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Heart 98:878-889 doi:10.1136/heartjnl-2011-300479
  • Education in Heart
  • Cardiac surgery

Heart transplantation: organisational aspects and current trends in immunosuppression—a view from Spain

  1. Pablo García-Pavía
  1. Advanced Heart Failure and Transplant Unit, Cardiology Department, Hospital Puerta de Hierro Majadahonda, Madrid, Spain
  1. Correspondence to Dr Javier Segovia, Cardiology Department, Hospital Puerta de Hierro Majadahonda, Madrid, Spain. C/Joaquin Rodrigo, 1. Madrid 28222, Spain; jsecu{at}telefonica.net
  1. Contributors Dr Alonso-Pulpón is the head of the group and contributed mainly to organisational aspects of heart transplantation and overall review of the manuscript. Dr Segovia wrote the main text after collecting contributions of all the authors, and prepared tables, figures, key points, and multiple choice questions. Dr Gomez Bueno contributed mainly to new trends in immunosuppression in heart transplant. Dr García-Pavía contributed mainly to classical concepts in heart transplant immunosuppression and tables 2 and 4.

Impact and limitations of heart transplantation: organisational aspects

In spite of recent advances in the treatment of patients with end stage heart failure, heart transplantation (HTx) still remains the best option for patients under 70 years of age suffering from this condition. It provides not only a dramatic change in expected survival, unequalled by any other intervention, but also a substantial improvement in the quality of life of patients.1–3 w1

According to the Global Observatory on Donation and Transplantation, approximately 100 000 solid organ transplants are performed every year in the world, 5000 of which are HTx.3 w2 Data derived from the voluntary Registry of the International Society for Heart and Lung Transplantation (ISHLT) show that median survival after HTx is 10 years, and >90% of recipients live without significant activity limitations.2 w1 Similar results are shown in the exhaustive Spanish National Registry of Heart Transplantation (RNTC).4 In our own series of 770 HTx starting in 1984, 25% of the patients transplanted ≥20 years ago are still alive, most of them leading satisfactory, independent lifestyles.

Several factors have contributed to the positioning of HTx as a standard therapy in western countries. On the one hand, advances in the field of immunology leading to the development of drugs (ie, ciclosporin A) have allowed safe immunomodulation strategies. Acute rejection is not a major barrier to graft survival any more, and newer generation, more specific immunosuppressive drugs have an acceptably low profile of adverse effects.4 w3–w5 On the other hand, refinements in the selection of recipients, improvement in surgical techniques, a better preservation of the graft during cold ischaemia, histological monitoring of acute rejection, and implementation of prophylactic strategies against specific infections have undoubtedly contributed to the success of HTx.5 6

However, the most important factor in the expansion of heart and other solid organ transplants has probably been the systematic organisation of organ harvesting and distribution of the grafts. An essential step was the introduction of the concept of brain death in 1959,w6 as well as the acceptance by the medical community and society in general of the importance of the ‘beating corpse’ as a source of donor organs. Later implementation of legal measures and development of an organisation for the detection, allocation, and collection of these organs has resulted not only in greater diffusion of the technique, but also in better overall results. Obviously, this organisation requires a significant amount of resources authorised by policymakers, and this may be the reason why transplant procedures are anecdotal in developing countries. There is a clear relationship between the degree of efficacy of these structures and the so called ‘Human Development Index’ in the different countries.

The problem of the shortage of donors

In Europe, with a population of 594.4 million, 2170 HTx were performed in 2008, which represents 3.65 HTx procedures per million population (pmp).3 w2 This includes combined heart–lung transplants. In Spain—which has had the highest rate of donations in the world during the last 20 years (34.2 deceased organ donors pmp in 2008)—with a population of 46.2 million, 292 HTx were performed in the same year, yielding a rate of 6.35 HTx pmp. This represents a 17.3% reduction when compared with figures for the year 2000, and is explained by a substantial reduction in traffic accidents.

Table 1 shows some key data on donation and HTx in some of the most populated western countries. Geographical differences between countries (central position within the continent versus peripheral or insular countries, abundance of mountains or other barriers to transportation, etc) may also have an important influence on transplantation activity and must be taken into account. From these data, two different organisational models can be inferred: at one end of the spectrum, represented by the UK, a few large referral centres perform all the HTx in the country; while at the opposite end, countries such as the USA, Spain, and others reflect more decentralised models, where the average reference population for each transplant programme is much lower (one transplant programme per 2.5 million inhabitants, approximately). Germany is somewhere between these two ends of the spectrum. Comparison of both models clearly shows that decentralised models achieve a higher number of HTx pmp. A remarkable finding is that, irrespective of the organisational model, the average number of procedures performed in each centre is rather consistent, between 14 and 19 HTx/year. In fact, when many different countries are considered, there seems to be a linear correlation between the relative number of HTx centres and the number of HTx performed each year (figure 1). Another reason in favour of decentralised organisation (ie, a high number of transplant programmes distributed across the country, each with a relatively small reference population) is the possibility to minimise the distance between donating and implanting centres, thus reducing the ischaemia time of the grafts. However, both for clinical and economic reasons, there must be a limit to the number of HTx in each country. The analysis of two large HTx registries suggests that low volume centres (those performing <10 procedures/year) obtain slightly worse results in terms of survival when compared with high volume programmes.2 w7

