Robert S. Rahimi M.D.

Rahimi, R.S., Safadi, R., Thabut, D., Bhamidimarri, K.R., Pyrsopoulos, N., Potthoff, A., Bukofzer, S. and Bajaj, J.S. (2020). “Efficacy and Safety of Ornithine Phenylacetate for Treating Overt Hepatic Encephalopathy in a Randomized Trial.” Clin Gastroenterol Hepatol Oct 15;S1542-3565(20)31432-4. [Epub ahead of print].

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BACKGROUND & AIMS: Hepatic encephalopathy (HE) is associated with increased morbidity, mortality, and healthcare resource use. In this phase 2b study, we evaluated the efficacy and safety of ornithine phenylacetate (OP), an ammonia scavenger, in hospitalized patients with cirrhosis, increased levels of ammonia at screening, and acute or overt HE. METHODS: We conducted a double-blind study of 231 patients with cirrhosis and HE at multiple sites in North America, Europe, Israel, and Australia from January 7, 2014, through December 29, 2016. Patients were randomly assigned to groups that received placebo or OP (10, 15, or 20 g/day, based on severity of liver disease), plus each institution’s standard of care (for example, lactulose to achieve 2-3 bowel movements with or without rifaximin, in accordance with guidelines). The primary endpoint was time to confirmed clinical response, defined as reduction to HE staging tool (HEST) stage 2 from baseline HEST stage 3/4 or improvement to HEST stage 0/1 from baseline stage 2, in the intent to treat population (all patients with increased levels of ammonia at screening, determined by a local laboratory). RESULTS: Median times to clinical improvement, based on ammonia measurements at local laboratories, did not differ significantly between the groups given OP vs the placebo group (P=.129). Analyses of central laboratory confirmed increases in levels of ammonia at baseline (n=201) revealed a clinical improvement in HE at a median of 21 hours sooner in groups given OP vs placebo. The percentages of patients with any specific adverse event did not differ significantly between groups. Serious adverse events occurred in 25% of patients in the OP group and 29% in the placebo group (P=.552). CONCLUSIONS: In a randomized controlled trial of patients with cirrhosis and HE, we found no significant difference in time to clinical improvement between patients given OP vs placebo. However, OP appears to be safe and should undergo further testing for treatment of hyperammonemia in hospitalized patients receiving treatment for the underlying precipitant of acute or overt HE.

Sundaram, V., N. Mahmud, G. Perricone, D. Katarey, R. J. Wong, C. J. Karvellas, B. E. Fortune, R. S. Rahimi, H. Maddur, J. H. Jou, M. Kriss, L. L. Stein, M. Lee and R. Jalan (2020). “Long-term outcomes of patients undergoing liver transplantation for acute-on-chronic liver failure.” Liver Transpl Jun 23. [Epub ahead of print.].

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AIMS: Recent data have demonstrated greater than 80% one-year survival probability after liver transplantation (LT) for patients with severe acute on chronic liver failure (ACLF). However, long term outcomes and complications are still unknown for this population. Our aim was to compare long-term patient and graft survival among patients transplanted across all grades of ACLF. METHODS: We analyzed the UNOS database, years 2004-2017. Patients with ACLF were identified using the EASL-CLIF criteria. Kaplan-Meier and Cox regression methods were used to determine patient and graft survival and associated predictors of mortality in adjusted models. RESULTS: A total of 75,844 patients were transplanted of which 48,854 (64.4%) had no ACLF, 9,337 (12.3%) had ACLF-1, 9,386 (12.4%) had ACLF-2 and 8,267 (10.9%) had ACLF-3. Patients transplanted without ACLF had a greater proportion of hepatocellular carcinoma within (23.8%) and outside (12.7%) Milan criteria. Five-year patient survival after LT was lower in the ACLF-3 patients compared with the other groups (67.7%, p<0.001), although after year 1, the percentage decrease in survival was similar among all groups. Infection was the primary cause of death among all patient groups in the first year. After the first year, infection was the main cause of death in patients transplanted with ACLF-1 (31.1%), ACLF-2 (33.3%) and ACLF-3 (36.7%), whereas malignancy was the predominant cause of death in those transplanted with no ACLF (38.5%). Graft survival probability at 5 years was above 90% among all patient groups. CONCLUSION: Patients transplanted with ACLF-3 have lower 5-year survival as compared to ACLF 0-2 but mortality rates were not significantly different after the first year following LT. Graft survival was excellent across all ACLF groups.

