Nicolás Manito

Multidisciplinary Insights on Clinical Guidance for the Use of Proliferation Signal Inhibitors in Heart Transplantation

Proliferation signal or mammalian target-of-rapamycin inhibitors (PSI/mTOR inhibitors), everolimus and sirolimus, provide attractive options for use in heart transplantation because they are immunosuppressive and anti-proliferative. PSI/mTOR inhibitors work synergistically with calcineurin inhibitors (CNIs) and thus permit the minimization of CNIs without compromising efficacy. This approach is advantageous for the majority of heart transplant recipients and might provide particular benefit in specific cases, such as patients with cardiac allograft vasculopathy, malignancies and renal dysfunction, or in patients intolerant to other immunosuppressive agents. Drawing on the expertise of transplant cardiologists, cardiac surgeons and nephrologists, we addressed the assessment of renal function; management of adverse events associated with this class of drugs; and clinical guidance, specifically for the use of everolimus, including patient selection, indications for treatment and practicalities of drug initiation and monitoring.

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.

Recommendations for management of Chagas disease in organ and hematopoietic tissue transplantation programs in nonendemic areas

The substantial immigration into Spain from endemic areas of Chagas disease such as Latin America has increased the number of potential donors of organs and tissues. In addition, an increasing number of patients with advanced Chagas heart disease may eventually be eligible to receive a heart transplant, a universally accepted therapeutic strategy for the advanced stages of this disease. Therefore, it is necessary to establish protocols for disease management. This document is intended to establish the guidelines to be followed when a potential donor or a tissue or organ recipient is potentially affected by Chagas disease and summarizes the action criteria against the possibility of Chagas disease transmission through the donation of organs, tissues, or hematopoietic stem cells and aims to help professionals working in this field. A single registry of transplants in Trypanosoma cruzi infected donors and/or recipients will provide and disseminate experience in this area, which has shown a low recorded incidence to date.

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.

The impact of the prevention strategies on the indirect effects of CMV infection in solid organ transplant recipients

Transplant recipients receiving immunosuppressive therapy are at increased risk of active cytomegalovirus (CMV) infection and disease. Without appropriate prophylaxis, as many as 80% of solid organ transplant recipients may experience CMV infection. In addition to the direct effects of CMV, infection may be associated with a range of indirect effects, including an increase in risk of other infections, as well as a higher incidence of rejection, graft loss and death. The indirect effects of CMV infection can vary depending on the transplanted organ. For example, CMV-infected kidney transplant recipients may be at increased risk of cardiovascular disease and diabetes, while CMV infection in liver transplant recipients may potentiate hepatitis C infection and increase the risk of post-transplant lymphoproliferative disease. Indirect effects result from a number of pathological processes, including immune modulation and immunosuppression, generation of cytotoxic, pro-inflammatory responses, and smooth muscle proliferation. Prophylactic treatment with antiviral medication can reduce the risk of CMV disease, thereby improving graft survival and overall outcomes, particularly in kidney and heart transplant recipients. Antiviral prophylaxis should be considered for all patients at risk of CMV infection after solid organ transplantation. In this paper we review the main indirect effects of CMV infection in solid organ transplant recipients, and the impact of CMV prophylaxis on these effects.

Valoración funcional en pacientes ancianos ingresados por insuficiencia cardiaca

Evaluamos la utilidad de la valoracion funcional de las actividades basicas e instrumentales de la vida diaria en pacientes muy ancianos ingresados por insuficiencia cardiaca (IC). Se incluyo a 188 pacientes > 79 anos, un 67% mujeres, con una edad media de 84,6 ± 3,5 anos. Durante el ingreso fallecieron 25 (13%) pacientes y hubo una mayor mortalidad en los que previamente eran mas dependientes para las actividades basicas e instrumentales, con una mayor comorbilidad (indice de Charlson), asi como con cifras mas bajas de hematocrito y mas altas de creatinina. En el analisis multivariable mantuvieron su significacion el indice de Barthel, el indice de Charlson y la creatinina serica. En los ingresos hospitalarios por IC en el paciente muy anciano, una valoracion funcional previa ayuda a identificar a los pacientes de riesgo.

Admission characteristics predicting longer length of stay among elderly patients hospitalized for decompensated heart failure

BACKGROUND Acutely decompensated heart failure (HF) has become the leading cause of hospitalization for people aged 65 or older. Hospital length of stay (LOS) is a key determinant of higher hospitals costs. The aim of our study is to identify the admission characteristics that predict a longer LOS for elderly patients admitted for an acute exacerbation of HF. METHODS We prospectively evaluated 324 patients (65 years of age or older), who were consecutively admitted for decompensated HF to a tertiary teaching hospital. Variables present at the time of emergency room evaluation that could predict a longer hospital LOS were determined by comparing the characteristics of patients hospitalized for less than 4 days with those of patients needing a longer stay. RESULTS There were 191 women (59%) and 133 men in the study, with an average age of 78.6 years and a mean LOS of 7.1 days. Multivariate regression models identified two independent predictors of a hospital stay longer than four days: female gender (p=0.03, OR 1.645, 95% CI 1.047-2.584) and poorer NYHA functional class (p<0.01, OR 1.699, 95% CI 1.135-2.542). CONCLUSION In elderly patients admitted for decompensated HF, the female gender and a worse functional class at the time of admission were associated with a longer subsequent LOS.

Predictors of In-Hospital Mortality Present at Admission among Patients Hospitalised because of Decompensated Heart Failure

Chronic heart failure (HF) is associated with a poor prognosis and causes considerable mortality. The aim of this study was to identify the admission characteristics useful to predict in-hospital mortality in patients admitted because of decompensation of HF. We evaluated 414 patients (age 76.2 years, 57% women). The hospital mortality rate was 11.1%. We identified 4 independent predictors of mortality: low Barthel index (odds ratio 1.03; 95% confidence interval 1.01–1.04), creatinine level >200 µmol/l (odds ratio 3.40; 95% confidence interval 1.51–7.66), peripheral oedema (odds ratio 3.12; 95% confidence interval 1.28–7.58) and the protective effect of the new onset of the disease (odds ratio 0.2; 95% confidence interval 0.08–0.77). In conclusion, the mortality of patients admitted to the hospital with an exacerbation of HF can be predicted if either poor functional capacity, renal insufficiency, peripheral oedema or previous diagnoses of HF are present. This clinical finding may help clinicians in their decision making in HF in the emergency room.