Table 1

Donation and heart transplantation (HTx) activity in western countries (data from 2009)

Figure 1

Pearson's linear correlation analysis showing a significant direct relationship between the number of heart transplant centres and the number of heart transplantation (HTx) procedures in different countries.

The shortage of donors is the main limitation of solid organ transplantation. In the EU, more than 4000 patients die each year while waiting for a heart, liver or kidney transplant. This is especially the case for cardiac transplantation, which is considered to have reached its ceiling in terms of expansion, at least as it is perceived nowadays. In comparison with other organ transplantation, HTx has a number of negative differential factors: the inability to obtain organs from living donors (accounting for up to 10–40% of donations in kidney transplantation), and the impossibility to expand the donor pool at the expense of older donors (>55 years), as the results with such organs are significantly worse than those achieved with younger donors.2 w1 w8 This is possibly related to the higher prevalence of silent coronary artery disease in the grafts from older donors.

In spite of the limitation in the number of potential procedures, the excellent results obtained with HTx have been followed by the inclusion on the waiting list of patients with progressively worsening general condition and a higher number of comorbidities. This determines longer waiting times and a higher level of mortality in the list. In 2009, 543 patients died in the EU while on the HTx waiting list.3

Different strategies have been attempted in order to alleviate donor shortage. The use of dedicated mechanical systems for the transportation of beating donor hearts perfused with warm blood may allow longer ischaemia times, thus obviating the problem of harvesting grafts from very distant locations.w9 Two clinical trials evaluating such perfusion machines were started in 2007 and are currently underway: the PROCEED trial in the USA, and the PROTECT-II trial in Europe. Results are awaited with interest. In addition, another way to expand the donor pool would be to undertake systematic coronary angiograms in ageing donorsw10; however, logistic difficulties have prevented the widespread use of this practice.

In recent years, the use of mechanical circulatory assistance devices (MCAD) has become the most promising option for reducing the need for donor hearts. MCAD can be used either as a ‘bridge to transplantation’ capable of maintaining recipients in a stable condition and allowing a more reasonable administration of the waiting lists, or as a ‘destination therapy’ intended to prolong lifespan in patients who are not candidates for HTx. The introduction of a new generation of continuous flow MCAD has been an important step forward in terms of reliability of the devices and survival of patients.7 Nevertheless, their limited durability in the long term (survival for more than 3–5 years without device malfunction is exceptional) and their high cost remain as major obstacles towards their more widespread use.

The ‘Spanish model’ of donation and transplantation

Spain occupies the first position in the world for the rate of donations pmp and, consequently, for the overall activity in solid organ transplantation. This fact was recognised by the Council of Europe where the concept of the ‘Spanish model of transplant’ was coined in 2002,8 referring to an efficient system which the Council recommended to all EU member countries.

The Spanish transplant model, integrated in the setting of a public system of health with almost universal coverage, is founded on three key pieces: first, a ‘Law of Transplants’ based on the presumed consent for the donation; second, a nationwide organisation that identifies, distributes, and controls the process of donation in the whole country; and finally, a high degree of social awareness that reduces the index of family denials to a minimal degree.

The presumed consent (opt-out), on which the Spanish ‘Law of Transplants’ is based, implies that if the deceased person had not expressed in life a wish to deny donation of his or her organs after death, he or she is considered in fact, and in agreement with the law, a potential donor. Nevertheless, in real life, the permission of close relatives is requested and their wishes respected.

Controversial data exist as to the benefits of this type of legislation versus that based on the expressed consent (opt-in),9 10 w11 in which donation is accepted only when the person has expressed in life the desire to be a donor after his or her death. This implies that in cases when there are no relatives inclined to take a decision, and in the absence of a registry of the affirmative will of the person, the organs cannot be used. Interestingly, a comparative study between countries of the EU with both models of legislation did not show significant differences in the rate of donations.w12 The effect of the legislative model in other geographical areas remains unknown.

The high efficiency of the Spanish system seems to take root in the organisational model, based on the transplant coordinator, acting on two different levels. First, the local or hospital coordinator, present in all hospitals of secondary and tertiary level, whose basic responsibilities are the following: detection of potential donors, diagnosis of brain death and assistance to patients in such a condition, the attainment of family or judicial permission when applicable, and, finally, coordination with the head office (National Organisation of Transplants), which is permanently on duty in Spain.

