Heart failure (HF) significantly impacts the health of many Americans, with a prevalence of 5.1 million in the year 2013.1 At the age of 40 years, the lifetime risk of developing HF for both men and women is one in five.2 Of those that are diagnosed, approximately 50% will survive 5 years.3 The initial management is medical, with heart transplantation reserved for those with end-stage disease.4 The impact of heart transplantation as a viable option remains limited secondary to the paucity of suitable donor organs.5 Approximately 10–15% of patients die annually while awaiting a heart transplant.5
As left ventricular assist devices (LVADs) have evolved and improved so has the quality of life and survival of these patients.6,7 Bridge to transplantation survival at 1 year in those with LVADs as compared with those treated medically was 91% and 77%, respectively.6 These support devices have allowed patients to survive longer while awaiting transplantation. Similarly, better symptom control and quality of life portends improved allocation of resources and placement of organs.8
Because of improved LVAD technology, the number of LVADs implanted annually continues to increase, thus causing an overall increase in the number of patients awaiting heart transplant.5,7 Despite this, the supply of donor organs has remained stagnant over the last decade, leading to the use of marginal donor organs.9 Previously, multiple studies have demonstrated that size mismatching may have an impact on post-transplantation survival10–12; however, it is unclear what effect donor size compared with recipient size has on survival outcomes specifically related to survival outcomes for patients with LVAD. Using the United Network for Organ Sharing (UNOS) database, we sought to evaluate how donor to recipient undersizing, based on body mass index (BMI) ratio, would affect long-term post-transplant survival in patients with and without an LVAD.
Data were obtained from the UNOS registry for patients listed for heart transplantation from January 2008 to December 2013. Patients were included in the study if they underwent heart transplantation and were ≥18 years. Patients were excluded if they did not undergo transplantation or had missing BMI data.
The study population was then divided into two groups: those without and with an LVAD at the time of heart transplantation. Patients in the LVAD group were included if they received either a HeartMate II (Thoratec Corporation, Pleasanton, CA) or HVAD (HeartWare, Inc., Miami Lakes, FL) and were excluded if they received any other device. Both of these groups were further subdivided into three groups: donor:recipient BMI ratio <0.8 (undersized), ≥0.8 and ≤1.2 (matched), and >1.2 (oversized). The full algorithm for the study design is shown in Figure 1. The primary outcome of this study was comparison of graft survival between patients who underwent heart transplant with 20% donor undersizing, matched sizing, and 20% oversizing in patients with and without an LVAD at the time of heart transplant.
All statistical analyses were completed using SPSS v. 22 (IBM, Armonk, NY). All reported results are at the time of transplantation unless otherwise specified. A normality test was performed and demonstrated a non-normal distribution of the study subjects. Therefore, Mann–Whitney, Kruskal–Wallis, and χ2 analysis using Fisher’s exact test were used to compare study group characteristics. Kaplan–Meier survival analysis was used to compare survival between study groups using the log-rank test. Multivariable Cox regression analysis was used to determine significant factors affecting graft survival time. The proportional hazards assumption was assessed for each variable included in the model. Variables that violated this assumption were time-adjusted and included in a second Cox regression analysis. Values are report as n (percent) or median (interquartile range). A p value of 0.05 or less was considered statistically significant.
A histogram representing the entire study population distributed by donor to recipient BMI ratio is shown in Figure 2. The median BMI ratio was 1.02 (0.87, 1.17). A total of 1,666 (15.8%), 6,789 (64.5%), and 2,064 (19.6%) patients were in the undersized, matched size, and oversized study groups, respectively. Five patients were excluded from the study because of missing BMI values.
The characteristics of the entire study population at the time of transplant are shown in Table 1 and are divided into two groups: those without and with an LVAD. These two groups were only similar for age, whereas the LVAD group had a higher proportion of males, recipient BMI, time on waiting list, ischemic time, history of diabetes, idiopathic HF, and patients in UNOS status 1A. The non-LVAD group had a higher mean pulmonary artery pressure (PAP), creatinine, proportion of patients in UNOS status 1B and 2, and proportion of patients who received hearts of gender mismatch at the time of transplant. Of the entire population, 2,798 (26.6%) received hearts from the opposite gender, and 1,578 (15.0%) of these patients were male recipients of a female donor heart. The LVAD group included 716 (22.1%) recipients of hearts from the opposite gender while 418 (12.9%) male recipients received female donor hearts.
