RESUMEN
BACKGROUND: High-density lipoprotein plays a key role in reverse cholesterol transport. In addition, high-density lipoprotein particles may be cardioprotective and reduce infarct size in the setting of myocardial injury. Lecithin-cholesterol acyltransferase is a rate-limiting enzyme in reverse cholesterol transport. MEDI6012 is a recombinant human lecithin-cholesterol acyltransferase that increases high-density lipoprotein cholesterol. Administration of lecithin-cholesterol acyltransferase has the potential to reduce infarct size and regress coronary plaque in acute ST-segment-elevation myocardial infarction. METHODS: REAL-TIMI 63B (A Randomized, Placebocontrolled Phase 2b Study to Evaluate the Safety and Efficacy of MEDI6012 in Acute ST Elevation Myocardial Infarction) was a phase 2B multinational, placebo-controlled, randomized trial. Patients with ST-segment-elevation myocardial infarction within 6 hours of symptom onset and planned for percutaneous intervention were randomly assigned 2:1 to MEDI6012 (2- or 6-dose regimen) or placebo and followed for 12 weeks. The primary outcome was infarct size as a percentage of left ventricular mass by cardiac MRI at 10 to 12 weeks, with the primary analysis in patients with TIMI Flow Grade 0 to 1 before percutaneous intervention who received at least 2 doses of MEDI6012. The secondary outcome was change in noncalcified plaque volume on coronary computed tomographic angiography from baseline to 10 to 12 weeks with the primary analysis in patients who received all 6 doses of MEDI6012. RESULTS: A total of 593 patients were randomly assigned. Patients were a median of 62 years old, 77.9% male, and 95.8% statin naive. Median time from symptom onset to randomization was 146 (interquartile range [IQR], 103-221) minutes and from hospitalization to randomization was 12.7 (IQR, 6.6-24.0) minutes, and the first dose of drug was administered a median of 8 (IQR, 3-13) minutes before percutaneous intervention. The index myocardial infarction was anterior in 69.6% and TIMI Flow Grade 0 to 1 in 65.1% of patients. At 12 weeks, infarct size did not differ between treatment groups (MEDI6012: 9.71%, IQR 4.79-16.38; placebo: 10.48%, [IQR, 4.92-16.61], 1-sided P=0.79. There was also no difference in noncalcified plaque volume (geometric mean ratio, 0.96 [95% CI, NA-1.10], 1-sided P=0.30). There was no significant difference in treatment emergent serious adverse events. CONCLUSIONS: Administration of MEDI6012 in patients with acute ST-segment-elevation myocardial infarction did not result in a significant reduction in infarct size or noncalcified plaque volume at 12 weeks. MEDI6012 was well tolerated with no excess in overall serious adverse events. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03578809.
Asunto(s)
Infarto de la Pared Anterior del Miocardio , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Fosfatidilcolina-Esterol O-Aciltransferasa , Infarto del Miocardio con Elevación del ST , Colesterol , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Lecitinas/uso terapéutico , Lipoproteínas HDL/uso terapéutico , Masculino , Persona de Mediana Edad , Fosfatidilcolina-Esterol O-Aciltransferasa/uso terapéutico , Infarto del Miocardio con Elevación del ST/diagnóstico por imagen , Infarto del Miocardio con Elevación del ST/tratamiento farmacológico , Esterol O-Aciltransferasa/uso terapéutico , Resultado del TratamientoRESUMEN
Huntington's disease (HD) is a hereditary neurodegenerative disorder of the basal ganglia for which disease-modifying treatments are not yet available. Although gene-silencing therapies are currently being tested, further molecular mechanisms must be explored to identify druggable targets for HD. Cytoplasmic polyadenylation element binding proteins 1 to 4 (CPEB1 to CPEB4) are RNA binding proteins that repress or activate translation of CPE-containing transcripts by shortening or elongating their poly(A) tail. Here, we found increased CPEB1 and decreased CPEB4 protein in the striatum of patients and mouse models with HD. This correlated with a reprogramming of polyadenylation in 17.3% of the transcriptome, markedly affecting neurodegeneration-associated genes including PSEN1, MAPT, SNCA, LRRK2, PINK1, DJ1, SOD1, TARDBP, FUS, and HTT and suggesting a new molecular mechanism in neurodegenerative disease etiology. We found decreased protein content of top deadenylated transcripts, including striatal atrophylinked genes not previously related to HD, such as KTN1 and the easily druggable SLC19A3 (the ThTr2 thiamine transporter). Mutations in SLC19A3 cause biotin-thiamineresponsive basal ganglia disease (BTBGD), a striatal disorder that can be treated with a combination of biotin and thiamine. Similar to patients with BTBGD, patients with HD demonstrated decreased thiamine in the cerebrospinal fluid. Furthermore, patients and mice with HD showed decreased striatal concentrations of thiamine pyrophosphate (TPP), the metabolically active form of thiamine. High-dose biotin and thiamine treatment prevented TPP deficiency in HD mice and attenuated the radiological, neuropathological, and motor HD-like phenotypes, revealing an easily implementable therapy that might benefit patients with HD.
