Pending Policies - Surgery


Heart Transplant

Number:SUR703.005

Effective Date:11-15-2018

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

Human heart transplant may be considered medically necessary in carefully selected patients with irreversible, refractory, and symptomatic end-stage heart failure who meet the United Network for Organ Sharing (UNOS) guidelines for 1A, 1B, or 2 Status and are not currently Inactive Status (formerly known as Status 7).

Heart retransplantation after a failed primary heart transplant may be considered medically necessary in patients who meet criteria for heart transplantation.

Heart transplantation is considered experimental, investigational and/or unproven in all other situations.

NOTE 1: For combined heart and lung transplantation, see policy SUR703.006, Heart and Lung Transplants.

NOTE 2: Refer to SUR703.001, Organ and Tissue Transplantation for general donor and recipient information.

Description:

A heart transplant and a retransplant consist of replacing a diseased heart with a healthy donor heart. Transplantation is used for patients with refractory end-stage cardiac disease.

Background

Heart Failure

In the United States, approximately 6.5 million people 20 years of age and older have heart failure and 309,000 die each year from this condition. (1) The reduction of cardiac output is considered to be severe when systemic circulation cannot meet the body’s needs under minimal exertion. Heart transplantation can potentially improve both survival and quality of life in patients with end-stage heart failure.

Heart failure may be due to a number of differing etiologies, including ischemic heart disease, cardiomyopathy, or congenital heart defects. The leading indication for heart transplant has shifted over time from ischemic to nonischemic cardiomyopathy. From 2009 to 2014, nonischemic cardiomyopathy was the dominant underlying primary diagnosis among patients 18 to 39 years (64%) and 40 to 59 years (51%) undergoing transplant operations. (2) Ischemic cardiomyopathy was the dominant underlying primary diagnosis among the heart transplant recipients 60 to 69 years (50%) and 70 years and older (55%).

Treatment

The demand for heart transplants far exceeds the availability of donor organs, and the length of time patients are on the waiting list for transplants has increased. According to data from the Organ Procurement and Transplantation Network (OPTN), in 2016, a total of 3191 heart transplants were performed in the United States. (3) As of July 16, 2017 there were 3996 patients on the waiting list for a heart transplant. In recent years, innovations in medical and device therapy for patients with advanced heart failure has also improved the survival of patients awaiting heart transplantation. The chronic shortage of donor hearts has led to the prioritization of patients awaiting transplantation to ensure greater access for patients most likely to derive benefit. Prioritization criteria are issued by the OPTN and fulfilled through a contract with the United Network for Organ Sharing (UNOS). (4)

From 2008 to 2015, approximately 4% of heart transplants were repeat transplantations. Heart retransplantation raises ethical issues due to the lack of sufficient donor hearts for initial transplants. UNOS does not have separate organ allocation criteria for repeat heart transplant recipients.

The factors below are potential contraindications subject to the judgment of the transplant center:

General

Known current malignancy, including metastatic cancer;

Recent malignancy with high risk of recurrence;

Untreated systemic infection making immunosuppression unsafe, including chronic infection;

Other irreversible end-stage disease not attributed to heart or lung disease;

History of cancer with a moderate risk of recurrence;

Systemic disease that could be exacerbated by immunosuppression;

Psychosocial conditions or chemical dependency affecting ability to adhere to therapy.

Cardiac Specific

Cardiac specific potential contraindications subject to the judgment of the transplant center:

1. Pulmonary hypertension that is fixed as evidenced by pulmonary vascular resistance (PVR) >5 Wood units, or transpulmonary gradient (TPG) >16 mm/Hg despite treatment.

2. Severe pulmonary disease despite optimal medical therapy, not expected to improve with heart transplantation.

NOTE 3: Patients must meet the UNOS guidelines for 1A, 1B, or 2 Status and not currently be in Inactive status.

Specific criteria for prioritizing donor thoracic organs for transplant are provided by the OPTN and implemented through a contract with UNOS. Donor thoracic organs are prioritized by UNOS on the basis of recipient medical urgency, distance from donor hospital, and pediatric status. Patients who are most severely ill (status 1A) are given highest priority. The following factors are considered in assessing the severity of illness: reliance on continuous mechanical ventilation, infusion of intravenous inotropes, and/or dependency on mechanical circulatory support (i.e., total artificial heart, intra-aortic balloon pump, extracorporeal membrane oxygenator, ventricular assist device). Additional criteria, which are considered in pediatric patients, include diagnosis of a OPTN-approved congenital heart disease diagnosis, presence of ductal dependent pulmonary or systemic circulation, and diagnosis of hypertrophic or restrictive cardiomyopathy while less than 1-year-old. Of note, pediatric heart transplant candidates who remain on the waiting list at the time of their 18th birthday without receiving a transplant continue to qualify for medical urgency status based on the pediatric criteria.

Specific criteria for prioritizing donor thoracic organs for retransplant include severe coronary allograft vasculopathy, mild or moderate coronary allograft vasculopathy with a left ventricular ejection fraction less than 45%, coronary allograft vasculopathy with restrictive physiology, or symptomatic graft dysfunction without evidence of active rejection.

Each heart transplant candidate is assigned a status that reflects the candidate’s medical urgency for transplant. Heart candidates at the time of registration may be assigned Status 1A, 1B, 2 or Inactive status. (5)

Adult Patients (18 years of age or older at the time of registration)

Status 1A

A candidate is admitted to the listing transplant center hospital and has at least one of the following devices or therapies in place from the following Table 1:

Table 1. Adult Status 1A Requirements for Candidates Currently Admitted to the Transplant Hospital

If the candidate meets this condition:

Then adult status 1A is valid for:

Has one of the following mechanical circulatory support devices in place:

Total artificial heart (TAH)

Intra-aortic balloon pump

Extracorporeal membrane oxygenation (ECMO)

14 days, and must be recertified by an attending physician every 14 days from the date of the candidate's initial registration as adult status 1A to extend the adult status 1A registration.

Requires continuous mechanical ventilation

14 days, and must be recertified by an attending physician every 14 days from the date of the candidate's initial registration as adult status 1A to extend the status 1A registration.

Requires continuous infusion of a single high-dose intravenous inotrope or multiple intravenous inotropes, and requires continuous hemodynamic monitoring of left ventricular filling pressures. The Organ Procurement and Transplantation Network (OPTN) Contractor will maintain a list of the OPTN-approved qualifying inotropes and doses.

7 days, and may be renewed for additional 7 day periods for each occurrence of an adult status 1A listing under this criterion for this candidate.

A candidate who may or may not be currently admitted to the transplant hospital, may be assigned adult status 1A if the candidate meets at least one of the requirements in the following Table 2:

Table 2. Adult Status 1A Requirements for Candidates – Current Hospitalization Not Required

If the candidate meets this condition:

Then adult status 1A is valid for:

Has one of the following mechanical circulatory support devices in place:

Left ventricular assist device (LVAD)

Right ventricular assist device (RVAD)

Left and right ventricular assist devices (BiVAD)

30 days, and the candidate may be registered as adult status 1A for 30 days at any point after being implanted once an attending physician determines the candidate is medically stable. The 30 days do not have to be consecutive. However, if the candidate undergoes a procedure to receive another device, then the candidate qualifies for a new term of 30 days. Any 30 days granted by the new device would substitute and not supplement any time remaining from the previous adult status 1A classification.

Candidate has mechanical circulatory support and there is medical evidence of significant device-related complications including, but not limited to, thromboembolism, device infection, mechanical failure, or life-threatening ventricular arrhythmias. A candidate’s sensitization is not an acceptable device-related complication to qualify as adult status 1A. If a transplant program reports a complication that is not listed here, the registration will be retrospectively reviewed by the heart regional review board (RRB)

14 days, and must be recertified by an attending physician every 14 days from the date of the candidate's initial registration as adult status 1A to extend the adult status 1A registration.