Characteristics of patients with an LVAD at the time of transplant divided into undersized, matched size, and oversized groups are provided in Table 2. All LVAD groups experienced similar time on the waiting list, ischemic time, mean PAP, creatinine, total bilirubin, proportion of patients listed in UNOS status 1A, 1B, and 2, and cardiac output. The three groups varied statistically significantly in age, gender, recipient BMI, diabetes, and patients that received gender-mismatched organs. The proportion of gender-mismatched organs was higher in the oversized group (32.7%) for patients on an LVAD at the time of transplant compared with undersized and matched groups (22.5% and 19.5%, respectively; p ≤ 0.001). Moreover, the amount of female-to-male organs was also proportionally higher in the oversized group (27.5%) when compared with the undersized and matched sized groups (3.7% and 12%, respectively; p ≤ 0.001).
Analyses of post-transplant outcomes were limited by the variables collected by the UNOS database. There was no significant difference in the rate of renal failure requiring dialysis after transplantation in the undersized, matched, and oversized LVAD groups (11.8%, 9.9%, and 8.4%, respectively; p = 0.165). The incidence of post-transplant-treated episodes of rejection was not significantly different between the three groups (p = 0.132); however, there was a significant number of missing data points in this category. Finally, length of stay was similar at a median of 15 days for each size group within the LVAD group (p = 0.413).
Kaplan–Meier analysis revealed no difference in survival for patients without an LVAD between the undersized, matched size, and oversized groups (p = 0.634, Figure 3). When survival was compared for patients with an LVAD between the undersized, matched size, and oversized, survival was significantly better for the oversized group (p = 0.032, Figure 4). Recipients of donors of the opposite gender (gender mismatch) were removed from the analysis to assess the effect of size mismatch on patient survival excluding the potential confounding with gender mismatch. There was no significant difference in survival for both patients with (p = 0.477) and without (p = 0.325) a continuous flow LVAD between the size groups after patients with gender mismatch were removed. When only recipients with gender mismatch were compared, there was no significant difference in survival for patients without an LVAD (p = 0.830) between the three size groups; however, survival was significantly worse for the undersized group for patients with an LVAD (p = 0.022).
Results of the unadjusted Cox regression analysis are shown in Table 3 for all patients and subdivided into those with and without a continuous flow LVAD. In this model, BMI ratio does not significantly affect survival for the entire population (p = 0.083); however, when the population is divided by presence of an LVAD at the time of transplant, the BMI ratio becomes a significant factor in survival for the LVAD population (0.034).
Variables that violated the proportional hazards assumption include age, BMI ratio, cardiac output, PAP, and UNOS status. The continuous variables were time-adjusted and included in the model. UNOS status, as a categorical variable, could not be adjusted. Thus, the model was stratified by UNOS status. Results of the adjusted Cox regression analysis are shown in Table 4 for all patients and subdivided into those with and without a continuous flow LVAD. All variables used in this model significantly affected survival with the exception of gender mismatch and a diagnosis of idiopathic HF when the population was divided into patients with and without a continuous flow LVAD.
Despite the increasing number of patients with advanced HF, the number of donor organs has remained stable.1,5 Furthermore, the patient population with LVADs awaiting heart transplantation is increasing steadily.14 This has led physicians to accept donor organs that may not be ideal for an individual recipient, including those organs that may be a size mismatch for the recipient.15–19 Current International Society of Heart and Lung Transplantation guidelines suggest a donor-to-recipient weight ratio of >0.8.4,20 Although size mismatching is a common occurrence,21 the survival outcomes for recipients of mismatched size organs, specifically those with VADs at the time of transplant, are unclear.
Previous studies have not shown a difference in survival based on donor-to-recipient weight ratios. Furthermore, most studies examining size differences between donors and recipients are limited to a single institution or as part of a larger analysis. In a retrospective analysis of the UNOS database, Patel et al.21 divided patients into three groups based on donor:recipient weight ratios: <0.8, 0.8–1.2, and >1.2. Kaplan–Meier survival analysis demonstrated equivalent 5 year survival for these groups. However, when the <0.8 weight ratio group was further analyzed, survival was worse for patients with high pulmonary vascular resistance (PVR) and for male patients with high PVR who received a donor heart from a female patient. In a single institution report, Sethi et al.22 also found no difference in survival for recipients of donor hearts that were >30% undersized (n = 27) compared with those who received normal sized hearts (n = 173). In a more recent study from a single institution, Taghavi et al.23 found no difference in 1, 5, or 10 year survival between same-sex patients with a donor:recipient weight ratio of <0.9 and female donor, male recipients with a donor:recipient weight ratio <0.7 with age and sex-matched control patients. Jayarajan et al.13 also examined the UNOS database comparing patients with a normal donor:recipient weight ratio (0.9 or greater) to those with a donor:recipient weight ratio of 0.6–0.89 and <0.59. They found that survival was only impacted with undersized heart when male recipients received a female donor heart and concluded that the guidelines should be expanded to allow for undersizing.
