Research Spotlight

Asrani, S. K., J. Trotter, J. Lake, A. Ahmed, A. Bonagura, A. Cameron, A. DiMartini, S. Gonzalez, G. Im, P. Martin, P. Mathurin, J. Mellinger, J. P. Rice, V. H. Shah, N. Terrault, A. Wall, S. Winder and G. Klintmalm (2020). “Meeting Report: The Dallas Consensus Conference on Liver Transplantation for Alcohol Associated Hepatitis.” Liver Transpl 26(1): 127-140.

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Liver transplantation (LT) for alcohol associated hepatitis (AH) remains controversial. We convened a consensus conference to examine various aspects of LT for AH. The goal was not to unequivocally endorse LT for AH; instead, it was to propose recommendations for programs that perform or plan to perform LT for AH. Criteria were established to determine candidacy for LT in the setting of AH and included the following: (1) AH patients presenting for the first time with decompensated liver disease that are nonresponders to medical therapy without severe medical or psychiatric comorbidities; (2) a fixed period of abstinence prior to transplantation is not required; and (3) assessment with a multidisciplinary psychosocial team, including a social worker and an addiction specialist/mental health professional with addiction and transplantation expertise. Supporting factors included lack of repeated unsuccessful attempts at addiction rehabilitation, lack of other substance use/dependency, acceptance of diagnosis/insight with a commitment of the patient/family to sobriety, and formalized agreement to adhere to total alcohol abstinence and counseling. LT should be avoided in AH patients who are likely to spontaneously recover. Short-term and longterm survival comparable to other indications for LT must be achieved. There should not be further disparity in LT either by indication, geography, or other sociodemographic factors. Treatment of alcohol-use disorders should be incorporated into pre- and post-LT care. The restrictive and focused evaluation process described in the initial LT experience for AH worldwide may not endure as this indication gains wider acceptance at more LT programs. Transparency in the selection process is crucial and requires the collection of objective data to assess outcomes and minimize center variation in listing. Oversight of program adherence is important to harmonize listing practices and outcomes.

Younossi, Z. M., V. Ratziu, R. Loomba, M. Rinella, Q. M. Anstee, Z. Goodman, P. Bedossa, A. Geier, S. Beckebaum, P. N. Newsome, D. Sheridan, M. Y. Sheikh, J. Trotter [ . . . ] and A. J. Sanyal (2019). “Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial.” Lancet 394(10215): 2184-2196.

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BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. METHODS: In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2-F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (>/=1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2-F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. FINDINGS: Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1-F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2-F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0.045), and 71 (23%) in the obeticholic acid 25 mg group (p=0.0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0.18], and 36 [12%] in the obeticholic acid 25 mg group [p=0.13]). In the safety population (1968 patients with fibrosis stages F1-F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). INTERPRETATION: Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes. FUNDING: Intercept Pharmaceuticals.

Mack, M., K. Al-Azizi and M. J. Reardon (2019). “Ninety-Day Outcome Assessment After Transcatheter and Surgical Aortic Valve Replacement-Is the Juice Worth the Squeeze?” JAMA Cardiol Dec 18. [Epub ahead of print].

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Measurement of outcomes after surgery and transcatheter valve interventions have become standard for quality assessment, performance improvement, and comparative effectiveness reporting and research. Public reporting of procedural outcomes has also become required in some states and is increasingly performed nationally. Initially, hospital performance measurement of outcomes after cardiac surgical procedures were limited to in-hospital mortality and major morbidity rates, because the data were readily available, relatively complete, and not overly burdensome for sites to collect. However, it soon became apparent that capturing in-hospital mortality and complication rates alone was not truly reflective of procedural outcomes, with up to one-third of periprocedural mortality occurring after hospital discharge but before 30 days. Hence, professional society–based clinical registries changed the main outcome performance metric to operative mortality and included any death that occurred during the initial hospital stay, independent of time, and any death within 30 days, independent of location. This hospital performance metric more accurately reflected the true outcomes after surgery and minimized the possibility of gaming reporting, but it did add a considerable burden of data collection to hospitals. Thus, 30-day mortality and major morbidity rates have become the foundation of procedure risk models and are the basis for the Society for Thoracic Surgeons’ 3-star hospital rating of cardiac surgery performance.

Menter, A., K. M. Cordoro, D. M. R. Davis, D. Kroshinsky, A. S. Paller, A. W. Armstrong, C. Connor, B. E. Elewski, J. M. Gelfand, K. B. Gordon, A. B. Gottlieb, D. H. Kaplan, A. Kavanaugh, M. Kiselica, D. Kivelevitch, N. J. Korman, M. Lebwohl, C. L. Leonardi, J. Lichten, H. W. Lim, N. N. Mehta, S. L. Parra, A. L. Pathy, E. A. Farley Prater, R. N. Rupani, M. Siegel, B. Stoff, B. E. Strober, E. B. Wong, J. J. Wu, V. Hariharan and C. A. Elmets (2020). “Joint American Academy of Dermatology-National Psoriasis Foundation guidelines of care for the management and treatment of psoriasis in pediatric patients.” J Am Acad Dermatol 82(1): 161-201.

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Psoriasis is a chronic, multisystem, inflammatory disease that affects approximately 1% of children, with onset most common during adolescence. This guideline addresses important clinical questions that arise in psoriasis management and provides evidence-based recommendations. Attention will be given to pediatric patients with psoriasis, recognizing the unique physiology, pharmacokinetics, and patient-parent-provider interactions of patients younger than 18 years old. The topics reviewed here mirror those discussed in the adult guideline sections, excluding those topics that are irrelevant to, or lack sufficient information for, pediatric patients.

Packer, M. (2019). “Why Are Physicians So Confused about Acute Heart Failure? Reply.” N Engl J Med 381(24): 2375-2376.

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[The author’s response to letters concerning his commentary, “Why are physicians so confused about acute heart failure?” N Engl J Med 2019; Aug 22; 381(8):776-777.]