SACRED: Effect of simvastatin on hepatic decompensation and death in subjects with high-risk compensated cirrhosis: Statins and Cirrhosis: Reducing Events of Decompensation.

BACKGROUND/AIMS: The development of decompensation in cirrhosis demarcates a marked change in the natural history of chronic liver disease. HMG-CoA reductase inhibitors (statins) exert pleiotropic effects that reduce inflammation and fibrosis as well as improve vascular reactivity. Retrospective studies uniformly have associated statin utilization with improved outcomes for patients with cirrhosis. Prospective human studies have shown that statins reduce portal hypertension and reduce death in patients with decompensated cirrhosis after variceal hemorrhage when added to standard therapy with an acceptable safety profile. This proposal aims to extend these findings to demonstrate that simvastatin reduces incident hepatic decompensation events among cirrhotic patients at high risk for hepatic decompensation. METHODS: We will perform the SACRED Trial (NCT03654053), a phase III, prospective, multi-center, double-blind, randomized clinical trial at 11 VA Medical Centers. Patients with compensated cirrhosis with clinically significant portal hypertension will be stratified based upon the concomitant use of nonselective beta-blockers and randomized to simvastatin 40 mg/day versus placebo for up to 24 months. Patients will be observed for the development of hepatic decompensation (variceal hemorrhage, ascites, encephalopathy), hepatocellular carcinoma, liver-related death, death from any cause, and/or complications of statin therapy. Ancillary studies will evaluate patient-reported outcomes and pharmacogenetic corollaries of safety and/or efficacy. CONCLUSION: Statins have a long track-record of safety and tolerability. This class of medications is generic and inexpensive, and thus, if the hypothesis is proven, there will be few barriers to widespread acceptance of the role of statins to prevent decompensation in patients with compensated cirrhosis. ClinicalTrials.gov Identifier: NCT03654053.

Effects of Metformin Exposure on Survival in a Large National Cohort of Patients With Diabetes and Cirrhosis.

BACKGROUND & AIMS: Type II diabetes mellitus worsens the prognosis of cirrhosis. Multiple medications including metformin and statins often are co-administered to manage patients with diabetes. The aim of this study was to assess the impact of metformin exposure on mortality, hepatic decompensation, and hepatocellular carcinoma in individuals with diabetes and cirrhosis, controlling for multiple concomitant exposures. METHODS: We performed a retrospective cohort study of patients with cirrhosis diagnosed between January 1, 2008, through June 30, 2016, in the Veterans Health administration. Marginal structural models and propensity-matching approaches were implemented to quantify the treatment effect of metformin in patients with pre-existing diabetes with or without prior metformin exposure. RESULTS: Among 74,984 patients with cirrhosis, diabetes mellitus was present before the diagnosis of cirrhosis in 53.8%, and was diagnosed during follow-up evaluation in 4.8%. Before the diagnosis of cirrhosis, 11,114 patients had active utilization of metformin. In these patients, metformin, statin, and angiotensinogen-converting enzyme inhibitor/angiotensin-2-receptor blocker exposure were associated independently with reduced mortality (metformin hazard ratio, 0.68; 95% CI, 0.61-0.75); metformin was not associated with reduced hepatocellular carcinoma or hepatic decompensation after adjustment for concomitant statin exposure. For patients with diabetes before a diagnosis of cirrhosis but no prior metformin exposure, metformin similarly was associated with reduced mortality (hazard ratio, 0.72; 95% CI, 0.35-0.97), but not with reduced hepatocellular carcinoma or hepatic decompensation. CONCLUSIONS: Metformin use in patients with cirrhosis and diabetes appears safe and is associated independently with reduced overall, but not liver-related, mortality, hepatocellular carcinoma, or decompensation after adjusting for concomitant statin and angiotensinogen-converting enzyme inhibitor/angiotensin-2-receptor blocker exposure.

Effects of Hypercholesterolemia and Statin Exposure on Survival in a Large National Cohort of Patients With Cirrhosis.