Bajaj, J. S., M. Lauridsen, E. B. Tapper, A. Duarte-Rojo, R. S. Rahimi, P. Tandon, D. L. Shawcross, D. Thabut, R. K. Dhiman, M. Romero-Gomez, B. C. Sharma and S. Montagnese (2020). “Important Unresolved Questions in the Management of Hepatic Encephalopathy: An ISHEN Consensus.” Am J Gastroenterol 115(7): 989-1002.

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Management of hepatic encephalopathy (HE) remains challenging from a medical and psychosocial perspective. Members of the International Society for Hepatic Encephalopathy and Nitrogen Metabolism recognized 5 key unresolved questions in HE management focused on (i) driving, (ii) ammonia levels in clinical practice, (iii) testing strategies for covert or minimal HE, (iv) therapeutic options, and (v) nutrition and patient-reported outcomes. The consensus document addresses these topical issues with a succinct review of the literature and statements that critically evaluate the current science and practice, laying the groundwork for future investigations.

Kardashian, A., J. Ge, C. E. McCulloch, M. R. Kappus, M. A. Dunn, A. Duarte-Rojo, M. L. Volk, R. S. Rahimi, E. C. Verna, D. R. Ganger, D. Ladner, J. L. Dodge, B. Boyarsky, M. McAdams-DeMarco, D. L. Segev and J. C. Lai (2020). “Identifying an Optimal Liver Frailty Index Cutoff to Predict Waitlist Mortality in Liver Transplant Candidates.” Hepatology June 3. [Epub ahead of print].

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BACKGROUND & AIMS: Frailty, as measured by the liver frailty index (LFI), is associated with liver transplant (LT) waitlist mortality. We sought to identify an optimal LFI cutoff that predicts waitlist mortality. APPROACH&RESULTS: Adults with cirrhosis awaiting LT without hepatocellular carcinoma at 9 LT centers in the United States with LFI assessments were included. Multivariable competing risk analysis assessed the relationship between LFI and waitlist mortality. We identified a single LFI cutoff by evaluating the fit of the competing risk models, searching for the cutoff that gave the best model fit (as judged by the pseudo-log-likelihood). We ascertained the area under the curve (AUC) in an analysis of waitlist mortality to find optimal cutoffs at 3, 6, or 12 months. We used the AUC to compare the discriminative ability of LFI+Model for End Stage Liver Disease-sodium (MELDNa) versus MELDNa alone in 3-month waitlist mortality prediction. Of 1,405 patients, 37(3%), 82(6%), and 135(10%) experienced waitlist mortality at 3, 6, and 12 months, respectively. LFI was predictive of waitlist mortality across a broad LFI range: 3.7-5.2. We identified an optimal LFI cutoff of 4.4 (95%CI:4.0-4.8) for 3-month, 4.2 (95%CI:4.1-4.4) for 6-month, and 4.2 (95%CI:4.1-4.4) for 12-month mortality. The AUC for prediction of 3-month mortality for MELDNa was 0.73; the addition of LFI to MELDNa improved the AUC to 0.79. CONCLUSIONS: LFI is predictive of waitlist mortality across a wide spectrum of LFI values. The optimal LFI cutoff for waitlist mortality was 4.4 at 3 months and 4.2 at 6 and 12 months. The discriminative performance of LFI+MELDNa was greater than MELDNa alone. Our data suggest that incorporating LFI with MELDNa can more accurately represent waitlist mortality in LT candidates.

Tapper, E. B. and R. S. Rahimi (2020). “Low-Value Levels: Ammonia Testing Does Not Improve the Outcomes of Overt Hepatic Encephalopathy.” Am J Gastroenterol 115(5): 685-686.

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Hepatic encephalopathy is a clinical diagnosis. However, many clinicians measure ammonia levels in hospitalized patients presenting with hepatic encephalopathy. In this editorial, we review the results of an important study by Haj and Rockey. The authors examined the management decisions effected affected by and outcomes associated with (i) ordering an ammonia level and (ii) knowing the ammonia level. They found that ammonia level determination did not impact affect clinical decision-making or patient outcomes. These persuasive data demonstrate the limited clinical utility of ammonia levels and highlight the need for testing stewardship to dissuade unnecessary use through educational efforts and decision supports.