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

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 studies to highlight important concepts in the outcomes after ReTx.

#### **4.1. Single-center studies**

reflects patients who have successfully undergone ReTx. The group of patients who may be

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

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

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, short-

term, and long-term complications after transplantation.

considered candidates are likely older with more medical co-morbidities.

ReTx candidates.

200 Heart Transplantation

ReTx population.

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


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

hypothesized that patients with ischemic cardiomyopathy may have atherosclerotic disease in other vascular beds leading to worse outcomes [16]. They also found improved survival in their population after excluding patients with acute graft failure and significant renal dysfunction [16]. A cohort of patients undergoing ReTx between 1984 and 1999 from Vienna had one-year survival as low as 48.2% in a cohort that was almost evenly split between acute and chronic indications for ReTx [17]. The authors suggested younger age, lack of peripheral vascular disease, and ability to actively rehabilitate after the primary transplant as criteria for ReTx candidacy [17]. These early studies were essential to identify the factors that influence survival, leading to better patient outcomes.

> of 46% [9]. By comparison, patients undergoing ReTx for CAV had a one-year survival of 74% [23]. These studies highlight the importance of considering the indication for ReTx, which is a

> Radovancevic 2002 CTRD 107 patients (49 acute, 58 chronic) 1-year survival 56%, 5-year survival 38%

1-year survival 65%, 3-year survival 55%

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203

Cardiac Re-Transplantation: A Growing Indication with Unique Considerations

1-year survival 70%, 5-year survival 54%

Survival after ReTx is also strongly influenced by the age of the recipient. Therefore, authors have suspected that survival in the pediatric population may be better compared to adult populations. Select studies are outlined in **Table 3**. Razzouk et al. reported a cohort of 12 pediatric patients undergoing ReTx between 1985 and 1997 [24]. They found similar 1-year survival in patients undergoing ReTx compared to patients undergoing initial cardiac transplant [24]. Dearani et al. reported an updated cohort from the same center including 22 patients who underwent ReTx before 1999 [25]. One-year and 3-year survival was numerically, but not statistically, superior compared to initial transplant patients, with 3-year survival of 81.9 compared to 77.3% [25]. A cohort of 26 pediatric ReTx patients from Denver had similar one-year survival of 83% [26]. Conway et al. identified patients who underwent initial cardiac transplantation before age 18 in the ISHLT database [7]. They identified 602 patients who underwent ReTx between 1988 and 2010 and found that early mortality was similar to patients undergoing initial cardiac transplant, with a hazard ratio of only 1.07 [7]. However, patients undergoing ReTx were more likely to develop CAV, late rejection, and late renal dysfunction [7]. An important consideration in this group is that pediatric patients who are listed on adult transplant waitlists will wait for a longer period of time and are more likely to die on the waitlist [27]. Given

Razzouk 1998 Loma Linda 12 patients 1-year survival 84.3 (vs. 83.3%), 4-year survival

acute)

acute)

chronic)

74.4 (vs 83.3%)

survival 81.9% (vs 77.3%)

1-year survival 81.9% (vs 84.1%), 3-year

1-year survival 83%, 5-year survival 67%

1-year survival 83%, 5-year survival 69%

consistent predictor of mortality after correcting for other patient factors.

**Author Year Center/registry Patients Results**

Dearani 2001 Loma Linda 22 (16 chronic, 6

Karamichalis 2011 Denver 26 (10 chronic, 16

Conway 2014 ISHLT 602 (acute and

**Table 3.** Pediatric studies of re-transplant survival.

**Author Year Registry Patients Results**

chronic)

acute)

Srivasta 2000 ISHLT 514 patients (155 acute, 359

Lund 2014 ISHLT 820 patients (77% chronic, 23%

**4.3. Outcomes in the pediatric population**

**Table 2.** Registry studies of re-transplant survival.

More contemporary cohorts have shown some improvement in ReTx outcomes through more rigorous patient selection. A single-center study from Germany reported a cohort of 41 patients who underwent ReTx prior to July 2006 [18]. Of those patients 18 underwent ReTx for acute graft failure and 23 for chronic graft failure [18]. They found decreased 1-year (64 compared to 83%) and 5-year survival (47 compared to 72%) in patients undergoing ReTx compared to initial transplant [18]. This finding was driven by high 30-day mortality (34.1 vs. 9.5%) in patients undergoing ReTx [18]. In their cohort, patients with chronic graft failure had better survival than those with acute graft failure as an indication for ReTx [18]. In a smaller Canadian study including patients transplanted bettween 1981 and 2011, patients who were retransplanted more than 1 year after initial implant had similar survival as patients undergoing initial transplantation [19]. Columbia reported improved survival in patients transplanted between 1992 and 2002 after selecting groups of patients with mostly CAV as the indication for ReTx [20]. The University of Pennsylvania heart transplant program had a similar experience in patients undergoing ReTx between 1987 and 2007 [20, 21]. While survival following ReTx is still lower compared to initial transplant patients, further improvements in patient selection may continue to decrease this disparity.