Conversely, there is evidence that undersizing impacts long-term survival. Reed et al.10 examined the effect of heart mass on survival in an analysis of the UNOS database and decreased survival within the first year post-transplant for male recipients of female donor hearts with the lowest heart mass mismatch group. Further findings demonstrated that this survival disadvantage was eliminated for sex mismatching when size mismatching was controlled for. Chen et al.24 also found in their single institution study that BMI mismatch of >20% had impact on short- and long-term mortality.
This study sought to examine size effects in patients with and without an LVAD at the time of cardiac transplantation. The LVAD versus no LVAD study populations differed statistically significantly for all characteristics other than age. Interestingly, the wait list time and BMI were higher for the LVAD group, which may have led the respective transplant center to accept a small donor organ. When the LVAD study population was divided into the undersized, matched size, and oversized groups, the groups were similar for time spent on the waiting list, ischemic time, creatinine, total bilirubin, and diagnostic distribution. The patients in the undersized patient subset were younger, were more likely to be female, had a higher proportion of people with diabetes, and had a higher cardiac output and PAP. Our results demonstrate that for those patients with an LVAD at the time of transplant, survival is worse for recipients of organs with a donor:recipient BMI undersizing of 20%. When survival is compared for the patients without an LVAD, there is no difference in mean survival. Because of the above findings, the decreased survival observed in the undersize group between patients with and without an LVAD likely represents a true survival disadvantage; however, gender mismatch does appear to be a confounding factor that negatively impacts long-term survival after heart transplant.
The unadjusted Cox regression analysis revealed that BMI ratio does not significantly affect survival for the entire population; however, when the population is divided by presence of an LVAD at the time of transplant, the BMI ratio becomes a significant factor in survival for the LVAD population (0.034). The adjusted Cox regression analysis demonstrates BMI ratio as a significant factor impacting survival in all patients, regardless of the presence of an LVAD. We believe that the unadjusted Cox regression analysis is more likely representative of clinical outcomes, whereas the adjusted Cox regression is a result of the data itself.
There are two main hypotheses for the findings in this study. Patients undergoing LVAD support must be anticoagulated and therefore by definition have dysregulation of the coagulation cascade. At the time of transplant, patients with an LVAD must undergo extensive dissection to prepare the chest to receive the donor heart. These factors may increase surgical bleeding and necessitate additional perioperative transfusions when compared with patients without an LVAD,25,26 leading to increased PVR.27 A recent study by Stone et al.26 found higher intraoperative transfusion requirements in patients with LVAD at the time of transplant when compared with patients without LVAD. This potential increase in PVR may negatively affect undersized allografts and increase the risk of early graft dysfunction and thus long-term survival.
Patients with an LVAD before heart transplantation often have a degree of pulmonary hypertension leading to right HF. After heart transplantation in patients with an LVAD, it is likely that a heart undersized for the recipient may not be able to overcome the developed pulmonary hypertension, thus leading again to right HF and decreased survival. Conversely, a normal or oversized heart in this patient population will allow adequate forward flow from the right ventricle in the face of pulmonary hypertension. Our data demonstrate that PAP was higher in all patients with an LVAD at the time of listing compared with patients without an LVAD. Although the PAP was lower in the LVAD group at the time of transplant, there may have been an underlying level of pulmonary arterial dysfunction caused by previously elevated PAP masked by unloading during LVAD support.
The study is limited by the use of a national database and retrospective analysis. Because of this, the donor:recipient BMI ratio was used as an approximation of heart size mismatch. Unfortunately, cardiac measurements are not recorded in the UNOS database. Additionally, the study populations were statistically dissimilar for most baseline characteristics likely caused by the use of a large sample size; however, many of the comparisons, although statistically significant, are not clinically significant.
In conclusion, patients with LVAD who receive a donor heart oversized by at least 20% have improved survival post-transplantation. Therefore, an oversized donor should be strongly considered for patients with an LVAD at the time of transplant. Additionally, donor undersizing in patients without an LVAD appears to be safe, and including these organs may allow for an increased donor pool. Overall, these considerations may decrease mortality for patients on the wait list and after cardiac transplantation.
The authors thank Dr. Douglas Lorenz, PhD, for his invaluable statistical guidance and Dr. Gretel Monreal, PhD, for editing.
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Keywords:Copyright © 2016 by the American Society for Artificial Internal Organs
left ventricular assist device; heart transplantation; survival