which may be even smaller than it seemed in the past. Nonselective β Blockers Increase Risk for Hepatorenal Syndrome and Death in Patients With Cirrhosis and Spontaneous Bacterial PeritonitisGastroenterologyVol. 146Issue 7PreviewNonselective β blockers (NSBBs) reduce portal pressure and the risk for variceal hemorrhage in patients with cirrhosis. However, development of spontaneous bacterial peritonitis (SBP) in these patients could preclude treatment with NSBBs because of their effects on the circulatory reserve. We investigated the effects of NSBBs in patients with cirrhosis and ascites with and without SBP. Full-Text PDF Covering the CoverGastroenterologyVol. 146Issue 7PreviewAbnormalities in ion channels, such as voltage-gated sodium channels, that are directly involved in gastrointestinal motility and visceral pain may be a genetic factor in the pathogenesis of irritable bowel syndrome (IBS). One of these, the tetrodotoxin-resistant sodium channel NaV1.5 (encoded by SCN5A), is expressed in human smooth muscle cells and the interstitial cells of Cajal, the gastrointestinal pacemakers that provide an electrical stimulus for contraction. Inhibition of NaV1.5, which is also expressed in human myocardium, by the anti-anginal agent, ranolazine, is associated with constipation and patients with arrhythmia-predisposing mutations in SCN5A are more likely to have gastrointestinal symptoms compared with patients with other arrhythmia-associated ion channel defects. Full-Text PDF
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