Abstract
Significant practice-changing developments have occurred in the care of heart transplantation candidates and recipients over the past decade. This Canadian Cardiovascular Society/Canadian Cardiac Transplant Network Position Statement provides evidence-based, expert panel recommendations with values and preferences, and practical tips on: (1) patient selection criteria; (2) selected patient populations; and (3) post transplantation surveillance. The recommendations were developed through systematic review of the literature and using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. The evolving areas of importance addressed include transplant recipient age, frailty assessment, pulmonary hypertension evaluation, cannabis use, combined heart and other solid organ transplantation, adult congenital heart disease, cardiac amyloidosis, high sensitization, and post-transplantation management of antibodies to human leukocyte antigen, rejection, cardiac allograft vasculopathy, and long-term noncardiac care. Attention is also given to Canadian-specific management strategies including the prioritization of highly sensitized transplant candidates (status 4S) and heart organ allocation algorithms. The focus topics in this position statement highlight the increased complexity of patients who undergo evaluation for heart transplantation as well as improved patient selection, and advances in post-transplantation management and surveillance that have led to better long-term outcomes for heart transplant recipients.
Résumé
Les pratiques relatives aux soins prodigués aux candidats à une transplantation cardiaque et aux receveurs d’un nouveau cœur ont beaucoup évolué depuis dix ans. Le présent énoncé de position conjoint de la Société canadienne de cardiologie et du Canadian Cardiac Transplant Network fait état des recommandations d’un groupe d’experts fondées sur des données probantes, et comprend des valeurs et des préférences ainsi que des conseils pratiques concernant les critères de sélection des patients, des populations de patients particulières et la surveillance post-transplantation. Ces recommandations ont été formulées à la suite d’une revue exhaustive de la littérature et au moyen du système GRADE (Grading of Recommendations Assessment, Development, and Evaluation). Les domaines d’importance en évolution abordés comprennent l’âge du receveur, l’évaluation de sa fragilité, l’évaluation de l’hypertension pulmonaire, l’usage de cannabis, la transplantation cardiaque jumelée à la greffe d’un autre organe solide, la cardiopathie congénitale chez l’adulte, l’amylose cardiaque, la sensibilisation élevée ainsi que la prise en charge des anticorps à l’antigène leucocytaire humain, du rejet du greffon, de l’artériosclérose accélérée du greffon cardiaque et des soins non cardiaques de longue durée après la transplantation. Il est aussi question des stratégies de prise en charge propres au Canada, notamment l’établissement de la priorité des candidats à la transplantation hautement sensibilisés (statut 4S) et les algorithmes d’attribution des organes. Les thèmes principaux de cet énoncé de position font ressortir la complexité croissante des cas des patients qui subissent une évaluation en vue d’une transplantation cardiaque ainsi que l’amélioration des critères de sélection des patients et les avancées dans la prise en charge et la surveillance après la transplantation, qui permettent aux receveurs d’une greffe cardiaque d’obtenir de meilleurs résultats à long terme.
The Canadian Cardiovascular Society published the first heart transplantation (HTx) guidelines in 2003, and a last update in 2009.
1
,2
Over the past decade, there have been significant practice-changing developments in patient evaluation and post transplantation care.3
The objective of this position statement is to provide a focused update, review, and recommendations to assist clinicians and health care workers managing HTx patients in 3 areas: (1) patient selection criteria; (2) selected patient populations; (3) post transplantation surveillance and management. The systematic review approach, and methods for formulating the recommendations, values and preferences, and practical tips are detailed on the Canadian Cardiovascular Society Web site (www.ccs.ca). The recommendations use the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system,4
which classifies the quality of evidence as high (further research very unlikely to change confidence in the estimate of effect), moderate (further research likely to have an important effect on confidence in the estimate of effect and might change the estimate), low (further research very likely to have an important effect on confidence in the estimate of effect and likely to change the estimate), and very low (estimate of the effect very uncertain). This system provides 2 grades of recommendations: “strong” (desirable effects clearly outweigh undesirable effects or clearly do not) and “weak” (trade-offs are less certain, either because of low-quality evidence or because the evidence suggests desirable and undesirable effects are closely balanced).Selection Criteria
Age
The median HTx recipient age has increased from 53 to 55 years over the past decade.
5
,6
Although increased age is associated with post transplantation mortality, HTx in septuagenarians is becoming more frequent.- Khush K.K.
- Cherikh W.S.
- Chambers D.C.
- et al.
The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: thirty-fifth adult heart transplantation report-2018; focus theme: multiorgan transplantation.
J Heart Lung Transplant. 2018; 37: 1155-1168
5
, 6
, - Khush K.K.
- Cherikh W.S.
- Chambers D.C.
- et al.
The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: thirty-fifth adult heart transplantation report-2018; focus theme: multiorgan transplantation.
J Heart Lung Transplant. 2018; 37: 1155-1168
7
Large registry analyses have shown similar post transplantation survival and morbidity in patients ≥ 70 years of age compared with younger patients, suggesting acceptable outcomes can be achieved through careful selection.8
,9
RECOMMENDATION
- 1.We recommend consideration of HTx for eligible patients with advanced heart failure (HF) who are ≤ 70 years of age (Strong Recommendation, Low-Quality Evidence).
- 2.We suggest HTx might be considered for carefully selected patients with advanced HF > 70 years of age (Weak Recommendation, Low-Quality Evidence).
Frailty
Frailty in patients with advanced HF is associated with increased morbidity and mortality with an approximate 25% reduction in 1-year post-HTx survival in frail patients.
10
The presence of cachexia, self-reported physical exhaustion or decrease in hand grip strength, walking speed, or physical activity11
have been used to define frailty.9
Several tools for assessing frailty have been used for patients who undergo HTx and left ventricular assist device (LVAD) placement including the Fried Frailty Phenotype score (≥ 3 of 5 measures), the Deficit Index (≥ 0.32), and the Edmonton Frailty Scale score (≥ 8; Table 1).10
Additionally, reduced preoperative muscle mass significantly increases postoperative morbidity and mortality. The prognostic value of a frailty assessment might be increased by including cognitive and depression measures such as a Montreal Cognitive Assessment score ≤ 26 and Depression in the Medically Ill-10 score ≥ 9, respectively.12
Prehabilitation has been shown to be beneficial in patients who receive cardiac surgery, but these studies have not included pre-HTx patients. LVADs can be implanted as a bridge to transplantation strategy and might promote an anabolic state thereby decreasing frailty while awaiting transplantation.13
However, there are conflicting data and uncertainty over the benefit of LVADs to reverse frailty in advanced HF patients.14
RECOMMENDATION
- 3.We recommend an assessment of frailty using the Fried Frailty Phenotype score, Deficit Index, or Edmonton Frailty Scale, for example, for all patients being considered for HTx (Strong Recommendation, Moderate-Quality Evidence).
Values and preferences. LVAD placement in selected patients might be considered to improve frailty before HTx.
Table 1Frailty assessment tools
| Model | Domain | Assessment | Calculation |
|---|---|---|---|
| Fried Frailty Phenotype | Grip strength | Handheld dynamometer (in kilograms) and stratified according to gender and body mass index quartiles; 1 point | All values are summed with ≥ 3 consistent with frailty in HF patients |
| Walk time | Time to walk 15 feet stratified according to gender and height; 1 point | ||
| Low level of physical activity | “How often do you engage in activities that require a low or moderate level of energy, such as walking, chores (moderately strenuous), mowing the lawn, raking, gardening, hiking, jogging, exercise cycling, dancing, aerobics, bowling, golf, tennis, racquetball, calisthenics, swimming.” Kcals per week expended are calculated using standardized algorithm | ||
| Men: Kcals per week < 383 are frail; 1 point | |||
| Women: Kcals per week < 270 are frail; 1 point | |||
| Exhaustion | The following 2 statements are read: “I felt that everything I did was an effort?” and “I could not get going?” “How often in the week did you feel that way?” (0 = rarely or none of the time (1 day), 1 = some or a little of the time (1-2 days), 2 = moderate amount of the time (3-4 days), 3 = most of the time. A response of “2” or “3” to either question is considered as exhaustion and categorized as frail; 1 point | ||
| Weight loss | “In the past year, have you lost more than 10 pounds unintentionally (ie, not due to dieting or exercise)?” If yes, then frail for weight loss criterion; 1 point | ||
| Deficit Index | Mobility | Walking speed; number of falls in the past 6 months | Points assigned using standard methods of assessments and divided by the total number of domains assessed. Value ≥ 0.32 considered significant for HF patients |
| Cognition | History of dementia; Mini-Cog test or Mini-Mental State Examination | ||
| Exhaustion | Dependency of activities in daily living | ||
| Function | Energy level | ||
| Burden of chronic disease | Charlson index; > 5 chronic medications | ||
| Mood | Depression, sadness, anxiety | ||
| Nutritional status | > 10-Pound weight loss in the past 6 months; low albumin, poor appetite | ||
| Social vulnerability | Presence of social support; lack of interactions with other people | ||
| Edmonton Frailty Scale | Cognition | Please imagine that this predrawn circle is a clock. I would like you to place the numbers in the correct positions then place the hands to indicate a time of “ten after eleven”; 0 points = no errors, 1 point = minor spacing errors, 2 points = other errors | Points are tallied with score ≥ 8 of 17 considered significant for frailty in HF patients |
| General health status | In the past year, how many times have you been admitted to a hospital? 0 points = 0, 1 point = 1-2, 2 points ≥ 2. In general, how would you describe your health? 0 points = excellent, very good, good; 1 point = fair; 2 points = poor | ||
| Functional independence | With how many of the following activities do you require help? (meal preparation, shopping, transportation, telephone, housekeeping, laundry, managing money, taking medications); 0 points = 0-1, 1 point = 2-4, 2 points = 5-8 | ||
| Social support | When you need help, can you count on someone who is willing and able to meet your needs? 0 points = always, 1 point = sometimes, 2 points = never | ||
| Medication use | Do you use 5 or more different prescription medications on a regular basis? 0 points = no, 1 point = yes. At times, do you forget to take your prescription medications? 0 points = no, 1 point = yes | ||
| Nutrition | Have you recently lost weight such that your clothing has become looser? 0 points = no, 1 point = yes | ||
| Mood | Do you often feel sad or depressed? 0 points = no, 1 point = yes | ||
| Continence | Do you have a problem with losing control of urine when you don’t want to? 0 points = no, 1 point = yes | ||
| Functional performance | I would like you to sit in this chair with your back and arms resting. Then, when I say “Go,” please stand up and walk at a safe and comfortable pace to the mark on the floor (approximately 3 m away), return to the chair and sit down. 0 points = 0-10 seconds, 1 point = 11-20 seconds, 2 points = > 20 seconds, unwilling, or unable |
HF, heart failure.
