Peripheral vascular disease (PVD) portends increased morbidity and mortality in patients with heart failure. In those with advanced heart failure, heart transplantation (HT) is the only causative therapy to increase survival. However, little is known about the impact of symptomatic PVD on survival of HT recipients in large multicenter cohorts. The aim of this study was to investigate an association between recipient symptomatic PVD and survival after HT. We analyzed 20,297 patients from the United Network of Organ Sharing data set. Survival analysis using a control cohort established by propensity matching was performed. There was an increased prevalence of traditional cardiovascular risk factors in 711 patients with symptomatic PVD compared with 19,586 patients without PVD. Patients with pretransplant symptomatic PVD had increased post-transplant mortality compared with those without PVD (1-, 5- and 10-year survival rate 91.5% vs 94.9%, 74.8% vs 82.6%, 48.6% vs 54.7%, respectively, log-rank p <0.001). On multivariate analysis based on the propensity matching, factors associated with a lower survival rate were presence of PVD (hazard ratio 1.20, 95% confidential interval 1.02 to 1.42, p = 0.030), and female gender (hazard ratio 1.22, 95% confidence interval 1.02 to 1.47, p = 0.034). In conclusion, patients with symptomatic PVD have a lower survival rate after HT. Symptomatic PVD should be considered an independent risk factor for poor prognosis in patients undergoing HT evaluation.
Highlights
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The present study included 20,297 adult heart transplant recipients from the United Network of Organ Sharing data registry.
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Patients with symptomatic peripheral vascular disease have a lower survival rate after heart transplantation.
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Symptomatic peripheral vascular disease should be considered an independent risk factor for poor prognosis in patients undergoing heart transplant evaluation.
Heart transplantation (HT) is the only causative treatment for patients with advanced heart failure (HF). However, because of the scarcity of donors, selection of appropriate candidates has become more rigorous. The screening methods for candidacy include evaluation for peripheral vascular disease (PVD) when warranted, and in those candidates with moderate-to-severe PVD, HT is contraindicated in 30% of US transplant centers. Furthermore, because of the longevity of HT recipients, there is still a concern for patients with HF and PVD to develop accelerated and new-onset atherosclerosis after HT. Previous studies have shown a 10% incidence of developing an accelerated form of atherosclerosis leading to PVD after HT. Additionally, the role of immunosuppression (i.e., prednisone, cyclosporine) may enhance metabolic abnormalities such as hyperlipidemia that may further advance atherosclerotic vascular disease. Earlier studies have shown that the presence of PVD is a risk factor for death from any cause after cardiac transplantation. Because of the paucity of data on the impact of survival in HT recipients with PVD, we sought to analyze the United Network of Organ Sharing (UNOS) database to examine the association between symptomatic PVD in patients with advanced HF and survival after HT.
Methods
Standard transplant analysis and research files with follow-up were obtained from the UNOS database. These data included all heart transplant recipients and donors in the United States and reported to the Organ Procurement and Transplantation Network from 1990 to 2010. There is one record per waiting list registration/transplantation event, and another record includes the most recent follow-up information (including patient and graft survival) reported to the Organ Procurement and Transplantation Network as of the date the file was created. To ensure the confidentiality of centers and patients, the data set does not include any patient or transplant center identifiers except for a unique patient identification number. Follow-up data are represented as 1 record per follow-up per transplantation event. Some patients have multiple records in a given year, whereas others have only 1 record. Patients lost to follow-up were censored at the time of last known follow-up. The Institutional Review Board of Columbia University Medical Center approved the present study.
Patients selected were of age ≥18 years undergoing first-time HT from 1990 to 2010 (n = 20,297). PVD was defined as the presence or absence of symptomatic PVD (yes or no) based on the UNOS Heart Transplant Recipient Registration Form. Thus, patients were stratified according to the presence or absence of symptomatic PVD and were excluded if they underwent other simultaneous organ transplantation or if demographical, diagnostic, or follow-up data were missing. Patients were monitored from the date of transplantation to 2010, which was the last day of follow-up provided by UNOS. Baseline characteristics including age, gender, body mass index, cause of HF, and renal and liver function parameters were collected.
