Luis Almenar

Multicenter randomized trial of a comprehensive hospital discharge and outpatient heart failure management program.

Disease management programs can reduce hospitalizations in high‐risk heart failure (HF) patients, but generalizability to the population hospitalized for HF remains to be proven. We aimed to assess the effectiveness of a discharge and outpatient management program in a non‐selected cohort of patients hospitalized for HF.

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.

Spanish Heart Transplantation Registry. 26th Official Report of the Spanish Society of Cardiology Working Group on Heart Failure and Heart Transplantation (1984-2014)

INTRODUCTION AND OBJECTIVES We present the characteristics and outcomes of heart transplantation in Spain since it was first performed in 1984. METHODS A descriptive analysis of the characteristics of recipients, donors, the surgical procedure, and the outcomes of heart transplantations performed in Spain until 31 December 2014. RESULTS In 2014, 266 procedures were performed, making a time series of 7289 transplantations. The temporal analysis confirmed a significant worsening of the clinical profile of recipients (higher percentage of older patients, patients with severe renal failure, insulin-dependent diabetes, previous cardiac surgery, and previous mechanical ventilation), of donors (higher percentage of older donors and greater weight mismatch), and of the procedure (higher percentage of emergency transplantations, reaching 41.4% in 2014, and ischemia time>240min). Mechanical assist devices were used less than in 2013; in 2014 they were used in 18.8% of all transplant recipients. Survival at 1, 5, 10, and 15 years was 76%, 65%, 52%, and 38%, respectively, and has remained stable since 1995. CONCLUSIONS Cardiac transplantation activity in Spain has remained stable in recent years, at around 250 procedures per year. Despite a clear deterioration in donor and recipient characteristics and surgical times, the mortality outcomes have remained comparable to those of previous periods in our environment. The growing use of circulatory assist devices before transplantation is also confirmed.

Thrombin‐activatable fibrinolysis inhibitor in young patients with myocardial infarction and its relationship with the fibrinolytic function and the protein C system

Summary. Thrombin‐activatable fibrinolysis inhibitor (TAFI) is a fibrinolytic inhibitor. Studies in coronary artery disease have reported increased TAFI activity (TAFI Act) and low TAFI antigen (TAFI Ag) levels. This controversy might be explained by the polymorphisms of its gene. Only the Thr325Ile polymorphism modulates both TAFI Ag and Act levels in vitro. This study assessed TAFI Ag and Act levels, TAFI Thr325Ile polymorphism, the fibrinolytic and protein C systems and some prothrombotic mutations in a young patient group (n = 127, aged < 51 years, with myocardial infarction) and a control group (n = 99) with similar characteristics. Patients exhibited hypofibrinolysis and higher plasminogen activator inhibitor‐1 (PAI‐1) levels. Although TAFI Ag was lower, TAFI Act level was significantly higher in patients and positively correlated with PAI‐1, protein C inhibitor and the euglobulin lysis time. No differences between groups were found according to the Thr325Ile polymorphism. Irrespective of the genotype, patients had higher TAFI Act levels. The Ile‐325 variant exhibited lower TAFI Ag levels. We suggest that the hypofibrinolysis observed in these patients results from an increase in both PAI‐1 and TAFI Act, which is not related to the Thr325Ile polymorphism. Patients have high TAFI Act with low TAFI Ag levels, probably because of an increased stability of TAFI related to a fibrinolytic hypofunction.

Everolimus with reduced cyclosporine versus MMF with standard cyclosporine in de novo heart transplant recipients.