BACKGROUND & AIMS: Concerns related to hepatotoxicity frequently lead to discontinuation or non-initiation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase therapy in patients with cirrhosis despite data supporting statin use. We investigated the independent effects of hyperlipidemia and statin exposure on mortality, hepatic decompensation, and hepatocellular carcinoma development in a large national cohort of patients with cirrhosis. METHODS: We performed a retrospective cohort study of patients with newly diagnosed cirrhosis from January 1, 2008 through June 30, 2016 in the Veterans Health Administration. Subjects were divided into 2 cohorts: 21,921 patients with prior statin exposure (existing users) and 51,023 statin-naïve individuals, of whom 8794 subsequently initiated statin therapy (new initiators) and 44,269 did not (non-initiators). Multivariable Cox proportional hazard models with inverse probability weighting were constructed to assess the effects of time-updating lipid profiles and cumulative exposure to statins on survival and hepatic decompensation. Statin-naïve new initiators were propensity matched with non-initiators to simulate a randomized controlled trial of statin use in cirrhosis. RESULTS: In statin-naïve subjects, every 10-mg/dL increase in baseline total cholesterol was associated with a 3.6% decrease in mortality. In existing users, each year of continued statin exposure was associated with a hazard ratio of 0.920 (95% confidence interval 0.0.897-0.943) for mortality. After risk-set matching, each year of statin exposure among new initiators was associated with a hazard ratio of 0.913 (95% confidence interval 0.890-0.937) for mortality. CONCLUSIONS: In a retrospective cohort study of veterans with a new diagnosis of cirrhosis, we associated hypercholesterolemia with well-preserved hepatic function and decreased mortality. Nonetheless, each cumulative year of statin exposure was associated with an independent 8.0%-8.7% decrease of mortality of patients with cirrhosis of Child-Turcotte-Pugh classes A and B.

Healthcare Costs Related to Treatment of Hepatocellular Carcinoma Among Veterans With Cirrhosis in the United States.

BACKGROUND & AIMS: It is important to quantify medical costs associated with hepatocellular carcinoma (HCC), the incidence of which is rapidly increasing in the United States, for development of rational healthcare policies related to liver cancer surveillance and treatment of chronic liver disease. We aimed to comprehensively quantify healthcare costs for HCC among patients with cirrhosis in an integrated health system and develop a model for predicting costs that is based on clinically relevant variables. METHODS: Three years subsequent to liver cancer diagnosis, costs accrued by patients included in the Veteran's Outcome and Cost Associated with Liver disease cohort were compiled by using the Department of Veterans Affairs Corporate Data Warehouse. The cohort includes all patients with HCC diagnosed in 2008-2010 within the VA with 100% chart confirmation as well as chart abstraction of tumor and clinical characteristics. Cancer cases were matched 1:4 with non-cancer cirrhosis controls on the basis of severity of liver disease, age, and comorbidities to estimate background cirrhosis-related costs. Univariable and multivariable generalized linear models were developed and used to predict cancer-related overall cost. RESULTS: Our analysis included 3188 cases of HCC and 12,722 controls. The mean 3-year total cost of care in HCC patients was $154,688 (standard error, $150,953-$158,422) compared with $69,010 (standard error, $67,344-$70,675) in matched cirrhotic controls, yielding an incremental cost of $85,679; 64.9% of this value reflected increased inpatient costs. In univariable analyses, receipt of transplantation, Barcelona Clinic Liver Cancer (BCLC) stage, liver disease etiology, hospital academic affiliation, use of multidisciplinary tumor board, and identification through surveillance were associated with cancer-related costs. Multivariable generalized linear models incorporating transplantation status, BCLC stage, and multidisciplinary tumor board presentation accurately predicted liver cancer-related costs (Hosmer-Lemeshow goodness of fit; P value ≅ 1.0). CONCLUSIONS: In a model developed to comprehensively quantify healthcare costs for HCC among patients with cirrhosis in an integrated health system, we associated receipt of liver transplantation, BCLC stage, and multidisciplinary tumor board with higher costs. Models that predict total costs on the basis of receipt of liver transplantation were constructed and can be used to model cost-effectiveness of therapies focused on HCC prevention.

Association of Provider Specialty and Multidisciplinary Care With Hepatocellular Carcinoma Treatment and Mortality.