Modified from Mauthner et al.
14
with permission from Elsevier; and Rolfson et al.15
with permission from Oxford University Press.Obesity
Elevated body mass index (BMI) is an important predictor of poor survival after HTx.
6
High BMI is also associated with up to 46% lower likelihood of finding a suitable donor and prolonged waiting time to HTx.- Khush K.K.
- Cherikh W.S.
- Chambers D.C.
- et al.
The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: thirty-fifth adult heart transplantation report-2018; focus theme: multiorgan transplantation.
J Heart Lung Transplant. 2018; 37: 1155-1168
16
Observational studies have shown that BMI ≥ 35 is associated with decreased patient survival post HTx and increased risk of infection, rejection, diabetes, and cardiac allograft vasculopathy (CAV).9
,16
, 17
, 18
Increased adverse outcomes after HTx have not been consistently shown for obese patients with BMI 30-34.9 compared to patients with BMI < 30. In selected obese patients, LVAD implantation as a bridge to transplantation achieves reasonable outcomes. A BMI ≥ 35 is associated with increased risk of complications such as thromboembolism and infection but no difference in survival post LVAD implantation.19
Weight loss can be achieved but is uncommon post LVAD placement, and additional weight loss strategies are generally recommended before transplant listing.RECOMMENDATION
- 4.We recommend caution in HTx for patients with a BMI ≥ 35 (Strong Recommendation, Low-Quality Evidence).
Pulmonary hypertension
Significant pulmonary hypertension (PH), typically defined as pulmonary vascular resistance > 3 Wood Units, transpulmonary gradient > 15 mm Hg and/or pulmonary artery systolic pressure > 50 mm Hg, is considered a contraindication for HTx
9
because of greater risk of post-transplantation right ventricular failure and early mortality.20
,21
All patients being evaluated for HTx should undergo right heart catheterization to evaluate pulmonary hemodynamics. An acute vasodilator challenge is recommended in patients with PH to assess for reversibility, which is defined as achieving all the following: pulmonary vascular resistance < 3 Wood Units, transpulmonary gradient ≤ 14, pulmonary artery systolic pressure < 50 mm Hg while maintaining a systolic blood pressure > 85 mm Hg. If unsuccessful, further medical optimization with inotropes, diuretics, and vasoactive therapies should be considered. Inhaled (eg, nitric oxide) or intravenous (eg, sodium nitroprusside, nitroglycerin) agents can be used for the vasodilator challenge; systemic effects such as hypotension are greater with intravenous compounds.9
Concomitant conditions that can exacerbate PH such as chronic obstructive pulmonary disease, sleep apnea, and pulmonary emboli should be aggressively treated.22
If medical therapy fails to achieve acceptable pulmonary hemodynamics and primary pulmonary causes of PH have been excluded, an LVAD should be considered to maximize left ventricular unloading and pulmonary vascular remodelling.23
Most studies have shown significant reduction in pulmonary pressures post LVAD placement.23
,24
Hemodynamic reevaluation is performed at 3-6 months after LVAD placement to ascertain PH reversibility. A small number of single-centre studies have successfully used phosphodiesterase-5 inhibitors to reduce PH and facilitate candidacy for HTx without LVAD placement.25
, 26
, 27
Their use needs to be balanced against the risks of systemic hypotension and worsening pulmonary edema, and are currently not routinely recommended in patients being considered for HTx. In the small subset of patients who have persistent PH after LVAD implantation, phosphodiesterase-5 inhibitors can be considered as adjunctive therapy.28
RECOMMENDATION
- 5.We recommend right heart catheterization for assessment of PH, PH severity, and reversibility in all patients being evaluated for HTx (Strong Recommendation, Low-Quality Evidence).
- 6.We recommend an acute vasodilator challenge for patients with evidence of PH on right heart catheterization (Strong Recommendation, Low-Quality Evidence).
- 7.We recommend LVAD implantation for eligible patients with significant PH who are otherwise candidates for HTx (Strong Recommendation, Moderate-Quality Evidence).
- 8.We recommend against routine use of phosphodiesterase-5 inhibitors to reduce pulmonary pressures in patients with advanced HF and PH (Weak Recommendation, Moderate-Quality Evidence).
Psychosocial considerations and substance use
The International Society of Heart and Lung Transplantation (ISHLT) recently published a consensus statement on pre-HTx psychosocial evaluation.
29
Contraindications to HTx included: repeated medical nonadherence, active alcohol or drug abuse, active smoking, and mental health and social conditions that are likely to affect ability to adhere to medication regimens.29
Psychosocial problems might be remediated and also inform care planning post HTx. However, there is minimal literature documenting the effect of interventions on HTx outcomes.RECOMMENDATION
- 9.We recommend psychosocial evaluation before HTx (Strong Recommendation, Low-Quality Evidence).
- 10.We recommend attempts to remediate modifiable psychosocial factors in candidates for whom these are barriers to transplant listing (Strong Recommendation, Very Low-Quality Evidence).
- 11.We do not recommend HTx for patients who show repeated nonadherence to medications, alcohol use disorder, smoking or illicit drug use, mental illness or other cognitive factors, and/or insufficient social support, which are likely to affect ability to adhere to medication and post-transplantation regimens (Strong Recommendation, Low-Quality Evidence).
Practical tip. To optimize post-HTx outcomes, the psychosocial assessment should attempt to answer the following 3 questions: will the patient take medications as ordered, attend clinic appointments, and call if there is a problem.
Cannabis
Cannabis refers to cannabis, its by-products, and synthetic cannabinoids. On October 17, 2018, the Federal Government of Canada passed Bill C-45—the Cannabis Act, which changed cannabis use from “illicit” drug use to an accepted recreational activity.
30
Government of Canada
Justice Laws Website. Cannabis Act.
Justice Laws Website. Cannabis Act.
https://laws-lois.justice.gc.ca/eng/acts/c-24.5/page-1.html
Date accessed: March 27, 2019
In a recent systematic review, cannabis use was shown to increase heart rate and reduce blood pressure, but there was insufficient evidence to determine whether cannabis was responsible for arrhythmia, ischemia, and sudden death.
31
The potential for pulmonary infections from smoking cannabis is described in case reports of immunosuppressed patients possibly because of inhalation of fungal elements.32
These reports are published in an era of illicit use and presumably nonregulated production. Other risks associated with smoking or vaping cannabis are unknown. Until evidence to the contrary emerges, smoking or vaping cannabis should be actively discouraged. Cannabis and immunosuppression drug interactions has not been well studied. A systematic review of 31 studies on whether cannabinoids could affect human drug-metabolizing enzymes (including cytochrome P-450) concluded insufficient evidence to confirm any interactions in humans. Moreover, it was difficult to determine the exact effects because of variable cannabis usage.33
One small study of 6 HTx cannabis users showed that calcineurin inhibitors (CNIs) cyclosporine and tacrolimus dose to trough ratio was reduced by 21% and 3%, respectively. There was no difference in outcomes compared with other HTx patients.34
RECOMMENDATION
- 12.We recommend 6 months abstinence from smoking, inhaling, or vaping cannabis before HTx listing (Strong Recommendation, Low-Quality Evidence).
