Robert S. Rahimi M.D.

Safadi, R., Rahimi, R. S., Thabut, D., Bajaj, J. S., Ram Bhamidimarri, K., Pyrsopoulos, N., Potthoff, A., Bukofzer, S., Wang, L., Jamil, K. and Devarakonda, K. R. (2022). “Pharmacokinetics/pharmacodynamics of L-ornithine phenylacetate in overt hepatic encephalopathy and the effect of plasma ammonia concentration reduction on clinical outcomes.” Clin Transl Sci.

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Hepatic encephalopathy (HE) is a serious neurocognitive complication of liver dysfunction, often associated with elevated plasma ammonia. Ornithine phenylacetate (OP), a potent ammonia scavenger, is being evaluated for the treatment of acute/overt HE. The pharmacokinetics and pharmacodynamics of OP in patients with HE were characterized in this phase IIb study (NCT01966419). Adult patients hospitalized with an overt HE episode, cirrhosis, and plasma ammonia above the upper limit of normal (ULN) who failed to improve after 48 hours’ standard care were randomly assigned to continuous intravenous OP (10, 15, or 20 g/day, based on Child-Turcotte-Pugh score) or matching placebo for 5 days. Plasma levels of ornithine and phenylacetic acid (PAA) and plasma/urinary levels of phenylacetylglutamine (PAGN) (primary metabolite of PAA) were regularly assessed; plasma ammonia level was the primary pharmacodynamic variable. PAA demonstrated dose-dependent pharmacokinetics; ornithine and PAGN levels increased with dose. PAGN urinary excretion represented ~50%-60% of administered PAA across all doses. Mean reduction in plasma ammonia with OP at 3 hours postinfusion was significantly greater versus placebo (p = 0.014); and time to achieve plasma ammonia less than or equal to the ULN was significantly reduced (p = 0.028). Achievement of clinical response based on HE stage was associated with a greater reduction in mean plasma ammonia level (p = 0.009). OP effects on plasma ammonia were consistent with its proposed mechanism of action as a primary ammonia scavenger, with a significant association between reduced plasma ammonia and improvement in HE stage. OP should be further evaluated as a promising treatment for hyperammonemia in patients with overt HE.

Sundaram, V., Patel, S., Shetty, K., Lindenmeyer, C. C., Rahimi, R. S., Flocco, G., Al-Attar, A., Karvellas, C. J., Challa, S., Maddur, H., Jou, J. H., Kriss, M., Stein, L. L., Xiao, A. H., Vyhmeister, R. H., Green, E. W., Campbell, B., Cranford, W., Mahmud, N. and Fortune, B. E. (2022). “Risk Factors for Posttransplantation Mortality in Recipients With Grade 3 Acute-on-Chronic Liver Failure: Analysis of a North American Consortium.” Liver Transpl.

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Although liver transplantation (LT) yields survival benefit for patients with acute-on-chronic liver failure grade 3 (ACLF-3), knowledge gaps remain regarding risk factors for post-LT mortality. We retrospectively reviewed data from 10 centers in the United States and Canada for patients transplanted between 2018 and 2019 and who required care in the intensive care unit prior to LT. ACLF was identified using the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) criteria. A total of 318 patients were studied, of whom 106 (33.3%) had no ACLF, 61 (19.1%) had ACLF-1, 74 (23.2%) had ACLF-2, and 77 (24.2%) had ACLF-3 at transplantation. Survival probability 1 year after LT was significantly higher in patients without ACLF (94.3%) compared with patients with ACLF (87.3%; P = 0.02), but similar between ACLF-1 (88.5%), ACLF-2 (87.8%), and ACLF-3 (85.7%; P = 0.26). Recipients with ACLF-3 and circulatory failure (n = 29) had similar 1-year post-LT survival (82.3%) compared with patients with ACLF-3 without circulatory failure (89.6%; P = 0.32), including those requiring multiple vasopressors. For patients transplanted with ACLF-3 including respiratory failure (n = 20), there was a trend toward significantly lower post-LT survival (P = 0.07) among those with respiratory failure (74.1%) compared with those without (91.0%). The presence of portal vein thrombosis (PVT) at LT for patients with ACLF-3 (n = 15), however, yielded significantly lower survival (91.9% versus 57.1%; P < 0.001). Multivariable logistic regression analysis revealed that PVT was significantly associated with post-LT mortality within 1 year (odds ratio, 7.3; 95% confidence interval, 1.9-28.3). No correlation was found between survival after LT and the location or extent of PVT, presence of transjugular intrahepatic portosystemic shunt, or anticoagulation. LT in patients with ACLF-3 requiring vasopressors yields excellent 1-year survival. LT should be approached cautiously among candidates with ACLF-3 and PVT.

Berry, K., Duarte-Rojo, A., Grab, J.D., Dunn, M.A., Boyarsky, B.J., Verna, E.C., Kappus, M.R., Volk, M.L., McAdams-DeMarco, M., Segev, D.L., Ganger, D.R., Ladner, D.P., Shui, A., Tincopa, M.A., Rahimi, R.S. and Lai, J.C. (2022). “Cognitive Impairment and Physical Frailty in Patients With Cirrhosis.” Hepatol Commun 6(1): 237-246.

