Would access to device therapies improve transplant outcomes for adults with congenital heart disease? Analysis of the United Network for Organ Sharing (UNOS)

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Would access to device therapies improve transplant outcomes for adults with congenital heart disease? Analysis of the United Network for Organ Sharing (UNOS) Melanie D. Everitt, MD,a,b Amy E. Donaldson, MS,a Josef Stehlik, MD,a,b Aditya K. Kaza, MD,a,b Deborah Budge, MD,b,c Rami Alharethi, MD,b,c Emily A. Bullock, RN,b Abdallah G. Kfoury, MDb,c and Anji T. Yetman, MDa,b From the aUniversity of Utah, the bUtah Transplant Affiliated Hospitals (U.T.A.H.) Cardiac Transplant Program, and c Intermountain Medical Center, Salt Lake City, Utah.

KEYWORDS: congenital heart disease; heart transplant; ventricular assist device; defibrillator

BACKGROUND: Patients with congenital heart disease (CHD) now survive into adulthood and often present with end-stage heart failure (HF). HF management and approach to orthotopic heart transplant (OHT) may differ from adults without CHD. We sought to compare OHT waitlist characteristics and outcomes for these 2 groups. METHODS: The Organ Procurement and Transplantation Network (OPTN)/United Network for Organ Sharing (UNOS) database was used to identify adults (ⱖ18 years) listed for OHT from 2005 to 2009. The cohort was divided into those with or without CHD. RESULTS: Of 9,722 adults included, 314 (3%) had CHD. Adults with CHD were younger (35 ⫾ 13 vs 52 ⫾ 12 years, p ⬍ 0.01) and more often had undergone prior cardiac surgery (85% vs. 34%, p ⬍ 0.01). Patients with CHD were less likely to have a defibrillator (44% vs 75%, p ⬍ 0.01) or ventricular assist device (5% vs 14%, p ⬍ 0.01) and were more likely to be listed at the lowest urgency status than patients without CHD (64% vs 44%, p ⬍ 0.01). Fewer CHD patients achieved OHT (53% vs 65%, p ⬍ 0.001). Although overall waitlist mortality did not differ between groups (10% vs 8%, p ⫽ 0.15), patients with CHD were more likely to experience cardiovascular death (60% vs 40%, p ⫽ 0.03), including sudden in 44% and due to HF in 16%. CONCLUSIONS: Despite lower urgency status, patients with CHD have greater cardiovascular mortality awaiting OHT than those without. Increased defibrillator use could improve survival to OHT, because sudden death is common. VAD support may benefit select patients, but experience in CHD is limited. Referral to specialized adult congenital heart centers can enhance utilization of device therapies and potentially improve waitlist outcomes. J Heart Lung Transplant 2011;30:395– 401 © 2011 International Society for Heart and Lung Transplantation. All rights reserved.

A greater number of patients with congenital heart disease (CHD) are now surviving into adulthood. Surgical survival rates for children born with complex CHD have improved from 10% in the 1940s1 to greater than 85% in the current era.2 As a result of improved survival after palliative and corrective cardiac surgery in infancy,

Reprint requests: Melanie D. Everitt, MD, Director, Pediatric & Congenital Heart Disease Transplant Program, Primary Children’s Medical Center, 100 Mario Capecchi Dr, Division of Pediatric Cardiology, Ste 1500, Salt Lake City, UT 84113. Telephone: 801-662-5400. Fax: 801-662-5404. E-mail address: [email protected]

it is now estimated that half of all patients with CHD are older than 18 years.2 Cardiovascular disease accounts for most deaths in adults with CHD. The mean age of death of these survivors remains greatly reduced at ⬍40 years overall and ⬍30 years for those with complex CHD.3 Orthotopic heart transplantation (OHT) is a life-saving option for many CHD survivors who present in adulthood with end-stage heart failure (HF). Recent studies have demonstrated that although adults with CHD have higher 30-day mortality after OHT than those without CHD,4,5 survival beyond the peri-operative period is comparable between patient groups.4 –7 Despite