The central coordinator manages the waiting lists of all the organs and of all the transplant teams of the country. He takes into account the different levels of priority and assigns the organs according to criteria previously agreed by consensus and checked annually by the teams involved in every organ transplant (box 1). He also organises the forces for harvesting and transportation of the grafts in direct connection with the local coordinators.

Box 1

Overview of current Spanish allocation policy for donor hearts.

Graphic

A designated committee ensures the transparency and equity in organ allocations, and an external committee arbitrates on the most doubtful cases in terms of priority and level of urgency.

Other important assignments of the head office of coordination include the education of coordinators, the development of programmes for the promotion of donation, and the maintenance of registries of activity.

Finally, public awareness about donation of organs is of the utmost importance. Campaigns directed through the media for improving the transmission of information on the delicate circumstances surrounding donation and death have turned out to be decisive in achieving a minimal rate of family denials. Spain is a country with established traditions regarding death that at first would seem to impede the process of donation. Nevertheless, by means of the policies described above, the positive awareness raised among the public with regard to donation/transplantation, to a rate of family refusals to donation of just 16% in 2009, compared with a refusal rate of 30–50% in other EU countries.3

Trends in heart transplant immunosuppression

Classical concepts

Long term success in HTx depends on the fine balance between a powerful immunosuppressive therapy which prevents organ rejection and a ‘too intense’ immunosuppression that facilitates development of infections and cancer. This balance is a moving target, because the risks of these complications change differentially over time after HTx—that is, acute rejection is more frequent during the first 6 months, while malignancies are the first cause of mortality among long term (>5 years) survivors.2 4

In an attempt to adapt immunosuppressive therapy to the needs of the majority of HTx recipients, the classical immunosuppression scheme includes three basic situations that require specific combinations of drugs.5 w3–w5. Figure 2 summarises the main immunologic mechanisms involved in graft rejection and the sites of action of immunosuppressive drugs.

Figure 2

Immunologic mechanisms involved in graft rejection and sites of action of immunosuppressive drugs (shown in red). The rejection cascade begins with recognition of the donor antigens by antigen presenting cells (APC). These antigens, combined with MHC (major histocompatibility complex) molecules of the APC, are recognised by the TCR (T cell receptor)/CD3 complex on the surface of the T cell. When co-stimulatory signals between APC and T cells (B7-CD28, CD40-CD154) are present, T cell activation occurs, resulting in activation of the calcineurin pathway. Calcineurin dephosphorylates transcription factors, such as NF-AT, which in turn migrate to the nucleus and stimulate promoters of interleukin 2 (IL2) and other cytokines. IL2 activates cell surface receptors (IL2R, CD25), resulting in clonal expansion of T helper cells and stimulation of other immune cells. Activation of IL2R stimulates the TOR (target of rapamycin) system, which promotes translation of mRNAs to proteins that regulate the cell cycle. ATG, antithymocyte globulin; Aza, azathioprine; MMF, mycophenolate mofetil; OKT3, muromonab, antiCD3 mAB.

Induction therapy

This is the intense immunosuppression administered intravenously during the first few perioperative days in order to facilitate graft acceptance and minimise the chance of early rejection.5 Induction immunosuppression typically consists of antibodies directed against lymphocyte receptors. Two groups of drugs are used as inductors: cytolytic agents and antiCD25 antibodies. Table 2 shows the specific preparations used for this purpose. Cytolytic agents include polyclonal anti-lymphocytic agents and muromonab (OKT3). These have a powerful anti-rejection effect, but their use has been associated with an increase in infections (mainly due to cytomegalovirus) and malignancies (especially lymphoproliferative disease).w13 w14 However, reduction in doses and use of concomitant antiviral prophylaxis has largely reduced these untoward effects.11 w15 w16 AntiCD25 antibodies daclizumab and basiliximab have been shown to have an excellent safety profile. Their use in HTx seems to provide a reduction in rejection episodes similar to or smaller than that achieved with cytolytic drugs, without an increased risk of infections or cancer.12 w17–w19

Table 2

Main immunosuppressive drugs currently used for induction in heart transplantation

Although induction immunosuppression was introduced in clinical HTx four decades ago, controversy about its safety and efficacy currently persists, when the proportion of HTx recipients receiving induction in the world is slightly over 50%.2 In the absence of prospective, well designed studies addressing its role in HTx, there is general agreement that induction immunosuppression does not provide any survival benefit.w14 w17 w18 w20 However, its main advantages include a reduction of the acute rejection rate in a period when graft dysfunction and multiorgan failure may hamper patient survival.w16–w18 It also allows a safe delay in the introduction of nephrotoxic calcineurin inhibitors in a critical post-HTx period, as part of a renal sparing strategy.w14 w21 w22

In accordance with the analysis of Higgins et alw20 and the opinion of Patel and Kobashigawa,13 we recommend the use of induction immunosuppression in patients at high risk for either early rejection or renal failure (box 2 shows a list of the main subgroups in which induction could be warranted). Since these risk factors are becoming increasingly prevalent among Htx recipients, most of our patients receive induction immunosuppression nowadays.