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Physical frailty and impaired cognition are common in patients with cirrhosis. Physical frailty can be assessed using performance-based tests, but the extent to which impaired cognition may impact performance is not well characterized. We assessed the relationship between impaired cognition and physical frailty in patients with cirrhosis. We enrolled 1,623 ambulatory adult patients with cirrhosis waiting for liver transplantation at 10 sites. Frailty was assessed with the liver frailty index (LFI; “frail,” LFI ≥ 4.4). Cognition was assessed at the same visit with the number connection test (NCT); continuous “impaired cognition” was examined in primary analysis, with longer NCT (more seconds) indicating worse impaired cognition. For descriptive statistics, “impaired cognition” was NCT ≥ 45 seconds. Linear regression associated frailty and impaired cognition; competing risk regression estimated subhazard ratios (sHRs) of wait-list mortality (i.e., death/delisting for sickness). Median NCT was 41 seconds, and 42% had impaired cognition. Median LFI (4.2 vs. 3.8) and rates of frailty (38% vs. 20%) differed between those with and without impaired cognition. In adjusted analysis, every 10-second NCT increase associated with a 0.08-LFI increase (95% confidence interval [CI], 0.07-0.10). In univariable analysis, both frailty (sHR, 1.63; 95% CI, 1.43-1.87) and impaired cognition (sHR, 1.07; 95% CI, 1.04-1.10) associated with wait-list mortality. After adjustment, frailty but not impaired cognition remained significantly associated with wait-list mortality (sHR, 1.55; 95% CI, 1.33-1.79). Impaired cognition mediated 7.4% (95% CI, 2.0%-16.4%) of the total effect of frailty on 1-year wait-list mortality. Conclusion: Patients with cirrhosis with higher impaired cognition displayed higher rates of physical frailty, yet frailty independently associated with wait-list mortality while impaired cognition did not. Our data provide evidence for using the LFI to understand mortality risk in patients with cirrhosis, even when concurrent impaired cognition varies.

Rahimi, R.S., Safadi, R., Thabut, D., Bhamidimarri, K.R., Pyrsopoulos, N., Potthoff, A., Bukofzer, S. and Bajaj, J.S. (2021). “Efficacy and Safety of Ornithine Phenylacetate for Treating Overt Hepatic Encephalopathy in a Randomized Trial.” Clin Gastroenterol Hepatol 19(12): 2626-2635.e2627.

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BACKGROUND & AIMS: Hepatic encephalopathy (HE) is associated with increased morbidity, mortality, and health care 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 assigned randomly to groups that received placebo or OP (10, 15, or 20 g/d, based on the severity of liver disease), plus each institution’s standard of care (eg, lactulose to achieve 2-3 bowel movements with or without rifaximin, in accordance with guidelines). The primary end point was time to confirmed clinical response, defined as reduction to HE staging tool (HEST) stage 2 from baseline HEST stages 3/4 or improvement to HEST stages 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) showed 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 in 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. ClinicalTrials.gov no: NCT01966419.

Lai, J.C., Shui, A.M., Duarte-Rojo, A., Ganger, D.R., Rahimi, R.S., Huang, C.Y., Yao, F., Kappus, M., Boyarsky, B., McAdams-Demarco, M., Volk, M.L., Dunn, M.A., Ladner, D.P., Segev, D.L., Verna, E.C. and Feng, S. (2021). “Frailty, Mortality, and Healthcare Utilization after Liver Transplantation: From the Multi-Center Functional Assessment in Liver Transplantation (FrAILT) Study.” Hepatology Dec 4. [Epub ahead of print].

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BACKGROUND: Frailty is a well-established risk factor for poor outcomes in patients with cirrhosis awaiting liver transplantation (LT), but whether it predicts outcomes among those who have undergone LT is unknown. METHODS: Adults LT recipients from 8 U.S. centers (2012-2019) were included. Pre-LT frailty was assessed in the ambulatory clinic using the Liver Frailty Index (LFI). “Frail” was defined by an optimal cut point of LFI≥4.5. We used the 75%ile to define “prolonged” post-LT length of stay (LOS; ≥12d), intensive care unit (ICU; ≥4d) days, and inpatient days within 90 post-LT days (≥17d). RESULTS: Of 1,166 LT recipients, 21% were frail pre-LT. Cumulative incidence of death at 1- and 5-years was 6% and 16% for frail and 4% and 10% for non-frail patients (overall logrank p=0.02). Pre-LT frailty was associated with an unadjusted 62% increased risk of post-LT mortality (95% CI 1.08-2.44); after adjustment for body mass index, HCC, donor age, and DCD status, the HR was 2.13 (95% CI 1.39-3.26). Patients who were frail versus non-frail experienced a higher adjusted odds of prolonged LT LOS [odds ratio (OR) 2.00, 95% CI 1.47-2.73], ICU stay (OR 1.56, 95% CI 1.12-2.14), inpatient days within 90 post-LT days (OR 1.72, 95% 1.25-2.37), and non-home discharge (OR 2.50, 95% 1.58-3.97). CONCLUSIONS: Compared to non-frail patients, frail LT recipients had a higher risk of post-LT death and greater post-LT healthcare utilization, although overall post-LT survival was acceptable. These data lay the foundation to investigate whether targeting pre-LT frailty will improve post-LT outcomes and reduce resource utilization.