Off-Label Immunosuppressant Drugs in Solid Organ Transplantation.

Once a solid organ transplantation (SOT) has been performed, it is necessary to prescribe immunosuppressant medication to prevent graft rejection. This task has the peculiarity that many of these drugs do not have specific indications for transplant use in the technical data sheets. We performed a review of different immunosuppressive drugs' information available at European and American regulatory agencies in order to analyze the approved indications by the type of SOT. In our work, besides showing these differences between different indication approvals in different SOT modalities, we also attempted to reflect other differences under the approved indications according to age group, formulation type, geographical area, etc. Although consensus documents on the subject have been published, the access to immunosuppressants depends on each country's regulation and healthcare system, and off-label prescription is a reality that healthcare professionals need to be familiar with.

Donor-Derived Cell-Free DNA at 1 Month after Kidney Transplantation Relates to HLA Class II Eplet Mismatch Load.

Kidney transplantation is the preferred therapeutic option for end-stage renal disease; however, the alloimmune response is still the leading cause of renal allograft failure. To better identify immunologic disparities in order to evaluate HLA compatibility between the donor and the recipient, the concept of eplet load has arisen. Regular kidney function monitoring is essential for the accurate and timely diagnosis of allograft rejection and the appropriate treatment. Donor-derived cell-free DNA (dd-cfDNA) has been proposed as a potential biomarker of acute rejection and graft failure in kidney transplantation. The proportion of plasma dd-cfDNA was determined in forty-two kidney patients at 1 month after transplantation. A total of eleven (26.2%) patients had a dd-cfDNA proportion of ≥1.0%. The only pretransplant variable related to dd-cfDNA > 1.0% was the HLA class II eplet mismatch load, mainly the HLA-DQB1 eplet mismatch load. Furthermore, dd-cfDNA was able to discriminate the patients with antibody-mediated rejection (AbMR) (AUC 87.3%), acute rejection (AUC 78.2%), and troubled graft (AUC 81.4%). Increased dd-cfDNA levels were associated with kidney allograft deterioration, particularly rejection, as well as a greater HLA class II eplet mismatch load. Consequently, combining dd-cfDNA determination and HLA eplet mismatch load calculation should improve the assessment of the risk of short- and long-term allograft damage.

Torque Teno Virus Load Predicts Opportunistic Infections after Kidney Transplantation but Is Not Associated with Maintenance Immunosuppression Exposure.

Measuring the non-pathogenic Torque Teno Virus (TTV) load allows assessing the net immunosuppressive state after kidney transplantation (KTx). Currently, it is not known how exposure to maintenance immunosuppression affects TTV load. We hypothesized that TTV load is associated with the exposure to mycophenolic acid (MPA) and tacrolimus. We performed a prospective study including 54 consecutive KTx. Blood TTV load was measured by an in-house PCR at months 1 and 3. Together with doses and trough blood levels of tacrolimus and MPA, we calculated the coefficient of variability (CV), time in therapeutic range (TTR) and concentration/dose ratio (C/D) of tacrolimus, and the MPA-area under the curve (AUC-MPA) at the third month. TTV load at the first and third month discriminated those patients at risk of developing opportunistic infections between months 1 and 3 (AUC-ROC 0.723, 95%CI 0.559-0.905, p = 0.023) and between months 3 and 6 (AUC-ROC 0.778, 95%CI 0.599-0.957, p = 0.028), respectively, but not those at risk of acute rejection. TTV load did not relate to mean tacrolimus blood level, CV, TTR, C/D and AUC-MPA. To conclude, although TTV is a useful marker of net immunosuppressive status after KTx, it is not related to exposure to maintenance immunosuppression.

Calcineurin inhibitors' impact on cardiovascular and renal function, a descriptive study in lung transplant recipients from the North of Spain.

Patients undergoing lung transplantation (LTx) need administration of immunosuppressive therapy following the procedure to prevent graft rejection. However, these drugs are not exempt from potential risks. The development of cardiovascular risk factors and impaired renal function in the post-transplantation period are conditions that may be favoured by the use of calcineurin inhibitor (CNI) drugs which could have repercussions on the quality of life and the post-transplantation evolution. To evaluate the cardiovascular and renal toxicity following the administration of CNI as maintenance immunosuppression in lung transplant recipients (LTRs) we reviewed a total number of 165 patients undergoing LTx between 01/01/2015 and 08/12/2018. They were divided into two groups according to the CNI drug administrated: cyclosporine (CsA-group) with 11 patients or tacrolimus (Tac-group), with 154 patients. We evaluated the de novo occurrence of arterial hypertension (HTN), diabetes mellitus (DM), hyperlipidemia and impaired renal function after initiation of CNI administration. In addition to that, the time until each of these events was assessed. A higher rate for developing HTN (p < 0.001) and impaired renal function (p = 0.047) was observed within the CsA-group. The new onset of hyperlipidemia was similar between both CNI groups and de novo appearance of DM was only documented in those LTRs receiving tacrolimus. In this LTRs retrospective study, it was observed that having ≥ 4 tacrolimus trough levels above the upper limit of the proposed interval for each specific post-LTx period was associated with an increased risk for developing renal impairment. No other statistically significant association was found between supratherapeutic CNIs blood levels and the evaluated toxicities.

