Primary Biliary Cholangitis in Medicare Population: The Impact on Mortality and Resource Use

Transcription

1 Hepatology, VOL. 69, NO. 1, 2019 AUTOIMMUNE, CHOLESTATIC AND BILIARY DISEASE Primary Biliary Cholangitis in Medicare Population: The Impact on Mortality and Resource Use Mehmet Sayiner, 1,2 Pegah Golabi, 1 Maria Stepanova, 3 Issah Younossi, 3 Fatema Nader, 3 Andrei Racila, 2,3 and Zobair M. Younossi 1,2 Primary biliary cholangitis (PBC) is a disease of small bile ducts, which can lead to morbidity and mortality. Our aim was to assess recent trends in mortality and healthcare use of PBC patients in the Medicare program. Data from Medicare beneficiaries between 2005 and 2015 (5% random samples) were used. The diagnosis of PBC was established with International Classification of Diseases-9 code used for both primary and secondary diagnoses. Mortality was assessed by Medicare-linked death registry. Healthcare use included episodes of care, length of stay, and total charges/payments. Independent predictors of outcomes were evaluated in multiple generalized linear or logistic regression models. The study cohort included a total of 6,375 inpatient/outpatient Medicare beneficiaries (mean age 69.8 years, 17% male, 88% white, and 18% with disability). Over the study period, 1-year mortality remained stable (9.1% to 14.3%, P = 0.11). Independent predictors of 1-year mortality were older age, male gender, black race, the presence of ascites, encephalopathy, hepatocellular carcinoma, and higher Charlson score. Outpatient total yearly charges and payments per beneficiary with PBC increased from $3,065 and $777 (2005) to $5,773 and $967 (2014), respectively. Similarly, inpatient total yearly charges and payments per beneficiary with PBC increased from $59,765 and $19,406 (2007), to $98,941 and $27,948 (2013), respectively (P < 0.05). The presence of ascites, portal hypertension, and higher Charlson score were independent predictors of higher payments for both inpatient and outpatient resource use, and the presence of hepatic encephalopathy was an additional predictor of higher inpatient resource use (all P < 0.02). Conclusion: The prevalence of PBC among the Medicare beneficiaries has increased. Despite stable mortality rates, resource use for Medicare patients with PBC continues to rise. (Hepatology 2019;69: ). Primary biliary cholangitis (PBC) is an immune-mediated disease of the intrahepatic small bile ducts (1-3) that can lead to cholestasis and potential progression to cirrhosis. (4) More than 90% of the affected individuals with PBC are female, and most of them are years old. (5) Although PBC is relatively rare, it is still considered the most common autoimmune liver disease. (6) The prevalence of PBC has been estimated to be approximately 65 per 100,000 people in the United States. (7) This prevalence rate appears to vary geographically, and rates are reported to be higher in northern European countries, United Kingdom, and Scandinavian countries. (8-12) Furthermore, PBC is more common among patients with a first-degree relative with the disease, reflecting a possible genetic susceptibility. (13,14) Not surprisingly, patients with PBC often have other autoimmune conditions, including autoimmune thyroid disease and Sjogren syndrome. (15,16) Although most PBC patients present asymptomatically, some may have fatigue and pruritus. Affected individuals usually have elevated serum Abbreviations: CCI, Charlson Comorbidity Index; HCC, hepatocellular carcinoma; ICD, International Classification of Diseases; PBC, primary biliary cholangitis; UDCA, ursodeoxycholic acid. Received December 19, 2017; accepted July 11, Additional Supporting Information may be found at onlinelibrary.wiley.com/doi/ /hep.30174/suppinfo. Supported by the Intercept Pharmaceuticals and the Center for Outcomes Research in Liver Diseases by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI /hep Potential conflict of interest: Zobair M. Younossi is a consultant for or has received research funds from Gilead Sciences, Intercept, BMS, NovoNordisk, GSK, Abbvie, Allergan, Viking, and Terns Pharmaceuticals. Other authors have no conflict. 237