Status 1B

A candidate has at least one of the following devices or therapies in place:

1. Left and/or right ventricular device implanted; or

2. Continuous infusion of intravenous inotropes.

Status 2

If the candidate does not meet the criteria for adult status 1A or 1B but is suitable for transplant, then the candidate may be assigned adult status 2. The candidate may retain adult status 2 for an unlimited period and this status does not require recertification, unless the candidate’s medical condition changes.

Pediatric Patients (less than 18 years old at the time of registration)

Status 1A

A candidate listed as status 1A meets at least one of the following criteria:

1. Requires continuous mechanical ventilation and is admitted to the hospital that registered the candidate.

2. Requires assistance of an intra-aortic balloon pump and is admitted to the hospital that registered the candidate.

3. Has ductal dependent pulmonary or systemic circulation, with ductal patency maintained by stent or prostaglandin infusion, and is admitted to the transplant hospital that registered the candidate.

4. Has a hemodynamically significant congenital heart disease diagnosis, requires infusion of multiple intravenous inotropes or a high dose of a single intravenous inotrope, and is admitted to the transplant hospital that registered the candidate. The OPTN Contractor maintains a list of OPTN-approved congenital heart disease diagnoses and qualifying inotropes and doses that qualify a candidate for pediatric status 1A.

5. Requires assistance of a mechanical circulatory support device.

Pediatric status 1A is valid for 14 days from the date of the candidate’s initial registration as pediatric status 1A. After the initial 14 days, status 1A must be recertified by the transplant program every 14 days to extend the status 1A registration.

When a candidate’s pediatric status 1A expires, the candidate will be assigned pediatric status 1B. Within 24 hours of the status change, the transplant program must report to the OPTN Contractor the criterion that qualifies the candidate to be registered as status 1B. The transplant program must classify the candidate as pediatric status 2 or inactive status if the candidate's medical condition does not qualify for pediatric status 1B.

Status 1B

A candidate listed as Status 1B meets at least one of the following criteria:

1. Requires infusion of one or more inotropic agents but does not qualify for pediatric status 1A. The OPTN Contractor maintains a list of the OPTN-approved status 1B inotropic agents and doses.

2. Is less than one-year-old at the time of the candidate’s initial registration and has a diagnosis of hypertrophic or restrictive cardiomyopathy.

The candidate may retain pediatric status 1B for an unlimited period and this status does not require any recertification, unless the candidate’s medical condition changes and the criteria used to justify that candidate’s status are no longer accurate.

Status 2

If the candidate does not meet the criteria for pediatric status 1A or 1B but is suitable for transplant, then the candidate may be assigned pediatric status 2. A candidate’s pediatric status 2 does not require any recertification.

Inactive Status (formerly known as Status 7).

If an adult or pediatric candidate is temporarily unsuitable for transplant, then the candidate’s transplant program may assign the candidate inactive status and the candidate will not receive any heart offers.

Regulatory Status

Heart transplantation is a surgical procedure and, as such, is not subject to regulation by the U.S. Food and Drug Administration.

Rationale:

This policy was originally created in 1990 and has been updated regularly with searches of the MedLine database. The most recent literature update was performed through July 20, 2017.

Assessment of efficacy for therapeutic intervention involves a determination of whether an intervention improves health outcomes. The optimal study design for this purpose is a randomized controlled trial (RCT) that includes clinically relevant measures of health outcomes. Intermediate outcome measures, also known as surrogate outcome measures, may also be adequate if there is an established link between the intermediate outcome and true health outcomes. Nonrandomized comparative studies and uncontrolled studies can sometimes provide useful information on health outcomes but are prone to biases such as noncomparability of treatment groups, placebo effect, and variable natural history of the condition.

Due to the nature of the population discussed herein, there are no randomized controlled trials (RCTs) comparing heart transplantation with alternatives, including ventricular assist devices. Systematic reviews are based on case series and registry data. RCTs have been published on related topics (e.g., comparing surgical technique, infection prophylaxis regimens, or immunosuppressive therapy) but are not germane to this policy. The following is a summary of evidence based on registry and case series data.

Prioritization of Candidates

Most heart transplant recipients are now hospitalized status 1 patients at the time of transplant. This shift has occurred due to the increasing demand on the scarce resource of donor organs resulting in an increased waiting time for recipients. Patients initially listed as status 2 candidates may deteriorate to a status 1 candidate before a donor organ becomes available. Alternatively, as medical and device therapy for advanced heart failure has improved, some patients on the transplant list will recover enough function to become delisted. In 2007, Lietz and Miller reported on patient survival on the heart transplant waiting list, comparing the era between 1990 and 1994 to the era of 2000 to 2005. (6) One-year survival for United Network for Organ Sharing (UNOS) status 1 candidates improved from 49.5% to 69.0%. Status 2 candidates fared even better, with 89.4% surviving 1 year compared with 81.8% in the earlier time period.

In 2010, Johnson et al. reported on waiting list trends in the United States between 1999 and 2008. (7) The proportion of patients listed as status 1 has continued to increase, even as waiting list and posttransplant mortality for this group decreased. Meanwhile, status 2 patients have decreased as a proportion of all candidates. Completed transplants have trended toward the extremes of age, with more infants and patients older than age 65 years having transplants in recent years.

As a consequence, aggressive treatment of heart failure has been emphasized in recent guidelines. Prognostic criteria have been investigated to identify patients who have truly exhausted medical therapy and thus are likely to derive the maximum benefit for heart transplantation. Maximal oxygen consumption (Vo2max), which is measured during maximal exercise, is a measure that has been suggested as a critical objective criterion of the functional reserve of the heart. The American College of Cardiology (ACC) and American Heart Association (AHA) have adopted Vo2max as a criterion for patient selection. (8) Studies have suggested that transplantation can be safely deferred in those patients with a Vo2max of greater than 14 mL/kg/min. The importance of the Vo2max has also been emphasized by the AHA when addressing heart transplant candidacy. (9) In past years, a left ventricular ejection fraction (LVEF) of less than 20% or a New York Heart Association class III or IV status may have been used to determine transplant candidacy. However, as indicated by the ACC criteria, these measurements are no longer considered adequate to identify transplant candidates. These measurements may be used to identify patients for further cardiovascular workup but should not be the sole criteria for transplant.

Methods other than Vo2max have been proposed as predictive models in adults. (10-13) The Heart Failure Survival Scale and Seattle Heart Failure Model (SHFM) are examples. In particular, the SHFM provides an estimate of 1-, 2-, and 3-year survival with the use of routinely obtained clinical and laboratory data. Information on pharmacologic and device usage is incorporated into the model, permitting some estimation of effects of current, more aggressive heart failure treatment strategies. In 2006, Levy et al. introduced the model using multivariate analysis of data from the PRAISE1 heart failure trial (n=1125). (14) Applied to the data of 5 other heart failure trials, SHFM correlated well with actual survival (r=0.98). SHFM has been validated in both ambulatory and hospitalized heart failure populations, (15-17) but with a noted underestimation of mortality risk, particularly in blacks and device recipients. (18, 19) None of these models has been universally adopted by transplant centers.

Initial Heart Transplant

Survival

According to the Organ Procurement and Transplantation Network (OPTN), 1-year Kaplan-Meier for heart transplants performed between 2008 and 2015, based on available U.S. data as of July 10, 2017, were 90.5% (95% confidence interval [CI], 89.9% to 91.2%) for men and 91.1% (95% CI, 90.1% to 92.1%) for women. (3) The 3-year survival rates were 85.1% (95% CI, 84.3% to 86.0%) for men and 85.2% (95% CI, 83.8 to 86.4%) for women, and the 5-year survival rates were 78.4% (95% CI, 77.3% to 79.3%) and 77.7% (95% CI, 76.0% to 79.2%), respectively. There was no major difference in 1-, 3-, and 5-year survival rates between different age groups among adult recipients (See Table 1).