Values and preferences. Recreational or medicinal noninhalational cannabis use is not an absolute contraindication for HTx. Cannabis use disorder is a contraindication to transplantation and specialist treatment programs are warranted. Transplantation may be reconsidered upon completion and successful abstinence for a minimum of 6 months. We suggest additional monitoring of CNI levels in HTx recipients using cannabis.
Selected Patient Populations
Cardiac amyloidosis
Cardiac amyloidosis is a systemic disease caused by extracellular cardiac deposition of light chain (AL) or transthyretin (ATTR) protein fibrils.
35
Transplantation for advanced AL cardiac amyloidosis is controversial because of high wait list mortality of up to 40%36
and inferior post transplantation survival compared with nonamyloid patients.35
Historically, isolated HTx for AL cardiac amyloidosis was associated with a dismal 1-year survival of 50% because of recurrence of amyloid in the allograft or progression of extracardiac amyloid disease. Recent advances in bortezomib-based chemotherapy strategies for AL amyloidosis and improved patient selection for HTx have led to better outcomes. Single-centre series using a staged approach of HTx followed by autologous bone marrow stem cell transplantation 6-12 months later have increased 1- and 5-year survival rates to 82%-100% and 65%, respectively.36
, 37
, 38
, 39
An analysis of the United Network for Organ Sharing database showed decreased post-transplantation mortality (hazard ratio, 0.49; P = 0.03) for patients with cardiac amyloidosis in 2008-2013 compared with an earlier 1987-2007 era.40
Recent studies of patients who received a heart transplantation within the past 5 years have shown an even smaller gap in outcomes between amyloid and nonamyloid patients with 90% survival at 1 year in one case series.39
Importantly, a detailed evaluative process is crucial to assess for multiorgan involvement that might preclude HTx.9
,41
A multidisciplinary management approach is required involving specialists from hematology, neurology, nephrology, and gastroenterology.Transthyretin amyloidosis might occur as hereditary ATTR (hATTR) or wild type ATTR (ATTRwt) forms. Liver or combined heart-liver transplantation (HLivT) are treatment options aimed at removing hepatic production of the mutant protein. Disease progression for ATTRwt is generally slower than for hATTR and ATTRwt is predominantly a disease of the elderly, who usually have comorbidities precluding HTx.
42
Emerging medical treatments for ATTR amyloid have shown potential to significantly reduce progression of cardiac disease.43
RECOMMENDATION
- 13.We suggest consideration of HTx in highly selected patients with isolated cardiac amyloidosis together with treatment to suppress the amyloidogenic process (Weak Recommendation, Low-Quality Evidence).
Values and preferences. HTx is feasible for highly selected patients with cardiac amyloidosis and nonadvanced systemic disease. In conjunction with contemporary chemotherapy regimens, outcomes post HTx for AL cardiac amyloidosis are comparable with nonamyloid cardiomyopathy. Patients should be managed by a multidisciplinary team involving expertise in solid organ and bone marrow transplantation.
Practical tip. Patients with isolated AL cardiac amyloidosis requiring HTx should be treated with chemotherapy and show appropriate reduction in light chains, followed by HTx and autologous bone marrow transplantation if eligible. For patients with hATTR amyloidosis, combined heart and liver transplantation may be considered. The long-term effects of the newer therapies targeting ATTR need to be evaluated.
Retransplantation
Cardiac retransplantation comprised 6% of HTx reported to the ISHLT in 2017.
6
Although retransplantation is often the only effective long-term treatment option for patients with allograft dysfunction, inferior outcomes compared with de novo HTx have been reported in multiple large registry analyses, and questioning appropriateness of retransplantation, particularly because of the shortage of donor organs.- Khush K.K.
- Cherikh W.S.
- Chambers D.C.
- et al.
The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: thirty-fifth adult heart transplantation report-2018; focus theme: multiorgan transplantation.
J Heart Lung Transplant. 2018; 37: 1155-1168
44
, 45
, 46
In a recent meta-analysis of 11 studies including 7446 patients with primary HTx and 345 with retransplantation (mean of 5 years post primary HTx, 35% retransplantation within 30 days of primary HTx), actuarial survival was significantly greater among primary HTx patients: 82% vs 59% at 1 year, 67% vs 41% at 5 years, 54% vs 32% at 10 years for primary and retransplantation, respectively.47
The mortality differences were largely because of greater early mortality of 28% for retransplantation compared with 11% for de novo HTx. Data from the joint ISHLT/United Network for Organ Sharing registries suggested that poor outcomes after retransplantation was associated with shorter time between transplantations, with an interval of < 2 years resulting in < 60% 2-year survival. Furthermore, data from the Cardiac Transplant Research Database showed that survival was lowest among patients who received retransplantation for acute rejection (AR; 32% at 1 year) and early graft failure (50% at 1 year).44
RECOMMENDATION
- 14.We recommend cardiac retransplantation for highly selected patients with severe chronic allograft dysfunction (Strong Recommendation, Moderate-Quality Evidence).
Values and preferences. Retransplantation should be avoided in patients with AR.
Adult congenital heart disease
There are no published evidence-based or consensus guidelines regarding adult congenital heart disease (ACHD) patients and HTx. Prognostication is difficult because most of the data are derived from retrospective single-centre
48
, 49
, 50
, 51
, 52
, 53
, 54
, 55
, 56
, 57
, 58
, 59
or registry-based studies60
, 61
, 62
, 63
, 64
, 65
, 66
, 67
, 68
, 69
, 70
with no randomized trials and only 1 meta-analysis published to date.71
Timing of referral for HTx assessment is difficult because of the lack of robust data correlating any specific factors with outcomes. Thus, the general practice is to consider transplantation for progressive symptoms when alternate management options are no longer effective and/or beneficial.RECOMMENDATION
- 15.We recommend early referral for assessment of HTx in patients with ACHD with progressive cardiac symptoms despite optimal medical, surgical, and interventional therapies (Strong Recommendation, Very Low-Quality Evidence).
Practical tip. ACHD patients should be referred early and followed by transplant and ACHD teams to determine optimal timing for transplant listing. HTx should be considered as a potential management strategy in ACHD patients even when some surgical options might be available.
Anatomic substrate, including systemic right vs left ventricle and single vs biventricular heart has been associated with pretransplantation outcomes.
59
,65
Brain natriuretic peptide (BNP) has been studied but normal and prognostically significant values in ACHD patients with different anatomical considerations are not well defined.52
,58
Serial cardiopulmonary exercise testing might have predictive value, but no thresholds predicting mortality have been defined.53
,54
Response to cardiac resynchronization therapy,55
PH and reversibility,67
and liver disease48
have all been reported to impact pre- and post-HTx outcomes but currently available data do not provide information about survival with or without transplantation, and/or guide listing or listing status decisions.The pretransplantation assessment must consider all factors relevant to a noncongenital patient but also requires input from specialized practitioners on factors unique to this patient population including: sensitization (higher prevalence), PH (different mechanisms requiring expertise to assess), complex anatomy with potential need for nonstandard anastomoses, previous surgeries (eg, reentry risk, vascular access, collaterals), liver disease (eg, cirrhosis, portal hypertension, varices), and Fontan physiology (eg, protein-losing enteropathy, plastic bronchitis, ascites and edema, cyanosis, lymphatic drainage abnormalities, pulmonary arteriovenous malformations). The decision regarding transplant candidacy is on the basis of the cumulative sum of multiple relative risk factors. The complexity of the decision-making, the lack of evidence, and the small, very diverse patient population warrant management at a centre with expertise in ACHD, transplantation, and mechanical circulatory support.
RECOMMENDATION
- 16.We recommend patients with ACHD undergo evaluation and HTx at centres with multidisciplinary expertise in congenital heart disease and transplantation (Strong Recommendation, Low-Quality Evidence).
Values and preferences. Factors unique to patients with ACHD must be considered during HTx assessment.
ACHD patients are disadvantaged in current organ allocation algorithms.
71
,72
They are listed at a lower status,62
,63
,66
less likely to reach criteria for higher status,62
,63
,66
wait longer at any given status,61
,62
,69
have a higher wait list mortality,64
and are less likely to get a transplant.62
,69
They are disadvantaged by the higher priority given to non-ACHD patients supported with a ventricular assist device,63
,72
and lower likelihood of being successfully supported with a ventricular assist device.63
,72
As such, review and revision of listing algorithms and allocation should be undertaken.Ischemic time has been shown to be a risk factor for early mortality in ACHD transplant recipients.