Box 2

Subgroups of patients in whom induction immunosuppression could be justified

  • Patients at increased risk of rejection:

    • Positive panel reactive antibodies/circulating HLA antibodies

    • History of mechanical circulatory support

    • Younger age

    • Female recipient

    • Black race

    • Previous transplantation or multiple blood transfusions

  • Patients at increased risk of renal failure (as a strategy to delay the introduction of calcineurin inhibitors):

    • Renal failure before heart transplantation

    • Cardiogenic shock at the time of heart transplantation

    • Diabetes mellitus

Alemtuzumab is a humanised rat monoclonal antibody directed against the CD52 antigen (expressed in lymphocytes, natural killer (NK) cells, and monocytes). A single 30 mg intravenous dose infused during transplantation achieves profound (>99%) and prolonged (>1 year) lymphocyte depletionw23; because of this unique feature, alemtuzumab may be classified both as an induction and a maintenance immunosuppression agent. In a retrospective study, 110 HTx recipients treated with alemtuzumab plus a reduced maintenance immunosuppression regimen showed a lower number of acute cellular rejection episodes at 1 year follow-up than a similar series of patients treated with classic triple therapy.14 However, no benefits in terms of survival, reduction of renal dysfunction or other post-HTx complications were seen in the alemtuzumab arm, which showed a non-significant trend to higher mortality/graft failure and frequent episodes of neutropenia needing filgastrim. The role of this powerful drug with largely irreversible effects is still unknown, and only prospective, well designed trials in HTx will help to elucidate its role.

Maintenance therapy

Maintenance therapy refers to the long term oral immunosuppression administered to HTx recipients in order to obtain chronic acceptance of the allograft. Maintenance therapy has been traditionally based on a combination of drugs, in an attempt to obtain powerful immunosuppression while avoiding severe adverse events associated with high doses of individual agents (table 3). The most commonly used immunosuppression regimens in HTx are ‘triple therapy’ combinations of a calcineurin inhibitor (CNI, either ciclosporin or tacrolimus), an antiproliferative agent (either azathioprine or mycophenolic compounds), and corticosteroids. In a randomised trial published in 1998, mycophenolate mofetil (MMF) improved rejection rates and 1 year survival over azathioprinew24; consequently MMF has become the antiproliferative agent used in most patients,2 and is only limited by its gastrointestinal and haematological side effects. Many other studies comparing different maintenance immunosuppressants have failed to show overall superiority of a given drug or combination.7

Table 3

Main drugs currently used for maintenance immunosuppression in heart transplantation

Specific maintenance regimens vary from one HTx programme to another, and depend on patient characteristics (age, gender, race, presensitisation, history of previous rejections, comorbidities, etc). The highest degree of immunosuppression is applied during the first 3 months after HTx, and most centres gradually reduce immunosuppression thereafter, in parallel with the declining trend of acute rejection, usually with the guidance of serial endomyocardial biopsies.

Sirolimus and everolimus are TOR (target of rapamycin) inhibitors, a family of immunosuppressants that has been added to HTx immunosuppression in the last decade.w3 w25–w27 As ‘second’ drugs, combined with CNI, they are more effective than azathioprine for the prevention of acute cellular rejection, at the cost of an exacerbation of the nephrotoxicity of the first drug. In several studies, TOR inhibitors have consistently shown a remarkable ability to reduce the progression of intimal growth in the arteries of the graft, a key component of cardiac allograft vasculopathy. Other very interesting features of TOR inhibitors in HTx are their antineoplastic effect (mainly against specific types of malignancies, such as non-melanoma skin cancers, Kaposi's sarcoma, and renal carcinomas), and also a certain anti-cytomegalovirus (CMV) activity. However, TOR inhibitors are associated with a significant number of adverse events, and their precise role in HTx is still to be defined.7

An important aspect in the management of immunosuppression in HTx recipients is the possible occurrence of drug–drug interactions. Table 4 summarises the most relevant interactions in clinical practice.

Table 4

Main pharmacokinetic interactions with commonly used immunosuppressants*

Rejection therapy

In spite of the efficacy of current maintenance regimens, 20–40% of recipients experience at least one episode of acute rejection after HTx. Most of these episodes are asymptomatic and are detected on routine endomyocardial biopsies (EMB) performed during the first 6–12 months after HTx. From a histological point of view, cellular rejection is classified into four categories of severityw28 (figure 3).