2 Sayiner et al. Hepatology, January 2019 alkaline phosphatase levels, and in fact, the presence of antimitochondrial antibody with elevated alkaline phosphatase establishes the diagnosis. (17) Ursodeoxycholic acid (UDCA) is the first-line treatment for PBC. (18) The use of UDCA slows disease progression and improves outcomes, especially in patients with mild histologic changes and good biochemical response. (18-22) Nevertheless, there is a group of patients with PBC who do not respond optimally to UDCA. This prompted a number of efforts to develop additional investigational agents for PBC. In May 2016, obeticholic acid was approved for patients who were not responsive or intolerant to UDCA. (23,24) Despite these advances, PBC continues to contribute to the development of cirrhosis and remains an important indication for liver transplantation. In this context, PBC contributes to the mortality and morbidity with significant clinical and economic burden. (25) In the United States, Medicare represents a major health-care coverage for the elderly and the disabled. (26) The impact of PBC on resource use and mortality of Medicare recipients can have important economic and budgetary implications. In the current study, our aim was to assess the trends in prevalence, mortality, and resource use in the Medicare recipients with PBC between 2005 and Methods We used Medicare inpatient and outpatient files with final action fee-for-service claims submitted by outpatient healthcare providers and by inpatient hospital providers for reimbursement of facility costs. For the purpose of this study, a 5% random sample of Medicare beneficiaries who received inpatient or outpatient care from 2005 to 2015 were used. All inpatient, outpatient, and denominator files were stripped of data elements that might allow identification of the sampled participants. The study was approved by the Inova Institutional Review Board, and a data-use agreement with the Centers for Medicare and Medicaid Services (CMS) was in place. In both inpatient and outpatient parts of the study, the International Classification of Diseases (ICD)-9 code and ICD-10 code K74.3 were used to establish the diagnosis of PBC. A claim was included in the study if the principal or any of the secondary diagnoses for that claim was PBC. A separate subgroup analysis was performed to select cases of PBC based on two or more PBC codes. This was done to see whether a more restrictive definition has any effect on the results. In addition the diagnosis, ICD-9 and ICD-10 codes were used to identify PBC patients with hepatic decompensation (ascites, hepatic encephalopathy, portal hypertension, variceal bleeding, and HCC) and to calculate their Charlson Comorbidity Index (CCI) (Supporting Table S1). The study outcomes included mortality, resource use parameters (the number of episodes of care, total charges and payments, Medicare spending, and patient s responsibility). The total payment per claim was the sum of payments made by Medicare, other third-party payers if applicable, and the patient s responsibility that included all applicable copayments, deductibles, and coinsurance. For the inpatient part, we also studied inpatient mortality and the length of inpatient stay (LOS), which was defined as the number of days of care in a claim, including the number of days of care that are chargeable and nonchargeable to Medicare facility use. If more than one inpatient or outpatient claim was reported for a patient in a given year, then, for that patient in that year, the resource use parameters were added up to yield the total yearly ARTICLE INFORMATION: From the 1 Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA; 2 Department of Medicine, Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, VA; 3 Center for Outcomes Research in Liver Diseases, Washington, DC. ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO: Zobair M. Younossi, M.D., M.P.H. Betty and Guy Beatty Center for Integrated Research Claude Moore Health Education and Research Building 3300 Gallows Road, Falls Church, VA zobair.younossi@inova.org Fax:

3 Hepatology, Vol. 69, No. 1, 2019 Sayiner et al. resource use. All charges and payments were adjusted to the 2016 dollars using the medical component of the Consumer Price Index ( STATISTICAL ANALYSIS Demographic and resource use parameters of the study cohort were summarized by year and were compared across the study years using a nonparametric Kruskal-Wallis test for continuous variables or chisquare test for categorical variables or Kendall test for trends. P values of 0.05 or less were considered potentially statistically significant. Generalized linear regression with log link function and gamma error distribution was used to identify independent predictors of the total payments. Independent predictors of inpatient and overall 1-year mortality were studied using multiple logistic regressions. Potential predictors of the outcomes included patients demographics and available clinical parameters (the presence of ascites, hepatic encephalopathy, portal hypertension, variceal bleeding, and HCC). All analyses were performed using SAS 9.4 (SAS Institute, Cary, NC). Results CLINICO-DEMOGRAPHIC CHARACTERISTICS OF THE STUDY POPULATION Between 2005 and 2015, the 5% random sample of Medicare data set yielded a study cohort of 6,375 patients with PBC, ranging from 467 (2005) to 726 (2014) patients per year (prevalence trend P = ) (Table 1). The mean age of the PBC cohort was 69.8 years, 83.2% were female, and 88.0% were white. Furthermore, approximately 70% of the patients were younger than age 75. In terms of Medicare eligibility, most patients were eligible due to age (80.8%) and disabled status (18.4%) (Table 2). Among the study PBC cohort, 7.6% also had ascites, 5.7% had hepatic encephalopathy, 0.6% had spontaneous bacterial peritonitis (SBP), 7.0% had portal hypertension, 7.3% had esophageal varices, and 1.5% had HCC. Furthermore, 54.9% of the total cohort had a CCI of 0 or 1 (Table 2). Over the study period ( ), there were no consistent changes in the demographics, disease severity, or complication of cirrhosis in the inpatient or outpatient setting (Supporting Table S2). TABLE 1. Changes in the Prevalence of PBC Over Time in the Medicare Cohort Unique Patients (N) Size of a Denominator Prevalence in a Medicare Set, per 100, ,232, ,273, ,327, ,385, ,440, ,499, ,580, ,674, ,758, ,836, ,912, All years ,921, MORTALITY AND HEALTHCARE USE INCURRED BY MEDICARE RECIPIENTS WITH PBC One year the mortality rate for the PBC cohort was 11.5% and remained stable over the study period (P = 0.11). Mortality data revealed that within 1 year of the outpatient encounter, 7.6% of Medicare PBC patients died (P = 0.65 over the study years). In contrast, 26.9% of the inpatient Medicare patients with PBC died within 1 year of the encounter (P = 0.13 between the study years). The resource use was calculated separately for outpatient and inpatient settings. Of the entire PBC Medicare cohort included in this study, 5,281 (82.8%) subjects received outpatient care. The number of Medicare recipients with PBC seen in the outpatient setting in 2015 had increased by 63.6% from the number of visits in In the outpatient setting, about 5% of the cohort had some evidence of hepatic decompensation (ascites 4.3%, hepatic encephalopathy 2.0%, SBP 0.02%, portal hypertension 4.5%, esophageal varices 5.2%, and HCC 1.4%; all P > 0.05 for the time trends). Another surrogate for resource use was number of claims. During 2005 and 2015, the average number of outpatient claims per year per patient was 2.1 (ranging from 1.9 to 2.2, P = 0.35 for the trend) and the average number of diagnoses per PBC claim was 3.8 (increased from 3.1 to 4.6, P = ) (Table 3). Furthermore, over the study period, the average total charges and average total payments were $4,184 (median $1,226) and $797 (median $243), which increased by 56.3% and 8.5%, respectively, from 2005 to 2015 (Fig. 1A). 239