BACKGROUND & AIMS: Little is known about provider and health system factors that affect receipt of active therapy and outcomes of patients with hepatocellular carcinoma (HCC). We investigated patient, provider, and health system factors associated with receipt of active HCC therapy and overall survival. METHODS: We performed a national, retrospective cohort study of all patients diagnosed with HCC from January 1, 2008 through December 31, 2010 (n = 3988) and followed through December 31 2014 who received care through the Veterans Administration (128 centers). Outcomes were receipt of active HCC therapy (liver transplantation, resection, local ablation, transarterial therapy, or sorafenib) and overall survival. RESULTS: In adjusted analyses, receiving care at an academically affiliated Veterans Administration hospital (odds ratio [OR], 1.97; 95% confidence interval [CI], 1.60-2.41) or a multi-specialist evaluation (OR, 1.60; 95% CI, 1.15-2.21), but not review by a multidisciplinary tumor board (OR, 1.19; 95% CI, 0.98-1.46), was associated with a higher likelihood of receiving active HCC therapy. In time-varying Cox proportional hazards models, liver transplantation (hazard ratio [HR], 0.22; 95% CI, 0.16-0.31), liver resection (HR, 0.38; 95% CI, 0.28-0.52), ablative therapy (HR, 0.63; 95% CI, 0.52-0.76), and transarterial therapy (HR, 0.83; 95% CI, 0.74-0.92) were associated with reduced mortality. Subspecialist care by hepatologists (HR, 0.70; 95% CI, 0.63-0.78), medical oncologists (HR, 0.82; 95% CI, 0.74-0.91), or surgeons (HR, 0.79; 95% CI, 0.71-0.89) within 30 days of HCC diagnosis, and review by a multidisciplinary tumor board (HR, 0.83; 95% CI, 0.77-0.90), were associated with reduced mortality. CONCLUSIONS: In a retrospective cohort study of almost 4000 patients with HCC cared for at VA centers, geographic, provider, and system differences in receipt of active HCC therapy are associated with patient survival. Multidisciplinary methods of care delivery for HCC should be prospectively evaluated and standardized to improve access to HCC therapy and optimize outcomes.

Identifying barriers to hepatocellular carcinoma surveillance in a national sample of patients with cirrhosis.

Hepatocellular carcinoma (HCC) is a leading cause of morbidity and mortality in cirrhosis patients. This provides an opportunity to target the highest-risk population, yet surveillance rates in the United States and Europe range from 10% to 40%. The goal of this study was to identify barriers to HCC surveillance, using data from the Veterans Health Administration, the largest provider of liver-related health care in the United States. We included all patients 75 years of age or younger who were diagnosed with cirrhosis from January 1, 2008, until December 31, 2010. The primary outcome was a continuous measure of the percentage of time up-to-date with HCC surveillance (PTUDS) based on abdominal ultrasound (secondary outcomes included computed tomography and magnetic resonance imaging). Among 26,577 patients with cirrhosis (median follow-up = 4.7 years), the mean PTUDS was 17.8 ± 21.5% (ultrasounds) and 23.3 ± 24.1% when any liver imaging modality was included. The strongest predictor of increased PTUDS was the number of visits to a specialist (gastroenterologist/hepatologist and/or infectious diseases) in the first year after cirrhosis diagnosis; the association between visits to a primary care physician and increasing surveillance was very small. Increasing distance to the closest Veterans Administration center was associated with decreased PTUDS. There was an inverse association between ultrasound lead time (difference between the date an ultrasound was ordered and requested exam date) and the odds of it being performed: odds ratio = 0.77, 95% confidence interval 0.72-0.82 when ordered > 180 days ahead of time; odds ratio = 0.90, 95% confidence interval 0.85-0.94 if lead time 91-180 days. CONCLUSIONS: The responsibility for suboptimal surveillance rests with patients, providers, and the overall health care system; several measures can be implemented to potentially increase HCC surveillance, including increasing patient-specialist visits and minimizing appointment lead time. (Hepatology 2017;65:864-874).

Recalibrating the Child-Turcotte-Pugh Score to Improve Prediction of Transplant-Free Survival in Patients with Cirrhosis.

BACKGROUND: The Child-Turcotte-Pugh (CTP) score is a widely used and validated predictor of long-term survival in cirrhosis. However, the cutpoints for stratifying laboratory variables in CTP have never been validated. OBJECTIVE: The objective of this study was to identify evidence-based cutpoints for the CTP laboratory subscores to improve its predictive capacity for transplant-free survival. DESIGN: Retrospective observational study. DATA SOURCE: Using a cohort of 30,897 cirrhotic US Veteran patients with at least 5 years of follow-up, we performed Cox proportional hazard survival model iterations varying the upper and lower cutpoints for INR, total bilirubin and albumin CTP subscores. Cutpoints yielding the highest Harrell's C-statistics for concordance with transplant-free survival were incorporated into a modified CTP (mCTP) score. Validation of the mCTP was performed at multiple time frames within the follow-up period of the cohort and within subsets defined by disease etiology. RESULTS: Modification of CTP cutpoints increased the Harrell's C-statistic for age- and gender-adjusted Cox proportional hazard models from 0.701 ± 0.002 to 0.709 ± 0.002 and the risk ratio per unit change from 1.49 (1.48-1.50) to 1.53 (1.52-1.54). The modified cutpoints showed superiority in predicting 5-year transplant-free survival in various disease etiology subgroups. A mCTP substituting serum creatinine for INR performed superiorly for predicting 5-year transplant-free survival. CONCLUSION: We propose an evidence-based recalibration of CTP score cutpoints that optimizes this model's capacity to predict transplant-free survival in patients with cirrhosis. The CTP score remains the best predictor of 5-year overall and transplant-free survival in patients with cirrhosis.