Figure 3

Microphotographs of endomyocardial biopsy samples showing different degrees of acute cellular rejectionw29 and antibody mediated (humoral) rejection. (A) Absence of cellular rejection (grade 0R). No evidence of mononuclear infiltrate or myocyte damage (haematoxylin and eosin (H&E), 600×). (B) Mild acute cellular rejection (grade 1R). Interstitial mononuclear infiltrate surrounding myocytes. There is neither evidence of damage to the myocytes, nor distortion of the normal architecture of the myocardium (H&E, 400×). (C) Moderate acute cellular rejection (grade 2R). Grade 2R requires two or more foci of mononuclear infiltrates (lymphocytes or macrophages) with associated myocyte damage/necrosis. Occasional eosinophils can be seen, and partial distortion of myocardial architecture may be present (H&E, 400×). (D) Severe acute cellular rejection (grade 3R). Intense and diffuse polymorphic inflammatory infiltrate (including lymphocytes, macrophages, eosinophils, neutrophils, and plasma cells) with extensive myocardial necrosis and disappearance of normal myocardial architecture. Oedema, interstitial haemorrhage, and vasculitis may be present (H&E, 600×). (E) Antibody mediated rejection. Immunochemistry technique staining C4d indicates diffuse, brownish linear deposits of complement C4d fragments in the wall of myocardial capillaries (arrowheads). Cellular infiltrate is not prominent in this case (600×). Images courtesy of Dr C Salas and Dr R Sánchez-Yuste, Hospital Universitario Puerta de Hierro.

The specific regimen of rejection therapy administered in each case depends on several factors, such as histological rejection grade, presence of allograft dysfunction, type of rejection (humoral vs T cell mediated), and time of appearance.

Asymptomatic acute cellular rejection episodes are usually treated when myocyte necrosis is present on EMB (grades 2R and 3R). High dose intravenous steroids (methylprednisolone 250–1000 g/day for 3 days) are the usual treatment during the first 3–6 months, and oral courses of prednisone (1–3 mg/kg/day for 3–7 days) are given for asymptomatic episodes occurring later. Rejection episodes accompanied by data on graft dysfunction (ie, heart failure symptoms, haemodynamic instability, arrhythmia or reduced left ventricular ejection fraction) are usually treated with a course of antilymphocytic antibodies (those described for induction therapy) added to intravenous steroids,7 as well as supportive measures. Cytolytic therapy is also used for rejection episodes that are recurrent or resistant to steroids. The same measures for premedication and antimicrobial prophylaxis recommended for induction apply in these cases.

The need for a change in immunosuppression: attempts at the frontline

A review of the main causes of death and morbidity among HTx recipients is revealing (figure 4).2 4 w1 During the first month after HTx, primary graft failure and complications related to surgical trauma are the leading causes. From the first month to the end of the first year, the period of maximal immunosuppression, infectious episodes account for 30% of deaths, while acute rejection causes 10% of the mortality. After 1 year, allograft vasculopathy (sometimes manifested as unspecified graft failure or sudden death) and malignancies are the main complications limiting survival, each of them accounting for 20–30% of deaths. In the late period, infections still cause 10–12% of mortality, while acute rejection after the third year only accounts for a low proportion (1–5%) of the deaths. Renal failure appears as a significant contributor to mortality in the late period, causing 6–9% of the deaths occurring >5 years after HTx. Humoral rejection, an increasingly recognised complication of HTx, may occur either during the early or the late period, but its impact on mortality seems to be low.w29

Figure 4

Relative incidence of the leading causes of death by time since transplantation, for deaths in adult heart transplant recipients included in the Registry of the International Society of Heart and Lung Transplantation occurring from January 1998 to June 2009. CAV, cardiac allograft vasculopathy; CMV, cytomegalovirus. Reprinted with permission from Stehlik J, Edwards LB, Kucheryavaya AY, et al. Registry of the International Society for Heart and Lung Transplantation: Twenty-seventh Official Adult Heart Transplant Report—2010. J Heart Lung Transplant 2010;29:1089–103.

In terms of morbidity, a majority of long term survivors after HTx suffer from conditions such as hypertension (>90%), dyslipidaemia (>90%), diabetes (30–40%), and renal failure (25–35%), all of them closely related to the use of immunosuppressants, especially CNI (either ciclosporin or tacrolimus) and steroids.

Summarising, the impact of complications related to excessive immunosuppression, such as infection, malignancy, and renal failure, is much stronger than that of acute rejection—the main effect of insufficient immunosuppression. The main attempts to reduce the amount of immunosuppression in HTx during the last decades are summarised below.