Lower Time in Therapeutic Range Relates to a Worse Kidney Graft Outcome.

Tacrolimus has a narrow therapeutic margin. Maintaining tacrolimus blood levels in the appropriate range is difficult because of its intrapatient variability. In fact, greater blood level variability has been related to worse kidney graft outcome, but only measuring variability does not consider the therapeutic range goal. Determining the time in therapeutic range (TTR) using the Rosendaal method allows dose optimization by considering the adverse events associated with both supratherapeutic and subtherapeutic doses. Some previous studies in kidney and lung transplantation have shown that the measurement of TTR has been related to the subsequent graft outcome. We performed a single-center, observational study including 215 consecutive kidney transplants performed in our center. The percentage of time that the patient remained with levels above 6 ng/mL between months 3 and 12 (%TTR3-12) was calculated using the Rosendaal method. A lower %TTR3-12 was associated with a higher risk of acute rejection (area under the receiver operating characteristic curve, 0.614; 95% confidence interval [CI], 0.513-0.714; P = .018) and with a higher risk of having a 1-year glomerular filtration rate < 30 mL/min/1.73 m2 (area under the receiver operating characteristic curve, 0.676; 95% CI, 0.542-0.811; P = .014). The lowest tertile of %TTR3-12 was independently associated with a higher risk of death-censored graft loss (hazard ratio, 10.773; 95% CI, 1.315-88.264; P = .027) after adjusting by 1-year glomerular filtration rate, expanded criteria donation, and acute rejection throughout the first year. To conclude, measuring TTR after kidney transplant is an easy way to estimate the time of exposure to adequate levels of tacrolimus and relates to kidney graft outcome.

Utilidad de la ficha técnica de los medicamentos como herramienta para mejorar la prescripción en pacientes mayores / Usefulness of the summary of product characteristics as a tool to improve prescription in elderly patients

ANTECEDENTES Y OBJETIVO: La ficha técnica debe contribuir a un uso seguro y efectivo de medicamentos en las personas de edad avanzada, proporcionando información precisa sobre la prescripción, sobre los posibles beneficios o riesgos de los medicamentos, o en su defecto comunicando la falta de información sobre su uso en este grupo. Nuestro objetivo fue cuantificar la información específica para personas mayores de 65 años contenida en las fichas técnicas de los fármacos comercializados en España, y que permite una adecuada prescripción en dicha población. MATERIALES Y MÉTODOS: Un grupo multidisciplinar revisó todas las fichas técnicas de los medicamentos autorizados por la Agencia Española de Medicamentos y Productos Sanitarios. Se clasificó la calidad de la información en 4 categorías: información referida específicamente a la población de más de 65 años, información referida específicamente a la población de más de 80 años, recomendaciones no específicas para los ancianos e información específica para los ancianos. RESULTADOS: Se revisaron un total de 1.462 fichas técnicas, de las cuales el 48% tenía información relativa a la prescripción en ancianos. La información sobre el uso en mayores de 80 años estaba presente en el 1,23% de las fichas. Solo 6,83% del total de las fichas revisadas incluía recomendaciones específicas para el anciano. CONCLUSIONES: Hay poca información específica para la adecuada prescripción en personas de edad avanzada, en las fichas técnicas de los fármacos comercializados en España. Para mejorar el conocimiento en este campo debemos incluir datos en las fichas basados en la literatura científica, de ensayos clínicos dirigidos a personas mayores o de estudios de farmacovigilancia centrados en esta población

BACKGROUND AND OBJECTIVE: The Drug Technical Data Sheet should contribute to a safe and effective use of medications in the elderly, providing accurate information on the prescription, on the possible benefits or risks of the medications, or failing that, communicating the lack of information on their use in this group. The aim of this article was to quantify the specific information for people over 65 years of age included in the data sheets of the drugs available in Spain, and enables an adequate prescription in this population. MATERIALS AND METHODS: A multidisciplinary group reviewed all the Technical Data Sheets of drugs approved by the Spanish Agency for Medicines and Health Devices (AEMPS). The quality of the information was classified into 4 categories: information specifically referring to the population over 65 years old; information specifically referring to the population over 80 years old; recommendations not specific to the elderly; and specific information for the elderly. RESULTS: A total of 1,462 Technical Sheets were reviewed, of which 48% had information regarding prescription in the elderly. Information on the use in patients over 80 years old was present in 1.23% of the sheets. Only 6.83% of all the sheets reviewed included specific recommendations for the elderly. CONCLUSIONS: There is little specific information regarding prescription in the elderly in the technical data sheets of drugs prescribed/sold in Spain. To improve knowledge in this field, data must be provided in the sheets that are based on the scientific literature, clinical trials for the elderly, or pharmacovigilance studies focused on this population

[Usefulness of the summary of product characteristics as a tool to improve prescription in elderly patients]. / Utilidad de la ficha técnica de los medicamentos como herramienta para mejorar la prescripción en pacientes mayores.