Continuous variables are reported as mean ± SD, and comparison was carried out with the Student t test. Categorical variables are reported as percentages, and comparison was done with the chi-square test. The outcome of interest was death after transplantation. The patients who were alive at the last follow-up were censored. The survival is presented with Kaplan-Meier plots and was compared with the log-rank test. In addition, median survival time was estimated along with its 95% confidence interval. The univariate and multivariate Cox proportional hazards regression analyses were carried out to assess the risk of PVD on survival. In addition, analysis was carried out using propensity score. The propensity score was calculated with a multivariate logistic regression model on the PVD status with the adjustment of following factors: age, gender, race/ethnicity, cause of HF (ischemic or nonischemic), hypertension, diabetes, dialysis, previous stroke, creatinine level, and total bilirubin. Then, 3 adjusted Cox proportional hazards models were fitted: one with 2 covariates (PVD and continuous propensity score), one with 3 covariates (PVD, gender, and continuous propensity score), the other with covariates identified in the analysis of total cohort. Furthermore, conditional logistic regression analysis was carried out with 5:1 ratio of propensity score matching. For all statistical analyses, a 2-tailed p <0.05 was considered significant. Statistical analyses were performed using SAS software, version 9.2 (SAS Institute Inc., Cary, North Carolina). Propensity score matching is done by “radius” matching with an allowable absolute difference 0.01 between exact propensity scores with an SAS macro on matching propensity score at 5:1 ratio.
Results
The demographic and clinical characteristics before matching and the balance achieved after matching are summarized in Tables 1 and 2 , respectively. The study population included 20,297 adult recipients from the UNOS data registry. Of these, 711 (3.5%) had symptomatic PVD and 19,586 (96.5%) did not have symptomatic PVD. After matching for significant imbalances in patient characteristics, patients in the PVD group compared with the no PVD group were mostly Caucasians and more frequently have a smoking history ( Table 2 ).
| Variables | Peripheral Vascular Disease | p-Value | |
|---|---|---|---|
| Yes (n = 711) | No (n = 19,586) | ||
| Age (years) | 56.4 ± 8.0 | 51.7 ± 11.8 | <0.001 |
| Male (n, %) | 591 (83.1%) | 14941 (76.3%) | <.0001 |
| White | 604 (85.0%) | 15166 (77.4%) | <.0001 |
| Black | 72 (10.1%) | 2702 (13.8%) | |
| Hispanic | 27 (3.8%) | 1216 (6.2%) | |
| Other | 8 (1.1%) | 502 (2.6%) | |
| Etiology | <.0001 | ||
| Ischemic | 529 (74.4%) | 9143 (46.7%) | |
| Non-ischemic | 131 (18.4%) | 8169 (41.7%) | |
| Other | 51 (7.2%) | 2274 (11.6%) | |
| Body mass index (kg/m 2 ) | 26.6 ± 4.8 | 26.3 ± 5.1 | 0.176 |
| Hypertension | 381 (53.6%) | 7352 (37.5%) | <.0001 |
| Diabetes mellitus | 270 (38.0%) | 3713 (19.0%) | <.0001 |
| Smoker | 95 (13.4%) | 1874 (9.6%) | <.0001 |