Background. Pharmacokinetic modeling supports trough monitoring of everolimus, but prospective data comparing this approach versus mycophenolate mofetil (MMF) in de novo cardiac transplant recipients are currently unavailable. Methods. In a 12-month multicenter open-label study, cardiac transplant patients received everolimus (trough level 3–8 ng/mL) with reduced cyclosporine A (CsA) or MMF (3 g/day) with standard CsA, both with corticosteroids±induction therapy. Results. In total, 176 patients were randomized (everolimus 92, MMF 84). Mean creatinine clearance was 72.5±27.9 and 76.8±32.1 mL/min at baseline, 65.4±24.7 and 72.2±26.2 mL/min at month 6, and 68.7±27.7 and 71.8±29.8 mL/min at month 12 with everolimus and MMF, respectively. The primary endpoint was not met since calculated CrCl at month 6 posttransplant was 6.9 mL/min lower with everolimus, exceeding the predefined margin of 6 mL/min. However, by month 12 the between-group difference had narrowed versus baseline (3.1 mL/min). All efficacy endpoints were noninferior for everolimus versus MMF. The 12-month incidence of biopsy-proven acute rejection International Heart and Lung Transplantation grade more than or equal to 3A was 21 of 92 (22.8%) with everolimus and 25 of 84 (29.8%) with MMF. Adverse events were consistent with class effects including less-frequent cytomegalovirus infection with everolimus (4 [4.4%]) than MMF (14 [16.9%], P=0.01). Conclusion. Concentration-controlled everolimus with reduced CsA results in similar renal function and equivalent efficacy compared with MMF with standard CsA at 12 months after cardiac transplantation.

A randomized multicenter comparison of basiliximab and muromonab (OKT3) in heart transplantation : SIMCOR study

Background. Antilymphocytic antibodies have been long used for the prevention of acute rejection early after heart transplantation (HTx), but their adverse effects have limited their widespread use. Our aim was to evaluate the safety, tolerability, and efficacy of the novel anti-CD25 antibody basiliximab (BAS) compared with muromonab (OKT3). Patients and methods. In this multicenter study, 99 patients were randomly assigned to receive either BAS or OKT3 in the early post-HTx period. The primary endpoint was safety and tolerability. Specific safety variables were predefined for a better comparison of adverse effects. Secondary endpoints concerning anti-rejection efficacy were also evaluated. Results. No adverse events related to study medication were found in the BAS group, whereas 23 were observed among patients receiving OKT3 (P<0.0001). The proportion of patients with predefined adverse events day 4 post-HTx was much higher with OKT3 than with BAS (43% vs. 4%; P<0.0001). Fever, acute pulmonary edema, hypotension, and other complications accounted for most of the difference. At 1-year follow-up, biopsy-proven rejection episodes grade ≥3A had occurred in 39.6% of BAS patients versus 40.4% of OKT3 patients (P=0.87). There were no differences in terms of severity and timing of acute rejection episodes. The number of infectious episodes, complications not related to study medication, and actuarial survival were similar in both groups. Conclusion. In this HTx study, induction therapy with BAS was safer and better tolerated than OKT3, without significant differences in efficacy outcomes.

Randomized controlled trial of sirolimus conversion in cardiac transplant recipients with renal insufficiency.

This randomized, comparative, multinational phase 3b/4 study of patients 1–8 years postcardiac transplantation (mean 3.9 years) evaluated the effect of conversion from a calcineurin inhibitor (CNI) to sirolimus on renal function in patients with renal insufficiency. In total, 116 patients on CNI therapy with GFR 40–90 mL/min/1.73m2 were randomized (1:1) to sirolimus (n = 57) or CNI (n = 59). Intent‐to‐treat analysis showed the 1‐year adjusted mean change from baseline in creatinine clearance (Cockcroft‐Gault) was significantly higher with sirolimus versus CNI treatment (+3.0 vs. −1.4 mL/min/1.73 m2, respectively; p = 0.004). By on‐therapy analysis, values were +4.7 and –2.1, respectively (p < 0.001). Acute rejection (AR) rates were numerically higher in the sirolimus group; 1 AR with hemodynamic compromise occurred in each group. A significantly higher treatment discontinuation rate due to adverse events (AEs; 33.3% vs. 0%; p < 0.001) occurred in the sirolimus group. Most common treatment‐emergent AEs significantly higher in the sirolimus group were diarrhea (28.1%), rash (28.1%) and infection (47.4%). Conversion to sirolimus from CNI therapy improved renal function in cardiac transplant recipients with renal impairment, but was associated with an attendant AR risk and higher discontinuation rate attributable to AEs.