Safety of Propofol Used as a Rescue Agent During Colonoscopy.

GOAL: The goal of this study was to evaluate the safety of propofol when used by gastroenterologists in patients who have an inadequate response to standard sedation (narcotics and benzodiazepines). BACKGROUND: Many patients fail to achieve adequate sedation from narcotics and benzodiazepines during colonoscopy. The administration of propofol for colonoscopy is increasing, although its use by gastroenterologists is controversial. STUDY: We performed a retrospective review of our hospital's colonoscopy records from January 2006 to December 2009 to identify 403 subjects undergoing screening colonoscopies who required propofol (20 to 30 mg every 3 min as needed) because of inadequate response to standard sedation. We also randomly selected 403 controls undergoing screening colonoscopies from the same time period that only required standard sedation. The incidence of adverse effects was then compared. RESULTS: There were no major adverse events in either group. The rates of minor adverse events in the propofol and control group were 0.02 and 0.01, respectively (P=0.56). Adverse effects in the propofol group included: transient hypotension (n=1), nausea/vomiting (n=3), agitation (n=2), and rash (n=1). Adverse effects seen with standard sedation included: transient hypotension (n=2), nausea/vomiting (n=1), and oversedation (n=2). Patients who received propofol were more likely to be younger, had a history of illicit drug use, and a longer procedure time (P<0.05). CONCLUSIONS: Adjunctive propofol administered by gastroenterologist for conscious sedation was not associated with increased incidence of adverse events. It may be of value in patients who do not respond to conventional sedation.

Development and Performance of an Algorithm to Estimate the Child-Turcotte-Pugh Score From a National Electronic Healthcare Database.

BACKGROUND & METHODS: The Child-Turcotte-Pugh (CTP) score is a widely used and validated predictor of long-term survival in cirrhosis. The CTP score is a composite of 5 subscores, 3 based on objective clinical laboratory values and 2 subjective variables quantifying the severity of ascites and hepatic encephalopathy. To date, no system to quantify CTP score from administrative databases has been validated. The Veterans Outcomes and Costs Associated with Liver Disease study is a multicenter collaborative study to evaluate the outcomes and costs of hepatocellular carcinoma in the U.S. Veterans Health Administration. We developed and validated an algorithm to calculate electronic CTP (eCTP) scores by using data from the Veterans Health Administration Corporate Data Warehouse. METHODS: Multiple algorithms for determining each CTP subscore from International Classification of Diseases version 9, Common Procedural Terminology, pharmacy, and laboratory data were devised and tested in 2 patient cohorts. For each cohort, 6 site investigators (Boston, Bronx, Brooklyn, Philadelphia, Minneapolis, and West Haven VA Medical Centers) were provided cases from which to determine validity of diagnosis, laboratory data, and clinical assessment of ascites and encephalopathy. The optimal algorithm (designated eCTP) was then applied to 30,840 cirrhotic patients alive in the first quarter of 2008 for whom 5-year overall and transplant-free survival data were available. The ability of the eCTP score and other disease severity scores (Charlson-Deyo index, Veterans Aging Cohort Study index, Model for End-Stage Liver Disease score, and Cirrhosis Comorbidity) to predict survival was then assessed by Cox proportional hazards regression. RESULTS: Spearman correlations for administrative and investigator validated laboratory data in the HCC and cirrhotic cohorts, respectively, were 0.85 and 0.92 for bilirubin, 0.92 and 0.87 for albumin, and 0.84 and 0.86 for international normalized ratio. In the HCC cohort, the overall eCTP score matched 96% of patients to within 1 point of the chart-validated CTP score (Spearman correlation, 0.81). In the cirrhosis cohort, 98% were matched to within 1 point of their actual CTP score (Spearman, 0.85). When applied to a cohort of 30,840 patients with cirrhosis, each unit change in eCTP was associated with 39% increase in the relative risk of death or transplantation. The Harrell C statistic for the eCTP (0.678) was numerically higher than those for other disease severity indices for predicting 5-year transplant-free survival. Adding other predictive models to the eCTP resulted in minimal differences in its predictive performance. CONCLUSION: We developed and validated an algorithm to extrapolate an eCTP score from data in a large administrative database with excellent correlation to actual CTP score on chart review. When applied to an administrative database, this algorithm is a highly useful predictor of survival when compared with multiple other published liver disease severity indices.

