**3. Characteristics of cardiac re-transplant recipients**

The first ReTx was performed in 1974 at Stanford, and the first group of patients was reported in 1977 by Copeland et al., which included 5 patients who underwent ReTx for either CAV or acute graft failure. ReTx currently comprises 3.0% of adult cardiac transplants [3, 5, 6], and a similar proportion of pediatric transplants [7]. While this proportion may seem small, it mirrors the proportion of patients transplanted for congenital heart disease, hypertrophic cardiomyopathy, restrictive cardiomyopathy, and valvulvar cardiomyopathy [5]. Additionally, as more patients survive to develop late complications, the number of patients who are candidates for ReTx will rise. Given this increase, ReTx will potentially outgrow these other indications for

The number of patients undergoing ReTx has been gradually increasing over time. Between 2000 and 2005, ReTx accounted for 2.9% of all heart transplants [3]. Between January 2009 and June 2015 there were 722 patients who underwent ReTx, which constituted 3.1% of heart transplants. While this seems like a small increase over time, there has been a simultaneous shift towards more rigorous patient selection for ReTx. This shift has been a response to the uniformly poor outcomes when patients undergo ReTx for acute events like primary graft failure. In this context, the median survival of patients undergoing cardiac transplantation has increased from 8.5 years in the era of 1982–1991 to almost 12 years for patients transplanted between 2002 and 2008. Median survival is even longer in young patients, with a median survival of 12.6 years in patients undergoing initial transplant between age 18 and 39, compared to 9.1 years in patients aged 60–69. Patients under age 40 comprise 17% of the adult heart transplant population, but also represent the population most likely to require to eventually require ReTx. There is no reason to believe that there will not be an ongoing trend towards

improved survival, potentially increasing the number of patients considered for ReTx.

Most of the data regarding the epidemiology of ReTx is only reflective of patients who successfully undergo ReTx. Therefore, in order to demonstrate the potential increase in candidates for ReTx, we have provided an estimate based on outcomes in current transplant recipients, shown in **Figure 1**. Currently 74% of patients are surviving at least 5 years after their initial transplant date [5]. We will assume that patients who die before this time are not candidates for ReTx given poor outcomes in patients undergoing ReTx for acute graft failure. The proportion of patients who are over age 60 at the time of initial cardiac transplant is 23.8% [5]. For the sake of a conservative estimate, we will assume that these patients are not candidates for ReTx due to advanced age. In patients who die more than 5 years after transplant, CAV accounts for 7–17% of deaths and graft dysfunction accounts for 22–40% of deaths [5]. If all patients under age 60 at initial transplant who eventually die from CAV or graft dysfunction are assessed for ReTx, then 17% of all transplant patients could potentially be ReTx eligible. There are several assumptions built into this estimate. Many patients who are potential ReTx candidates due to CAV will not be eligible due to sudden death [8], or co-morbidities that preclude ReTx. However, if even half of the patients we estimated undergo ReTx this would

cardiac transplant.

198 Heart Transplantation

**2. Epidemiology of cardiac re-transplantation**

essentially triple the current rate of ReTx.

Patients who undergo ReTx have characteristics distinct from those undergoing initial transplant. Some of these characteristics are related to procedures and immunosuppression required for the initial cardiac transplant. Meanwhile, other characteristics are related to surviving long enough to be considered for ReTx. However, as noted previously, this data only reflects patients who have successfully undergone ReTx. The group of patients who may be considered candidates are likely older with more medical co-morbidities.

**4. Patient outcomes following cardiac re-transplantation**

studies to highlight important concepts in the outcomes after ReTx.

**Author Year Center Patients Results**

John 1999 Columbia 43 (13 within 2 years, 30

Alturi 2008 Pennsylvania 15 patients (11 chronic,

Ontario

Saito 2013 London,

**Table 1.** Single-center studies of re-transplant survival.

Smith 1995 Stanford 66 (26 acute, 40 chronic) 1-year survival 55% (vs 81%), 5-year

after 2 years)

4 acute)

Schnetzler 1998 Paris 24 (11 acute, 13 chronic) 1-year survival 45.5% (vs. 71.6%), 5-year

Schlechta 2001 Vienna 31 (16 acute, 15 chronic) 1-year survival 48.2% (vs. 80.2%), 5-year

Topkara 2005 Columbia 41 patients 1-year survival 72.2% (vs. 85.5%), 5-year

Goerler 2008 Hannover 41 (18 acute, 23 chronic) 1-year survival 64% (vs. 83%), 5-year

survival 33% (vs 62%)

survival 31.2% (vs. 63.4%)

survival 51% (vs. 60%).

survival 36.8% (vs. 66.6%)

survival 47.5 (vs. 72.9%)

survival 71.4% (vs. 79.1%)

93.0%) if surviving 30 days

survival 47% (vs 72%)

22 (12 acute, 10 chronic) Conditional 1-year survival 93.3% (vs.

