M.G. Crespo-Leiro

Superior prevention of acute rejection by tacrolimus vs. cyclosporine in heart transplant recipients--a large European trial.

We compared efficacy and safety of tacrolimus (Tac)‐based vs. cyclosporine (CyA) microemulsion‐based immunosuppression in combination with azathioprine (Aza) and corticosteroids in heart transplant recipients. During antibody induction, patients were randomized (1:1) to oral treatment with Tac or CyA. Episodes of acute rejection were assessed by protocol biopsies, which underwent local and blinded central evaluation. The full analysis set comprised 157 patients per group. Patient/graft survival was 92.9% for Tac and 89.8% for CyA at 18 months. The primary end point, incidence of first biopsy proven acute rejection (BPAR) of grade ≥ 1B at month 6, was 54.0% for Tac vs. 66.4% for CyA (p = 0.029) according to central assessment. Also, incidence of first BPAR of grade ≥ 3A at month 6 was significantly lower for Tac vs. CyA; 28.0% vs. 42.0%, respectively (p = 0.013). Significant differences (p < 0.05) emerged between groups for these clinically relevant adverse events: new‐onset diabetes mellitus (20.3% vs. 10.5%); post‐transplant arterial hypertension (65.6% vs. 77.7%); and dyslipidemia (28.7% vs. 40.1%) for Tac vs. CyA, respectively. Incidence and pattern of infections over 18 months were comparable between groups, as was renal function. Primary use of Tac during antibody induction resulted in superior prevention of acute rejection without an associated increase in infections.

Malignancy After Heart Transplantation: Incidence, Prognosis and Risk Factors

The Spanish Post‐Heart‐Transplant Tumour Registry comprises data on neoplasia following heart transplantation (HT) for all Spanish HT patients (1984–2003). This retrospective analysis of 3393 patients investigated the incidence and prognosis of neoplasia, and the influence of antiviral prophylaxis. About 50% of post‐HT neoplasias were cutaneous, and 10% lymphomas. The cumulative incidence of skin cancers and other nonlymphoma cancers increased with age at HT and with time post‐HT (from respectively 5.2 and 8.9 per 1000 person‐years in the first year to 14.8 and 12.6 after 10 years), and was greater among men than women. None of these trends held for lymphomas. Induction therapy other than with IL2R‐blockers generally increased the risk of neoplasia except when acyclovir was administered prophylactically during the first 3 months post‐HT; prophylactic acyclovir halved the risk of lymphoma, regardless of other therapies. Institution of MMF during the first 3 months post‐HT reduced the incidence of skin cancer independently of the effects of sex, age group, pre‐HT smoking, use of tacrolimus in the first 3 months, induction treatment and antiviral treatment. Five‐year survival rates after first tumor diagnosis were 74% for skin cancer, 20% for lymphoma and 32% for other tumors.

Preoperative INTERMACS Profiles Determine Postoperative Outcomes in Critically Ill Patients Undergoing Emergency Heart Transplantation: Analysis of the Spanish National Heart Transplant Registry

Background—Postoperative outcomes of patients with advanced heart failure undergoing ventricular assist device implantation are strongly influenced by their preoperative Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profiles. We sought to investigate whether a similar association exists in patients undergoing emergency heart transplantation. Methods and Results—By means of the Spanish National Heart Transplant Registry database, we identified 704 adult patients treated with emergency heart transplantation in 15 Spanish centers between 2000 and 2009. Post-transplant outcomes were analyzed pertaining to patient preoperative INTERMACS profiles, which were retrospectively assigned by 2 blinded cardiologists. Before transplantation, INTERMACS profile 1 (critical cardiogenic shock) was present in 207 patients, INTERMACS profile 2 (progressive decline) in 291, INTERMACS profile 3 (inotropic dependence) in 176, and INTERMACS profile 4 (resting symptoms) was present in 30 patients. In-hospital postoperative mortality rates were, respectively, 43%, 26.8%, and 18% in patients with profiles 1, 2, and 3 to 4 (P<0.001). INTERMACS 1 patients also presented the highest incidence of primary graft failure (1: 31.3%, 2: 22.3%, 3–4: 21.8%; P=0.03) and postoperative need for dialysis (1: 33.2%, 2: 18.9%, 3–4: 21.5%; P<0.001). Adjusted odds-ratios for in-hospital postoperative mortality were 4.38 (95% confidence interval, 2.51–7.66) for profile 1 versus 3 to 4, 2.49 (95% confidence interval, 1.56–3.97) for profile 1 versus 2, and 1.76 (95% confidence interval, 1.02–3.03) for profile 2 versus 3 to 4. Long-term survival after hospital discharge was not influenced by preoperative INTERMACS profiles. Conclusions—Preoperative INTERMACS profiles determine outcomes after emergency heart transplantation. Results call for a change in policies related to the management of heart transplant candidates presenting with INTERMACS profiles 1 and 2.

