Socioeconomic Position, Ethnicity, and Outcomes in Heart Transplant Recipients

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1 Socioeconomic Position, Ethnicity, and Outcomes in Heart Transplant Recipients Tajinder P. Singh, MD, MSc a,f, *, Michael M. Givertz, MD b,f, Marc Semigran, MD c,f, David DeNofrio, MD d, Fred Costantino, BS e, and Kimberlee Gauvreau, ScD a,g The purpose of the present study was to assess whether a low socioeconomic (SE) position is associated with outcomes in heart transplant recipients. We used the US Census 2000 database to derive a summary SE score for 520 patients who had undergone underwent a first heart transplant at 1 of 4 Boston hospitals during 1996 to 2005 and compared the outcomes in the lowest quartile SE group (n 129) to those for the remaining patients (n 391). The low SE group and controls were similar with respect to cardiac diagnosis, hemodynamic support, listing status, year of transplant, and initial immune suppression. Low SE patients were more likely to be nonwhite. Graft loss occurred in 142 patients (135 deaths and 7 repeat transplants). Hospital mortality after transplantation was not associated with race/ethnicity or low SE position. In patients who survived the transplant hospitalization, nonwhite ethnicity (hazard ratio 1.8, 95% confidence interval 1.1 to 2.9) and low SE group (hazard ratio 1.7, 95% confidence interval 1.1 to 2.5) were associated with a greater risk of subsequent graft loss. In the adjusted analysis, the risk of graft loss remained greater for both nonwhite race/ethnicity (hazard ratio 1.7, 95% confidence interval 1.0 to 2.9) and low SE position (hazard ratio 1.5, 95% confidence interval 1.0 to 2.4). Rejection episodes were more frequent in nonwhite transplant recipients and in those in the low SE group. In conclusion, among heart transplant recipients who survive the transplant hospitalization, nonwhite recipients and those in a low SE position are at greater risk of rejection and graft loss Elsevier Inc. All rights reserved. (Am J Cardiol 2010;105: ) Because socioeconomic (SE) data are not routinely collected as a part of the medical records, its association with patient outcomes after transplantation has been difficult to study. Analyses using proxy SE variables such as median income in the zip code of patient residence have not demonstrated an association of SE position with the outcomes of transplant recipients. 1,2 Zip codes have an average population of 30,000, are administrative units established by the US Postal Service for the most efficient delivery of mail, and can have a large internal heterogeneity in the SE position of their residents. 3 A much smaller unit of population, a block group, with an average population of 1,000 residents, is the smallest geographic unit for which census SE data are tabulated. Block groups are designed to be relatively homogenous with respect to the economic status and living conditions of their residents. 3,4 A block group has a Department of Cardiology, Children s Hospital Boston, Boston, Massachusetts; b Cardiovascular Division, Brigham and Women s Hospital, Boston, Massachusetts; c Heart Failure and Transplant Service, Massachusetts General Hospital, Boston, Massachusetts; d Department of Cardiology, Tufts Medical Center, Boston, Massachusetts; e New England Organ Bank, Newton, Massachusetts; f Harvard Medical School, Boston, Massachusetts; and g Harvard School of Public Health, Boston, Massachusetts. Manuscript received August 3, 2009; revised manuscript received and accepted November 13, This study was supported by the Heart Transplant Education and Research Fund, Children s Hospital Boston, Boston, Massachusetts. *Corresponding author: Tel: (617) ; fax: (617) address: TP.Singh@cardio.chboston.org (T.P. Singh). been described as the neighborhood of a person s residence. 4 Previous studies using block group SE data in population studies have demonstrated an association of low SE position with incident coronary heart disease, cancer, and all-cause mortality. 