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good long-term outcomes after OHT, relatively few adults with CHD undergo OHT, accounting for only 3% of all adult OHTs performed. This low proportion of adult recipients has remained steady for many years despite a growing number of adults with CHD.7 It is not known whether the proportion of adult CHD patients evaluated and listed for OHT has increased. Does the low proportion of adult CHD patients undergoing OHT reflect underutilization of this treatment strategy for this patient group, or do these patients experience greater mortality after listing? We sought to describe the characteristics of adults with CHD listed for OHT and to assess their waitlist outcomes. The primary study objectives were to determine if waitlist outcomes differed among adults with CHD compared with adults without CHD (non-CHD) and to compare and contrast clinical characteristics between groups to determine factors that may contribute to the waitlist outcomes described.

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cation justifies an extension as status 1A, or high dose or multiple inotropes in the hospital with continuous hemodynamic monitoring of left ventricular filling pressure. Status 1B criteria state that patients are receiving low dose inotropes or have a ventricular assist device beyond the 30-day period used for 1A listing. Status 2 refers to patients who do not meet 1A or 1B criteria.8

Whether the patient had a prior cardiac operation or had an implantable cardioverter defibrillator (ICD) at the time of listing was collected. Information pertaining to invasive support at the time of listing was noted and included the use of mechanical ventilation, intravenous inotropes, and MCS. The form of MCS was also identified as extracorporeal membrane oxygenation (ECMO), intra-aortic balloon pump (IABP), total artificial heart (TAH), or ventricular assist device (VAD). The total number of days on the waitlist was extracted for each patient. Data regarding the end points of OHT, death, waitlist removal for deterioration, and waitlist removal for improvement were obtained. For patients who died before removal from the waitlist, primary cause of death was noted. For patients who underwent OHT, UNOS medical urgency at the time of transplant was gathered.

Methods Statistical analysis Study group and data source After administrative review and approval by our Institutional Research Ethics Board, we retrospectively reviewed de-identified patient data extracted from the Organ Procurement and Transplantation Network (OPTN)/United Network for Organ Sharing (UNOS) research database. We identified all patients aged 18 years or older listed for primary OTH between January 1, 2005, and May 26, 2009. The cohort was divided into groups based on the presence or absence of CHD as determined by the primary diagnosis indicated at the time of listing. Primary diagnosis is a required field entered into the UNOS computerized database at listing for OHT. The pre-determined entry selection includes the following diagnoses: CHD, cardiomyopathy, coronary artery disease (CAD), cancer, valvular heart disease, re-transplantation, and “other.” Patients with a general diagnosis of CHD and patients with a diagnosis of “other” for whom the specified entry was determined to be a congenital heart defect were included in the study and analyzed in the CHD group. Patients with a general diagnosis of cardiomyopathy, CAD, and cancer as well as those with a diagnosis of “other” for whom the specific diagnosis was identified as cardiomyopathy, CAD, or cancer were included in the study and comprised the non-CHD group. Patients with a primary diagnosis of “valvular heart disease” were excluded because it was unclear from the data set whether the valvular heart disease was congenital or acquired. Patients with a diagnosis of “re-transplantation,” primary rhythm disorder, or for whom the diagnosis was unknown were also excluded. Patients listed for heart-lung transplantation were excluded. Data collected at listing included the demographics of age, gender, weight, height, race, and blood type. Additional medical factors were sought, including the presence of diabetes, cerebrovascular disease, creatinine level, and need for dialysis. The UNOS medical urgency status at the time of initial listing was noted. Medical urgency status for the purpose of organ allocation is defined by UNOS as follows: ●

Status 1A (highest urgency) is reserved for patients receiving continuous mechanical ventilation, mechanical circulatory support (MCS), valid for 30 days unless a device-related compli-