Asunto(s)
Enfermedad de Huntington , Poliadenilación , Factores de Transcripción/genética , Factores de Escisión y Poliadenilación de ARNm/genética , Humanos , Enfermedad de Huntington/genética , Enfermedad de Huntington/terapia , Proteínas de Transporte de Membrana , TranscriptomaRESUMEN
BACKGROUND: Andexanet alfa (andexanet) is a recombinant modified human factor Xa decoy protein that has been shown to reverse the inhibition of factor Xa in healthy volunteers. METHODS: In this multicenter, prospective, open-label, single-group study, we evaluated 67 patients who had acute major bleeding within 18 hours after the administration of a factor Xa inhibitor. The patients all received a bolus of andexanet followed by a 2-hour infusion of the drug. Patients were evaluated for changes in measures of anti-factor Xa activity and were assessed for clinical hemostatic efficacy during a 12-hour period. All the patients were subsequently followed for 30 days. The efficacy population of 47 patients had a baseline value for anti-factor Xa activity of at least 75 ng per milliliter (or ≥0.5 IU per milliliter for those receiving enoxaparin) and had confirmed bleeding severity at adjudication. RESULTS: The mean age of the patients was 77 years; most of the patients had substantial cardiovascular disease. Bleeding was predominantly gastrointestinal or intracranial. The mean (±SD) time from emergency department presentation to the administration of the andexanet bolus was 4.8±1.8 hours. After the bolus administration, the median anti-factor Xa activity decreased by 89% (95% confidence interval [CI], 58 to 94) from baseline among patients receiving rivaroxaban and by 93% (95% CI, 87 to 94) among patients receiving apixaban. These levels remained similar during the 2-hour infusion. Four hours after the end of the infusion, there was a relative decrease from baseline of 39% in the measure of anti-factor Xa activity among patients receiving rivaroxaban and of 30% among those receiving apixaban. Twelve hours after the andexanet infusion, clinical hemostasis was adjudicated as excellent or good in 37 of 47 patients in the efficacy analysis (79%; 95% CI, 64 to 89). Thrombotic events occurred in 12 of 67 patients (18%) during the 30-day follow-up. CONCLUSIONS: On the basis of a descriptive preliminary analysis, an initial bolus and subsequent 2-hour infusion of andexanet substantially reduced anti-factor Xa activity in patients with acute major bleeding associated with factor Xa inhibitors, with effective hemostasis occurring in 79%. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327 .).
Asunto(s)
Inhibidores del Factor Xa/efectos adversos , Factor Xa/uso terapéutico , Hemorragia/tratamiento farmacológico , Proteínas Recombinantes/uso terapéutico , Enfermedad Aguda , Anciano , Anciano de 80 o más Años , Enfermedades Cardiovasculares/complicaciones , Enoxaparina/efectos adversos , Factor Xa/efectos adversos , Inhibidores del Factor Xa/metabolismo , Inhibidores del Factor Xa/uso terapéutico , Femenino , Hemorragia Gastrointestinal/inducido químicamente , Hemorragia Gastrointestinal/tratamiento farmacológico , Hemorragia/inducido químicamente , Humanos , Infusiones Intravenosas , Hemorragias Intracraneales/inducido químicamente , Hemorragias Intracraneales/diagnóstico , Hemorragias Intracraneales/tratamiento farmacológico , Masculino , Estudios Prospectivos , Pirazoles/efectos adversos , Piridonas/efectos adversos , Proteínas Recombinantes/efectos adversos , Rivaroxabán/efectos adversos , Trombosis/etiologíaRESUMEN
AIMS: Fluoroscopy is necessary to implant cardioverter defibrillators using the conventional approach. Modern electroanatomic navigation systems allow the visualization of multiple catheters and, as they are capable of rendering precise geometrical reconstructions of cardiac chambers, have been used for fluoroscopy-free electrophysiological procedures. The aim of our study was to assess the feasibility of non-fluoroscopic implants using a three-dimensional navigation system. METHODS AND RESULTS: The NavX system was used to create the virtual anatomies of heart chambers and thoracic veins. Defibrillator leads were placed at stable positions using exclusively the electrical and anatomical information provided by the navigator. A single fluoroscopy shot confirmed final