Neostigmine Administered With MoviPrep Improves Bowel Preparation for Elective Colonoscopy in Patients With Spinal Cord Injury: A Randomized Study.

BACKGROUND: Poor preparation for elective colonoscopy is exceedingly common in persons with spinal cord injury (SCI). This unsatisfactory outcome is likely due to long-standing difficulty with evacuation and decreased colonic motility, which may result in inadequate responses to conventional bowel preparation regimens. We determined whether the addition of neostigmine to MoviPrep before elective colonoscopy produced a higher percentage of acceptable bowel preparations in patients with SCI. METHODS: Twenty-seven SCI subjects were prospectively randomized to 1 of 2 arms: low-volume polyethylene glycol-electrolyte lavage with ascorbic acid (MoviPrep) or MoviPrep plus neostigmine methylsulfate and glycopyrrolate (MoviPrep+NG); 28 able-bodied subjects received MoviPrep alone. The quality of the cleansing preparation for colonoscopy was determined by gastroenterologists "calibrated" to use the Ottawa Scoring System, with an acceptable Ottawa Score (OS) considered to be ≤3. RESULTS: The administration of MoviPrep alone resulted in suboptimal bowel cleansing in the SCI group compared with the able-bodied group (50% vs. 89% of subjects had an acceptable OS; χ=7.94, P=0.05). However, when NG was added to MoviPrep in the SCI group, it markedly improved the quality of the bowel preparation, with 85% of patients then having an acceptable OS. The use of NG resulted in minimal bloating and distention before bowel evacuation (P=0.0005), and eye and muscle twitching; these were resolved within 1 hour after NG administration. No significant differences were noted among the preparation groups for adenoma detection rate (P=0.41). CONCLUSIONS: The combination of MoviPrep+NG was safe, well tolerated, and an effective approach to prepare the bowel for elective colonoscopy in patients with SCI. The side effects of this preparation were significant compared with the other treatment groups but were considered mild and anticipated.

Comparison between pulsed irrigation enhanced evacuation and polyethylene glycol-electrolyte lavage solution for bowel preparation prior to elective colonoscopy in veterans with spinal cord injury.

BACKGROUND: Poor preparation for elective colonoscopy is common in persons with spinal cord injury (SCI). This unsatisfactory outcome is likely due to long-standing difficulty with evacuation and decreased colonic motility. Our objective was to determine the most effective preparation for elective colonoscopy applying a novel and traditional approach to bowel cleansing. METHODS: Twenty-four subjects with SCI were consented and scheduled to receive one of the two possible arms: pulsed irrigation enhanced evacuation (PIEE) or polyethylene glycol-electrolyte lavage solution (PEG; CoLyte(®)). The quality of the preparation was scored during the colonoscopy by applying the Ottawa scoring system. RESULTS: Patients with SCI who received PIEE tended to have lower Ottawa scores and a higher percentage of acceptable preparations than did those who received PEG; however, the results were not statistically different. CONCLUSION: In this preliminary study in subjects with SCI, neither PIEE nor PEG produced acceptable bowel preparation for elective colonoscopy. Future studies should confirm our findings and consider studying alternative, more efficacious approaches to bowel cleansing prior to colonoscopic procedures in patients with SCI, which should provide better outcomes. Registration number for clinicaltrials.gov: NCT00745095.

Predictors of candidate maturation among potential living donors.

The shortage of deceased donor allografts and improved outcomes in partial organ transplantation have led to widespread application of adult-to-adult living donor liver transplantation. Donor selection limits overall utilization of this technique and predictors of candidate maturation have been inadequately studied to date. We therefore collected data on 237 consecutive potential donors including their age, sex, ethnicity, relationship to the recipient, education, employment and religious beliefs and practices. Of these 237 candidates, 91 (38%) were excluded for medical and psychosocial reasons, 53 (22%) withdrew from the process predonation and 93 (39%) underwent partial liver donation. In multivariate analyses, the relationship between the donor and the recipient was highly predictive of successful donation. For pediatric recipients, no parents voluntarily withdrew from the evaluation process. For adult recipients, spouses are the most likely to donate, followed by parents, children and siblings. Additional predictors for donation included self-description as religious but not regularly practicing, part-time employment and higher education. Race, ethnicity, gender and age did not predict donation in multivariate analysis. Further understanding of the complex decision to donate may improve donation rates as well as permit more efficient and cost-effective donor evaluation strategies.