4 Sayiner et al. Hepatology, January 2019 In contrast to the outpatient setting, 1,924 (30.2%) of the PBC cohort had at least one inpatient encounter. Between 2005 and 2015, the number of Medicare TABLE 2. General Characteristics of the Study Population by the Type of Healthcare Setting Outpatient Inpatient Number 5,281 1,924 Age (years) < 65 1,122 (21.2%) 370 (19.2%) ,480 (28.0%) 460 (23.9%) ,179 (22.3%) 367 (19.1%) (15.3%) 324 (16.8%) (9.2%) 242 (12.6%) > (3.9%) 161 (8.4%) Gender Male 842 (15.9%) 333 (17.3%) Female 4,439 (84.1%) 1,591 (82.7%) Race White 4,647 (88.3%) 1,674 (87.1%) Black 270 (5.1%) 120 (6.2%) Asian 63 (1.2%) 23 (1.2%) Hispanic 142 (2.7%) 50 (2.6%) Native American 66 (1.3%) 33 (1.7%) Medicare eligibility Age 4,240 (80.3%) 1,578 (82.0%) Disability 1,005 (19.0%) 326 (16.9%) End-stage renal disease 17 (0.3%) 10 (0.5%) Complications Ascites 226 (4.3%) 319 (16.6%) Hepatic encephalopathy 108 (2.0%) 299 (15.5%) Spontaneous bacterial peritonitis 1 (0.0%) 35 (1.8%) Portal hypertension 236 (4.5%) 252 (13.1%) Varices 274 (5.2%) 242 (12.6%) HCC 76 (1.4%) 32 (1.7%) Disease severity CCI 0-1 3,522 (66.7%) 406 (21.1%) CCI 2-3 1,759 (33.3%) 1,518 (78.9%) 1-year mortality 399 (7.6%) 517 (26.9%) patients with PBC in the inpatient setting increased by 17.9%. As expected, the rates of hepatic complications in the inpatient setting were higher than those reported for the outpatient setting (ascites 16.6%, hepatic encephalopathy 15.5%, spontaneous bacterial peritonitis 1.8%, portal hypertension 13.1%, esophageal varices 12.6%, and HCC 1.7%; all-time trend P > 0.05). Furthermore, 78.9% of such patients had a CCI of at least 2. Of the PBC patients who received inpatient care at least once, the mean number of inpatient claims per year was 1.4 (P = 0.88) and total yearly LOS was 8.4 days (P = 0.76) (Table 3). The average total charge was $72,233 (median $38,212) and the average total payment was $22,860 (median $13,459) (Fig. 1B). INDEPENDENT PREDICTORS OF MORTALITY AND HEALTHCARE USE Multivariate analysis revealed that the strongest predictors of 1-year mortality in all Medicare beneficiaries with PBC were presence of ascites and hepatic encephalopathy (odds ratios 4.1 and 2.4, respectively; both P < ). Other predictors of mortality in PBC included older age, male gender, black race, the presence of HCC, higher CCI score, receiving inpatient care in that year at least once, and longer inpatient stay (all P < 0.001). No association with calendar year was found (P = 0.49), suggesting no significant time trend in the outcome (Table 4). In the outpatient setting, independent predictors of increased annual payments were younger age, female gender, higher CCI, and indicators of advanced liver disease (ascites, portal hypertension, esophageal varices, and HCC) (all P < 0.002) (Table 5). Among inpatients, independent predictors TABLE 3. Summary of Healthcare Use of the Study Population (Mean ± SD and Median [Interquartile Range]) Outpatient Inpatient No. of claims per year 2.1 ± 2.01 (1-2) 1.5 ± 1.01 (1-2) No. of diagnoses per claim 3.8 ± 3.03 (2-5) 11.6 ± 5.39 ( ) Length of stay (days) 8.5 ± (3-10) Total charge ($$) 4,184 ± 9,3181,226 (431-4,194) 72,233 ± 119,33938,212 (19,992-79,246) Total payment ($$) 797 ± 1, ( ) 22,860 ± 38,74613,459 (7,974-23,613) Total Medicare payment ($$) 589 ± 1, (74-605) 20,335 ± 35,95611,731 (6,366-20,890) Total patient s payment ($$) 166 ± (0-190) 1,254 ± 1,4171,304 (1,296-1,314) Proportion of Medicare payment (%) 80.4 ± (74-100) 85.8 ± ( ) Proportion of patient s payment (%) 17.3 ± (0-24.8) 10.4 ± ( ) 240