Nguyen et al. (2017) investigated the benefit of heart transplantation compared with a waiting list while accounting for the estimated risk of a given donor-recipient match among 28,548 heart transplant candidates in OPTN between 2006 and 2015. (20) The net benefit from heart transplantation was evident across all estimates of donor-recipient status 1A candidates (lowest risk quartile hazard ratio [HR], 0.37; 95% CI, 0.31 to 0.43; highest-risk quartile HR=0.52; 95% CI, 0.44 to 0.61) and status 1B candidates (lowest-risk quartile HR=0.41; 95% CI, 0.36 to 0.47; highest-risk quartile HR=0.66; 95% CI, 0.58 to 0.74). Status 2 candidates showed a benefit from heart transplantation; however, the survival benefit was delayed. For the highest-risk donor-recipient matches, a net benefit of transplantation occurred immediately for status 1A candidates, after 12 months for status 1B candidates, and after 3 years for status 2 candidates.

Rana et al. (2015) retrospectively analyzed solid organ transplant recipients registered in the UNOS database from 1987 to 2012, including 54,746 patients who underwent a heart transplant. (21) Transplant recipients were compared with patients listed for transplant but who did not receive one; transplant recipients were awarded the transplant based on propensity score matching, which served to measure a variety of clinical characteristics. After matching, the median survival was 9.5 years in transplant recipients compared with 2.1 years in waiting list patients.

Several studies have analyzed factors associated with survival in heart transplant patients. For example, a 2012 study by Kilic et al. analyzed prospectively collected data from the UNOS registry. (22) The analysis included 9404 patients who had survived 10 years after heart transplant, and 10,373 patients who had died before 10 years. Among individuals who had died, mean survival was 3.7 years posttransplant. In multivariate analysis, statistically significant predictors of surviving at least 10 years after heart transplant included age younger than 55 years (odds ratio [OR], 1.24; 95% CI, 1.10 to 1.38), younger donor age (OR=1.01; 95% CI, 1.01 to 1.02), shorter ischemic time (OR=1.11; 95% CI, 1.05 to 1.18), white race (OR=1.35; 95% CI, 1.17 to 1.56), and annual center volume of 9 or more heart transplants (OR=1.31; 95% CI, 1.17 to 1.47). Factors that significantly decreased the likelihood of 10-year survival in multivariate analysis included use of mechanical ventilation (OR=0.53; 95% CI, 0.36 to 0.78) and diabetes (OR=0.67; 95% CI, 0.57 to 0.78).

A 2013 study examined characteristics of patients who survived longer than 20 years after heart transplantation at a single center in Spain. (23) Thirty-nine heart transplant recipients who survived over 20 years posttransplant were compared with 98 patients who died between 1 and 20 years posttransplant. Independent factors associated with long-term survival were younger recipient age (i.e., <45 years versus >45 years; OR=3.9; 95% CI, 1.6 to 9.7) and idiopathic cardiomyopathy (i.e., versus other etiologies; OR=3.3; 95% CI, 1.4 to 7.8).

Lund et al. (2016) examined the risk factors associated with 10-year posttransplant mortality among patients undergoing heart transplantation between 2000 and 2005 using the International Society for Heart and Lung Transplantation (ISHLT) Registry. (2) Markers of pretransplant severity of illness, such as pretransplant ventilator use (HR=1.35; 95% CI, 1.17 to 1.56; n=338), dialysis use (HR=1.51; 95% CI, 1.28 to 1.78; n=332), underlying diagnoses of ischemic (HR=1.16; 95% CI: 1.10 to 1.23; n=7822), congenital (HR=1.21; 95% CI, 1.04 to 1.42; n=456) or restrictive (HR=1.33; 95% CI, 1.13 to 1.58; n=315) heart disease (versus nonischemic cardiomyopathy), and retransplant (HR=1.18; 95% CI, 1.02 to 1.35; n=489) were associated with posttransplant mortality risk at 10 years.

Table 3. Kaplan-Meier Patient Survival Rates for Heart Transplants Performed from 2008 to 2015

Years Posttransplant

1 Yeara

3 Yearsa

5 Yearsa

Recipient Age

No. Alive

Survival Rate (95% CI), %

No. Alive

Survival Rate (95% CI), %

No. Alive

Survival Rate (95% CI), %

<1 year

378

87.6 (84.2 to 90.3)

327

85 (81.3 to 88.0)

277

77.1 (72.8 to 80.8)

1-5 years

313

92.3 (89.1 to 94.6)

253

87 (82.9 to 90.2)

232

81.4 (76.8 to 85.2)

6-10 years

198

92.2 (88.1 to 95.0)

168

89.7 (84.8 to 93.1)

154

89.3 (84.1 to 92.9)

11-17 years

478

96.8 (94.9 to 98.0)

417

92.3 (89.5 to 94.3)

318

80 (76.0 to 83.4)

18-34 years

791

91.8 (89.8 to 93.4)

659

83.6 (81.0 to 85.9)

550

74.8 (71.7 to 77.7)

35-49 years

1478

90.9 (89.4 to 92.1)

1286

85.4 (83.6 to 87.0)

1148

79 (76.9 to 80.9)

50-64 years

3647

90.7 (89.8 to 91.6)

3103

85.2 (84.1 to 86.3)

2723

78.5 (77.1 to 79.7)

65+ years

1414

88.3 (86.7 to 89.8)

1088

82.1 (80.0 to 84.0)

808

75.2 (72.6 to 77.5)

Source: Organ Procurement and Transplantation Network, https://optn.transplant.hrsa.gov.

CI: confidence interval.

a One-year survival based on 2012-2015 transplants, 3-year survival based on 2010-2013 transplants, 5-year survival based on 2008-2011 transplants.

No: Number

Pediatric Considerations

According to OPTN, patients between the ages of 11 and 17 years old held the highest 1- and 3- year survival rates among pediatric patients who underwent a heart transplant in the U.S. between 2008 and 2015. Patients younger than 1 year of age had the lowest 1-, 3-, and 5-year survival rates among pediatric patients (see Table 3).

Rossano et al. (2016) examined survival among pediatric heart transplant recipients using the ISHLT Registry. (24) Among 12,091 pediatric patients undergoing heart transplantation between 1982 and 2014, the overall median survival was 20.7 years for infants (n=2994), 18.2 years for children between the ages of 1-to-5 years old (n=2720), 14.0 years for those ages 6-to-10 years old (n=1743), and 12.7 years for those ages 11-to-17 years old (n=4684). Because the first year posttransplant represents the greatest risk for mortality, survival conditional on survival to 1 year was longer.

Authors conducted a multivariable analysis of pediatric patients undergoing heart transplant between 2003 and 2013 to identify the factors associated with 1-year mortality. Infection requiring intravenous drug therapy within 2 weeks of transplant (HR=1.36; 95% CI, 1.10 to 1.68; n=681), ventilator use (HR=1.41; 95% CI, 1.13 to 1.76; n=826), donor cause of death (cerebrovascular accident versus head trauma; HR=1.59; 95% CI, 1.20 to 2.09; n=396), diagnosis (congenital heart disease [CHD] versus cardiomyopathy; HR=1.91; 95% CI, 1.46 to 2.52; n=1979; retransplant versus cardiomyopathy; HR=2.23; 95% CI, 1.53 to 3.25; n=304), recipient dialysis (HR=2.36; 95% CI, 1.57 to 3.57; n=146), extracorporeal membrane oxygenation (ECMO) with a diagnosis of CHD versus no ECMO (HR=2.42; 95% CI, 1.74 to 3.35; n=145), ischemic time (p<0.001), donor weight (p<0.001), estimated glomerular filtration rate (eGFR; p=0.002), and pediatric center volume (p<0.001) were risk factors for 1-year mortality. Earlier era (1999-2000 versus 2007-2009), CHD (versus dilated cardiomyopathy), use of ECMO (versus no device), and pediatric center volume were risk factors for 5-, 10-, and 15-year mortality. A panel-reactive antibody greater than 10% was associated with worse 5- and 10-year survival and eGFR was associated with 5- and 10-year mortality.