#### **4.2. Registry studies**

Survival after cardiac retransplantation has also been assessed using registry data, outlined in **Table 2**. An analysis from the International Society of Heart and Lung Transplant (ISHLT) database identified a total of 514 patients undergoing ReTx between 1987 and 1998, of whom more than 50% underwent ReTx for CAV. [22]. In this population, one-year survival was only 65%, but was higher after excluding patients who underwent ReTx within 2 years of the initial transplant [22]. However, post-transplant survival remained inferior in the subset of patients undergoing ReTx for chronic graft failure compared to patients undergoing initial transplant [22]. Patients undergoing ReTx at a low-volume center, older recipient age, and requiring ICU care prior to ReTx were associated with increased mortality [22]. An analysis of 107 patients undergoing ReTx between 1990 and 1999 in the Cardiac Transplant Research Database reported 56% 1-year survival [23]. In this cohort, patients undergoing ReTx for acute graft failure had 1-year survival of 50%, and in patients with acute rejection 1-year survival was even lower at 32% [23]. However, they found that retransplantation for CAV was associated with better survival with improvements in survival over time [23]. In the most recent analysis of the ISHLT database, patients undergoing ReTx between 2006 and June 2013 had one-year survival of 70%, but patients undergoing ReTx for primary graft failure had a one-year survival


**Table 2.** Registry studies of re-transplant survival.

hypothesized that patients with ischemic cardiomyopathy may have atherosclerotic disease in other vascular beds leading to worse outcomes [16]. They also found improved survival in their population after excluding patients with acute graft failure and significant renal dysfunction [16]. A cohort of patients undergoing ReTx between 1984 and 1999 from Vienna had one-year survival as low as 48.2% in a cohort that was almost evenly split between acute and chronic indications for ReTx [17]. The authors suggested younger age, lack of peripheral vascular disease, and ability to actively rehabilitate after the primary transplant as criteria for ReTx candidacy [17]. These early studies were essential to identify the factors that influ-

More contemporary cohorts have shown some improvement in ReTx outcomes through more rigorous patient selection. A single-center study from Germany reported a cohort of 41 patients who underwent ReTx prior to July 2006 [18]. Of those patients 18 underwent ReTx for acute graft failure and 23 for chronic graft failure [18]. They found decreased 1-year (64 compared to 83%) and 5-year survival (47 compared to 72%) in patients undergoing ReTx compared to initial transplant [18]. This finding was driven by high 30-day mortality (34.1 vs. 9.5%) in patients undergoing ReTx [18]. In their cohort, patients with chronic graft failure had better survival than those with acute graft failure as an indication for ReTx [18]. In a smaller Canadian study including patients transplanted bettween 1981 and 2011, patients who were retransplanted more than 1 year after initial implant had similar survival as patients undergoing initial transplantation [19]. Columbia reported improved survival in patients transplanted between 1992 and 2002 after selecting groups of patients with mostly CAV as the indication for ReTx [20]. The University of Pennsylvania heart transplant program had a similar experience in patients undergoing ReTx between 1987 and 2007 [20, 21]. While survival following ReTx is still lower compared to initial transplant patients, further

improvements in patient selection may continue to decrease this disparity.

Survival after cardiac retransplantation has also been assessed using registry data, outlined in **Table 2**. An analysis from the International Society of Heart and Lung Transplant (ISHLT) database identified a total of 514 patients undergoing ReTx between 1987 and 1998, of whom more than 50% underwent ReTx for CAV. [22]. In this population, one-year survival was only 65%, but was higher after excluding patients who underwent ReTx within 2 years of the initial transplant [22]. However, post-transplant survival remained inferior in the subset of patients undergoing ReTx for chronic graft failure compared to patients undergoing initial transplant [22]. Patients undergoing ReTx at a low-volume center, older recipient age, and requiring ICU care prior to ReTx were associated with increased mortality [22]. An analysis of 107 patients undergoing ReTx between 1990 and 1999 in the Cardiac Transplant Research Database reported 56% 1-year survival [23]. In this cohort, patients undergoing ReTx for acute graft failure had 1-year survival of 50%, and in patients with acute rejection 1-year survival was even lower at 32% [23]. However, they found that retransplantation for CAV was associated with better survival with improvements in survival over time [23]. In the most recent analysis of the ISHLT database, patients undergoing ReTx between 2006 and June 2013 had one-year survival of 70%, but patients undergoing ReTx for primary graft failure had a one-year survival

ence survival, leading to better patient outcomes.