Reversal of Cardiac Cirrhosis Following Orthotopic Heart Transplantation

Irreversible hepatic cirrhosis greatly increases the risks attending heart transplantation (HT), and is accordingly considered to be an absolute contraindication for HT unless combined heart and liver transplantation can be performed. It is now recognized that hepatic cirrhosis can undergo regression if the source of insult is removed, but no cases of post‐HT regression of cirrhosis of cardiac origin have hitherto been reported. Here we report a case of cardiac cirrhosis that underwent complete regression following orthotopic HT, and we discuss the implications of this case.

Heart transplantation using allografts from older donors: Multicenter study results

BACKGROUND The lengthy waiting time for heart transplantation is associated with high mortality. To increase the number of donors, new strategies have emerged, including the use of hearts from donors ≥50 years old. However, this practice remains controversial. The aim of this study was to evaluate outcomes of patients receiving heart transplants from older donors. METHODS We retrospectively analyzed 2,102 consecutive heart transplants in 8 Spanish hospitals from 1998 to 2010. Acute and overall mortality were compared in patients with grafts from donors ≥50 years old versus grafts from younger donors. RESULTS There were 1,758 (84%) transplanted grafts from donors < 50 years old (Group I) and 344 (16%) from donors ≥50 years old (Group II). Group I had more male donors than Group II (71% vs. 57%, p = 0.0001). The incidence of cardiovascular risk factors was higher in older donors. There were no differences in acute mortality or acute rejection episodes between the 2 groups. Global mortality was higher in Group II (rate ratio, 1.40; 95% confidence interval, 1.18-1.67; p = 0.001) than in Group I. After adjusting for donor cause of death, donor smoking history, recipient age, induction therapy, and cyclosporine therapy, the differences lost significance. Group II had a higher incidence of coronary allograft vasculopathy at 5 years (rate ratio, 1.67; 95% confidence interval, 1.22-2.27; p = 0.001). CONCLUSIONS There were no differences in acute and overall mortality after adjusting for confounding factors. However, there was a midterm increased risk of coronary allograft vasculopathy with the use of older donors. Careful selection of recipients and close monitoring of coronary allograft vasculopathy are warranted in these patients.

Use of mTOR inhibitors in chronic heart transplant recipients with renal failure: Calcineurin-inhibitors conversion or minimization?

BACKGROUND In the last decade, mTOR inhibitors (mTOR-is) have become the cornerstone of the calcineurin inhibitor (CNI)-reduced/free regimens aimed to the preservation of post-transplant renal function. We compared utility and safety of the total replacement of calcineurin inhibitors with a mTOR-i with a strategy based on calcineurin inhibitor minimization and concomitant use of m-TOR-i. METHODS In a retrospective multi-center cohort of 394 maintenance cardiac recipients with renal failure (GFR<60 mL/min/1.73 m(2)), we compared 235 patients in whom CNI was replaced with a mTOR-i (sirolimus or everolimus) with 159 patients in whom mTOR-is were used to minimize CNIs. A propensity score analysis was carried out to balance between group differences. RESULTS Overall, after a median time of 2 years from mTOR-i initiation, between group differences for the evolution of renal function were not observed. In a multivariate adjusted model, improvement of renal function was limited to patients with mTOR-i usage within 5years after transplantation, particularly with the conversion strategy, and in those patients who could maintain mTOR-i therapy. Significant differences between strategies were not found for mortality, infection and mTOR-i withdrawal due to drug-related adverse events. However, conversion group tended to have a higher acute rejection incidence than the minimization group (p=0.07). CONCLUSION In terms of renal benefits, our results support an earlier use of mTOR-is, irrespective of the strategy. The selection of either a conversion or a CNI minimization protocol should be based on the clinical characteristics of the patients, particularly their rejection risk.