Steroid withdrawal

Because of their powerful antirejection effect, steroids are considered essential in the early post-HTx period and in the treatment of acute rejection episodes. Chronic maintenance of steroids is controversial because of their known long term side effects (hypertension, hyperlipidaemia, diabetes mellitus, osteopenia, infections, poor wound healing, cosmetic effects, emotional instability, proximal myopathy, cataracts, gastric ulcer, etc). Children, postmenopausal women, and patients with severe osteoporosis, diabetes mellitus, and obesity are among the subgroups to derive higher potential benefit from steroid-sparing protocols.

Unfortunately, most publications on this topic reflect small single centre experiences. They can be grouped into two categories according to the timing of steroid weaning. ‘Early’ strategies, in which prednisone is withdrawn a few weeks or months after HTx, are usually applied to patients with a low baseline risk for rejection, and are based on the concomitant use of induction antibodies, such as antilymphocytic agents or alemtuzumab.14 w30 w31 One study was able to show benefits in the steroid avoidance patients in terms of muscle strength and bone densitometry.w31 However, a significant number of patients in these studies developed acute rejection episodes during follow-up, and only 50–70% of them could be successfully weaned off steroids in the long term.

‘Late’ steroid withdrawal protocols initiate a gradual weaning >6 months post-HTx, once the risk of rejection is diminished. Even with this safer approach, 20–25% of patients develop acute rejection episodes, and <80% can be successfully weaned.w32 w33 In both steroid sparing strategies, patients in whom the attempt is unsuccessful are exposed not only to the risks of rejection, but also to the adverse events associated with pulse-dose steroids and increased long term immunosuppression.

Taken as a whole, the evidence on the potential benefits and risks of steroid withdrawal is not conclusive. Because of this, many groups, including ours, advocate a practical approach based on the use of minimal long term doses of prednisone (typically 5 mg/day) with concomitant preventive measures against its adverse effects (such as osteoprotective strategies, antimicrobial prophylaxis, and primary prevention of obesity, hypertension, dyslipidaemia, etc). In patients with steroid related complications or at high risk for them, withdrawal attempts with histological surveillance are implemented with frequent success.w34 Recently published ISHLT guidelines are in accordance with this strategy.7 In the ISHLT Registry, 92% and 57% of recipients were receiving prednisone 1 and 5 years after HTx, respectively, reflecting that most groups do not adhere to aggressive steroid sparing protocols.2 w1

CNI minimisation protocols

Different strategies for the reduction of recipients' exposure to ciclosporin have been tested over the last decade, and are usually directed at diminishing the nephrotoxicity of this CNI. After demonstration of the superiority of mycophenolate mofetil over azathioprine in terms of prevention of rejection episodes and survival,w24 different studies proved that a change from azathioprine to mycophenolate allowed for a 15–40% reduction in ciclosporin values that resulted in lower rates of renal failure and arterial hypertension without an increase in the incidence of rejection episodes.w35–w37

Monitoring of ciclosporin concentrations at 2 h after dosing (C2) may be a better parameter of ciclosporin exposure and efficacy than trough values (C0). In one study, low C2 ranges in combination with basiliximab induction preserved renal function without an increase in the risk of acute rejection or other complications.w38 However, true benefits of C2 monitoring remain to be determined in further trials.

Since their introduction in HTx one decade ago, TOR inhibitors have been tested as a means to minimise ciclosporin dosing. Due to their more powerful antirejection effect, they can replace either azathioprine or mycophenolate, allowing a reduction of >50% in ciclosporin levels without an increase in the incidence of rejection episodes.w25–w27 However, their benefit is limited by the fact that they exacerbate the nephrotoxicity of CNI and also by their inherent adverse effects. The results of a large randomised trial comparing everolimus (high and low dose arms) with reduced ciclosporin concentrations versus mycophenolate mofetil with standard ciclosporin dosing in 721 de novo HTx recipients were released during the 2011 meeting of the ISHLT. The high dose everolimus arm was prematurely stopped because of an increased mortality due to infectious disease and other causes. A higher rate of infectious mortality was also evident in the low dose everolimus group when patients had received induction with thymoglobulin, probably reflecting excessive overall immunosuppression. Rejection was not different in both arms, and renal failure was significantly higher among everolimus patients, especially when ciclosporin was not appropriately reduced according to the study protocol.w39 Other adverse effects associated with everolimus included hyperlipidaemia, pericardial effusion, and bacterial infection.w40

The potential of the late TOR inhibitor introduction strategy was tested in a study by Fiocchi et al, in which 213 HTx recipients (median 9 years after HTx) were randomised to everolimus with a strong (>75%) reduction in ciclosporin values versus maintaining conventional immunosuppression. After 3 years of follow-up, patients in the everolimus arm had a lower incidence of renal failure and lymphoproliferative diseases, without an increase in rejection episodes or total mortality.w41 The degree of minimisation of CNI in this trial seems to be crucial, since other studies with less notable reductions in ciclosporin values have failed to show a similar benefit.w40 w42