49
,50
Increasing ischemic time is associated with reduced survival, and the probability of death is further increased in the older recipient with an older donor and longer ischemic time.69
ACHD transplant recipients have increased perioperative and early post-transplantation mortality,60
,61
,66
,69
, 70
, 71
due to hemorrhage, renal failure, multisystem organ failure, and primary graft failure.70
,71
However, they have better long-term survival and outcomes because of younger age, fewer comorbidities, and reduced risk for infection.49
,50
,60
,61
,69
, 70
, 71
RECOMMENDATION
- 17.We recommend particular attention be paid to the effect of older donor age and/or longer ischemic time on survival outcomes when considering a donor organ for a patient with ACHD (Strong Recommendation, Moderate-Quality Evidence).
Values and preferences. Because of the high early postoperative mortality but better long-term outcomes in ACHD transplant recipients, there is a need to better define indications and timing of listing, as well as pre-, peri-, and postoperative care needs to reduce perioperative mortality.
Combined solid organ transplantation
Combined organ transplantation volumes have increased over the past several years, but continue to represent a very small proportion of overall HTx. In the 2016 ISHLT registry, heart-kidney transplantation (HKT) and HLivT accounted for approximately 4% of all HTxs, and heart-lung transplantation (HLungT) accounted for < 2% of all lung transplants performed.
6
,- Khush K.K.
- Cherikh W.S.
- Chambers D.C.
- et al.
The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: thirty-fifth adult heart transplantation report-2018; focus theme: multiorgan transplantation.
J Heart Lung Transplant. 2018; 37: 1155-1168
73
Because of the relatively small numbers, data on combined heart-other organ transplantation are primarily derived from single centres and large registries. Despite these limitations, common themes have emerged, namely a more complex perioperative course with longer critical care and hospital length of stays post combined organ transplantation.- Chambers D.C.
- Cherikh W.S.
- Goldfarb S.B.
- et al.
The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: thirty-fifth adult lung and heart-lung transplant report-2018; focus theme: multiorgan transplantation.
J Heart Lung Transplant. 2018; 37: 1169-1183
6
Strikingly, 1-year waitlist mortality is approximately 2-fold higher than for isolated HTx candidates.- Khush K.K.
- Cherikh W.S.
- Chambers D.C.
- et al.
The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: thirty-fifth adult heart transplantation report-2018; focus theme: multiorgan transplantation.
J Heart Lung Transplant. 2018; 37: 1155-1168
74
,75
This suggests combined organ transplantation candidates are disadvantaged in the current organ allocation system, and a need to revise allocation schemes and consider prioritizing access to donor organs.HKT
Most available data regarding HKT reflects simultaneous rather than sequential “kidney after heart” transplantation. Approximately half of all patients who undergo HKT are dialysis-dependent while listed.
74
In this context, large registries of > 1300 HKT candidates suggests that HKT confers a survival benefit over isolated HTx among patients who are dialysis-dependent or who have very low glomerular filtration rate (typically < 30-40 mL/min/1.73 m2) at the time of transplantation.74
,76
Recent ISHLT registry data confirm modestly improved survival for HKT patients and similar incidence of long-term comorbidities compared with heart-alone transplant patients.6
- Khush K.K.
- Cherikh W.S.
- Chambers D.C.
- et al.
The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: thirty-fifth adult heart transplantation report-2018; focus theme: multiorgan transplantation.
J Heart Lung Transplant. 2018; 37: 1155-1168
RECOMMENDATION
- 18.We recommend combined HKT (simultaneous or sequential) be considered to improve survival in HTx candidates with severe renal failure for whom the probability of renal recovery is very low (Strong Recommendation, Moderate-Quality Evidence).
Values and preferences. The decision to list patients for simultaneous HKT vs planned sequential heart followed by kidney transplantation should be individualized and consider several factors, including dialysis dependency before transplantation, centre experience, potential for further recipient sensitization, and anticipated waitlist mortality. There are no universally accepted criteria for listing patients for combined HKT.
HLivT
The common indications for HLivT are advanced HF with cardiac cirrhosis, HF with concomitant noncardiac cirrhosis, or advanced HF with associated liver disease in which the liver is transplanted to avoid ongoing damage to the cardiac allograft. Amyloidosis is the prototypical example of the latter, and remains the most common indication, accounting for 25%-30% of combined HLivT.
77
A consistent observation is that the Model for End-Stage Liver Disease score, which is used to assess severity of liver disease, is generally lower in HLivT than for patients listed for liver alone, and in most cases, cardiac dysfunction is the primary driver of combined organ transplant.77
Data from the United Network for Organ Sharing including nearly 100 HLivT demonstrate excellent liver and cardiac allograft survival and similar to isolated liver or HTx.
77
These findings have been corroborated by a number of single-centre reports and a consistent signal toward reduced incidence of cardiac allograft rejection in patients with HLivT has also been observed.78
Of note, the subgroup of patients with ACHD who undergo HLivT has similar outcomes compared with non-ACHD patients.78
It should be emphasized that observational studies to date have reported on highly selected patients. At present, criteria and candidacy for HLivT are not standardized.RECOMMENDATION
- 19.We suggest combined HLivT be undertaken in highly selected patients with advanced HF who have cardiac or noncardiac cirrhosis or systemic disease for whom simultaneous liver transplantation would be expected to improve cardiac allograft outcomes (Weak Recommendation, Moderate-Quality Evidence).
Fontan-associated liver disease in patients with Fontan circulation is an emerging indication for HLivT. Experience is limited to single centres and small numbers of registry patients. In highly selected patients, outcomes are generally excellent and might be superior to isolated HTx in Fontan patients whose mortality exceeds 15%-25% in some series.
79
RECOMMENDATION
- 20.We recommend patients with failing Fontan circulation and severe Fontan-associated liver disease should be referred to experienced centres for evaluation for isolated heart or combined HLivT (Strong Recommendation, Very Low-Quality Evidence).
HLungT
The main indications for HLungT are Eisenmenger physiology or idiopathic pulmonary arterial hypertension with severe cardiac dysfunction. Median survival is approximately 5.8 years and similar to lung-alone transplantation,
73
however, this improves to 11.5 years among patients who survive beyond the first year after transplantation. Functional status post HLungT is generally excellent and greater freedom from cardiac rejection and CAV have been observed in this population. Bronchiolitis obliterans syndrome remains the leading cause of death in HLungT transplantation patients and occurs in approximately a third of patients 5 years post transplantation.- Chambers D.C.
- Cherikh W.S.
- Goldfarb S.B.
- et al.
The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: thirty-fifth adult lung and heart-lung transplant report-2018; focus theme: multiorgan transplantation.
J Heart Lung Transplant. 2018; 37: 1169-1183
73
- Chambers D.C.
- Cherikh W.S.
- Goldfarb S.B.
- et al.
The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: thirty-fifth adult lung and heart-lung transplant report-2018; focus theme: multiorgan transplantation.
J Heart Lung Transplant. 2018; 37: 1169-1183
RECOMMENDATION
- 21.We recommend patients being considered for simultaneous HLungT be referred to centres experienced in evaluation, surgical management, and postoperative care of HLungT recipients (Strong Recommendation, Low-Quality Evidence).
Values and preferences. This recommendation reflects the low number of HLungTs performed in Canada each year, and the need to balance high up-front perioperative risks with excellent long-term conditional survival.
Highly sensitized
The percentage calculated panel reactive antibody (cPRA) is an estimate of the proportion of organ donors with whom an HTx candidate might be incompatible on the basis of detectable antibodies against human leukocyte antigen (HLA) in the serum. Sensitization, measured according to elevated cPRA, is well recognized to be associated with adverse outcomes in HTx. Management strategies for a sensitized HTx candidate include desensitization, avoidance of donor-specific antibody (DSA) using virtual cross-matching, or a combination of the 2 approaches. In Canada, the current approach favours primarily avoiding DSA using the virtual cross-match and status 4S listing, whereby highly sensitized patients with cPRA > 80% have national access to organs and are second in priority only to highest urgency status 4 patients. The 4S status listing does not preclude desensitization therapy or mandate inclusion of all detected antibodies because of the complexity and variability in assessing antibody-specific immunologic risk. The status 4S system has shown effective expansion of the donor pool with satisfactory post-transplantation outcomes.
80
Revision of the 4S listing status category will yield a change to give ranking priority to the highest cPRA in descending fashion; cPRA 100% higher priority than 99%, followed by 98%, 90%-97%, and 80%-89% (Supplemental Tables S1 and S2).RECOMMENDATION
- 22.We recommend using the cPRA calculator in the Canadian Transplant Registry for determination of cPRA (Strong Recommendation, High-Quality Evidence).
Practical tip. HLA antibody assessment and reporting are standardized across Canadian HLA laboratories. The Canadian cPRA calculator includes all loci including DQA1, DPA1, and DPAB1 (https://ctr2.transplantregistry.ca/otd-cpra-client/ctr2.jsp).
RECOMMENDATION
- 23.We recommend collaborative consultation with the HLA laboratory to fully characterize immunologic risk of identified HLA antibodies in HTx candidates (Strong Recommendation, Moderate-Quality Evidence).