5 Hepatology, Vol. 69, No. 1, 2019 Sayiner et al. FIG. 1. Trends in (A) outpatient and (B) inpatient inflation-adjusted charges and payments ($). of increased payments were also younger age, the presence of ascites, portal hypertension, and hepatic encephalopathy (all P < 0.001) but not calendar year (P = 0.35) (Table 5). SUBGROUP ANALYSIS OF PATIENTS WITH TWO OR MORE ICD CODES FOR PBC To use a more restrictive definition of PBC, we ran a subgroup analysis of the same outcomes using patients with two or more claims with a code for PBC. From the original cohort, approximately 47% (n = 2,990) had two or more inpatient or outpatient PBC codes. In comparison to patients with only one claim for PBC, patients with two or more claims were more frequently female and were sicker as indicated by higher Charlson comorbidity scores and more evidence of hepatic decompensation (ascites, hepatic encephalopathy, esophageal varices, portal hypertension, and HCC) (all P < 0.01) (Supporting Table S3). Patients with two or more codes also incurred more resource use (Supporting Table S3 and Supporting Fig. S1). Despite this higher disease severity, the independent predictors of the study outcomes (mortality and resource use) in this subgroup were nearly identical to those reported for the entire group of patients with PBC (Supporting Table S4). 241

6 Sayiner et al. Hepatology, January 2019 TABLE 4. Predictors of 1-Year Mortality in Medicare Beneficiaries With PBC Discussion Odds Ratio (95% CI) Calendar year, per year ( ) 0.49 Age, per year ( ) < Male gender ( ) < Black race ( ) Hispanic race ( ) 0.36 Asian race ( ) 0.49 Eligible due to disability ( ) 0.15 Ascites ( ) < Hepatic encephalopathy ( ) < HCC ( ) CCI > ( ) < Had inpatient services ( ) < Total length of inpatient stay, per day ( ) < Abbreviation: CI, confidence interval. This study assessed the clinical and economic burden of PBC on Medicare beneficiaries in the United States. Our data show that among Medicare recipients, the prevalence of PBC is on the rise. In fact, the number of Medicare recipients with PBC has increased both in the inpatient and outpatient settings. In our study cohort, which included 5% random sample of the Medicare database for the United States, the prevalence of PBC was 20.9 per 100,000 in 2005, which increased to 24.4 per 100,000 individuals by These findings are consistent with previous published data. (27-30) In fact, the prevalence for PBC ranges from P 1.91 to per 100,000 people. (30) In this context, the prevalence of PBC in the Canadian population has been shown to have increased from 10 per 100,000 in 1996 to 22.7 per 100,000 in (28) In contrast, the prevalence of definite PBC was reported to have been higher in the United Kingdom, and these rates were reported to increase from 114 per 100,000 in 1987 to 157 per 100,000 in (27) Although our data are consistent with the data reported from North America, it is somewhat lower than the rates reported from the United Kingdom. This may be due to underestimation of PBC diagnosis using the Medicare database or an ascertainment bias in the reported rates. (27) Nevertheless, the consistency of our data with what is reported from the United States provides some validation for our findings. It is important to note that despite this increase in the number of cases of PBC during the study period, the short-term mortality of patients with PBC with Medicare coverage remained relatively stable. As expected, that mortality was driven by signs of advanced liver disease (e.g., ascites, hepatic encephalopathy) and higher rates of comorbidities (CCI scores), which are both consistent with previous reports. (30-34) In contrast, the lack of improvement in mortality over 1 decade of the study is intriguing. It is possible that there is greater impact of competitive mortality in this study s Medicare population with PBC, who are almost 70 years old throughout the study period. Alternatively, it is also plausible that UDCA use or the time of initiating UDCA in the Medicare PBC patients is not optimal. (35-37) Further TABLE 5. Predictors of Annual Total Payment in the Outpatient and Inpatient Settings for Medicare Beneficiaries With PBC Outpatient Inpatient Beta (95% CI), % P Value Beta (95% CI), % P Value Intercept, $$ 331 ( ) 20,846 (16,075-27,030) Calendar year, per year 1.1 ( ) ( ) 0.35 Age, per year 0.8 ( 1.3 to 0.4) < ( 1.2 to 0.5) < Male gender 17.4 ( 25.5 to 8.4) ( ) 0.48 Black race 5.4 ( ) ( ) 0.56 Hispanic race 1.3 ( ) ( ) 0.14 Asian race 34 ( ) ( ) 0.62 Ascites 88.7 ( ) < ( ) < Hepatic encephalopathy 31.4 ( ) ( ) < Portal hypertension 48.8 (16-91) ( ) Esophageal varices 55.1 ( ) ( ) 0.39 HCC 36.8 ( ) ( ) 0.42 CCI > ( ) < ( )