| Dialysis at registration | 17 (2.4%) | 262 (1.3%) | 0.018 |
| Stroke | 114 (16.0%) | 1048 (5.4%) | <.0001 |
| Creatinine (mg/dL) | 1.49 ± 0.9 | 1.39 ± 1.2 | 0.004 |
| Total bilirubin (mg/dL) | 1.21 ± 2.1 | 1.35 ± 3.2 | 0.098 |
| Albumin (g/dL) | 3.72 ± 0.8 | 3.65 ± 0.8 | 0.108 |
| Variables | Peripheral Vascular Disease | p-Value | |
|---|---|---|---|
| Yes (n = 711) | No (n = 3,526) | ||
| Age (years) | 56.4 ± 8.0 | 56.5 ± 10.3 | 0.598 |
| Male (n, %) | 591 (83.1%) | 2959 (84.5%) | 0.362 |
| White | 604 (85.0%) | 2914 (82.6%) | <.0001 |
| Black | 72 (10.1%) | 276 (7.8%) | |
| Hispanic | 27 (3.8%) | 194 (5.5%) | |
| Other | 8 (1.1%) | 142 (4.0%) | |
| Etiology | <.0001 | ||
| Ischemic | 529 (74.4%) | 2931 (83.1%) | |
| Non-ischemic | 131 (18.4%) | 416 (11.8%) | |
| Other | 51 (7.2%) | 179 (5.1%) | |
| Body mass index (kg/m 2 ) | 26.6 ± 4.8 | 26.8 ± 5.1 | 0.428 |
| Hypertension | 381 (53.6%) | 1944 (55.8%) | 0.521 |
| Diabetes mellitus | 270 (38.0%) | 1526 (43.4%) | 0.011 |
| Smoker | 95 (13.4%) | 416 (11.8%) | 0.002 |
| Dialysis at registration | 17 (2.4%) | 97 (2.8%) | 0.594 |
| Stroke | 114 (16.0%) | 579 (16.4%) | 0.829 |
| Creatinine (mg/dL) | 1.49 ± 0.9 | 1.49 ± 1.6 | 0.960 |
| Total bilirubin (mg/dL) | 1.21 ± 2.1 | 1.23 ± 2.5 | 0.813 |
| Albumin (g/dL) | 3.72 ± 0.8 | 3.63 ± 0.8 | 0.039 |
Multivariate analysis in the entire data set demonstrated that the presence of PVD, black race, hypertension, diabetes mellitus, and dialysis at registration were independent factors associated with increase mortality in HT recipients ( Table 3 ). After propensity analysis, only the presence of PVD and female gender were independent predictors of mortality ( Table 4 ).
| Variable | Univariate | Multivariate | ||
|---|---|---|---|---|
| HR (95% CI) | p-Value | HR (95% CI) | p-Value | |
| PVD (yes = 1, no = 0) | 1.26 (1.11–1.44) | 0.0003 | 1.16 (1.01–1.33) | 0.033 |
| Age (year-old) | 1.00 (0.99–1.00) | 0.483 | ||
| Gender (female = 1, male = 0) | 1.06 (1.00–1.12) | 0.036 | 1.06 (0.99–1.13) | 0.059 |
| White (reference) | 1 | 1 | ||
| Black | 1.18 (1.10–1.27) | <0.0001 | 1.18 (1.09–1.27) | <0.0001 |
| Hispanic | 1.07 (0.97–1.19) | 0.187 | 1.06 (0.95–1.18) | 0.329 |
| Other | 1.21 (1.05–1.41) | 0.011 | 1.21 (1.02–1.43) | 0.027 |
| Etiology (ischemic = 1, non-ischemic = 0) | 1.05 (0.99–1.10) | 0.064 | 1.05 (0.99–1.11) | 0.093 |
| Hypertension (yes = 1, no = 0) | 1.10 (1.05–1.16) | <0.0001 | 1.07 (1.02–1.13) | 0.012 |
| Diabetes mellitus (yes = 1, no = 0) | 1.22 (1.15–1.30) | <0.0001 | 1.23 (1.15–1.31) | <0.0001 |
| Smoker (yes = 1, no = 0) | 0.99 (0.86–1.15) | 0.929 | ||
| Dialysis at registration (yes = 1, no = 0) | 1.42 (1.16–1.73) | 0.0006 | 1.28 (1.01–1.61) | 0.042 |
| Stroke (yes = 1, no = 0) | 1.12 (1.01–1.24) | 0.028 | 1.10 (0.99–1.23) | 0.090 |
| Creatinine (mg/dL) | 1.01 (0.99–1.03) | 0.096 | 1.01 (0.99–1.02) | 0.457 |
| Total bilirubin (mg/dL) | 0.99 (0.99–1.01) | 0.654 | ||
| Albumin (mg/dL) | 1.01 (0.96–1.05) | 0.810 | ||
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