We compared patient and clinical characteristics, including device use, at the time of listing for CHD and non-CHD patients. Counts and percentages were used to describe categoric data and continuous variables were summarized as mean ⫾ standard deviation. Differences between the CHD and non-CHD groups were evaluated using the chi-square or Fisher exact test for categoric variables and the Wilcoxon rank sum test for continuous variables. The primary outcome of interest was time to one of several competing events: transplant, death, or waitlist removal for deterioration, waitlist removal for improvement, and other. Data of patients who were still awaiting transplant at the study end were censored. The cumulative incidence function for each competing outcome was estimated and compared between CHD and nonCHD groups using methods described by Gray.9 We used competing risks regression with weighted estimating equations to model the sub-distribution of time to transplant in the presence of other outcomes. The hazard ratios of the sub-distribution are presented with corresponding 95% confidence intervals (CI), with and without adjustment for UNOS medical urgency status at initial listing. We assessed proportional hazards assumptions by examining residual plots and considering inclusion of interactions between the predictor variables and time.10 A significance level of 0.05 was used for all analyses. Analyses were performed using SAS 9.2 software (SAS Institute Inc, Cary, NC) and the statistical package R (cmprsk analysis package used for competing risks).

Results Study cohort During the study period, 10,135 adults were listed for primary OHT only and 413 were excluded on the basis of primary diagnosis. The primary diagnosis of valvular heart disease resulted in the exclusion of 228 adults, accounting for 55% of those excluded. The primary diagnosis was not

Everitt et al. Table 1

Effect of Device Therapy on Pre-transplant Outcome

397

Demographics and Clinical Characteristics at Initial Listing for Heart Transplantation

Variables at listing

CHD

Non-CHD

p-value

Age, mean ⫾ SD, years Male gender, No. (%) Race, white Weight, median (IQR), kg Height, median (IQR), cm BMI, median (IQR), kg/m2 Blood group, No. (%) O A B AB Prior cardiac surgery, No. (%) Symptomatic CVD, No. (%) Dialysis, No. (%) Creatinine ⱖ 2.0 mg/dl, No. (%) Diabetes, No. (%)

35 ⫾ 13 198 (63) 261 (83) 70 (69–85) 170 (163–178) 25 (21–29)

52 ⫾ 12 7186 (76) 6528 (69) 82 (70–95) 175 (168–180) 27 (24–30)

⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001

152 112 41 9 266 15 6 22 15

4050 3705 1253 400 3174 407 217 973 2658

0.21 ⬍0.001 0.65 0.64 0.06 ⬍0.001

(48) (36) (13) (3) (85) (4.9) (1.9) (7.2) (4.8)

(43) (39) (13) (4) (34) (4.4) (2.3) (11) (28)

CHD, congenital heart disease; CVD, cerebrovascular disease; IQR, interquartile range; SD, standard deviation.

reported in 167 adults, 40% of those excluded. The primary reason for exclusion for the remaining 18 adults was a primary rhythm disorder diagnosis. Among the 9,722 adults listed for heart transplant and included in the study, 314 (3%) comprised the CHD group and 9,408 formed the comparative group without CHD. The baseline demographics and clinical characteristics by patient group are summarized in Table 1. Adults with CHD were younger, less often male, and more often categorized as white race than adults without CHD. In contrast to those without CHD, most of the adults with CHD had undergone at least one prior cardiac operation. Table 2 details the UNOS medical urgency status at listing as well as the presence of ventilator or circulatory support grouped by patient diagnosis. At the time of the initial listing, adults with CHD were predominantly placed at the lowest urgency level (status 2). In contrast, most adults without CHD were listed as status 1A or 1B, 19% and 36%, respectively. The

33 adults listed as status 1A in the CHD group were receiving the following forms of support: 36% VAD, 24% another form of MCS, 21% mechanical ventilation, and 45% intravenous inotropes. Among the 1,825 status 1A candidates without CHD, 34% were supported by VAD, 21% another form of MCS, 11% were receiving mechanical ventilation, and 46% were receiving inotropes.