Data from the Pediatric Heart Transplant Study (2013), which includes data on all pediatric transplants at 35 participating institutions, suggest that 5-year survival for pediatric heart transplants has improved over time (76% for patients transplanted from 2000 to 2004 versus 83% for patients transplanted from 2005 to 2009). (25)

A retrospective analysis of OPTN data focusing on the adolescent population was published by Savla et al. (2014). (26) From 1987 to 2011, heart transplants were performed in 99 adolescents (age, 13-18 years) with myocarditis and 456 adolescents with CHD. Among adolescent transplant recipients with myocarditis, median graft survival was 6.9 years (95% CI, 5.6 to 9.6 years), which was significantly lower than other age groups (i.e., 11.8 years and 12.0 years in younger and older adults, respectively). However, adolescents with CHD had a graft survival rate of 7.4 years (95% CI, 6.8 to 8.6 years), similar to that of other age groups.

Noting that children listed for heart transplantation have the highest waiting list mortality of all solid organ transplant patients, Almond et al. (2009) analyzed data from the U.S. Scientific Registry of Transplant Recipients to determine if the pediatric heart allocation system, as revised in 1999, was prioritizing patients optimally and to identify high-risk populations that may benefit from pediatric cardiac assist devices. (27) Of 3098 children (<18 years of age) listed between 1999 and 2006, a total of 1874 (60%) were listed as status 1A. Of the 1874, 30% were placed on ventilation and 18% were receiving ECMO. Overall, 533 (17%) died, 1943 (63%) received transplants, 252 (8%) recovered, and 370 (12%) remained listed. The authors found that status 1A patients were a heterogeneous population with large variation in mortality based on patient-specific factors. Predictors of waiting list mortality included ECMO support (HR=3.1), ventilator support (HR=1.9), listing status 1A (HR=2.2), congenital heart disease (HR=2.2), dialysis support (HR=1.9), and nonwhite race/ethnicity (HR=1.7). The authors concluded that the pediatric heart allocation system captures medical urgency poorly, specific high-risk subgroups can be identified, and further research is needed to better define the optimal organ allocation system for pediatric heart transplantation.

A retrospective review of pediatric cardiac transplantation patients was published by Auerbach et al. in 2012. (28) A total of 191 patients who underwent primary heart transplantation at a single center in the United States were included; their mean age was 9.7 years (range, 0-23.6 years). Overall graft survival was 82% at 1 year and 68% at 5 years; the most common causes of graft loss were acute rejection and graft vasculopathy. Overall patient survival was 82% at 1 year and 72% at 5 years. In multivariate analysis, the authors found that congenital heart disease (HR=1.6; 95% CI, 1.02 to 2.64) and requiring mechanical ventilation at the time of transplantation (HR=1.6; 95% CI, 1.13 to 3.10) were both significantly and independently associated with an increased risk of graft loss. Renal dysfunction was a significant risk factor in univariate analysis but was not included in the multivariate model due to the small study group. Limitations of the study included its retrospective design and single center sample.

Section Summary: Initial Heart Transplant

The evidence supports a net benefit for heart transplantation compared with waitlist for status 1A and 1B candidates. Data from national and international registries have also found high patient survival rates after initial heart transplant among adult and pediatric patients (e.g., a 5-year survival rate, 78%).

Heart Retransplantation

Survival

An analysis of the OPTN data from 2008 to 2015 reported that 724 (3.9%) retransplants (of 18,676 heart transplants) were performed. Kaplan-Meier patient survival rates at 1-, 3-, and 5- years were lower among the retransplant recipients than among primary transplant recipients (see Table 4).

A 2014 analysis of OPTN data from 1995 to 2012 reported that 987 (3.5%) retransplants were performed from a sample of 28,464 heart transplants. (29) Median survival among retransplant recipients was 8 years. The estimated survival at 1-, 5-, 10-, and 15-years following retransplant were 80%, 64%, 47% and 30%, respectively. Compared with primary transplant recipients, retransplant patients had a somewhat higher risk of death (relative risk [RR], 1.27, 95% CI, 1.13 to 1.42).

Table 4. Kaplan-Meier Patient Survival Rates for Primary and Repeat Heart Transplants Performed Between 2008 and 2015

Transplant Type

Primary Transplant

Repeat Transplant

Years

No. Alivea

Survival Rate, %

95% CI, %

No. Alivea

Survival Rate, %

95% CI, %

Posttransplant

1 year

8396

90.9

90.3 to 91.4

301

86.9

83.0 to 90.0

3 years

7038

85.5

84.8 to 86.2

263

76.2

71.6 to 80.2

5 years

5991

78.5

77.6 to 79.4

219

69.3

64.2 to 73.9

CI: confidence interval.

a: One-year survival rates based on 2012-2015 transplants, 3-year survival rates based on 2010-2013 transplants, 5- year survival rates based on 2008-2011 transplants.

No: Number

A number of studies have reviewed clinical experience with heart retransplantation in adults. In 2008, Tjang et al. published a systematic review of the literature on clinical experience with adult heart retransplantation; reviewers identified 22 studies. (30) The most common indications for retransplantation were cardiac allograft vasculopathy (55%), acute rejection (19%) and primary graft failure (17%). The early mortality rate in individual studies was 16% (range, 5%-38%). Some of the factors associated with poorer outcome after retransplantation were shorter transplant interval, refractory acute rejection, primary graft failure and an initial diagnosis of ischemic cardiomyopathy.

Goldraich et al. (2016) examined the survival in adult heart recipients with cardiac allograft vasculopathy who were retransplanted (n=65) or managed medically (n=4530). (31) During a median follow-up of 4 years, there were 24 deaths among those who underwent retransplantation and 1466 deaths among those medically managed. There was no significant difference in survival rates at 9 years (55% in retransplant recipients versus 51% in medically managed patients, p=0.88). In subgroup analysis, overall the retransplant group (n=65) had longer survival than medically managed group with systolic graft dysfunction at 1 year after development of coronary allograft vasculopathy (n=124; p=0.02).

A representative study was published in 2013 by Saito et al. (32) This retrospective review of data evaluated 593 heart transplant patients performed at their institution, 22 (4%) of whom required retransplants. The mean interval between initial and repeat transplant was 5.1 years. The indications for a repeat transplant were acute rejection in 7 (32%) patients, graft vascular disease in 10 (45%) patients, and primary graft failure in 5 (23%) patients. The 30-day mortality rate after cardiac retransplantation was 32% (7/22 patients). Among patients who survived the first 30 days (n=15), 1-, 5-, and 10-year survival rates were 93.3%, 79% and 59%, respectively. Comparable survival rates for patients undergoing primary cardiac transplants at the same institution (n=448) were 93%, 82%, and 63%, respectively. An interval of 1 year or less between the primary and repeat transplantation significantly increased the risk of mortality. Three of 9 (33.3%) patients with less than 1 year between the primary and retransplantation survived to 30 days; by comparison, 12 (92%) of 13 patents with at least 1 year between primary and retransplantation were alive at 30 days after surgery.