BACKGROUND AND OBJECTIVE: The Drug Technical Data Sheet should contribute to a safe and effective use of medications in the elderly, providing accurate information on the prescription, on the possible benefits or risks of the medications, or failing that, communicating the lack of information on their use in this group. The aim of this article was to quantify the specific information for people over 65 years of age included in the data sheets of the drugs available in Spain, and enables an adequate prescription in this population. MATERIALS AND METHODS: A multidisciplinary group reviewed all the Technical Data Sheets of drugs approved by the Spanish Agency for Medicines and Health Devices (AEMPS). The quality of the information was classified into 4 categories: information specifically referring to the population over 65 years old; information specifically referring to the population over 80 years old; recommendations not specific to the elderly; and specific information for the elderly. RESULTS: A total of 1,462 Technical Sheets were reviewed, of which 48% had information regarding prescription in the elderly. Information on the use in patients over 80 years old was present in 1.23% of the sheets. Only 6.83% of all the sheets reviewed included specific recommendations for the elderly. CONCLUSIONS: There is little specific information regarding prescription in the elderly in the technical data sheets of drugs prescribed/sold in Spain. To improve knowledge in this field, data must be provided in the sheets that are based on the scientific literature, clinical trials for the elderly, or pharmacovigilance studies focused on this population.

Study Design and Rationale of "A Multicenter, Open-Labeled, Randomized Controlled Trial Comparing MIdazolam Versus MOrphine in Acute Pulmonary Edema": MIMO Trial.

PURPOSE: Morphine has been used for several decades in cases of acute pulmonary edema (APE) due to the anxiolytic and vasodilatory properties of the drug. The non-specific depression of the central nervous system is probably the most significant factor for the changes in hemodynamics in APE. Retrospective studies have shown both negative and neutral effects in patients with APE and therefore some authors have suggested benzodiazepines as an alternative treatment. The use of intravenous morphine in the treatment of APE remains controversial. METHODS: The MIdazolan versus MOrphine in APE trial (MIMO) is a multicenter, prospective, open-label, randomized study designed to evaluate the efficacy and safety of morphine in patients with APE. The MIMO trial will evaluate as a primary endpoint whether intravenous morphine administration improves clinical outcomes defined as in-hospital mortality. Secondary endpoint evaluation will be mechanical ventilation, cardiopulmonary resuscitation, intensive care unit admission rate, intensive care unit length of stay, and hospitalization length. CONCLUSIONS: In the emergency department, morphine is still used for APE in spite of poor scientific background data. The data from the MIMO trial will establish the effect-and especially the risk-when using morphine for APE.

Effect of intravenous and intracoronary melatonin as an adjunct to primary percutaneous coronary intervention for acute ST-elevation myocardial infarction: Results of the Melatonin Adjunct in the acute myocaRdial Infarction treated with Angioplasty trial.

The MARIA randomized trial evaluated the efficacy and safety of melatonin for the reduction of reperfusion injury in patients undergoing revascularization for ST-elevation myocardial infarction (STEMI). This was a prespecified interim analysis. A total of 146 patients presenting with STEMI within 6 hours of chest pain onset were randomized to receive intravenous and intracoronary melatonin (n=73) or placebo (n=73) during primary percutaneous coronary intervention (PPCI). Primary endpoint was myocardial infarct size as assessed by magnetic resonance imaging (MRI) at 6 ± 2 days. Secondary endpoints were changes in left ventricular volumes and ejection fraction (LVEF) at 130 ± 10 days post-PPCI and adverse events during the first year. No significant differences in baseline characteristics were observed between groups. MRI was performed in 108 patients (86.4%). Myocardial infarct size by MRI evaluated 6 ± 2 days post-PPCI, did not differ between melatonin and placebo groups (P=.63). Infarct size assessed by MRI at 130 ± 10 days post-PPCI, performed in 91 patients (72.8%), did not show statistically significant differences between groups (P=.27). The recovery of LVEF from 6 ± 2 to 130 ± 10 days post-PPCI was greater in the placebo group (60.0 ± 10.4% vs 53.1 ± 12.5%, P=.008). Both left ventricular end-diastolic and end-systolic volumes were lower in the placebo group (P=.01). The incidence of adverse events at 1 year was comparable in both groups (P=.150). Thus, in a nonrestricted STEMI population, intravenous and intracoronary melatonin was not associated with a reduction in infarct size and has an unfavourable effect on the ventricular volumes and LVEF evolution. Likewise, there is lack of toxicity of melatonin with the doses used.