Competing outcomes The cumulative incidence of competing risks outcomes for the overall cohort is illustrated in Figure 1. Most outcomes occurred within 180 days of listing. A comparison of waitlist outcomes by group can be seen in Figure 2. There was a significantly longer expected wait time to transplantation in the CHD group (p ⬍ 0.001). The non-CHD group was

Table 2 United Network for Organ Sharing (UNOS) Urgency Status and Medical Therapies at Initial Listing for Heart Transplantation Variables at listing UNOS urgency status 1A 1B 2 Mechanical circulatory support Mechanical ventilation Intravenous inotropes

CHD No. (%)

Non-CHD No. (%)

33 (11) 80 (25) 201 (64)

1825 (19) 3421 (36) 4162 (44)

⬍0.001

27 (9)

1793 (19)

⬍0.001

9 (2.9) 74 (24)

284 (3.0) 3135 (33)

0.88 ⬍0.001

p-value ...

CHD, congenital heart disease.

Figure 1 The probability of competing outcomes after listing is shown for the entire study cohort. Most events occurred within 180 days of listing.

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Figure 2 The probability of competing outcomes is shown by patients with congenital heart disease (CHD) and those without CHD. The groups differed significantly with respect to the outcome of transplant. Adults without CHD were more likely to achieve transplant at any given time after listing than those with CHD (p ⬍ 0.001). Note: The outcome of “Other” occurred in 367 patients, with similar specified reasons in both groups. These included refused transplant, 13%; transferred to another center, 29%; candidate removed in error, 3%; and not specified, 54%. Not shown is the outcome of still waiting: 27% in the CHD group and 17% in the non-CHD group.

more likely to achieve OHT at any given time, with a hazard ratio of 1.5 (95% CI, 1.3–1.7). After adjusting for status at listing, the hazard ratio remained significant, with the nonCHD group being 1.3 times more likely to achieve OHT at any given time than the CHD group (95% CI, 1.1–1.5). The predicted probabilities of transplant by status at listing and CHD group are shown in Figure 3. During the study period, 53% of CHD patients achieved OHT compared with 65% of non-CHD patients (p ⬍ 0.001). Despite the younger age of the CHD patients and the lower UNOS medical urgency status at listing, there was no difference between groups in death or removal from the waitlist for deterioration by competing outcomes analysis (p ⫽ 0.97). The overall waitlist mortality was 10% for CHD patients and 8% for nonCHD patients (p ⫽ 0.15).

Cause of death The primary cause of death was reported in 30 of 32 (94%) deaths in the CHD group and in 652 of 747 (87%) deaths in the non-CHD group. Adults with CHD who died while awaiting OHT were more likely to die of cardiac-related causes (Table 3). Although 40% of deaths in the non-CHD group were of cardiovascular causes, 60% of deaths in the CHD group were due to cardiac causes (p ⫽ 0.03). Sudden death or arrhythmia contributed to 13 deaths (43%) with a known cause in the CHD group. HF or cardiogenic shock occurred in an additional 5 CHD patients (17%).

Figure 3 The probability that a patient will receive an allograft is shown by patient group and initial listing status. Within each listing status, the predicted probability of achieving heart transplant is less for patients with congenital heart disease (CHD) compared with those without CHD.

Device therapies Because most deaths in the CHD group were sudden due to arrhythmias or related to HF, the use of device therapies was analyzed by groups (Table 4). At initial listing for OHT, only 44% of adults with CHD had an ICD vs 75% of adults without CHD (p ⬍ 0.001). The non-CHD group was more likely to be receiving any type of MCS (19% vs 9%, p ⬍ 0.001). When looking at the form of MCS, the non-CHD group was more likely to receive IABP and VAD support than the CHD group. ECMO was infrequent in both but was used more often in adults with CHD. Table 3 Primary Cause of Death for Those Who Died While Listed for Heart Transplant

Cause of deatha

CHD (n ⫽ 30) No. (%)

Non-CHD (n ⫽ 652) No. (%)

Cardiac causes Cardiac arrest Cardiogenic shock Arrhythmia Ventricular failure Other CV-related Non-cardiac causes Organ failure Infection Pulmonary Peri-operative Cerebrovascular Hemorrhage Other non-CV-related

18 11 4 2 1 0 12 5 3 3 1 0 0 0

264 128 39 23 30 44 388 132 78 22 9 84 12 51

(60) (37) (13) (7) (3) (40) (17) (10) (10) (3)

(40) (20) (6) (3) (5) (7) (60) (20) (12) (3) (1) (13) (2) (8)

CHD, congenital heart disease; CV, cardiovascular. a Patients with an unknown cause of death were excluded: 2 in the CHD group and 95 in the non-CHD group.