A 2014 study using UNOS data reported no survival differences between third and second transplants (76% for third transplant versus 80% for second transplant at 1 year; 62% for third transplant versus 58% for second transplant at 5 years; 53% for third transplant versus 34% for second transplant at 10 years, p=0.73). (33) However, conclusions from this study’s results may be limited because of the small number (n=25) of third heart transplants.

Pediatric Considerations

As with initial heart transplants, children awaiting heart retransplantation have high waitlist mortality. A 2015 study by Bock et al. evaluated data on 632 pediatric patients who were listed for a heart retransplant at least 1 year (median, 7.3 years) after the primary transplant. (34) Patients’ median age was 4 years at the time of the primary transplant and 14 years when relisted. Median waiting time was 75.3 days, and mortality was 25.2% (159/632). However, waitlist mortality decreased significantly after 2006 (31% before 2006 and 17% after 2006, p<0.01).

Conway et al. (2014) analyzed the ISHLT Registry to compare the outcomes after retransplantation with primary transplantation among pediatric (<18 years of age) heart transplant recipients from 1998 to 2010. (35) Of the 9882 heart transplant recipients with available clinical outcomes data, 9248 (93.6%) were primary transplants, 602 (6.1%) were retransplants (second graft), and 32 (0.3%) were third or fourth grafts. The median ages at primary transplant and retransplant were 7 years (range, 0-14 years) and 14 years (range, 1-26 years), respectively. The mean intertransplant interval was 6.8 years after primary transplant. The most common indications for retransplantation were coronary allograft vasculopathy (n=352 [59%]), nonspecific graft failure (n=52 [9%]), and acute rejection (n=49 [8%]). Retransplantation was associated with similar early survival but decreased long-term survival when compared with initial transplantation. After primary transplantation, the survival rate was 84% at 1 year, 72% at 5 years, 60% at 10 years, and 42% at 20 years, compared with 81% at 1 year, 63% at 5 years, 46% at 10 years, and 26% at 20 years after retransplantation, respectively. The median survival rate was longer in primary transplant recipients, reaching 15 years (vs 8.7 years after retransplantation). The most common causes of death after retransplantation were cardiovascular other than vasculopathy (28%), graft failure (10%), infection (9%), noncardiac organ failure (9%), coronary allograft vasculopathy (4%), and acute rejection (3%).

Section Summary: Heart Retransplantation

In both the adult and pediatric studies, poorer survival after retransplantation compared with initial transplantation is not surprising given that patients undergoing retransplantation experienced additional clinical disease or adverse events.

Data from national and international registries have found high patient survival rates after heart retransplant among adult and pediatric patients (e.g., a 5-year survival rate, 69%). Cardiac allograft vasculopathy is the most common indication for heart retransplantation both among adult and pediatric patients. Considering the scarcity of heart donors and the few treatment options for cardiac allograft vasculopathy, additional studies must be done to further examine the survival benefit of cardiac retransplantation over medical management among patients with cardiac allograft vasculopathy. Perhaps in doing so, retransplantation could be limited to highly selected patients with cardiac allograft vasculopathy.

Potential Contraindications to Heart Transplant (Applies to all indications)

Individual transplant centers may differ in their guidelines, and individual patient characteristics may vary within a specific condition. In general, heart transplantation is contraindicated in patients who are not expected to survive the procedure or in whom patient-oriented outcomes (e.g., morbidity, mortality) are not expected to change due to comorbid conditions unaffected by transplantation (e.g., imminently terminal cancer or other disease). Moreover, consideration is given to conditions in which the necessary immunosuppression would lead to hastened demise, such as active untreated infection. However, stable chronic infections have not always been shown to reduce life expectancy in heart transplant patients.

Malignancy

Pretransplant malignancy is considered a relative contraindication for heart transplantation because malignancy has the potential to reduce life expectancy and could prohibit immune suppression after transplantation. However, with improved cancer survival over the years and use of cardiotoxic chemotherapy and radiotherapy, the need for heart transplantation has increased in this population. Mistiaen et al. (2015) conducted a systematic review to study posttransplant outcomes of patients with pretransplant malignancy. (36) Most selected studies were small case series (median sample size, 17 patients; range, 7-1117 patients; mean age range, 6-52 years). Hematologic malignancy and breast cancer were the most common types of pretransplant malignancies. Dilated, congestive, or idiopathic cardiomyopathy were the most common reasons for transplantation in 4 case series, chemotherapy-related cardiomyopathy was the most important reason for transplantation in the other series. Hospital mortality rates varied between 0% and 33%, with small sample size potentially explaining the observed variation. One large series (2012) reported similar short- and long-term posttransplant survival rates for patients who received chemotherapy-related (n=232) and for those with other nonischemic-related cardiomyopathy (n=8890). (37) The 1-, 3-, and 5-year survival rates of were 86%, 79%, and 71% for patients with chemotherapy-related cardiomyopathy compared with 87%, 81%, and 74% for other transplant patients, respectively. Similar findings were observed for 1-year survival in smaller series. Two-, 5-, and 10-year survival rates among patients with pretransplant malignancy were also comparable with other transplant patients. In addition to the non-malignancy-related factors such as cardiac, pulmonary, and renal dysfunction, 2 malignancy-related factors were identified as independent predictors of 5-year survival. Malignancy-free interval (the interval between treatment of cancer and heart transplantation) of less than 1 year was associated with lower 5-year survival (<60%) than with a longer interval (>75%).

Patients with prior hematologic malignancies had increased posttransplant mortality rates in 3 small series. Recurrence of malignancy was more frequent among patients with a shorter disease-free interval (63%, 26%, and 6% among patients with <1 year, 1-5 years, and >5 years of disease-free interval, respectively). (38)

Yoosabai et al. (2015) retrospectively reviewed data on 23,171 heart transplant recipients in the OPTN/UNOS database to identify whether pretransplant malignancy increases the risk of posttransplant malignancy. (39) Posttransplant malignancy was diagnosed in 2673 (11.5%) recipients during the study period. A history of any pretransplant malignancy was associated with increased risk of overall posttransplant malignancy (subhazard ratio [SHR], 1.51; p<0.01), skin malignancies (SHR=1.55, p<0.01), and solid organ malignancies (SHR=1.54, p<0.01) on multivariate analysis.

The evaluation of a candidate who has a history of cancer must consider the prognosis and risk of recurrence from available information including tumor type and stage, response to therapy, and time since therapy was completed. Although evidence is limited, patients for whom cancer is thought to be cured should not be excluded from consideration for transplant. ISHLT guidelines have recommended stratifying each patient with pretransplant malignancy as to his or her risk of tumor recurrence and that cardiac transplantation should be considered when tumor recurrence is low based on tumor type, response to therapy, and negative metastatic work-up. The guidelines also recommended that the specific amount of time to wait to transplant after neoplasm remission will depend on these factors and no arbitrary time period for observation should be used.

Human Immunodeficiency Virus (HIV) Infection

Solid organ transplant for patients who are HIV-positive was historically controversial, due to the long-term prognosis for HIV positivity and the impact of immunosuppression on HIV disease. The availability of highly active antiretroviral therapy (HAART) has markedly changed the natural history of the disease. Aguero et al. (2016) reported of a review on heart transplants among HIV-infected patients. (40) Since 2001, 12 heart transplantations in HIV-infected patients have been reported and 3 patients acquired HIV after heart transplantation. Fourteen (93%) of these 15 patients were younger than 50 years of age, with cluster of differentiation 4 (CD4) counts greater than 200 cells/mm3, and all recipients were taking antiretroviral therapy. Thirteen were alive with normal graft function at the end of follow-up. One patient had suboptimal adherence to antiretroviral therapy and died of multiorgan failure. The cause of death in the other patient was not reported. (41) There are few data directly comparing outcomes for patients with and without HIV.