3 6 The purpose of the present study was to evaluate whether low patient SE position, determined by the SE characteristics of the block group of patient residence, is associated with graft loss and risk of graft rejection in heart transplant recipients. Methods The present study was a multicenter, retrospective cohort study. All patients who underwent a first heart transplant at 1 of 4 Boston Transplant Centers (Children s Hospital Boston, Massachusetts General Hospital, Brigham and Women s Hospital, Tufts Medical Center, all Boston, Massachusetts) from January 1, 1996 to December 31, 2005 were eligible. The patients who underwent repeat transplant or were non-united States residents (international patients) who came to the United States for heart transplantation were excluded. The institutional review boards of all 4 hospitals approved the study, with a waiver of informed consent. Each patient s home address at transplantation was used to extract the block group of residence from the US Census Web site. Using a previously described measure of SE position from the SE characteristics of block group of residence, a summary SE score was derived for each transplant recipient. This score was used as the main indicator of the SE position of the patient. 4,6 The 6 SE variables selected for the summary /10/$ see front matter 2010 Elsevier Inc. All rights reserved. doi: /j.amjcard

2 Miscellaneous/SE Position and Heart Transplantation Outcomes 1025 Table 1 Comparison of patient demographic and clinical characteristics by socioeconomic (SE) group Variable Low SE Group (n 129) Control Group (n 391) p Value Age at transplant (years) 0.02 Median Range Age at transplant (years) (2.3%) 8 (2.1%) (13.2%) 34 (8.7%) (7.8%) 33 (8.4%) (11.6%) 37 (9.5%) (51.9%) 185 (47.3%) (13.2%) 94 (24%) Race/ethnicity White 88 (68.2%) 355 (90.8%) Black 19 (14.7%) 12 (3.1%) Hispanic 20 (15.5%) 17 (4.3%) Other 2 (1.6%) 7 (1.8%) Female 31 (24.0%) 92 (23.5%) 0.91 Diagnosis 0.20 Idiopathic dilated 76 (58.9%) 197 (50.4%) cardiomyopathy Ischemic cardiomyopathy 32 (24.8%) 116 (29.7%) Congenital heart disease 15 (11.6%) 42 (10.7%) Other 6 (4.7%) 36 (9.2%) United Network of Organ 0.53 Sharing status at transplantation 1 23 (17.8%) 63 (16.1%) 1A 46 (35.7%) 125 (32.0%) 1B 26 (20.2%) 73 (18.7%) 2 34 (26.4%) 130 (33.2%) Transplant era (28.7%) 142 (36.3%) (38.8%) 109 (27.9%) (32.5%) 140 (35.8%) Insurance Public 60 (46.5%) 106 (27.1%) Private 63 (48.8%) 276 (70.6%) Missing 6 (4.7%) 9 (2.3%) Diabetes 19 (14.8%) 60 (15.4%) 1.00 Hypertension 29 (22.7%) 89 (23.5%) 0.90 History of smoking 70 (54.3%) 185 (47.3%) 0.31 Extracorporeal membrane 10 (7.8%) 15 (3.8%) 0.09 oxygenation Ventricular assist device 12 (9.3%) 33 (8.4%) 0.72 Panel reactive antibody 10% 7 (8.3%) 22 (9.4%) 1.0 Positive cross-match 2 (1.6%) 5 (1.3%) 0.69 Induction therapy 13 (10.1%) 49 (12.5%) 0.53 Early hospital death 11 (8.5%) 31 (7.9%) 0.85 Graft loss/death 45 (34.9%) 97 (24.8%) 0.03 Data are expressed as n (%), unless otherwise noted. score were originally described by Diez Roux et al 4 using factor analysis, a statistical technique to determine which variables of a large set (eg, a large set of Census SE variables) can be meaningfully combined into a composite score. To determine this score, the data for the 6 SE variables for each subject s block group were collected from the US Census 2000 Report. These variables represented 3 dimensions of wealth and income (log of the median household Table 2 Comparison of socioeconomic (SE) characteristics between groups Variable Low SE Group (n 129) Control Group (n 391) Composite socioeconomic score Median household income ($ thousands) Median value of houses ($ thousands) Households with rental, dividend, % % or interest income Residents 25 years old with high % % school graduation Residents 25 years old with % % college degree Employed as manager, professional, % % or executive Those living below poverty level % % Data are expressed as mean SD. Range of summary SE score was 15.9 to 3.6 for low SE group and 3.55 to 14.8 for controls. All comparisons, p income, log of the median value of housing units, and the percentage of households receiving interest, dividends, or net rental income), 2 dimensions of education (the percentage of adults 25 years old who had completed high school and the percentage 25 years old who had completed college), and 1 dimension of occupation (the percentage of employed persons 16 years old in executive, managerial, or professional specialty occupations) for the residents of the block group. For each variable, a z-score for each block group was calculated by subtracting the overall mean of that variable (across all block groups in the sample) from the value of the variable for that block group and dividing by the standard deviation. The summary SE score for each subject was obtained by summing the 6 z-scores (1 for each of the 6 variables) for that subject. The data on a simple measure of block group SE position, the proportion of persons living in the block group who were below the federally defined poverty level, were also collected. 