**4.2. Registry studies**

202 Heart Transplantation

of 46% [9]. By comparison, patients undergoing ReTx for CAV had a one-year survival of 74% [23]. These studies highlight the importance of considering the indication for ReTx, which is a consistent predictor of mortality after correcting for other patient factors.

#### **4.3. Outcomes in the pediatric population**

Survival after ReTx is also strongly influenced by the age of the recipient. Therefore, authors have suspected that survival in the pediatric population may be better compared to adult populations. Select studies are outlined in **Table 3**. Razzouk et al. reported a cohort of 12 pediatric patients undergoing ReTx between 1985 and 1997 [24]. They found similar 1-year survival in patients undergoing ReTx compared to patients undergoing initial cardiac transplant [24]. Dearani et al. reported an updated cohort from the same center including 22 patients who underwent ReTx before 1999 [25]. One-year and 3-year survival was numerically, but not statistically, superior compared to initial transplant patients, with 3-year survival of 81.9 compared to 77.3% [25]. A cohort of 26 pediatric ReTx patients from Denver had similar one-year survival of 83% [26]. Conway et al. identified patients who underwent initial cardiac transplantation before age 18 in the ISHLT database [7]. They identified 602 patients who underwent ReTx between 1988 and 2010 and found that early mortality was similar to patients undergoing initial cardiac transplant, with a hazard ratio of only 1.07 [7]. However, patients undergoing ReTx were more likely to develop CAV, late rejection, and late renal dysfunction [7]. An important consideration in this group is that pediatric patients who are listed on adult transplant waitlists will wait for a longer period of time and are more likely to die on the waitlist [27]. Given


**Table 3.** Pediatric studies of re-transplant survival.

the improved proportional survival of pediatric ReTx patients compared to adult cohorts, it is likely that outcomes will also be acceptable in the younger adult population.

heart-kidney transplant compared heart transplant alone [29]. Therefore, poor renal function should be considered a relative contraindication to ReTx unless the patient is a candidate for

Cardiac Re-Transplantation: A Growing Indication with Unique Considerations

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The number of previous sternotomies should also be considered when deciding if a patient is a candidate for ReTx. Multiple previous sternotomies from prior palliative congenital procedures or coronary artery bypass grafting adds to the burden of scar tissue, in addition to potentially complicated anastamotic sites from the initial transplant. Some authors have argued that this contributes to the high rates of multi-system organ failure in patients after ReTx, as well as high rates of early mortality [18, 28]. These findings are attributed to an increased incidence of mediastinitis, intrathoracic bleeding requiring reintervention, and primary graft failure [30]. These findings have also been seen in pediatric ReTx, many of which have had previous palliative procedures [26]. Lastly, patients admitted to ICU prior to ReTx, and particularly those requiring mechanical circulatory support, have worse outcomes [31]. In these patients it is important to not only ensure that organ dysfunction is reversible, but also that the patient will be capable of undergoing rehabilitation if the operation is successful. Consideration of these

factors may help identify patients with the greatest potential benefit from ReTx.

**6. Management of patients following re-transplantation**

operative care in order to attain the best possible outcomes.

Patients undergoing ReTx are more highly sensitized than patients undergoing initial cardiac transplant [5]. Higher sensitization increases the risk of CAV, acute rejection and posttransplant mortality [32, 33]. Therefore, it may be necessary to consider options to desensitize patients prior to ReTx in order to improve the chance of successful graft matching as well as

Many studies have highlighted the high early mortality seen after ReTx and patient factors that might be driving this observation. This may reflect the increased complexity of the surgical operation as well as medical frailty in patients undergoing ReTx, but highlights the importance of careful early management. As mentioned previously, the most important aspect of patient management is careful selection of patients who are likely to benefit from ReTx. However, once an appropriate patient has been selected, it is important to optimize the peri-

From a surgical perspective, it is important to identify the surgical technique used in the initial transplant. It may be especially pertinent to determine if the patient underwent bicaval or bi-atrial anastomosis as well as the level of anastomosis of the pulmonary artery and aorta. Dedicated thoracic imaging, either computed tomographic or magnetic resonance, may help identify anastomotic sites and areas with significant fibrotic tissue. It is not clear if it is necessary to completely excise all of the tissue from the initial cardiac transplant and no guidelines exist to advise clinical practice. Theoretically, it may help to reduce the potential for immunogenicity in those patients; however, this benefit needs to be weighed against increasing the complexity of the operation, which could potentially prolong bypass time and increase peri-operative complications. Finally, careful attention to hemostasis is important as always, but may be particularly

important in ReTx patients in whom peri-operative bleeding is more frequent.

simultaneous heart-kidney transplant.

improving outcomes following ReTx.