As of February 2013, the OPTN policy 4 on HIV-positive transplant candidates stated: “A potential candidate for organ transplantation whose test for HIV is positive should not be excluded from candidacy for organ transplantation unless there is a documented contraindication to transplantation based on local policy.” (42)

In 2017, the British HIV Association and the British Transplantation Society updated their guidelines on kidney transplantation in patients with HIV disease. (43) These criteria may be extrapolated to other organs:

Adherent with treatment, particularly antiretroviral therapy.

CD4 count greater than 100 cells/mL (ideally >200 cells/mL) for at least 3 months.

Undetectable HIV viremia (<50 HIV-1 RNA copies/mL) for at least 6 months.

No opportunistic infections for at least 6 months.

No history of progressive multifocal leukoencephalopathy, chronic intestinal cryptosporidiosis, or lymphoma.

Age

The maximum acceptable age for heart transplantation is an issue for debate. While the maximum recipient age for heart transplantation was set at 55 years during the early years of heart transplantation, with increasing evidence of comparable survival rates among older population following heart transplantation, transplant centers have been accepting older recipients. However, the upper age limit for heart transplant candidates is still controversial and is generally defined by the transplant centers.

Cooper et al. (2016) analyzed UNOS data to assess the long-term outcomes of older recipients of orthotopic heart transplantation (OHT) in the United States between 1987 and 2014. (44) During this period, 50,432 patients underwent OHT; 71.8% (n=36,190) were 18 to 59 years old, 26.8% (n=13,527) were 60 to 69 years old, and 1.4% (n=715) were 70 years old of age or older. The 5-year mortality rate was 26.9% for recipients 18 to 59 years old, 29.3% for recipients 60 to 69 years old, and 30.8% for recipients 70 years of age and older. Survival between the oldest group and the 60- to 69-year-old group did not differ significantly (p=0.48).

Awad et al. (2016) reported on a single-center retrospective review of 704 adults who underwent heart transplantation from 1988 to 2012 to investigate the mortality and morbidity rates of heart transplantations among recipients 70 years of age and older (n=45) compared with recipients younger than 70 years (n=659). (45) The older and younger groups had similar 1-year (93.0 versus 92.1; p=0.79), 5-year (84.2 versus 73.4; p=0.18), and 10-year (51.2 versus 50.2; p=0.43) survival rates, respectively.

In 2012, Kilic et al. analyzed UNOS data on 5330 patients age 60 and older (mean age, 63.7 years) who underwent heart transplantation between 1995 and 2004. (46) A total of 3492 (65.5%) patients survived to 5 years. In multivariate analysis, statistically significant predictors of 5-year survival included younger age (OR=0.97; 95% CI, 0.95 to 1.00), younger donor age (OR=0.99; 95% CI, 0.99 to 1.00), white race (OR=1.23; 95% CI, 1.02 to 1.49), shorter ischemic time (OR=0.93; 95% CI, 0.87 to 0.99), and lower serum creatinine (OR=0.92; 95% CI, 0.87 to 0.98). In addition, hypertension, diabetes, and mechanical ventilation each significantly decreased the odds of surviving to 5 years. Patients with 2 or more of these factors had a 12% lower rate of 5-year survival than those with none of them.

Section Summary: Age

There is consistent evidence that there is no significant difference in posttransplant survival rates between heart transplant recipients greater than 70 years and those who are younger.

Pulmonary Hypertension

Findings of several studies published in 2012 and 2013 suggest that patients with pulmonary hypertension who successfully undergo treatment can subsequently have good outcomes after heart transplant. (47-50) For example, Tsukashita et al. (2015) retrospectively investigated the effect of continuous-flow left ventricular assist device support on pulmonary hypertension and compared posttransplantation outcomes among 227 potential OHT candidates with preexisting pulmonary hypertension. (51) Patients were divided into 2 groups based on preimplantation pulmonary vascular resistance (PVR): low (<5 Wood units) (n=182) and high (≥5 Wood units) (n=45). After left ventricular assist device implantation, PVR in the high PVR group decreased significantly (7.13 Wood units to 2.82 Wood units, p<0.001) to a level similar that in the low PVR group (2.70 Wood units, p=0.91) and remained low after heart transplantation. The mean follow-up period after OHT was 3.5 years (range, 1 month to 9.3 years). The in-hospital mortality rate after OHT was significantly higher in the high PVR group (20.7%) than in the low PVR group (5.8%; p<0.05). The survival rates at 3 years post-OHT were 85.0% for the low PVR group and 79.0% for the high PVR group (p=0.45).

De Santo et al. (2012) reported on 31 consecutive patients diagnosed with unresponsive pulmonary hypertension at baseline after right heart catheterization. (47) After 12 weeks of treatment with oral sildenafil, right heart catheterization showed reversibility of pulmonary hypertension, allowing patients to be listed for heart transplant. Oral sildenafil treatment resumed following transplant. One patient died in the hospital. A right heart catheterization at 3 months posttransplant showed normalization of the pulmonary hemodynamic profile, thereby allowing weaning from sildenafil in the 30 patients who survived hospitalization. The reversal of pulmonary hypertension was confirmed at 1 year in the 29 surviving patients. Similarly, in a study by Perez-Villa et al. (2013), 22 patients considered high risk for heart transplant due to severe pulmonary hypertension were treated with bosentan. (47) After 4 months of treatment, mean PVR decreased from 5.6 to 3.4 Wood units. In a similar group of 9 patients who refused participation in the study and served as controls, mean PVR during this time increased from 4.6 to 5.5 Wood units. After bosentan therapy, 14 patients underwent heart transplantation and the 1-year survival rate was 93%.

Renal Insufficiency

The 2016 ISHLT criteria for heart transplantation recommended irreversible renal dysfunction (eGFR <30 mL/min/1.73 m2) as a relative contraindication for heart transplantation alone. The cutoff for eGFR in the previous recommendation was 35 mL/min/1.73 m2. Hong et al. (2016) conducted a study among 17,459 adult OHT recipients with results between 2001 and 2009 in the UNOS database to determine whether survival after OHT was associated with pretransplant eGFR and to define ranges of pretransplant eGFR associated with differences in posttransplant survival. (52) Posttransplant graft survival in the group with an eGFR less than 34 mL/min/1.73 m2 was significantly worse than in the groups with an eGFR 35 to 49 mL/min/1.73 m2 or an eGFR greater than 49 mL/min/1.73 m2 (p<0.001). Median survival in the 3 groups was 8.2 years, 10.0 years, and 10.3 years, respectively. At 3 months, graft survival rates were 82.1%, 90.7%, and 94.0% in the groups with an eGFR less than 34 mL/min/1.73 m2, an eGFR 35 to 49 mL/min/1.73 m2, and an eGFR greater than 49 mL/min/1.73 m2, respectively. In multivariable logistic regression analysis, eGFR less than 34 mL/min/1.73 m2 and eGFR 35 to 49 mL/min/1.73 m2 were significant risk factors for death at 1 year (p<0.001). Rossano et al. (2016) also reported eGFR to be an independent risk factor for 1-, 5- and 10-year posttransplant mortality among pediatric transplant recipients (described under pediatric considerations for survival after heart transplant). (24)

Children with Intellectual Disability

Considering the shortage of available donor organs, heart transplantation in children with intellectual disability has been debated. In 2016, ISHLT removed explicit mention of “mental retardation” as a relative contraindication to heart transplantation from its official guidelines. Multiple studies in recent years have examined whether intellectual disability in children is associated with significantly lower survival following heart transplantation compared with children without intellectual disability.