6 Race/ethnicity was defined as designated by the transplant center for the state and national databases. The patients were divided into white and nonwhite (black, Hispanic, and other) categories for data analysis. Because the determinants of post-transplant hospital mortality and postdischarge mortality can be different, 2 primary outcome variables were analyzed: (1) the posttransplant hospital mortality (as a binary outcome), and (2) the interval to graft loss (death or retransplantation) in patients who survived the transplant hospitalization. The patients were followed up until graft loss (event) or were censored on June 1, We also evaluated the association of low SE position with 2 secondary outcomes: (1) the interval to the first rejection episode, and (2) the incidence rate of rejection (number of rejection episodes/patient-years of follow-up). We defined a rejection episode as meeting one of the following criteria: (1) endomyocardial biopsy showing International Society of Heart and Lung Transplantation grade 2R (old grade 3A), (2) antibody-mediated rejection, or (3) rejection as determined from clinical and/or

3 1026 The American Journal of Cardiology ( Table 3 Predictors of early hospital deaths (odds ratio) and graft loss (hazard ratio) in survivors of transplant hospitalization Predictor Univariate Analysis Multivariate Analysis HR/OR (95% CI) p Value HR/OR (95% CI) p Value Early hospital deaths Transplantation * 2.1 ( ) ( ) Extracorporeal membrane oxygenation/ventricular assist device 6.9 ( ) ( ) Ethnicity (nonwhite) 1.4 ( ) ( ) 0.46 Low socioeconomic group 1.1 ( ) ( ) 0.52 Graft loss in hospital survivors Transplant * 1.2 ( ) 0.51 Extracorporeal membrane oxygenation/ventricular assist device 1.6 ( ) 0.17 Low socioeconomic group 1.7 ( ) ( ) 0.06 Ethnicity (nonwhite) 1.8 ( ) ( ) 0.05 History of smoking 1.5 ( ) ( ) 0.03 Age, gender, diabetes, hypertension, listing status at transplantation were not associated with early or later outcomes. * Reference group, transplantation performed during HR hazard ratio; OR odds ratio. Figure 1. Kaplan-Meier survival curves comparing interval to graft loss in nonwhite versus white group for patients surviving to hospital discharge. The difference in survival between the 2 groups was statistically significant (p 0.02). Figure 2. Kaplan-Meier survival curves comparing interval to graft loss in low SE group and control group for patients surviving to hospital discharge. The difference in survival between the 2 groups was statistically significant (p 0.02). echocardiographic findings of graft dysfunction resulting in acute augmentation of immune suppression. 7 9 The patients were divided into 2 groups according to their summary SE scores: the low SE group (quartile with the lowest summary SE scores, n 129) and the control group (the remaining patients, n 391). The decision to compare the low SE group with the remaining patients rather than to compare 4 equal-size groups (quartiles) was made both because of the study hypothesis (ie, that the low SE group would be at risk) and because a preliminary analysis suggested similar outcomes for patients in quartiles 2 to 4. The 2 groups were compared for the distribution of demographic variables using Fisher s exact test or the Wilcoxon rank-sum test, and the SE variables (of the block groups of residence) were compared using t tests. The association of early hospital mortality (a binary outcome) with the potential risk factors was evaluated using a logistic regression model and that of subsequent graft loss in those surviving the transplant hospitalization using Kaplan-Meier survival curves (with the log-rank test) and a Cox proportional hazard model. A Cox model was also used to evaluate the interval to the first rejection episode. A Poisson regression model was used to evaluate the incidence rate of rejection. Multivariate models were constructed by evaluating all variables that had a univariate p value of 0.2; however, the SE group and race/ethnicity were included regardless of statistical significance. The models for rejection were adjusted for individual hospitals. Potential interactions of SE position with age, ethnicity, or medical insurance were explored. All tests were 2-sided. The data were analyzed using Statistical Analysis Systems, version 9.1 (SAS Institute, Cary, North Carolina) and Stata, version 10.0 (StataCorp, College Station, Texas). We had full access to the data and take responsibility for its integrity; all of us have read and agreed to the report as written. Results A total of 560 United States residents underwent their first heart transplant at the participating institutions from