1-year survival 66% (vs 76%), 5-year

1-year survival 86.6% (vs 90.9%), 5-year

**4.1. Single-center studies**

There have been several attempts to characterize outcomes after ReTx. These studies span several eras of transplant management and reflect temoporal changes in patient selection criteria. What follows is not a comprehensive review of the available evidence, but a selected group of

Cardiac Re-Transplantation: A Growing Indication with Unique Considerations

http://dx.doi.org/10.5772/intechopen.74585

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There have been several single-center studies outlining outcomes following ReTx, outlined in **Table 1**. Stanford reported a cohort of 66 patients who underwent ReTx before 1994 [14]. They found decreased one-year survival compared to primary heart transplant recipients (55 compared to 81%), with better survival in patients undergoing ReTx for CAV [14]. Schnetzler et al. investigated 24 patients who underwent ReTx before 1996 and found significantly reduced one-year survival for patient undergoing ReTx within a year (27.3%) compared to those undergoing ReTx after more than 1 year (61.5%) [15]. The patients transplanted within 1 year were exclusively patients with primary graft failure or intractable rejection [15]. A group from Columbia described a cohort of 43 patients undergoing ReTx before 1997 where 1-year and 5-year survival were decreased (66 vs. 76% and 51 vs. 60%) compared to initial transplant recipients [16]. They found that a shorter interval between ReTx and initial transplant as well as initial transplant for ischemic cardiomyopathy were associated with increased mortality compared to patients without those factors [16]. They

Many characteristics of patients undergoing ReTx are associated with better outcomes, and generally reflect being young and healthy enough to be considered for a second operation. ReTx patients are younger compared to patients undergoing initial cardiac transplant, with a mean age of 46 years compared to 54 years in the ISHLT database [9]. Amiodarone exposure at any time point is also less frequent in patients undergoing ReTx, occurring in 10% of patients compared to 32% of initial transplant recipients [9]. This is interesting in light of emerging evidence suggesting amiodarone use is associated with higher 1-year mortality after transplant [10]. This finding is likely due to the low incidence of atrial and ventricular arrhythmias in the transplant population [11]. Finally, patients undergoing ReTx have lower pulmonary vascular resistance compared to other indications for transplant [5]. Overall these characteristics reflect the selection bias inherent in selection of ReTx candidates.

In ReTx populations, the characteristics that predict improved survival after cardiac transplant are more than outweighed by characteristics associated with adverse outcomes. Most patients undergoing ReTx have been exposed to calcineurin inhibitors after the initial cardiac transplant. As a consequence, they are more likely to have hypertension and renal dysfunction. In the ISHLT database 15.6% of patients undergoing ReTx had received prior dialysis compared to 3.9% in patients undergoing initial transplant [9]. Baseline creatinine was also higher in the ReTx group, 1.6 mg/dl compared to 1.2 mg/dL in initial transplant patients [9]. Hypertension is present in 57% of ReTx compared to 46% of initial transplant patients [9]. Additionally, ReTx patients have been exposed to a previous allograft and blood products during the initial cardiac transplant. Due to previous exposures, patients undergoing ReTx are more likely to be sensitized or highly sensitized. Almost 10% of patients undergoing ReTx have a Panel of Reactive Antibodies (PRA) greater than 80% compared to 2% of the primary transplant group [9]. Conversely, less than 50% of ReTx patients have a PRA of 0 compared to 65% of initial transplant patients [9]. High degrees of sensitization may complicate ReTx, requiring desensitization treatments prior to transplant or more aggressive induction therapy after transplant. All patients undergoing ReTx have had a prior sternotomy, which increases operative mortality as well as increasing cardiopulmonary bypass time, which increases morbidity and 90 day mortality associated with the operation [12, 13]. Finally, patients undergoing ReTx are more likely to be hospitalized at time of transplant, with 52% of ReTx patients admitted at the time of transplant compared to 44% of initial transplant patients [9]. This may reflect a trigger point for considering ReTx. These factors highlight the high risk nature of the ReTx population.

The characteristics outlined above reflect the population of patients who successfully undergo ReTx. The broader population of patients who may have been considered candidates for ReTx includes patients who may be too old, have co-morbidities that result in prohibitive risk, or are too highly sensitized to be successfully matched for ReTx. This suggests that, overall, the population considered for ReTx will be at significantly higher risk for peri-operative, shortterm, and long-term complications after transplantation.
