Development of a novel frailty index to predict mortality in patients with end‐stage liver disease

Cirrhosis is characterized by muscle wasting, malnutrition, and functional decline that confer excess mortality not well quantified by the Model for End‐Stage Liver Disease (MELD) Sodium (MELDNa) score. We aimed to develop a frailty index to capture these extrahepatic complications of cirrhosis and enhance mortality prediction in patients with cirrhosis. Consecutive outpatients listed for liver transplantation at a single transplant center without MELD exceptions were assessed with candidate frailty measures. Best subset selection analyses with Cox regression identified subsets of frailty measures that predicted waitlist mortality (=death or delisting because of sickness). We selected the frailty index by balancing statistical accuracy with clinical utility. The net reclassification index (NRI) evaluated the %patients correctly reclassified by adding the frailty index to MELDNa. Included were 536 patients with cirrhosis with median MELDNa of 18. One hundred seven (20%) died/were delisted. The final frailty index consisted of: grip strength, chair stands, and balance. The ability of MELDNa and the frailty index to correctly rank patients according to their 3‐month waitlist mortality risk (i.e., concordance‐statistic) was 0.80 and 0.76, respectively, but 0.82 for MELDNa+frailty index together. Compared with MELDNa alone, MELDNa+frailty index correctly reclassified 16% of deaths/delistings (P = 0.005) and 3% of nondeaths/delistings (P = 0.17) with a total NRI of 19% (P < 0.001). Compared to those with robust frailty index scores (<20th percentile), cirrhotics with poor frailty index scores (>80th percentile) were more impaired by gait speed, difficulty with Instrumental Activities of Daily Living, exhaustion, and low physical activity (P < 0.001 for each). Conclusion: Our frailty index for patients with cirrhosis, comprised of three performance‐based metrics, has construct validity for the concept of frailty and improves risk prediction of waitlist mortality over MELDNa alone. (Hepatology 2017;66:564–574).

[1]  L. Ferrucci,et al.  Short Physical Performance Battery and all-cause mortality: systematic review and meta-analysis , 2016, BMC Medicine.

[2]  R. Fontana,et al.  Decision Making in Liver Transplant Selection Committees , 2011, Annals of Internal Medicine.

[3]  Khalid Yusoff,et al.  Prognostic value of grip strength: findings from the Prospective Urban Rural Epidemiology (PURE) study , 2015, The Lancet.

[4]  L. Ferrucci,et al.  A short physical performance battery assessing lower extremity function: association with self-reported disability and prediction of mortality and nursing home admission. , 1994, Journal of gerontology.

[5]  M. Manns,et al.  The number connection tests A and B: interindividual variability and use for the assessment of early hepatic encephalopathy. , 1998, Journal of hepatology.

[6]  T. Therneau,et al.  A model to predict survival in patients with end‐stage liver disease , 2001 .

[7]  M. Makary,et al.  Frailty as a predictor of surgical outcomes in older patients. , 2010, Journal of the American College of Surgeons.

[8]  George M. Furnival,et al.  Regressions by leaps and bounds , 2000 .

[9]  T M Therneau,et al.  A model to predict survival in patients with end‐stage liver disease , 2001, Hepatology.

[10]  S. Katz.  Studies of illness in the aged , 1963 .

[11]  Ewout W Steyerberg,et al.  Extensions of net reclassification improvement calculations to measure usefulness of new biomarkers , 2011, Statistics in medicine.

[12]  K. Mekeel,et al.  Six‐minute walk distance predicts mortality in liver transplant candidates , 2010, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[13]  V. Mathiowetz,et al.  Grip and pinch strength: normative data for adults. , 1985, Archives of physical medicine and rehabilitation.

[14]  R. Varadhan,et al.  Frailty and Mortality in Kidney Transplant Recipients , 2015, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[15]  P. Blanc,et al.  Frailty Is Common in Lung Transplant Candidates and Associated with Poorer Health-Related Quality of Life , 2013 .

[16]  G. Collins,et al.  Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD): The TRIPOD Statement , 2015, Annals of Internal Medicine.

[17]  K. Covinsky,et al.  Clinician assessments of health status predict mortality in patients with end‐stage liver disease awaiting liver transplantation , 2015, Liver international : official journal of the International Association for the Study of the Liver.

[18]  S. Katz,et al.  STUDIES OF ILLNESS IN THE AGED. THE INDEX OF ADL: A STANDARDIZED MEASURE OF BIOLOGICAL AND PSYCHOSOCIAL FUNCTION. , 1963, JAMA.

[19]  P. Macdonald,et al.  The Prevalence and Prognostic Significance of Frailty in Patients With Advanced Heart Failure Referred for Heart Transplantation , 2016, Transplantation.

[20]  L. Fried,et al.  Frailty in older adults: evidence for a phenotype. , 2001, The journals of gerontology. Series A, Biological sciences and medical sciences.

[21]  D. Landsittel,et al.  Frailty as Tested by Gait Speed is an Independent Risk Factor for Cirrhosis Complications that Require Hospitalization , 2016, The American Journal of Gastroenterology.

[22]  M. Lawton,et al.  Assessment of Older People: Self-Maintaining and Instrumental Activities of Daily Living , 1969 .

[23]  J. Habbema,et al.  Internal validation of predictive models: efficiency of some procedures for logistic regression analysis. , 2001, Journal of clinical epidemiology.

[24]  V. Mathiowetz,et al.  Reliability and validity of grip and pinch strength evaluations. , 1984, The Journal of hand surgery.

[25]  David C. Cron,et al.  Depression and Frailty in Patients With End‐Stage Liver Disease Referred for Transplant Evaluation , 2016, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[26]  K. Covinsky,et al.  Functional decline in patients with cirrhosis awaiting liver transplantation: Results from the functional assessment in liver transplantation (FrAILT) study , 2016, Hepatology.

[27]  Ack,et al.  LOWER-EXTREMITY FUNCTION IN PERSONS OVER THE AGE OF 70 YEARS AS A PREDICTOR OF SUBSEQUENT DISABILITY , 2001 .

[28]  Robert Gray,et al.  A Proportional Hazards Model for the Subdistribution of a Competing Risk , 1999 .

[29]  K. Covinsky,et al.  Frailty Predicts Waitlist Mortality in Liver Transplant Candidates , 2014, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[30]  N. Peel,et al.  Frailty and post-operative outcomes in older surgical patients: a systematic review , 2016, BMC Geriatrics.

[31]  M. Mittleman,et al.  Standard assessments of frailty are validated predictors of mortality in hospitalized patients with cirrhosis , 2015, Hepatology.

[32]  T. Oberg,et al.  Basic gait parameters: reference data for normal subjects, 10-79 years of age. , 1993, Journal of rehabilitation research and development.

[33]  S. Studenski,et al.  Gait speed and survival in older adults. , 2011, JAMA.

[34]  R. Wiesner,et al.  Model for end-stage liver disease (MELD) and allocation of donor livers. , 2003, Gastroenterology.