7 Hepatology, Vol. 69, No. 1, 2019 Sayiner et al. studies with added medication use data are needed to check these hypotheses. Another finding of our study was the data on inpatient and outpatient resource use for Medicare recipients with PBC. Our study showed that, between 2005 and 2015, total charges increased in both inpatient and outpatient settings, whereas the total yearly payments remained stable, as did the proportions of patients responsibility in those payments (17.3% for outpatient, 10.4% for inpatient, both trend P > 0.05). Use of services (the number of episodes of care, the total length of stay) also remained stable. Not surprisingly, complications of cirrhosis, such as ascites, hepatic encephalopathy and portal hypertension, were independent predictors of higher healthcare use. It is important to note that although previous studies have focused on the cost-effectiveness of UDCA and the cost of liver transplantation for PBC patients, (25,38-40) this study assessed the economic burden on the US Medicare system, which is the major payer for approximately 40% of all PBC patients who are 65 and older. (18) It has been suggested that patients with a specific condition such as PBC may be more accurately identified from the administrative databases such as Medicare, if we had focused on those with two or more diagnostic codes for PBC. (28) In fact, this approach appears to bias PBC patients with more severe liver disease. Furthermore, a more recent study did not provide any evidence that the single-code approach to diagnosis of PBC would compromise accuracy. (41) Nevertheless, for the purpose of sensitivity analysis, we validated our findings in a subgroup of patients with two or more claims with a PBC code; this reduced the study cohort by approximately half. In addition, we found that PBC patients with two or more codes were sicker and consumed substantially more resources, although the reported trends and associations were reliably reproduced. Given these results, we believe that requiring the presence of two or more disease codes in Medicare data is not a mere way of validation but rather an indicator of a more severe disease and, thus, may be biased against PBC patients with earlier stages of the disease, an important clinical cohort that should be identified and managed properly. It is important to note, however, that in this study, administrative data were sampled annually; it is possible that with longer look-back periods, that bias might not be as profound. Our study has limitations. The first is the use of an administrative database with its inherent limitations discussed previously. (28,41,42) Furthermore, there was a change in disease codes used by Medicare in 2015, from ICD-9 to ICD-10. This change resulted in better categorization of medical conditions. Nevertheless, misclassifications during the transition period may have affected the accuracy of the data. In this context, validation of ICD codes for PBC will be important. Another potential limitation of the Medicare data set is the age of qualification for enrollment. Because PBC is known to predominantly affect women in their 40s and 50s, the Medicare database may underestimate the true prevalence of PBC. A similar study with a real-world cohort could possibly result in a higher prevalence rate. (43) Finally, a subset of patients in our study might be on medications that could potentially alter the complications and prognosis of PBC, such as ursodeoxycholic acid; because our data set did have pharmacy information, future studies that contain this information will be important. (43) In conclusion, our study revealed that the number of patients diagnosed with PBC has been increasing in the Medicare population. 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