4 Miscellaneous/SE Position and Heart Transplantation Outcomes 1027 Table 4 Univariate and multivariate predictors of rejection risk Predictor Univariate Analysis Multivariate Analysis* HR (95% CI) p Value HR (95% CI) p Value First rejection Age at transplant (years) 0.99 (0.98, 0.99) (0.98, 1.01) 0.34 Female gender 1.5 (1.1, 2.0) (0.9, 1.8) 0.12 Any ventricular assist device 1.5 ( ) (1.0, 3.0) 0.06 Nonwhite race 1.3 (0.9, 1.9) (0.7, 1.6) 0.68 Low socioeconomic group 1.4 (1.1, 1.9) ( ) 0.06 Rejection incidence Female gender 1.8 (1.4, 2.2) (1.1, 1.8) Any ventricular assist device 2.6 (1.7, 4.0) (1.5, 3.9) Transplantation (0.5, 0.8) (0.6, 1.0) 0.05 Transplantation (0.6, 1.0) (0.6, 1.1) 0.22 Nonwhite race 1.8 (1.4, 2.3) (1.1, 1.9) Low socioeconomic group 1.5 (1.2, 1.9) (1.0, 1.7) 0.03 * Multivariate models were adjusted for hospitals. Hazard ratio for interval to first rejection, incidence rate ratio for rejection incidence. Reference group, transplantation during Abbreviations as in Table to 2005 and were eligible for the present study. Of these, 40 (7%) did not have a home address in the medical records (only a post office box number was available) to determine their block group and SE data. The remaining 520 patients formed the analytic cohort for the present study. The median age of these patients was 51 years (range 7 days to 71 years); 105 (20%) were 19 years old and 111 (21%) were 60 years old. Of the 520 patients, 397 (76%) were male, 443 (85%) were white, and 77 were nonwhite (31 black, 37 Hispanic, and 9 other). The underlying diagnosis was dilated cardiomyopathy in 273 (52%), ischemic cardiomyopathy in 148 (29%), congenital heart disease in 57 (11%), and other in 42 (8%). The medical insurance was private for 339 patients (65%) and public for 166 (32%); 15 patients had missing insurance data. A comparison of the clinical and demographic variables between the low SE group and the control group is listed in Table 1. The groups were similar with respect to the distribution of gender, cardiac diagnoses, diabetes, hypertension, history of smoking (ever smoked), year (era) of transplant, and management with extracorporeal membrane oxygenation or ventricular assist device before transplantation. The low SE group was slightly younger, had a greater proportion of black and Hispanic subjects, and had a lower proportion of white subjects. The low SE group patients were more likely to have public medical insurance than were the controls. The 2 groups did not differ with respect to the proportion with a positive cross-match or a primary cytomegalovirus mismatch with their donor, the proportion who received induction therapy at transplantation, or their maintenance immune suppression regimen 2 weeks after transplantation. The SE characteristics of the block groups of patient residence of the low SE and control groups are compared in Table 2. The differences between the 2 groups were statistically significant for all SE variables. Thus, patients in the low SE group lived in neighborhoods with lower median household incomes and housing values; fewer adults who had completed high school or college education; fewer workers in managerial, professional, or executive professions; and fewer households with rental, interest, or dividends as income sources (p for all comparisons). The low SE group lived in neighborhoods with a significantly greater percentage of persons living below the poverty level. Cardiac allograft loss occurred in 142 patients (135 deaths and 7 repeat transplantations). The graft survival rate was 87.7% (95% confidence interval 84.6% to 90.2%), 84.6% (95% confidence interval 81.2% to 87.4%), and 79.0% (95% confidence interval 75.1% to 82.4%) 1, 3, and 5 years, respectively, after transplantation for the study cohort. Overall, graft loss was observed in 45 low SE patients (35%) and 97 control patients (25%). A total of 42 early deaths occurred during the transplant hospitalization (8.1%). On both univariate and adjusted analyses, early hospital