Values and preferences. Defining immunologic risk involves considerations beyond HLA antibody median fluorescence intensity. Collaborative consultation with histocompatibility laboratory specialists is recommended to determine the significance of the detected antibody and if further antibody characterization is warranted.
Desensitization therapies have evolved over the past 15 years (Table 2). However, the optimal strategy to improve immunologic and long-term outcomes remains unclear, because most studies have been of low quality with small patient numbers and with short follow-up.
81
, 82
, 83
Intravenous immune globulin (IVIG), targeted B cell (rituximab), and plasma cell therapies (bortezomib) form the foundation of desensitization treatments. Plasmapheresis and immunoadsorption treatments involve mechanical filtration of antibodies. Because of rebound effects, these can be effective in the short term, but adjunctive therapies are required for definitive control. There is limited experience with the complement inhibitor eculizumab.84
Existing data on the efficacy of desensitization are primarily extrapolated from renal literature. Strategies involving IVIG and rituximab have increased transplantation rates, reduced wait list time, and reported graft outcomes similar to those of nonsensitized patients.85
, 86
, 87
, 88
To our knowledge, there are no randomized trials on efficacy of desensitization therapy in HTx. Single-centre experiences in HTx have shown comparable short-term outcomes with varying combinations of IVIG, rituximab, bortezomib, plasmapheresis, and immunoadsorption compared with patients who receive a transplant with no DSA.82
,89
, 90
, 91
, 92
In addition, a strategy of intra and post-operative desensitization therapy involving plasmapheresis, IVIG and thymoglobulin (ATG) induction has been reported to have satisfactory short-term outcomes in highly sensitized HTx patients transplanted across DSA.93
RECOMMENDATION
- 24.We suggest consideration of desensitization therapies to facilitate transplantation and improve short-term transplantation-specific outcomes in highly sensitized populations such as patients with cPRA 50%-79% and previous positive virtual crossmatches; patients in urgent need of transplantation (status 4); and patients with very high cPRA listed status “S” (Weak Recommendation, Moderate-Quality Evidence).
Values and preferences. Most pretransplantation desensitization protocols include IVIG 2 g/kg divided over 2 days (and continued monthly) with the additional use of rituximab in either a single 375 mg/m2 or 1 g dose. Effective B-cell depletion can be assessed by measuring lymphocyte cell subsets 2 days post administration with target CD19 < 2%. If there is no reduction in antibody after 3 months, alternative therapies such as bortezomib and eculizumab may be considered. Concurrent plasmapheresis may be reserved for short-term antibody depletion peri-, intra-, and postoperatively.
Table 2Desensitization agents
| Agent | Mechanism of action | Dosing | Complications |
|---|---|---|---|
| PLEX | Extracorporeal plasma antibody filtration
| 1-2 volume exchange per cycle
| Access/line-related complications: bleeding, hypotension, allergic reactions; infection |
| IVIG | Pooled immunoglobulin G antibodies (human blood donors) Immunomodulatory effects:
| If given with PLEX: 0.1 g/kg after each cycle and 2g/kg over 2 days after the final cycle If given without PLEX: 2g/kg over 2 days every 2-4 weeks
| Infusion reactions, hemolysis, venous thromboembolism, renal insufficiency, volume overload, hypertension |
| Rituximab | Monoclonal antibody with targeted B-cell CD20 inhibition
| 1 g single dose or 375 mg/m2
| Infusion reactions, fever, hypotension, edema, nausea, anemia, myalgia |
| Bortezomib | Proteasome inhibitor; selectively depletes plasma cells
| 1.3 mg/m2 | Neuropathy, thrombocytopenia, neutropenia |
| Eculizumab | Complement C5 inhibitor; monoclonal antibody binds C4 and prevents cleavage into C5a/b, preventing formation of membrane attack complex |
| Meningococcal infection |
IVIG, intravenous immune globulin; PLEX, plasmapheresis.
Practical tip. Desensitization decisions are made on an individual basis and should take into consideration patient- and institution-specific factors. Patient-specific risks include infection, renal function and risk of deterioration, HF status, and personal preferences. Institution-specific factors include accessibility of organs, and historical wait times.
Organ Allocation
Please see the Supplemental Material for information on Canadian heart organ allocation (Supplemental Tables S1 and S2) and current matching and allocation policies for interprovincial sharing of high-status hearts (Supplemental Appendices S1-S5).
Post-Transplantation Management
Maintenance immunosuppression
Maintenance immunosuppression refers to the period following induction therapy post HTx. Most patients are maintained with a combination of 2-3 different class agents: CNIs, antimetabolites, corticosteroids, and proliferation signal inhibitors (PSIs). CNIs form the mainstay of immunotherapy. Several trials have evaluated CNI-free regimens, and have shown prevention of deterioration in renal function but at the cost of increased risk of rejection.
94
,95
Importantly, improvement in renal function after conversion to a CNI-free regimen is less likely in patients with advanced chronic kidney disease.94
,96
Small randomized trials and 2 meta-analyses that compared CNI tacrolimus and cyclosporin showed lower rejection risk for tacrolimus and a more favourable side effect profile.97
Tacrolimus is available in immediate and extended release formulations with the immediate release formulation best studied in HTx. The 2 formulations were compared in 2 small trials no significant differences in rejection, infection, or adverse events were observed.98
Mycophenolic acid is the preferred antimetabolite post HTx and has been shown to be superior to azathioprine. In one small randomized trial mycophenolate mofetil and enteric-coated mycophenolate-sodium were compared in HTx recipients and showed no difference in outcomes including rejection, graft loss, and death.
99
- Kobashigawa J.A.
- Renlund D.G.
- Gerosa G.
- et al.
Similar efficacy and safety of enteric-coated mycophenolate sodium (EC-MPS, myfortic) compared with mycophenolate mofetil (MMF) in de novo heart transplant recipients: results of a 12-month, single-blind, randomized, parallel-group, multicenter study.
J Heart Lung Transplant. 2006; 25: 935-941
RECOMMENDATION
- 25.We recommend a CNI and mycophenolic acid-based immunosuppression regimen after HTx for most patients (Strong Recommendation, Moderate-Quality Evidence).
Values and preferences. A CNI-free regimen is associated with increased risk of rejection, but might be justified in selected patients, particularly individuals with renal dysfunction.
- 26.We recommend tacrolimus over cyclosporin as the preferred CNI (Strong Recommendation, Low-Quality Evidence).
Values and preferences. Compared with cyclosporin, tacrolimus provides superior protection against rejection and has a more favourable side effect profile than cyclosporin.
The PSI sirolimus and everolimus have not been directly compared. Currently, everolimus is not approved in Canada for post-HTx immunosuppression. De novo treatment with PSI has been shown to reduce the development and progression of CAV and is associated with lower incidence of cytomegalovirus infection.
100
, 101
, 102
A PSI-based regimen can also facilitate CNI withdrawal to preserve renal function. Early post-transplantation PSI use has been associated with increased rejection in CNI-free regimens, pericardial effusions, wound healing problems, and infection. Similar survival and rejection rates have been observed in trials in which PSI and CNI have been compared vs CNI and mycophenolate mofetil. However, PSI has a lower tolerability profile with approximately twice as many patients needing to discontinue treatment because of adverse effects.RECOMMENDATION
- 27.We recommend treatment with PSI to delay CAV progression and/or enable CNI withdrawal/minimization to preserve renal function in selected patients (Strong Recommendation, Moderate-Quality Evidence).
Values and preferences. Immunosuppression regimens should be individualized, balancing the risk of rejection, CAV, and cytomegalovirus infection with the adverse effects profile of each immunotherapy.
PSIs have intrinsic antitumour activity and have been successfully used as a therapy for cancer. Several studies in noncardiac solid organ transplantation have suggested a malignancy risk reduction in patients who receive PSIs.
103
,104
The ongoing A Secondary Prevention Study of Skin Cancers in Heart Transplant Patients. Everolimus Versus Calcineurin Inhibitors Multicenter Trial (CERTICOEUR) trial (NCT00799188), in which everolimus is being compared with CNI in HTx recipients with skin cancer, is the only randomized trial examining cancer reduction with PSI use in the HTx population. Most published trials that have compared PSIs with other immunotherapy did not include malignancy as an outcome or had a short follow-up time. However, retrospective studies suggest a reduction in cutaneous and noncutaneous malignancies in patients treated with a PSI, with either reduced-dose CNIs or a CNI-free regimen.103
,105
, 106
, 107
RECOMMENDATION
- 28.We suggest reducing maintenance immunotherapy and including a PSI in patients diagnosed with cancer after HTx (Weak Recommendation, Low-Quality Evidence).
Early weaning or low-dose maintenance corticosteroid therapy are both acceptable post-HTx with paucity of data to favour any single approach. However, in most recent trials of immunosuppression, corticosteroids are weaned 6-12 months post HTx.