Risk factors associated with cytomegalovirus infection in heart transplant patients: a prospective, epidemiological study

J.F. Delgado, N. Manito, L. Almenar, M. Crespo‐Leiro, E. Roig, J. Segovia, J.A. Vázquez de Prada, E. Lage, J. Palomo, M. Campreciós, J.M. Arizón, J.L. Rodríguez‐Lambert, T. Blasco, L. de la Fuente, D. Pascual, G. Rábago. Risk factors associated with cytomegalovirus infection in heart transplant patients: a prospective, epidemiological study
Transpl Infect Dis 2011: 13: 136–144. All rights reserved

Lung Cancer after Heart Transplantation: Results from a Large Multicenter Registry

In this study we analyzed Spanish Post‐Heart‐Transplant Tumour Registry data for adult heart transplantation (HT) patients since 1984. Median post‐HT follow‐up of 4357 patients was 6.7 years. Lung cancer (mainly squamous cell or adenocarcinoma) was diagnosed in 102 (14.0% of patients developing cancers) a mean 6.4 years post‐HT. Incidence increased with age at HT from 149 per 100 000 person‐years among under‐45s to 542 among over‐64s; was 4.6 times greater among men than women; and was four times greater among pre‐HT smokers (2169 patients) than nonsmokers (2188). The incidence rates in age‐at‐diagnosis groups with more than one case were significantly greater than GLOBOCAN 2002 estimates for the general Spanish population, and comparison with published data on smoking and lung cancer in the general population suggests that this increase was not due to a greater prevalence of smokers or former smokers among HT patients. Curative surgery, performed in 21 of the 28 operable cases, increased Kaplan–Meier 2−year survival to 70% versus 16% among inoperable patients.

Transplantation for complex congenital heart disease in adults: a subanalysis of the Spanish Heart Transplant Registry

Congenital heart diseases (CHDs) have high infant mortality in their severe forms. When adulthood is reached, a heart transplant (HTx) may be required. Spanish adult population transplanted for CHD was analyzed and compared with the most frequent causes of HTx and between different subgroups of CHD.

Steroid Use in Heart Transplant Patients in Spain in the Current Era: A Multicenter Survey

OBJECTIVE Steroid withdrawal (SW) from maintenance therapy in heart transplant patients is still a controversial subject. We designed a questionnaire to ascertain the attitudes and procedures of a number of Spanish heart transplant units (16) regarding the use/withdrawal of steroids as part of the immunosuppressive maintenance therapy. MATERIALS AND METHODS We sent an 11-item questionnaire to the clinical director in charge of each unit. The questionnaire was completed and returned by 14 units. RESULTS In 21.5% of the centers SW was performed in all patients, while 78.5% of the centers only performed SW in selected patients. In 57% of units SW was performed at 12 months posttransplantation and between 6 and 12 months in the rest. Fewer than 20% of patients were steroid-free in 46% of units while in 23% of units this proportion was >50%. In 11 units, the minimum prednisone dose administered was <or=5 mg/d. More than 80% used the following selection criteria for SW: no acute rejection episodes (ARE) in the first 3 to 6 months, low immunological risk, and concomitant immunosuppression. The main expected benefits were: a decrease in the incidence of diabetes, bone problems, and obesity, and improved dyslipidemia, hypertension, and overweight. Twenty-eight percent of units performed an endomyocardial biopsy (EMB) before SW, while 3 units also repeated it after SW. In most cases (72%), an EMB was always performed at 1 month after withdrawal. In a low percentage of cases (<30%), all units had to reintroduce steroids in the maintenance regimen due to an ARE (73%). CONCLUSIONS Most heart transplant units (78.5%) performed SW at 1 year after transplantation in selected patients: those without an ARE in the first 3 to 6 months and those with low immunological risk. The main benefits were to avoid or reduce diabetes and bone problems, and to a lesser extent, overweight, hypertension, and hypercholesterolemia. In <30% of patients steroids had to be reintroduced due to an ARE.