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Table 4 Device Therapies at the Time of Initial Listing by Patient Groups At listing

CHD No. (%)

Mechanical circulatory support ECMO 5 Intra-aortic balloon pump 7 Total artificial heart 0 Ventricular assist device 16 ICD 137

Non-CHD No. (%)

p-value

(1.6) 33 (0.4) 0.007 (2.2) 580 (6.2) 0.004 (0) 19 (0.2) ⬎0.99 (5.1) 1276 (14) ⬍0.001 (44) 7005 (75) ⬍0.001

CHD, congenital heart disease; ECMO, extracorporeal membrane oxygenation; ICD, implantable cardioverter defibrillator.

Discussion Despite numerous advances in cardiovascular surgery, adults with CHD continue to experience early death related to residual structural defects, ventricular systolic and/or diastolic dysfunction, arrhythmias, and other comorbidities related to their underlying heart disease. For these adult survivors of CHD, OHT can be a life-saving procedure; however, relatively few OHTs are performed in adults for the indication of CHD. This study demonstrates that CHD is also a rare indication for transplant listing in the adult population and demonstrates that OHT waitlist outcomes for adults with CHD are less favorable than for adults without CHD. There are many potential reasons for the increased incidence of adverse outcome seen in adults with CHD awaiting OHT. We have shown that despite sudden cardiac death being a leading cause of waitlist mortality for adults with CHD, these patients are less likely to undergo ICD placement compared with non-CHD cohorts. The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)11–13 demonstrated that ICD therapy reduced all-cause mortality in patients with New York Heart Association class II and III symptoms and a left ventricular ejection fraction ⬍ 35%. As a result, ICD therapy has been recommended as a bridge to OHT in all non-CHD adults with refractory HF who are to be listed for OHT.14 Unfortunately, the relative rarity and marked anatomic variability among adults with CHD have prevented these guidelines from being readily applied to CHD. Numerous studies have documented a high incidence of arrhythmias and sudden cardiac death in adults with CHD, suggesting that many would indeed benefit from ICD therapy.15–17 Documentation of a high rate of appropriate ICD shocks in adults with CHD who receive an ICD for primary prevention of sudden cardiac death due to ventricular dysfunction further supports this argument.18 Despite such data, ICD therapy is not routinely undertaken for primary prevention. The apparent underutilization of ICD therapy is likely multifactorial and may relate to limited data pertinent to sudden cardiac death risk stratification in this population, lack of published guidelines for defibrillator use as primary preven-