mortality was associated with pretransplant mechanical support (extracorporeal membrane oxygenation or ventricular assist device) and with heart transplantation during the earlier years (1996 to 2001) but not with ethnicity or low SE group (Table 3). In patients who survived to discharge after the transplant hospitalization, the era of transplantation and use of pretransplantation mechanical support (extracorporeal membrane oxygenation/ ventricular assist device) were not associated with subsequent graft loss. In these patients, nonwhite patients (Figure 1), those in the low SE group (Figure 2), and those with a history of smoking were at a greater risk of subsequent graft loss on univariate analysis (Table 3). The multivariate model that best predicted the risk of graft loss in hospital survivors included nonwhite race/ethnicity, low SE position, and pretransplant history of smoking (Table 3). The addition of SE group to a model that included race/ethnicity and smoking (but not SE group) lowered the hazard ratio for nonwhite ethnicity from 2.0 to 1.7. Of note, the type of medical insurance (public vs private) was not associated with either hospital deaths or subsequent graft loss in hos-

5 1028 The American Journal of Cardiology ( Figure 3. Kaplan-Meier curves comparing interval to first rejection in low SE group and controls (p 0.02). pital survivors. Overall, a greater proportion of patients in the low SE group died from acute rejection (3.9% vs 0.8% controls, p 0.01) or from acute rejection, coronary artery disease, or chronic graft dysfunction (10% vs 3% controls, p 0.002). A total of 348 rejection episodes were diagnosed in the study cohort (median 0, interquartile range [twenty-fifth to seventy-fifth percentile] 0 to 1). Of these episodes, 8 (2.3%) were antibody mediated. At least one rejection episode occurred in 208 (40%) of the 520 patients. The incidence rate of rejection was 0.11 episodes per patient-year for the study cohort. Table 4 lists the univariate and multivariate predictors of the interval to the first rejection and the incidence rate of rejection. On univariate analysis, the low SE group was more strongly associated with a risk of a first rejection episode (Figure 3) than was nonwhite race/ethnicity. On multivariate analysis, a history of pretransplant ventricular assist device and low SE position were associated with first rejection but not race/ethnicity. The incidence rate of rejection was greater in nonwhite patients (0.17/patient-year) than in white patients (0.10/ patient-year) and greater in the low SE group (0.15/patientyear) than in the control group (0.10/patient-year). The low SE group and nonwhite ethnicity were both independently associated with a greater incidence rate of rejection in an adjusted analysis controlling for era, history of pretransplant ventricular assist device use, and gender (Table 4). Discussion In the present study, we sought to determine the effect of low SE position on outcomes in heart transplant recipients who had undergone transplantation during a 10-year period in 1 of 4 transplant centers in Boston, Massachusetts. We found that after transplantation, predischarge hospital mortality was not affected by race/ethnicity or SE position. However, among the recipients who survived the transplant hospitalization, nonwhite patients and those living in low SE neighborhoods were at a greater risk of subsequent allograft loss. These groups also had a greater incidence rate of rejection. A low SE position modestly lowered the risk associated with nonwhite ethnicity when added to the models that included race/ethnicity and appeared to have additional independent predictive value as a risk factor in the presence of race/ethnicity. Previous studies have linked race/ethnicity to post-transplant outcomes through donorrecipient HLA mismatching and differences in metabolic/ immunologic pathways. Specifically, a pro-inflammatory state has been demonstrated in blacks. 10 Our results suggest that a low SE position might not only partially mediate the association of nonwhite ethnicity with worse outcomes in heart transplant recipients, but might also be an independent risk factor for graft loss in survivors of transplant hospitalization. Thus, SE factors might amplify the effect of biologic differences in racial groups on outcomes. The SE position is known to have biologic consequences for health. Population studies have convincingly demonstrated that SE position is associated with health inequities within all racial/ethnic groups Furthermore, SE differences between different racial/ethnic groups might play a causal role in health outcome disparities (eg, the frequency of low birth weight, life expectancy, and all-cause mortality) across these groups. 