Goel et al. (2017) conducted a retrospective cohort study using UNOS data from 2008 to 2015 to evaluate the prevalence and outcomes of heart transplantation in this population. (53) Intellectual disability was assessed by using the cognitive development, academic progress, and academic level (5-point Likert scale scores for each of those) reported by transplant centers to UNOS. There were 565 pediatric (<19 years) patients with definite (n=131) or probable (n=434) intellectual disability who received their first heart transplant, accounting for 22.4% of all first pediatric heart transplants (n=2524). Intellectual disability was associated with prolonged waitlist time (p<0.001). Patient survival rates at 1 and 3 years, respectively, were 88.9% and 86.0% for the definite intellectual disability group, 91.6% and 82.4% for probable intellectual disability group, and 91.8% and 86.2% for no intellectual disability group. Patient survival did not differ between groups at any time posttransplant (p=0.578). Intellectual disability status at listing was not associated with graft mortality hazards in univariate and multivariate analyses.

Wightman et al. (2017) performed a retrospective cohort analysis of 1204 children receiving a first isolated heart transplant for whom cognitive and educational data were available in the UNOS dataset between 2008 and 2013. (54) Children categorized as “definitely cognitive delay/impairment” by their transplant center using the Likert scales for cognitive development. All other recipients were classified as “no intellectual disability.” Kaplan-Meier curves and log-rank tests did not suggest a significant difference in graft survival during the first 4 years after transplantation (p=0.07), however, they did suggest poorer patient survival among the intellectual disability group during the first 4 years following transplantation (p=0.05). In unadjusted Cox regression, intellectual disability was associated with poorer graft (HR=1.66; 95% CI, to 2.72; p=0.05) and patient survival (HR=1.71; 95% CI, 0.99 to 2.94; p=0.05). However, after adjusting for covariates, there was no association between intellectual disability and graft survival (HR=0.95; 95% CI, 0.49 to 1.88; p=0.89) or patient survival (HR=0.80; 95% CI, 0.36 to 1.75; p=0.58).

Prendergast et al. (2017) assessed the impact of cognitive delay on pediatric heart transplantation outcomes using academic progress as a surrogate for cognitive performance among pediatric heart transplant recipients (2004-2014) with data reporting academic progress in the OPTN database (n=2245). (55) Of the patients with complete academic progress data, 1707 (76%) were within 1 grade level of peers (WGL), 269 (12%) had delayed grade level, and 269 (12%) required special education. There was no significant difference in posttransplant survival between patients WGL and those who required special education. However, patients with delayed grade level demonstrated worse posttransplant survival than patients WGL and those who required special education (p<0.001). Delayed grade level remained as an independent predictor of posttransplant graft loss (adjusted HR=1.4; 95% CI, 1.02 to 1.79; p=0.03) in multivariate analysis. Authors conducted a secondary analysis substituting cognitive delay for academic progress; patients were divided into 2 groups based on whether any concerns for cognitive delay (questionable, probable, or definite) were ever reported at the time of heart transplantation or during follow-up (1176 with cognitive delay, 1783 with no documented cognitive delay). There was no significant difference in posttransplant graft survival based on the presence of cognitive delay (p=0.57). Cognitive delay remained a statistically nonsignificant predictor in multivariate analysis (adjusted HR=1.01; 95% CI, 0.83 to 1.22; p=0.953).

Because all these studies assessed the patients who received transplants and did not evaluate children who were refused listing by a transplant center or never referred to transplant center, the prevalence of intellectual disability among potential candidates of heart transplantation might have been underestimated. With low-risk intellectual disability patients receiving heart transplant and individuals with intellectual disability and other high-risk conditions being excluded, results might also have a positive selection bias.

Practice Guidelines and Position Statements

American College of Cardiology Foundation and American Heart Association (ACCF/AHA)

Guidelines from the ACCF/AHA on management of heart failure, updated in 2013, recommended evaluation for cardiac transplantation for patients with stage D heart failure despite guideline-directed medical therapy, device, and surgical management. (56)

International Society for Heart and Lung Transplantation (ISHLT)

In a 2004 statement, the ISHLT recommended that children with the following conditions be evaluated for heart transplantation (see Table 5). (57)

Table 5. Recommendations for Pediatric Heart Transplant

Recommendation

LOE

Diastolic dysfunction that is refractory to optimal medical/surgical management because they are at high risk of developing pulmonary hypertension and of sudden death

B

Advanced systemic right ventricular failure (Heart Failure Stage C described as patients with underlying structural or functional heart disease and past or current symptoms of heart failure) that is refractory to medical therapy

C

LOE B is based on a single randomized trial or multiple nonrandomized trials; LOE C is based primarily on expert consensus opinion.

LOE: level of evidence.

In 2016, ISHLT published a 10-year update to its listing criteria for heart transplantation. (58) The guidelines recommended updates or changes to the 2006 guideline:

Recommended use of heart failure prognosis scores (e.g., Seattle Heart Failure Model, Heart Failure Survival Score) along with cardiopulmonary exercise test to determine prognosis and guide listing for transplantation for ambulatory patients.

Periodic right heart catheterization for routine surveillance is not recommended in children.

Carefully selected patients >70 years of age may be considered for cardiac transplantation.

Pre-existing neoplasm, BMI of ≥35 kg/m2, diabetes with “end-organ damage (other than non- proliferative retinopathy) or poor glycemic control … despite optimal effort,” irreversible renal dysfunction, clinically severe symptomatic cerebrovascular disease, peripheral vascular disease, and frailty are considered relative contraindications to heart transplantation.

Considering active smoking during previous 6 months as a risk factor for poor outcomes after transplantation, active tobacco smoking is considered a relative contraindication for heart transplantation. Similarly, patients who remain active substance abusers (including alcohol) are nor recommended to receive heart transplantation.

The 2010 guidelines from the ISHLT include the following recommendations on cardiac retransplantation (59):

“Retransplantation is indicated in children with at least moderate systolic heart allograft dysfunction and/or severe diastolic dysfunction and at least moderate CAV (cardiac allograft vasculopathy).”

“It is reasonable to consider listing for retransplantation those adult HT [heart transplant] recipients who develop severe CAV not amenable to medical or surgical therapy and symptoms of heart failure or ischemia.”

“It is reasonable to consider listing for retransplantation those HT recipients with heart allograft dysfunction and symptomatic heart failure occurring in the absence of acute rejection.”

“It is reasonable to consider retransplantation in children with normal heart allograft function and severe CAV.”

American Heart Association (AHA)

The AHA indicated in 2007 that, based on level B (nonrandomized studies) or level C (consensus opinion of experts), heart transplantation is indicated for pediatric patients as therapy for the following indications: (60)

Stage D heart failure (interpreted as abnormal cardiac structure and/or function, continuous infusion of intravenous inotropes, or prostaglandin E1 to maintain patency of a ductus arteriosus, mechanical ventilatory and/or mechanical circulatory support) associated with systemic ventricular dysfunction in patients with cardiomyopathies or previous repaired or palliated congenital heart disease.

Stage C heart failure (interpreted as abnormal cardiac structure and/or function and past or present symptoms of heart failure) associated with pediatric heart disease and severe limitation of exercise and activity, in patients with cardiomyopathies or previously repaired or palliated congenital heart disease and heart failure associated with significant growth failure attributed to heart disease, pediatric heart disease with associated near sudden death and/or life-threatening arrhythmias untreatable with medications or an implantable defibrillator, or in pediatric restrictive cardiomyopathy disease associated with reactive pulmonary hypertension.

The guideline states that heart transplantation is feasible in the presence of other indications for heart transplantation, “in patients with pediatric heart disease and an elevated pulmonary vascular resistance index >6 Woods units/m2 and/or a transpulmonary pressure gradient >15 mm Hg if administration of inotropic support or pulmonary vasodilators can decrease pulmonary vascular resistance to <6 Woods units/m2 or the transpulmonary gradient to <15 mm Hg.”