CNI avoidance and CNI withdrawal strategies

As ‘first’ drugs used in place of CNI, and in combination with mycophenolate and steroids, TOR inhibitors seem to have less potency than CNI, and several attempts to use TOR inhibitor based triple therapy in de novo HTx have shown higher rejection and death rates.w43 Conversely, a switch from CNI based to TOR based immunosuppression more than 1 year after HTx is feasible in a subgroup of patients under appropriate rejection surveillance (rejection episodes develop after switch in approximately 25% of patients), and may be justified in the presence of severe late adverse effects of CNI, such as nephrotoxicity or neurotoxicity.w27 w44 w45

CNI monotherapy

This strategy has been evaluated in the recently published TICTAC trial,15 a prospective, randomised comparison between a combination of tacrolimus plus mycophenolate (n=71) and tacrolimus in monotherapy (n=79) during a follow-up period of 3 years. Average tacrolimus concentrations were in the upper limit of the therapeutic range (10–11 ng/ml), and steroids were discontinued in both arms of the study 8–9 weeks after HTx. Surprisingly, none of the patients required reintroduction of prednisone. There were no significant differences in terms of rejection incidence or severity (although there was a 10% increase in treated rejection at 1 year follow-up with tacrolimus monotherapy), allograft vasculopathy, and all cause mortality. Overall incidence rates of these events were low in comparison with other HTx series.

The results of the TICTAC trial pose a challenge for the HTx community. However, they must be viewed with caution before recommending a widespread use of tacrolimus monotherapy, due to several weaknesses present in the design and results of the study.w46 Given the low incidence of events, the study was clearly underpowered with respect to its primary end point. In addition, high trough values of tacrolimus resulted in significant renal insufficiency rates (average creatinine increased from 1.24 to 1.64 mg/dl during the first year), thus limiting the potential benefits of this treatment protocol. In addition, monotherapy strategies are extremely dependent on patient compliance and the stability of trough values of the drug.

The future in immunosuppression: from the ‘one-size-fits-all’ approach towards tailored therapy

There is little doubt that, in general, we should use less immunosuppression in HTx. However, indiscriminate attempts to reduce immunosuppression following a fixed protocol—the so called ‘one-size-fits-all’ approach—could be dangerous for a proportion of patients (those prone to rejection, typically 20–25% in previous weaning off steroidsw33 or in conversions from ICN to mTOR inhibitorsw44 w45) and still insufficient for others. The fact that a high percentage of patients may be in CNI monotherapy for years without adverse consequences15 implies that many HTx recipients are currently exposed to deleterious effects of unnecessary drugs.

Therefore, the real challenge is to administer the appropriate amount of immunosuppression to each recipient, tailoring it to his/her particular needs at each post-HTx stage. The main problem for achieving this target is the lack of reliable markers of the immunological status of each individual at a given time point.w46 However, a number of parameters may be of help in adjusting immunosuppression to individual needs, as shown in table 5.

Table 5

Potentially useful data for decision making in immunosuppression tailoring after heart transplantation*

Surveillance of immunological status has been classically based on clinical detection of data of graft dysfunction/rejection, infection or malignancy, and on monitoring of blood concentrations of immunosuppressants. Monitoring of acute rejection by means of echocardiography and other imaging techniques is helpful, especially when serial studies are performed, although none of these techniques has proven to be accurate enough to make EMB unnecessary.w47 Serial EMBs are invasive, and hardly justified beyond the first post-HTx year in stable patients.w48 A certain approximation to rejection risk may be derived from baseline recipient characteristics (box 2). Recipient/donor immunological matching data may also help to select or exclude certain subgroups of recipients from immunosuppression minimisation protocols. The number of human leucocyte antigen (HLA) mismatches, especially in the DR loci, was long ago demonstrated to correlate with rejection episodes after steroid weaning.w49 The presence of panel reactive antibodies (PRAs) both pre- and post-HTx is also a predictor of rejection, allograft vasculopathy, and adverse outcomes, even if the detected antibodies are not directed against donor antigens.w50–w52 Periodic detection and quantitation of PRA as a guide for immunosuppression could be justified on this basis.

In the last few years, two different laboratory assays more specifically directed at detecting the degree of immunological activation have been applied in HTx. Gene expression profiling from peripheral blood samples (AlloMap) has been developed and tested in HTx. A score >30 is related to a higher likelihood of acute rejection, and sequential testing in a given recipient may help to monitor changes in the patient's immunosuppression status. Currently, its main usefulness is provided by the high negative predictive value of score values <30–34, which allow avoidance of EMB in the late post-HTx period.16 w48 w53 Its value for selecting those patients in which immunosuppression can be safely minimised is still unknown, but seems a promising approach.