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tion in the adult with CHD, and barriers to transvenous lead placement, namely limited or no venous access to the heart. To impact waitlist mortality by reducing sudden cardiac death, risk factors in adults with CHD need to be recognized. Moreover, alternatives to epicardial placement of the ICD in patients with lack of venous access need to be further explored. Such options may include the wearable cardioverter defibrillator or placement of a subcutaneous array through a minithoracotomy.19,20 Referral to adult congenital heart specialists who possess knowledge of both the underlying CHD and HF management may help to bridge the gap in practice guidelines for these patients. In this study, there was a significant disparity in the use of VADs in adults with and without CHD awaiting OHT. The anatomic complexities of CHD, the diverse pathophysiology of HF in CHD, and a general lack of experience with VAD use in adult CHD patients are all possible reasons why adults with CHD are less like to undergo VAD implantation for end-stage heart disease. In addition to its direct effect on HF mortality,21–24 VAD support is linked to UNOS status listing criteria: All patients supported with a VAD are eligible for 30 days of status 1A listing time and, thus, more urgent priority for a donor organ.8 Adults with complex CHD in whom VAD insertion is uncommon are thus disadvantaged by the current UNOS allocation criteria. Furthermore, clinical improvement with respect to end-organ function and nutritional state that occurs with VAD support may decrease the transplant peri-operative risk that is noted for adults with CHD. The risk/benefit assessment for VAD implantation, however, is influenced by several factors in the adult with CHD. Most of these patients have had prior sternotomies that could complicate VAD insertion and their recovery. Comorbidities of CHD such as protein-losing enteropathy and occult liver disease25–27 may increase the risk of infection, contribute to hemorrhage or thrombosis, and impair wound healing after VAD implantation. This study sheds light on the uncommon usage of VADs in adults with CHD awaiting OHT. Consideration for VAD implant in the adult with complex CHD should be a part of HF management but is probably best undertaken by a team of specialists who understand the cardiovascular anatomy and physiology of the specific heart defects, the additional surgical risks incurred, and the suitability of device types and configurations for different forms of CHD. Whether the application of these devices would improve waitlist outcomes of death or transplant is unclear, but it is important to recognize that the assessment of an individual’s benefit or lack thereof requires the expertise and collaboration of cardiologists, surgeons, and transplant physicians with expertise in the adult with complex CHD and HF. Numerous other factors may play a key role in suboptimal waitlist outcomes for adults with CHD. These include the lack of uniform HF treatment guidelines, lack of applicable criteria for listing for OHT,28 concerns regarding peri-operative risk,4 – 6,29 and the prevalence of pre-formed antibodies in the CHD population with multiple prior operations.4,30 The development of HF treatment guidelines is

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hindered by the differences between HF due to ischemic or nonischemic cardiomyopathy and HF due to CHD. Many patients with CHD and HF have a systemic right, rather than left ventricle, which may not manifest the same response to a variety of cardiac medications. Studies show conflicting results regarding the effects of digoxin,31,32 angiotensin-converting enzyme inhibition,33–35 and ␤-blocker therapy36 –39 in these patients. Thus, patients may not be receiving medical treatment that is optimal for their cardiac anatomy. With regard to peri-operative risk, criteria for donor suitability with respect to size, distance, and graft quality may be more selective in an effort to decrease surgical risk factors for the adult with CHD whose 30-day mortality after OHT is higher than the adult recipient without CHD.4 – 6 Restrictive donor selection criteria coupled with the need for a negative prospective crossmatch or the avoidance of donor grafts with unacceptable antigens in the setting of a highly sensitized waitlist candidate reduces the donor pool.4,30 The availability of an experienced congenital heart surgeon at the time of donor availability can also affect the decision to accept a donor organ for a patient with complex CHD. The consequences are increased wait times for OHT and decreased likelihood of undergoing transplant. We have found that at any given time after listing, adults with CHD are less likely to undergo OHT, even when an adjustment is made for listing urgency status. The anticipation of longer waitlist times for adults with CHD supports earlier listing for transplant and further emphasizes the need for risk stratification for sudden cardiac death and progressive HF to be able to determine those that will benefit from device therapies. This study has limitations related to the use of an administrative database. Our analysis focused on data elements with mandatory reporting requirements such that most variables were complete for the patients analyzed. However, the accuracy of data input could not be verified. In addition, certain variables were not available for analysis, such as specific details regarding the CHD diagnosis, history of surgeries, and panel reactive antibody level for patients listed but who did not receive an allograft. Data regarding surgical CHD experience of the individual transplant centers and how such experience influenced outcome could not be ascertained. In summary, with increasing numbers of patients with CHD surviving into adulthood, more are presenting for HF management and transplant listing. Knowing that posttransplant outcome for this group of adults is favorable, we must focus on methods to improve waitlist outcomes and to ensure equal access to life-saving device therapies as well as subsequent transplantation. Collaboration between CHD specialists, congenital heart surgeons, and adult HF specialists to better determine the risk and modality of death is warranted. Such risk-stratification should aid in timely utilization of device therapies and transplant listing. As the number of adults with CHD being listed for OHT increases, it may be appropriate to assess the current UNOS organ allocation policies so that they are applicable to this cohort of patients as well.

Disclosure statement This work was supported in part by Health Resources and Services Administration contract 234-2005-37011C. The content is the responsibility of the authors alone and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.

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