Patients with decompensated cirrhosis who were already taking nonselective beta-blockers when they developed acute kidney injury were more likely to recover kidney function and less likely to die within 28 days than patients who were not taking the drugs, according to a large international prospective cohort study. The findings also suggest that routinely stopping these medications after acute kidney injury develops may not improve outcomes, raising questions about current practice recommendations, which are based largely on expert opinion rather than clinical evidence.
The study, published in the Journal of Hepatology, examined the use of nonselective beta-blockers (NSBBs) in patients hospitalized with acute decompensation of cirrhosis and acute kidney injury (AKI). Current European and Baveno guidelines recommend stopping NSBBs when AKI develops because of concerns that they may further reduce cardiac output and blood flow to the kidneys, potentially worsening kidney injury. However, the investigators noted that no prospective study had previously tested whether this approach improves clinical outcomes.
Corresponding author Salvatore Piano, MD, PhD, of the unit of internal medicine and hepatology in the department of medicine at the University of Padova, Italy, and colleagues conducted a post hoc analysis of the International Club of Ascites GLOBAL AKI study, a prospective cohort that enrolled patients at 65 centers in 27 countries between July 2022 and May 2023. The analysis included 1,238 adults hospitalized with decompensated cirrhosis and AKI. At the time AKI was diagnosed, 503 patients were taking propranolol or carvedilol and 735 were not. Among those receiving nonselective beta-blockers, about 55% were taking propranolol, 45% were taking carvedilol, and nearly 90% were receiving relatively low doses.
To account for differences between the treatment groups, the investigators used inverse probability of treatment weighting to balance patient characteristics, including demographics, liver disease severity, hemodynamic status, AKI stage, and acute-on-chronic liver failure (ACLF). The primary outcome was complete recovery of kidney function within 28 days, defined as serum creatinine returning to within 0.3 mg/dL of baseline. The secondary outcome was death within 28 days.
After adjustment, patients who were taking NSBBs when AKI was diagnosed were 29% more likely to recover kidney function completely than those who were not taking the drugs. Overall, complete AKI recovery occurred in 67% of patients taking NSBBs vs. 54% of those who were not.
NSBB treatment also was associated with a lower risk for short-term death. By 28 days, adjusted mortality was 22% among patients taking NSBBs vs. 28% among those who were not. Overall, 286 patients died and 64 underwent liver transplantation within 28 days after AKI was diagnosed. After adjustment, patients receiving NSBBs were 30% less likely to die than those who were not taking the drugs.
The survival benefit was most consistent among patients taking low-dose beta-blockers, those with a mean arterial pressure of at least 70 mm Hg, a serum sodium level of at least 130 mmol/L, ascites, stage 2 or 3 AKI, and no ACLF. Outcomes were similar with propranolol and carvedilol.
The investigators also examined whether continuing NSBB therapy after hospitalization affected outcomes. Among patients who were taking NSBBs when they were admitted, treatment was reassessed 48 to 72 hours after AKI was diagnosed. After excluding patients with circulatory failure requiring vasopressors or grade 3 ACLF, 122 patients continued taking NSBBs at the same dose, while 290 had their dose reduced or the medication stopped.
After adjustment, continuing NSBB therapy was not linked to either better or worse outcomes. Rates of complete AKI recovery and 28-day mortality were similar whether patients continued treatment or had their dose reduced or the medication stopped. Likewise, among patients whose NSBBs were discontinued during hospitalization, restarting treatment at discharge was not associated with a significant difference in 28-day survival. The investigators cautioned, however, that this analysis was exploratory because of the short follow-up period.
For practicing physicians, the findings suggest that AKI alone may not be a reason to automatically stop NSBB therapy. Instead, treatment decisions should be based on the patient's overall clinical condition, the investigators suggested. The investigators noted that stopping NSBBs remains appropriate for patients with severe hypotension or circulatory failure but suggested that routine discontinuation may not be necessary for all patients with AKI.
The authors noted several limitations. Because this was an observational study rather than a randomized trial, residual confounding cannot be ruled out despite statistical adjustment. Patients already taking NSBBs may also have been healthier because they had previously tolerated the drugs. The investigators did not have information on how long patients had been taking NSBBs before developing AKI, reasons for stopping treatment during hospitalization were not consistently recorded, and data on refractory ascites were unavailable. In addition, nearly 90% of treated patients received low-dose therapy, limiting conclusions about higher doses. Finally, the study defined kidney recovery using serum creatinine, which may overestimate recovery in patients with cirrhosis and sarcopenia.
The study was funded by a European Association for the Study of the Liver Registry Grant and a grant from the Italian Association for Internal Medicine. Dr. Piano and multiple authors reported relationships with pharmaceutical companies, including advisory board, consulting, speaking, research funding, and patent-related activities.
Expert Insight
GI & Hepatology News asked Dr. Piano to put the findings into clinical perspective.
How should these findings change your approach to NSBB management in decompensated cirrhosis with AKI?
Dr. Piano: Our findings argue against the reflex of stopping NSBB in every patient who develops AKI. In more than 1,200 patients from 65 centers worldwide, being on an NSBB at AKI diagnosis was associated with a higher likelihood of AKI resolution and lower 28-day mortality. We found no signal that early tapering or withdrawal improved either renal recovery or survival. Practically, this means NSBB management should be individualized rather than automatic. Decisions should be guided by the patient’s hemodynamic status and overall clinical condition rather than by the diagnosis of AKI alone. It is worth noting that in our study only 24% of patients on NSBB had them continued after AKI, highlighting how common routine withdrawal remains in clinical practice.
Which patients should still have NSBB discontinued?
Dr. Piano: For sure patients with severe arterial hypotension or circulatory failure requiring vasopressors. No patient in whom NSBB were continued had circulatory failure or grade 3 ACLF at 48–72 hours, so these 59 patients were deliberately excluded from the comparative analysis because treatment continuation was not clinically feasible. Therefore, our findings should not be extrapolated to this high-risk population.
Effects in that high-risk group simply could not be estimated. Beyond that, I would remain cautious in patients with a mean arterial pressure below 65 mm Hg, where impaired kidney perfusion makes the hemodynamic effects of NSBB potentially detrimental.
What additional evidence is needed before guidelines change?
Dr. Piano: First, it is important to recognize that current recommendations to discontinue NSBB during AKI are based largely on expert opinion and relatively small observational studies rather than robust prospective evidence.
Our study provides substantially stronger evidence, but it remains observational despite the use of inverse probability of treatment weighting adjustment, and we cannot exclude residual confounding. We also lacked information on the duration of prior NSBB exposure and the reasons clinicians chose to discontinue treatment.
A randomized trial comparing continuation versus withdrawal in hemodynamically stable patients with AKI would provide the strongest evidence, although such a study is unlikely to be feasible.
Beyond that, we need mechanistic studies to better understand whether the observed benefit is primarily related to anti-inflammatory effects, hemodynamic effects, or both. Additional data in patients with refractory ascites, those receiving higher NSBB doses, and studies identifying the subgroup that truly benefits from NSBB withdrawal would be particularly valuable.