108
Corticosteroid regimens should be individualized according to the patient’s risk of rejection and adverse effects.RECOMMENDATION
- 29.We suggest weaning corticosteroids within 1-year post HTx for most patients (Weak Recommendation, Low-Quality Evidence).
Rejection surveillance
Endomyocardial biopsy
Endomyocardial biopsy remains the standard for AR surveillance post HTx despite its weak reliability.
109
Moreover, routine surveillance endomyocardial biopsy beyond the first year has poor clinical utility and is not cost effective.110
The molecular microscope platform (MMDx) has shown promise in improving the diagnostic accuracy and utility of endomyocardial biopsy for detecting acute cellular rejection, antibody-mediated rejection, and other injury patterns through molecular phenotyping. The ongoing INTERHEART study (NCT02670408) should provide further insight.111
RECOMMENDATION
- 30.We recommend routine surveillance endomyocardial biopsy for 6-12 months post HTx (Strong Recommendation, Moderate-Quality Evidence).
Noninvasive surveillance strategies
Studies have shown that BNP or N-terminal proBNP are associated with biopsy rejection scores after 6 months post HTx,
112
although some inconsistencies exist.113
High-sensitivity cardiac troponin might help rule out significant rejection.114
Echocardiographic tissue Doppler and strain imaging parameters, especially speckle tracking, have shown promise for AR monitoring. Clinical implementation is problematic because of the lack of validated cutoff values and the unclear reliability early post HTx.115
Cardiac magnetic resonance imaging parameters, especially T2 relaxation times, have good sensitivity and specificity in detecting AR beyond 6 months.116
The ongoing Detection of Acute Graft Rejection in Heart Transplant Patients by Estimation of T2 (Détection des Rejets Aigus de Greffe par Evaluation du T2 [DRAGET]) study (NCT02261870) is evaluating the utility of cardiac magnetic resonance imaging for detecting AR in the first year post HTx.117
Gene expression profiling from peripheral blood polynuclear cells has good negative predictive value for cellular rejection in low-risk patients beyond 6 months post HTx.- Bonnemains L.
- Cherifi A.
- Girerd N.
- Odille F.
- Felblinger J.
Design of the DRAGET study: a multicentre controlled diagnostic study to assess the detection of acute rejection in patients with heart transplant by means of T2 quantification with MRI in comparison to myocardial biopsies.
BMJ Open. 2015; 5e008963
118
Although a small study showed no adverse outcomes when gene expression profiling is used early, starting at 55 days, evidence for use in the early phase is lacking.119
Circulating donor-derived cell-free DNA measurements in patients post HTx appears to correlate with acute cellular rejection or antibody-mediated rejection, especially after 4 months post HTx.120
A larger study including patients from 55 days to 5 years showed weaker correlation but still showed good negative predictive value.121
MicroRNAs have been shown to differentiate rejection and nonrejection states.122
However, in these small studies, their expression varied depending on type of rejection and tissue.123
RECOMMENDATION
- 31.We suggest using gene expression profiling as an alternative initial surveillance strategy in low-risk patients beyond 6 months post HTx (Weak Recommendation, Moderate-Quality Evidence).
- 32.We do not recommend circulating donor-derived cell-free DNA or microRNA testing as an alternative initial surveillance strategy for acute cellular rejection (Strong Recommendation, Moderate-Quality Evidence).
Values and preferences. Cardiac magnetic resonance imaging is safe and has very good resolution for structural and functional changes. However, the equipment and necessary expertise for this test are not broadly available. The lack of wide availability in Canada and relatively high expense of the currently available gene expression profiling platform (AlloMap; CareDx, Inc) might be an obstacle to its utility.
Rejection diagnosis and treatment
Pathological-based diagnosis of rejection using endomyocardial biopsy remains the gold standard (Supplemental Tables S3 and S4). Endomyocardial biopsy is performed for routine surveillance and when there is clinical suspicion of rejection. Rejection is classified as hyperacute, acute cellular rejection, or antibody-mediated rejection. Hyperacute rejection is usually fatal, occurring because of the presence of preformed anti-HLA class I antibodies against the donor. Routine performance of donor-recipient cross-matching at the time of transplantation has almost eliminated hyperacute rejection. Acute cellular rejection remains common in the first 3-6 months post HTx, occurring in 24% of HTx recipients. Approximately 13% will have significant acute cellular rejection in the first year post HTx to warrant treatment.
124
Antibody-mediated rejection is less common, affecting 10%-20% of HTx recipients.125
Patients with either preformed or de novo anti-HLA antibodies are at increased risk of antibody-mediated rejection. Graft dysfunction is common with antibody-mediated rejection, accompanying up to two-thirds of early post HTx and 10%-15% of late antibody-mediated rejection episodes.126
Recommendation
- 33.We recommend standardized endomyocardial biopsy reporting of rejection according to the ISHLT grading for cellular and antibody-mediated rejection. (Strong Recommendation, Moderate-Quality Evidence).
Practical tip. Most rejection episodes are asymptomatic.
Treatment of rejection depends on the pathological severity, symptoms, allograft function, and timing post transplantation. Most patients with moderate ISHLT grade ≥ 2R cellular rejection are asymptomatic with normal hemodynamics, and can be treated with oral pulsed corticosteroids.
127
Symptomatic patients with ISHLT grade 2R or patients with 3R cellular rejection should be treated with intravenous pulsed corticosteroids. Patients with acute cellular rejection and hemodynamic compromise should be treated aggressively with pulse intravenous corticosteroids and thymoglobulin. Repeat endomyocardial biopsy is usually performed 7-14 days after treatment.Treatment of antibody-mediated rejection is directed at removal of circulating antibodies and decreasing antibody production. Most treatment protocols use a combination of corticosteroids, plasmapheresis, and IVIG.
128
, 129
, 130
Newer, B-lymphocyte (rituximab)- and plasma cell (bortezomib)-depleting therapies have been used with variable reported success. Follow-up endomyocardial biopsy should be delayed for 2-4 weeks because of the delayed clearance of C4d stains. Additionally, after treating an episode of rejection, maintenance immunosuppression should be optimized, and graft function monitored.RECOMMENDATION
- 34.We recommend oral pulsed corticosteroids for treatment of asymptomatic ISHLT 2R cellular rejection (Strong Recommendation, Low-Quality Evidence).
- 35.We recommend intravenous pulsed corticosteroids for treatment of ISHLT 3R or symptomatic ISHLT 2R cellular rejection (Strong Recommendation, Low-Quality Evidence).
- 36.We recommend thymoglobulin therapy for ISHLT 3R or 2R cellular rejection in the presence of graft dysfunction and/or hemodynamic compromise (Strong Recommendation, Low-Quality Evidence).
- 37.We recommend performing follow-up endomyocardial biopsy > 7-14 days after treatment of rejection (Strong Recommendation, Low-Quality Evidence).
- 38.We suggest treatment of antibody-mediated rejection for ISHLT pathologic antibody mediated rejection (pAMR) ≥ 2 or pAMR 1 with graft dysfunction and/or symptoms (Weak Recommendation, Low-Quality Evidence).
- 39.We suggest treatment for antibody-mediated rejection include a combination of intravenous pulsed corticosteroids, plasmapheresis, IVIG and/or thymoglobulin (Weak Recommendation, Low-Quality Evidence).
- 40.We suggest consideration of adjunctive rituximab and/or bortezomib for treatment of antibody-mediated rejection (Weak Recommendation, Low-Quality Evidence).
HLA-antibody/DSA monitoring and management
The prevalence of DSA post HTx ranges between 15% and 33%.
131
Although DSA is associated with rejection, CAV, graft dysfunction, and mortality, post transplantation DSA monitoring and treatment in stable grafts have not been proven to improve outcomes.132
Moreover, available treatments are costly and not benign. Additionally, evaluation for rejection, graft function, and CAV are important to determine the effect of DSA (Fig. 1). In general, early antibody-mediated rejection is more responsive to treatment and therefore, testing in the early postoperative period is recommended for patients with increased immune risk such as those with known DSA at the time of transplantation or a history of sensitizing events.133
Monitoring for DSA at later time points and in otherwise stable low immune risk recipients is more controversial.RECOMMENDATION
- 41.We recommend routine post HTx DSA testing if DSA has been crossed at the time of transplantation (Strong Recommendation, High-Quality Evidence).
- 42.We suggest post HTx DSA testing in stable recipients without DSA before transplantation (Weak Recommendation, Low-Quality Evidence).
Values and preferences. Patients with preformed DSA are at risk of an amnestic response and resulting high levels of DSA with increased risk for rejection and graft dysfunction. Detection of de novo DSA identifies increased-risk individuals but many patients remain stable and it is unknown whether intervention for DSA changes outcomes.
Figure 1Post transplantation de novo donor-specific antibody (DSA) management. Routine surveillance of DSA is suggested at week 1 and 2, months 1, 3, 6, 9, and 12, followed by annually post transplantation. Patients with newly detected DSA post transplantation should be evaluated for clinical symptoms, evidence of allograft dysfunction, and rejection. Antibody-mediated rejection (AMR) should be treated if detected on endomyocardial biopsy. All patients with DSA should have optimization of maintenance immunosuppression and increased clinical surveillance (2 assessments of graft function 1-3 months apart).