13,14 Our results suggest that a greater incidence rate of rejection might mediate the association of low SE position with the greater risk of graft loss although other co-morbidities not assessed in the present study could also have contributed to this association. Transplant recipients might have better long-term outcomes if they understand their complex medical condition and have the resources that allow them access to medical care at all times. Almost all patients in our study had medical insurance and thus had access to healthcare providers and medications. The differences in outcomes between the low SE and control groups might suggest that the control group patients used the available resources better than did the low SE group patients. This speculation has not been supported by data, however. The association of SE position with transplant outcomes in previous reports has not been consistent. In studies that used zip code-based SE variables, the association was absent or weak. 1,15 However, when patient-specific variables such as private insurance or college or greater education were used to determine SE position, the results supported such an association. 15,16 The negative results in cohorts using the zip code-based SE measures are not surprising. Previous population-based studies have shown that even when SE measures obtained from block groups (average population of 1,000) and census tracts (average population of 4,000) demonstrated significant relations with health outcomes (eg, all-cause and cause-specific mortality rates and cancer incidence), the zip code measures of SE position for the same population demonstrated either no gradients for outcomes or those contrary to the results observed for block groups and census tracts. 3 The association of a social construct such as low SE position to outcomes in transplant recipients has important implications for improving the outcomes of these patients. The potential targets for interventions are not only patients and their families, but also providers and healthcare organizations. 17 Potential strategies for improving the outcomes of transplant recipients should include an emphasis on understanding patient resources, SE position, and education

6 Miscellaneous/SE Position and Heart Transplantation Outcomes 1029 and designing individualized interventions to help improve the outcomes in high-risk groups. Our findings also make a case for routine collection of SE variables in transplant registries and prospective studies designed to examine immunologic differences between transplant recipients of different racial groups to better understand their role in patient outcomes. The present study had a few limitations. First, SE position was defined entirely by the SE characteristics of the neighborhood of residence. The only patient-specific SE variable in this study (public vs private insurance) was not associated with outcome. Some researchers have advocated the collection of SE data at multiple levels (individual, family, and neighborhood) to understand their relative contribution to health and disease. 18 Second, the change in SE position of transplant recipients over time was not assessed. SE position was characterized similar to any baseline demographic or biologic variable. 6,19,20 Third, because the study population was predominantly white (85%), it might not have provided a reliable estimate of the magnitude of the confounding effect of SE variables in the race outcome association. A more precise assessment of this estimate would require a greater representation of racial/ethnic minorities. Fourth, we excluded 7% of the 560 transplant recipients from analysis because their home address, and thus neighborhood SE data, was not available. Although the distribution of their demographic and clinical variables and their post-transplant outcomes were not different from those of the study cohort (data not reported), we could not be certain that their SE data were missing at random. Finally, we could not conclude from the present results that the observed associations were causal. 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