From the AGA Journals

Stop beta-blockers in spontaneous bacterial peritonitis

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The closing window on beta-blocker therapy in cirrhosis

The beta-blocker controversy continues in this issue of Gastroenterology, with an exciting study from Mandorfer and colleagues on the detrimental effect of beta-blocker treatment after the development of spontaneous bacterial peritonitis in patients with cirrhosis. In this retrospective cohort study, nonselective beta-blockers were shown to increase transplant-free survival in patients without SBP. However, following the first diagnosis of SBP, nonselective beta-blockers were associated with hemodynamic compromise and decreased blood pressures, reduced transplant-free survival, increased hospitalization rates, and increased incidence of hepatorenal syndrome and acute kidney injury. The authors conclude that patients with cirrhosis and SBP should not receive beta-blocker therapy.

The clinical implications of this study are far-reaching. Beta-blockers are well established in the primary and secondary prevention of variceal hemorrhage in patients with cirrhosis, and critics are likely to point out the retrospective nature of this study. However, several recent and similarly controversial studies have also suggested harm with beta-blocker therapy in patients with advanced cirrhosis. This has led to the proposal of a "window hypothesis," in which beta-blockers improve survival within a limited window in the natural history of cirrhosis.

The current study adds to the mounting body of evidence in support of the "window hypothesis," and suggests furthermore that the therapeutic window closes at the first onset of SBP. Whether or not the window reopens is up for debate; however, it is increasingly clear that beta-blocker therapy in patients with cirrhosis is only beneficial within a small window of opportunity, quite possibly smaller than previously thought.

Dr. Phillip S. Ge and Dr. Bruce A. Runyon are with the division of digestive diseases/hepatology, Santa Monica-UCLA [University of California, Los Angeles] Medical Center. The authors disclosed no potential conflicts of interest.



Nonselective beta-blockers are contraindicated in cirrhosis with spontaneous bacterial peritonitis, wrote Dr. Mattias Mandorfer and his colleagues in the June issue of Gastroenterology (doi: 10.1053/j.gastro.2014.03.005).

Indeed, in a retrospective analysis, the drugs increased the length of hospitalization and the rate of hepatorenal syndrome, while decreasing overall transplant-free survival.

"These observations suggest that nonselective beta-blocker treatment should be discontinued at the first development of spontaneous bacterial peritonitis (SBP), raising the question of whether to permanently discontinue or to restart ... treatment after resolving the SBP episode," they added.

Dr. Mandorfer, of the Medical University of Vienna, and his colleagues followed 607 consecutive cirrhosis patients who underwent their first paracentesis at that institution between 2006 and 2011.

Overall, 245 patients were taking beta-blockers, including propranolol, with doses ranging from 20 to 120 mg, and carvedilol, with doses between 6.25 and 25 mg.

Spontaneous bacterial peritonitis was defined as an ascitic polymorphonuclear neutrophil count greater than 250 cells/mL with no evident source of infection.

A total of 182 cases of a first SBP infection were detected during the study period and included for analysis (86 in beta-blocker patients), with incidence rates comparable between beta-blocker and non–beta-blocker cohorts (0.107 vs, 0.117 per person-year, respectively).

The authors found that a higher proportion of beta-blocker patients were hemodynamically unstable, with 38% registering mean systolic arterial pressures less than 100 mm Hg at the time of first paracentesis during an SBP episode, compared with 18% of non–beta-blocker patients (P = .002).

And although variceal bleeding rates were similar between cohorts, beta-blocker patients tallied overall longer durations of hospitalization than did their untreated counterparts (33.4 vs. 28.8 days per person-year).

Looking at the development of hepatorenal syndrome, Dr. Mandorfer also noted that the incidence was significantly higher in patients taking beta-blockers (24%) than in patients who were not (11%; P = .027).

Perhaps most importantly, while beta-blocker treatment was associated with improved transplant-free survival generally, after SBP diagnosis, taking beta-blockers resulted in a lower transplant-free survival (hazard ratio, 1.58; 95% confidence interval, 1.098-2.274; P = .014) after adjustment for the presence of varices and the Child-Pugh score.

According to Dr. Mandorfer, the present study adds another voice to the "lively debate" that began after a 2010 study showed that beta-blockers had deleterious effects on survival (Hepatology 2010;52:1017-22).

And while these findings support the "window hypothesis," which posits that the optimal "window" for beta-blocker treatment opens at the diagnosis of cirrhosis but closes at the development of SBP, "whether the therapeutic window for [beta-blocker] treatment reopens after resolving the SBP episode remains unclear," they wrote.

Indeed, "The development of bacterial infections might define a distinct group of critically ill patients with cirrhosis with a highly restricted prognosis in which maintaining the circulatory reserve is crucial not only during the acute phase of infection but also later on," they added.

"Prospective studies are highly encouraged to investigate the appropriate, stage-dependent use of this cornerstone in the treatment of portal hypertension."

The authors stated that they had no conflicts of interest and disclosed no funding for this study.

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