31551-X&id=gr1.jpg){kind=link}
Practical tip. Suggested frequency of DSA testing in stable grafts is at week 1 and 2, months 1, 3, 6, 9, and 12, followed by annually post transplantation.
RECOMMENDATION
- 43.We recommend de novo DSA be confirmed within 2-3 months post detection (Strong Recommendation, Moderate-Quality Evidence).
- 44.We suggest assessment for rejection, graft function, and CAV if DSA is persistent (Weak Recommendation, Moderate-Quality Evidence).
Values and preferences. The measurement of antibody median fluorescence intensity level has some correlation with outcomes and might guide response to treatment. Median fluorescence intensity alone is not ideal and additional assays including titers, complement fixing assays, and immunoglobulin G subclasses are often performed to identify antibodies that might pose a greater risk. Lower level DSAs are still associated with inferior outcomes and multiple weak antibodies to the same target might bind complement in vivo although the assay might be negative.
Practical tip. If additional information is required for clinical care, consultation with the histocompatibility laboratory team is recommended to determine if further testing is indicated.
RECOMMENDATION
- 45.We suggest optimization of maintenance immunosuppression if DSA is detected (Weak Recommendation, Low-Quality Evidence).
- 46.We recommend treatment of DSA if there is evidence of antibody-mediated rejection or graft dysfunction (Strong Recommendation, Moderate-Quality Evidence).
Values and preferences. No evidence exists to guide management of DSA, but at a minimum, review and optimization of immunosuppression is warranted. If there is rejection, immunomodulating agents should be added. The presence of CAV might prompt conversion/additional use of PSIs. Because of the poor prognosis associated with graft dysfunction and DSA, many would elect to treat despite the lack of evidence.
CAV
CAV is prevalent and a major determinant of long-term survival after HTx; surveillance and prevention are the cornerstone of management.
6
Imaging evaluation is a challenge because of preserved coronary calibre in early disease and diffuse epicardial and microvascular involvement. Up to 5 years post transplantation, annual invasive coronary angiography and intravascular ultrasound are preferred to diagnose early-stage CAV, and detect donor atherosclerosis and rapidly progressive CAV (intravascular ultrasound maximal intimal thickness ≥ 0.5 mm increase in first transplantation year), which are predictive of cardiac events and disease progression.- Khush K.K.
- Cherikh W.S.
- Chambers D.C.
- et al.
The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: thirty-fifth adult heart transplantation report-2018; focus theme: multiorgan transplantation.
J Heart Lung Transplant. 2018; 37: 1155-1168
134
,135
High-resolution optical coherence tomography improves evaluation of intimal hyperplasia and plaque composition. Intracoronary flow measures of microvascular endothelial dysfunction such as coronary flow reserve and index of microcirculatory resistance are predictors of CAV and cardiovascular outcomes.136
,137
Prospective studies are needed to define the role of optical coherence tomography and intracoronary flow in CAV screening. There is no established robust noninvasive technique for CAV surveillance. Commonly used stress echocardiography and radionuclide perfusion imaging have modest accuracy for angiographic CAV but high negative predictive value for adverse cardiac events.138
,139
Computed tomography coronary angiography has high sensitivity, specificity, and negative predictive value for > 50% angiographic stenosis but reduced sensitivity compared with intravascular ultrasound.140
Myocardial blood flow quantification using positron emission tomography has good diagnostic accuracy for CAV but is less widely available.141
,142
RECOMMENDATION
- 47.We recommend invasive coronary angiography and intravascular ultrasound for CAV surveillance up to 5 years post transplantation (Strong Recommendation, Moderate-Quality Evidence).
- 48.We suggest invasive coronary angiography and intravascular ultrasound at 6-12 weeks post transplantation to detect donor atherosclerotic disease and rapidly progressive CAV (Weak Recommendation, Moderate-Quality Evidence).
Values and preferences. Screening for CAV is typically performed annually, individualized to donor and recipient characteristics. An invasive strategy with intracoronary imaging to visualize the vessel wall is preferred early post transplantation to improve sensitivity for detecting early CAV and for prognostication but is expensive and not widely available. Patients with kidney disease should undergo less frequent invasive angiography. A noninvasive strategy is preferred in the long term post transplantation with the choice of testing according to institutional expertise and preference. This considers the high prevalence of CAV with increasing time from transplantation as well as reduced accuracy of commonly available noninvasive tests.
Statins and PSIs reduce the incidence of CAV.
101
,143
,144
Other pharmacologic treatments suggested to reduce CAV development include calcium antagonists, angiotensin converting enzyme inhibitors, and aspirin.145
,146
In randomized controlled studies, de novo PSI treatment with CNI reduction or withdrawal decreased plaque progression.101
,144
Attenuation of CAV progression is greater when PSIs are initiated early, < 2 years post transplantation.147
,148
For patients with established CAV, percutaneous coronary intervention is effective, with drug eluting stents reducing stent restenosis but not improving survival.149
Retransplantation is often the only option in advanced CAV but reserved for patients with advanced disease with allograft dysfunction (Fig. 2).150
RECOMMENDATION
- 49.We recommend aggressive management of cardiovascular risk factors including hypertension, diabetes, and hyperlipidemia for prevention of CAV (Strong Recommendation, Low-Quality Evidence).
- 50.We recommend a statin regardless of serum lipid levels (Strong Recommendation, High-Quality Evidence).
- 51.We suggest angiotensin converting enzyme inhibitor or calcium channel blocker as first-line therapies for hypertension because of possible benefits of reducing CAV (Weak Recommendation, Low-Quality Evidence).
- 52.We suggest aspirin for prevention of CAV (Weak Recommendation, Low-Quality Evidence).
- 53.We recommend PSIs for prevention and treatment of CAV in patients < 5 years post transplantation (Strong Recommendation, High-Quality Evidence).
Values and preferences. Most de novo PSI studies used everolimus, which is not available in Canada. Available evidence supports early institution of PSIs with late treatment less effective for attenuating progression of CAV.
- 54.We suggest suitable patients with CAV undergo percutaneous revascularization, and retransplantation be considered for severe CAV and allograft dysfunction (Weak Recommendation, Moderate-Quality Evidence).
Figure 2Cardiac allograft vasculopathy (CAV) surveillance and management. Invasive coronary angiography and intravascular ultrasound are suggested at 6-12 weeks post transplantation to detect donor disease and recommended at 1 year and up to 5 years post transplantation to detect early CAV. Beyond 5 years, annual noninvasive imaging according to institutional preference can guide the need for invasive testing. Preventive therapy for CAV are initiated immediately post transplantation, and include statin, proliferation signal inhibitor (PSI), and aggressive risk factor management. Treatments for CAV include conversion to PSI to delay progression of disease, particularly for early CAV < 5 years post transplantation; percutaneous coronary intervention for focal obstructive disease; and retransplantation in selected patients with severe CAV and associated allograft dysfunction.
31551-X&id=gr2.jpg){kind=link}
Long-term noncardiac care post HTx
Long-term noncardiac care post HTx is briefly summarized in Table 3, including de novo malignancies, vascular disease, and infection monitoring.
Table 3Post heart transplantation noncardiac surveillance
| Recommended screening | Test | Interval | Comment | |
|---|---|---|---|---|
| De novo malignancies | ||||
| Breast cancer | General population screening | Mammogram | Every 2 years | Women age 54-75 years |
| Cervical cancer | General population screening | Pap smear | Every 3 years | Women age 21-69 years |
| Prostate cancer | Not recommended | |||
| Colon cancer | General population screening | Fecal occult blood test | Every 2 years | Men and women age 50-74 years |
| Skin cancer | High-risk population screening | Skin check | Every year | Increase screening frequency for high risk: skin type, high sun exposure, history of skin cancer |
| Vascular disease | ||||
| CVD and PVD | Not recommended | |||
| Infection monitoring | ||||
| CMV | High-risk population screening | CMV QNAT | Weekly for 12 weeks | After completion of universal prophylaxis |
| EBV | Not recommended | |||
| PJP | Not recommended | |||
CMV, cytomegalovirus; CVD, cerebrovascular disease; EBV, Epstein Barr virus; PJP, Pneumocystis jirovecii pneumonia; PVD, peripheral vascular disease; QNAT, quantitative nucleic acid amplification testing.
De novo malignancies
Compared with the general population, HTx patients are at a 2- to 4-fold higher risk of malignancy, and de novo malignancy is the leading cause of mortality beyond 3 years post transplantation, accounting for 7.8% of deaths after 5 years.