Cylex Immuknow assay is also performed in peripheral blood samples, and assesses the net state of immunosuppression by measuring the ATP concentration in lymphocytes. A study including recipients of different solid organs showed that high values were associated with subsequent rejection episodes, while low values preceded infectious episodes.w54 The grey area between both values could represent an appropriate balance of immunosuppression, and achievement of that range could guide decisions referring to reducing immunosuppression on an individual basis. Studies in HTx are promising,17 but cut-off points with high negative predictive values for rejection and infection have not been established. While values <250 ng ATP/ml are more common in patients developing infections, a clear relation between high ATP concentrations and rejection was not found in all cases.w55 Immuknow has not been used to guide attempts of immunosuppression reduction. As in the case of AlloMap, clinical utility of this assay should be tested in prospective trials.

The achievement of tolerance—a state in which there is selective desensitisation of recipients to donor antigens without the use of immunosuppression—remains the ‘holy grail’ in solid organ transplantation. For the time being, immunosuppression therapy is essential to achieve long term graft survival. Tailoring immunosuppression to each recipient's needs requires proper selection of low risk patients and close surveillance for rejection during and after weaning attempts. New techniques for immunologic monitoring, including detection of alloantibodies, gene expression profiling, and immune cell function assays, could be of some help in this regard. However, advances in the design of more effective immunosuppression regimens will more likely result from collaborative efforts of basic scientists, clinical researchers, health institutions, and transplant recipients alike.w56

Trends in heart transplantation—a view from Spain: key points

  • Heart transplantation is still the best option for patients with end stage congestive heart failure, because it provides substantial improvement in both patient survival and quality of life.

  • The main limitation for heart transplantation is the shortage of donors. An appropriate organisation for the detection, allocation, and collection of donor organs is essential for the optimisation of heart transplant results.

  • The ‘Spanish model of organ transplantation’ has been an efficient system for more than two decades. It is based on a specific ‘Transplant Law’, a dedicated organisation of transplant coordinators, and a high degree of public awareness on donation needs.

  • Classical immunosuppression regimens in heart transplantation consist of maintenance triple therapy protocols including a calcineurin inhibitor, an antiproliferative drug, and steroids. Although drug regimens have improved substantially, their adverse effects continue to cause significant morbidity and even mortality.

  • Different strategies to reduce overall immunosuppression have been evaluated in the last two decades. Steroid weaning, especially in the late post-transplant period, is common practice. However, systematic application of low intensity immunosuppressive regimens increases rejection risk in a significant percentage of patients.

  • Tailoring immunosuppression to the needs of each heart transplant recipient requires correct stratification of their risk and close rejection surveillance during and after minimisation of immunosuppression. Risk stratification is based on clinical characteristics, immunological features of donor and recipient, and data from imaging techniques and cardiac biopsies. New techniques for immunologic monitoring, including detection of alloantibodies, gene expression profiling and immune cell function assays, are promising, but need to be tested in future trials.

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Footnotes

  • Competing interests In compliance with EBAC/EACCME guidelines, all authors participating in Education in Heart have disclosed potential conflicts of interest that might cause a bias in the article. Luis Alonso-Pulpón has received speaking fees from Novartis, Roche, Wyeth, and Astellas and research grants from the Spanish Heart Foundation and from the Spanish Ministry of Health. Javier Segovia has received research grants from the Spanish Heart Foundation and from Novartis.

  • Provenance and peer review Commissioned; internally peer reviewed.

References

  1. An updated review on indications of heart transplant in the era of mechanical circulatory support devices.
  2. Based upon the data of a voluntary registry including more than 60% of heart transplants performed worldwide, this article gives an excellent overview of the current status of the technique. It also contains data on trends in immunosuppression, risk factors for post- transplant mortality, impact of the main complications, and functional status of heart recipients.
  3. A reliable source of information about ‘real life’ transplantation, since the Spanish registry includes each and every heart transplant performed in this country since 1984, totalling over 6000 cases. It Includes information on waiting lists, overall results of the procedure, and analysis of the causes of mortality.
  4. First of a series of four articles in consecutive issues of the same journal (see refs w3–w5) providing a comprehensive, broad-scope review of classic immunosuppressive therapy in heart transplantation.
  5. Conceived and written in the style of Clinical Practice Guidelines so successful in other areas of cardiology, these guidelines—necessarily lacking in evidence on which to be based—are a list of experts' opinions in different areas of the care of cardiac transplant recipients.
  6. This systematic registry of all the implants of mechanical circulatory assist devices performed in the USA since 2006 is the most updated source of information on the achievements and limitations of these devices. It includes a specific analysis of the results of devices implanted as destination therapy, the only real alternative to heart transplantation.
  7. Exhaustive description of all malignancies diagnosed in a large consecutive series of heart transplant recipients from the Spanish Registry of Heart Transplantation.
  8. Insightful review of the different strategies to minimise immunosuppression in heart transplantation over the last 25 years.

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