European Society of Cardiology (ESC)

The 2016 ESC guidelines on the diagnosis and treatment of acute and chronic heart failure recommended considering heart transplantation for patients with end-stage heart failure with severe symptoms, poor prognosis, and no alternative treatment options. (61) Active infection, severe peripheral arterial or cerebrovascular ischemia, pharmacologically irreversible pulmonary hypertension, cancer, renal insufficiency, systemic disease with multiorgan involvement, pretransplant body mass index greater than 35 kg/m2, current alcohol or drug abuse, and insufficient social support to achieve compliant care in outpatient setting were considered relative contraindications for heart transplantation.

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov in July 2017 did not identify any ongoing or unpublished trials that would likely influence this review.

Summary of Evidence

For individuals who have end-stage heart failure who receive a heart transplant, the evidence includes case series and registry data. Relevant outcomes are overall survival, symptoms, morbid events, and treatment-related morbidity and mortality. Despite improvements in the prognosis for many patients with advanced heart disease, heart transplant remains a viable treatment for those with severe heart dysfunction despite appropriate medical management with medication, surgery, or medical devices. Given the exceedingly poor survival rates without transplantation for these patients, evidence of posttransplant survival is sufficient to demonstrate that heart transplantation provides a survival benefit. Heart transplantation is contraindicated in patients for whom the procedure is expected to be futile due to comorbid disease or in whom posttransplantation care is expected to worsen comorbid conditions significantly. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have had a prior heart transplant complicated by graft failure or severe dysfunction of the heart who receive a heart retransplant, the evidence includes case series and registry data. Relevant outcomes are overall survival, symptoms, morbid events, and treatment-related morbidity and mortality. Despite improvements in the prognosis for many patients with graft failure, cardiac allograft vasculopathy, and severe dysfunction of the transplanted heart, heart retransplant remains a viable treatment for those who have exhausted other medical or surgical remedies, yet are still with severe symptoms. Given the exceedingly poor survival rates without retransplantation for patients who have exhausted other treatments, evidence of posttransplant survival is sufficient to demonstrate that heart retransplantation provides a survival benefit in appropriately selected patients. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

33940, 33944, 33945

HCPCS Codes

S2152

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does have a national Medicare coverage position.

A national coverage position for Medicare may have been changed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

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23. Jaramillo N, Segovia J, Gomez-Bueno M, et al. Characteristics of patients with survival longer than 20 years following heart transplantation. Rev Esp Cardiol. Oct 2013; 66(10):797-802. PMID 24773860

24. Rossano JW, Dipchand AI, Edwards LB, et al. The Registry of the International Society for Heart and Lung Transplantation: Nineteenth Pediatric Heart Transplantation Report-2016; Focus Theme: Primary Diagnostic Indications for Transplant. J Heart Lung Transplant. Oct 2016; 35(10):1185-1195. PMID 27772670

25. Dipchand AI, Kirk R, Mahle WT, et al. Ten yr of pediatric heart transplantation: a report from the Pediatric Heart Transplant Study. Pediatr Transplant. Mar 2013; 17(2):99-111. PMID 23442098

26. Savla J, Lin KY, Lefkowitz DS, et al. Adolescent age and heart transplantation outcomes in myocarditis or congenital heart disease. J Heart Lung Transplant. Sep 2014; 33(9):943-949. PMID 24929645

27. Almond CS, Thiagarajan RR, Piercey GE, et al. Waiting list mortality among children listed for heart transplantation in the United States. Circulation. Feb 10 2009; 119(5):717-727. PMID 19171850

28. Auerbach SR, Richmond ME, Chen JM, et al. Multiple risk factors before pediatric cardiac transplantation are associated with increased graft loss. Pediatr Cardiol. Jan 2012; 33(1):49-54. PMID 21892650

29. Belli E, Leoni Moreno JC, Hosenpud J, et al. Preoperative risk factors predict survival following cardiac retransplantation: analysis of the United Network for Organ Sharing database. J Thorac Cardiovasc Surg. Jun 2014; 147(6):1972-1977, 1977 e1971. PMID 24636155

30. Tjang YS, Tenderich G, Hornik L, et al. Cardiac retransplantation in adults: an evidence-based systematic review. Thorac Cardiovasc Surg. Sep 2008; 56(6):323-327. PMID 18704853

31. Goldraich LA, Stehlik J, Kucheryavaya AY, et al. Retransplant and medical therapy for cardiac allograft vasculopathy: international society for heart and lung transplantation registry analysis. Am J Transplant. Jan 2016; 16(1):301-309. PMID 26274617

32. Saito A, Novick RJ, Kiaii B, et al. Early and late outcomes after cardiac retransplantation. Can J Surg. Feb 2013; 56(1):21-26. PMID 23187039

33. Friedland-Little JM, Gajarski RJ, Yu S, et al. Outcomes of third heart transplants in pediatric and young adult patients: analysis of the United Network for Organ Sharing database. J Heart Lung Transplant. Sep 2014; 33(9):917-923. PMID 24861821

34. Bock MJ, Nguyen K, Malerba S, et al. Pediatric cardiac retransplantation: Waitlist mortality stratified by age and era. J Heart Lung Transplant. Apr 2015; 34(4):530-537. PMID 25016920

35. Conway J, Manlhiot C, Kirk R, et al. Mortality and morbidity after retransplantation after primary heart transplant in childhood: an analysis from the registry of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. Mar 2014; 33(3):241-251. PMID 24462559

36. Mistiaen WP. Heart transplantation in patients with previous malignancy. An overview. Acta Cardiol. Apr 2015; 70(2):123-130. PMID 26148371

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39. Yoosabai A, Mehta A, Kang W, et al. Pretransplant malignancy as a risk factor for posttransplant malignancy after heart transplantation. Transplantation. Feb 2015; 99(2):345-350. PMID 25606783

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41. Uriel N, Jorde UP, Cotarlan V, et al. Heart transplantation in human immunodeficiency virus-positive patients. J Heart Lung Transplant. Jul 2009; 28(7):667-669. PMID 19560693

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Policy History:

DateReason
11/15/2018 Reviewed. No changes.
12/15/2017 Document updated with literature review. The following change was made to Coverage: Updated terminology from “Status 7” to “Inactive Status”.
3/1/2016 Reviewed. No changes.
6/1/2015 Document updated with literature review. Coverage unchanged.
12/1/2014 Document updated with literature review. The following statements were added to coverage: 1) Heart retransplantation after a failed primary heart transplant may be considered medically necessary in patients who meet criteria for heart transplantation. 2) Heart transplantation is considered experimental, investigational and/or unproven in all other situations.
11/1/2013 Document updated with literature review. Coverage changed to: Human heart transplant may be considered medically necessary in carefully selected patients with irreversible, refractory, and symptomatic end-stage heart failure who meet the United Network for Organ Sharing (UNOS) guidelines for 1A, 1B, or 2 Status and are not currently Status 7. CPT/HCPCS code(s) updated.
4/15/2009 Editorial revision to clarify end-stage cardiomyopathy coverage criteria; references revised
6/1/2008 Revised/updated entire document; this policy is no longer scheduled for routine literature and update
2/1/2005 Revised/updated entire document
9/1/1998 Revised/updated entire document
5/1/1996 Medical policy number changed
4/1/1996 Revised/updated entire document
1/1/1992 Revised/updated entire document
5/1/1990 New medical document

Archived Document(s):

Title:Effective Date:End Date:
Heart Transplant12-15-201711-14-2018
Heart Transplant03-01-201612-14-2017
Heart Transplant06-01-201502-29-2016
Heart Transplant12-01-201405-31-2015
Heart Transplant11-01-201311-30-2014
Heart Transplant06-01-200810-31-2013
Heart Transplant02-01-200505-31-2008
Heart Transplant09-01-199801-31-2005
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