151
, 152
, 153
The 2018 ISHLT registry showed increasing trends in the cumulative incidence of de novo malignancies after HTx.153
Skin, post transplantation lymphoproliferative disorders (PTLD), and prostate and lung cancers are the most common causes of de novo malignancies after HTx.153
,154
Risk factors associated with de novo malignancies include older age at the time of transplantation, male sex, and aggressive immunosuppressive therapy. There are limited data to guide recommendations for malignancy screening post HTx.105
,155
RECOMMENDATION
- 55.We recommend that general population screening for breast, cervical, colon, and prostate cancer be applied to HTx recipients (Strong Recommendation, Low-Quality Evidence).
Values and preferences. There is no evidence to support reduction of immunosuppression in patients with nonlymphoid solid tumours, however, use of maintenance immunosuppression should be minimized.
Skin malignancy
Early detection of skin cancer can facilitate early removal that might in turn improve the post diagnosis survival among transplant recipients.
156
Annual skin cancer screening is recommended, with increased surveillance frequency guided by individual risk.153
,157
,158
RECOMMENDATION
- 56.We recommend HTx recipients have annual skin cancer surveillance by a family physician or a specialist (Strong Recommendation, Low-Quality Evidence).
PTLD
HTx patients who have received induction therapy or high-dose immunosuppression, those with Epstein-Barr virus donor-recipient mismatch are at higher risk of PTLD.
159
PTLD has a mortality rate of up to 70% within the first year of diagnosis.160
Early diagnosis is key to improving survival. Preventative strategies including recommendations on screening are lacking. Furthermore, there is equipoise surrounding whether an immunosuppression reduction reduces PTLD incidence and improves prognosis.161
Treatment for PTLD has traditionally included reduction of immunosuppression and in the contemporary era anti-CD20 rituximab-based regimens.161
RECOMMENDATION
- 57.We do not recommend routine PTLD screening for asymptomatic HTx recipients (Strong Recommendation, Low-Quality Evidence).
Vascular complications
HTx patients are at risk of accelerated vascular disease due to adverse effects of immunosuppressive therapy in combination with coexistent vascular risk factors.
162
Cerebrovascular complications occur in 5%-11% of patients after HTx.163
, 164
, 165
Ischemic stroke is the most common cause, accounting for 60% of cerebrovascular complications. Approximately 20% of cerebrovascular complications occur in the immediate postoperative period within 2 weeks of HTx.164
,166
Previous stroke is the key risk factor associated with increased risk of cerebrovascular complications post HTx.167
Peripheral vascular disease occurs in 10% of HTx patients.164
Patients with symptomatic peripheral vascular disease before HTx have a lower survival rate compared with patients without peripheral vascular disease; 1-, 5-, and 10-year survival rates are 91.5% vs 94.9%, 74.8% vs 82.6%, 48.6% vs 54.7%, respectively.168
Furthermore, the prevalence of abdominal aortic aneurysm is reported at 2%-10%, with rupture rates of 11%-38%.169
The role of vascular screening post HTx in asymptomatic patients is unclear.170
Targeting modifiable risk factors including hypertension, diabetes, hyperlipidemia, smoking and alcohol cessation are important for reducing vascular complications.171
RECOMMENDATION
- 58.We recommend aggressive risk factor management, including optimizing blood pressure, serum lipid level, and glucose as well as smoking and alcohol cessation (Strong Recommendation, Low-Quality Evidence).
Infection monitoring after HTx
Infectious complications are a major cause of death, accounting for 14% of deaths during the initial 3 years and 11% thereafter.
153
Cytomegalovirus infection
Cytomegalovirus infections account for 1% of deaths and approximately 3% of infectious complication-related death within 1 year after HTx.
6
Universal cytomegalovirus prophylaxis in high-risk recipients using valganciclovir or ganciclovir post HTx for 3-6 months significantly reduces the risk of cytomegalovirus disease.- Khush K.K.
- Cherikh W.S.
- Chambers D.C.
- et al.
The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: thirty-fifth adult heart transplantation report-2018; focus theme: multiorgan transplantation.
J Heart Lung Transplant. 2018; 37: 1155-1168
153
,172
,173
Patients at high risk of cytomegalovirus infection include donor-positive (D+) and recipient-negative (R−) serostatus and higher levels of immunosuppression, particularly those receiving antilymphocyte depleting induction. Surveillance with cytomegalovirus quantitative nucleic acid testing should be undertaken after completion of universal prophylaxis and should be used to guide the need for preemptive therapy.173
, 174
, 175
Either prophylaxis or preemptive therapy can be used to prevent cytomegalovirus infection in intermediate-risk patients (R+ without lymphocyte-depleting induction).153
,173
RECOMMENDATION
- 59.We recommend universal cytomegalovirus prophylaxis for high-risk patients (ie, D+/R− and R+ receiving lymphocyte-depleting induction) using valganciclovir post HTx for 3-6 months. Cytomegalovirus prophylaxis for D−/R− is not recommended (Strong Recommendation, Moderate-Quality Evidence).
- 60.We recommend universal cytomegalovirus prophylaxis or preemptive therapy for intermediate-risk patients (R+ not receiving lymphocyte depletion therapy) using valganciclovir post HTx for 3 months (Strong Recommendation, Moderate-Quality Evidence).
- 61.We recommend weekly cytomegalovirus quantitative nucleic acid testing for 12 weeks after universal prophylaxis. A preemptive treatment approach should be adopted for viral load past institutional-defined threshold levels (Strong Recommendation, Low-Quality Evidence).
Epstein-Barr virus infection
There is no clear evidence supporting universal Epstein-Barr virus polymerase chain reaction monitoring post HTx. However, monitoring might benefit high-risk Epstein-Barr virus D+ and R− patients. An increasing Epstein-Barr virus polymerase chain reaction in this patient population identifies patients at risk of PTLD.
Pneumocystis jirovecii pneumonia infection
P jirovecii pneumonia infection occurs in 2%-10% of HTx patients, and is associated with poor survival.
176
, 177
, 178
Universal prophylaxis, using trimethoprim-sulfamethoxazole for 1 year reduced the incidence of P jirovecii pneumonia and related mortality by 85% and 83%, respectively.179
No differences in incidence, mortality, or adverse events have been shown for daily vs thrice-weekly prophylaxis.179
The highest risk of P jirovecii pneumonia is during the initial 6 months post transplantation. Because of the low < 0.6% incidence of P jirovecii pneumonia during the second year, universal prophylaxis is typically limited to 1 year.176
,179
RECOMMENDATION
- 62.We recommend universal P jirovecii pneumonia prophylaxis with trimethoprim-sulfamethoxazole for 1 year minimum after HTx (Strong Recommendation, Moderate-Quality Evidence).
Practical tip. Patients with a contraindication to trimethoprim-sulfamethoxazole such as sulfa allergy may be treated with dapsone, pentamidine, or atovaquone.
Psychosocial depression, family caregiver burden
Recipients
HTx recipients and their caregivers experience a range of mental health problems post transplantation. There is little evidence to guide practitioners in their care and much of the literature is > 10 years old. Depression and anxiety are the most common psychiatric disorders post transplantation. There is evidence that depression is an independent risk factor for long-term outcome,
180
,181
but no studies have examined the effect of treating depression on mortality. There is increasing interest in post-traumatic stress disorder secondary to transplantation.182
RECOMMENDATION
- 63.We recommend HTx recipients be asked about mental health symptoms and substance use as part of standard follow-up visits (Strong Recommendation, Moderate-Quality Evidence).
- 64.We recommend HTx recipients describing mental health or addiction symptoms be referred for further evaluation and treatment (Strong Recommendation, Moderate-Quality Evidence).
Values and preferences. Optimizing quality of life and reducing morbidity and mortality is the focus of post transplantation care. Identifying and then managing mental health and addiction symptoms is integral to this goal.
Caregivers
Caregivers of HTx recipients are vulnerable to the development of depressive, anxiety, and post-traumatic stress disorders
181
as well as declining physical functioning and increased pain.183
Caregiver general health is a significant, independent predictor of patients’ mortality risk.183
RECOMMENDATION
- 65.We recommend caregivers of potential HTx recipients be made aware of the potential effect on their own health and encouraged to obtain professional support to optimize their own health (Strong Recommendation, Moderate-Quality Evidence).
Values and preferences. Caregiver support is essential to optimal post transplantation recipient outcomes.
Acknowledgements
The authors acknowledge Dr Rohan Sanjanwala, Janet Rothney, and Katie McLean for their contribution and support during the literature search and review process.
Supplementary Material
- Supplemental Material
References
- 2001 Canadian Cardiovascular Society consensus conference on cardiac transplantation.Can J Cardiol. 2003; 19: 620-654
- Canadian Cardiovascular Society consensus conference update on cardiac transplantation 2008: executive summary.Can J Cardiol. 2009; 25: 197-205
- New horizons on the 50th anniversary of heart transplantation in Canada: “Where there is death, there is hope”.Can J Cardiol. 2018; 34: 694-695
- GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.BMJ. 2008; 336: 924-926