New concepts and best practices for management of pre- and post-transplantation cancer

Solid-organ transplant recipients are at increased risk of developing cancer compared with the general population. Tumours can arise de novo, as a recurrence of a preexisting malignancy, or from the donated organ. The ATOS (Aula sobre Trasplantes de Órganos Sólidos; the Solid-Organ Transplantation Working Group) group, integrated by Spanish transplant experts, meets annually to discuss current advances in the field. In 2011, the 11th edition covered a range of new topics on cancer and transplantation. In this review we have highlighted the new concepts and best practices for managing cancer in the pre-transplant and post-transplant settings that were presented at the ATOS meeting. Immunosuppression plays a major role in oncogenesis in the transplant recipient, both through impaired immunosurveillance and through direct oncogenic activity. It is possible to transplant organs obtained from donors with a history of cancer as long as an effective minimization of malignancy transmission strategy is followed. Tumour-specific wait-periods have been proposed for the increased number of transplantation candidates with a history of malignancy; however, the patients individual risk of death from organ failure must be taken into consideration. It is important to actively prevent tumour recurrence, especially the recurrence of hepatocellular carcinoma in liver transplant recipients. To effectively manage post-transplant malignancies, it is essential to proactively monitor patients, with long-term intensive screening programs showing a reduced incidence of cancer post-transplantation. Proposed management strategies for post-transplantation malignancies include viral monitoring and prophylaxis to decrease infection-related cancer, immunosuppression modulation with lower doses of calcineurin inhibitors, and addition of or conversion to inhibitors of the mammalian target of rapamycin.

Primary graft failure after heart transplantation: Characteristics in a contemporary cohort and performance of the RADIAL risk score

BACKGROUND Primary graft failure (PGF) is the leading cause of early heart transplantation (HT) mortality. Our aim was to analyze PGF currently and explore the ability of a dedicated score for PGF risk stratification. METHODS After applying a dedicated PGF definition, we analyzed its incidence, mortality, and associated factors in a multicenter cohort of 857 HTs performed in 2006 to 2009. We used the following criteria: recipient right (R) atrial pressure ≥ 10 mm Hg; age (A) ≥ 60 years; diabetes (D) mellitus, and inotrope (I) dependence; donor age (A) ≥ 30 years, and length (L) of ischemia ≥ 240 minutes to calculate the RADIAL score for PGF risk prediction. RESULTS PGF incidence was 22%. The right ventricle was almost always affected, alone (45%) or as part of biventricular failure (47%). Mechanical circulatory support was used in 55%. Mortality attributable to PGF was 53% and extended through the third month after HT, but thereafter, PGF had little influence in long-term outcome. The RADIAL score was higher in PGF patients (2.78 ± 1.1 vs. 2.42 ± 1.1, p = 0.001) and stratified 3 groups with incremental PGF incidence: low risk (12.1%), intermediate risk (19.4%), and high risk (27.5%, p = 0.001). CONCLUSIONS PGF had a strong impact, with an incidence of 22% and a mortality exceeding 50% that extends through the third post-HT month. The RADIAL score classified patients into 3 groups with incremental risk for PGF and may be useful for its prevention and early therapy.

The use of proliferation signal inhibitors in the prevention and treatment of allograft vasculopathy in heart transplantation

Cardiac allograft vasculopathy (CAV) currently represents one of the most important causes of long-term morbidity and mortality in the heart transplant population. In well-designed studies with de novo patients, the use of proliferation signal inhibitors (PSIs; everolimus and sirolimus) has been shown to significantly prevent the intimal growth of graft coronary arteries in comparison to other immunosuppressive regimens, reducing the incidence of vasculopathy at 12 and 24 months. In addition, conversion to PSIs in maintenance patients with established CAV has also shown promising results in the reduction of the progression of the disease and its clinical consequences. For these reasons the interest shown by various transplantation units in the potential role of PSIs in this field is growing. The aim of the present article is to review the information obtained to date on the use of PSIs in heart transplant recipients, both in the prevention and the treatment of CAV. The principal published recommendations on the introduction and appropriate management of these drugs in clinical practice are also collected, as well as certain recommendations given by the authors based on their experience.