lead positions. Thirty-five consecutive patients had 30 single-chamber and 5 dual-chamber defibrillators implanted. Cardiac chambers geometries were developed in 10 ± 4.3 min. Ventricular and atrial leads were implanted, with suitable positions and electrical parameters being achieved, in 18 ± 22 and 16 ± 9 min, respectively. The final confirmatory shot was the only fluoroscopy needed in 31 (89%) cases. Two patients needed fluoroscopy-guided relocation of the ventricular lead due to high defibrillation threshold and a breakdown of the active-fixation mechanism, respectively. In one patient the ventricular lead was totally extracted and reimplanted because a loop has formed in the vena cava, and one patient required fluoroscopy-guided subclavian puncture. In five cases (16%), the position of the proximal defibrillation coil was minimally modified with fluoroscopy due to incomplete geometric reconstruction of the superior vena cava. CONCLUSION: Fluoroscopy-free defibrillators implantation is feasible using a navigation system. Suitable placement of the proximal coil is a critical stage and requires a reliable and complete reconstruction of the superior vena cava.
Asunto(s)
Desfibriladores Implantables , Cardioversión Eléctrica/instrumentación , Técnicas Electrofisiológicas Cardíacas/métodos , Imagenología Tridimensional , Implantación de Prótesis , Cirugía Asistida por Computador , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Factibilidad , Femenino , Fluoroscopía , Humanos , Interpretación de Imagen Asistida por Computador , Masculino , Persona de Mediana Edad , Tempo Operativo , Implantación de Prótesis/efectos adversos , Implantación de Prótesis/instrumentación , Implantación de Prótesis/métodos , Radiografía Intervencional/métodos , Cirugía Asistida por Computador/efectos adversos , Cirugía Asistida por Computador/instrumentación , Cirugía Asistida por Computador/métodos , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
La embolia sistémica y el accidente cerebrovascular están entre las complicaciones más importantes de la fibrilación auricular. La estrategia principal para prevenirlos es la anticoagulación a largo plazo, y durante los últimos 50 años los únicos anticoagulantes orales disponibles han sido los derivados de la warfarina. En el estudio ROCKET, la anticoagulación con el antagonista del factor Xa rivaroxabán demostró claras ventajas clínicas en la prevención de la embolia sistémica y las hemorragias intracraneales en comparación con la anticoagulación con warfarina, sin necesidad de realizar controles periódicos de anticoagulación. Los resultados de este estudio, junto con los de los estudios con apixabán y dabigatrán, tendrán en el futuro un impacto terapéutico y desplazarán a los dicumarínicos en la prevención de embolias en pacientes con fibrilación auricular (AU)
Systemic embolism and stroke are two of the most important complications of atrial fibrillation. The main strategy used for their prevention is long-term oral anticoagulation therapy and, during the last 50 years, the only oral anticoagulants available were derivatives of warfarin. In the ROCKET study, anticoagulation therapy with the factor-Xa antagonist rivaroxaban demonstrated clear clinical advantages over warfarin in the prevention of systemic embolism and intracranial hemorrhage. Moreover, there was no need for regular anticoagulation monitoring. The results of that study, combined with those of studies on apixaban and dabigatran, will lead to a change in treatment in the future, and these new compounds will displace coumarins in the prevention of embolism in patients with atrial fibrillation (AU)
Asunto(s)
Humanos , Dabigatrán/uso terapéutico , Rivaroxabán/uso terapéutico , Trombosis/prevención & control , Anticoagulantes/uso terapéutico , Fibrilación Atrial/tratamiento farmacológico , Vitamina K/antagonistas & inhibidores , Resultado del Tratamiento , Trombina/antagonistas & inhibidores , Inhibidores del Factor Xa/uso terapéuticoRESUMEN
Durante 50 años, los inhibidores de la vitamina K han sido los únicos anticoagulantes orales disponibles para el tratamiento crónico en la prevención de embolias en pacientes con fibrilación auricular. Recientemente, se han completado y publicado tres estudios con fármacos antitrombóticos con un mecanismo de acción diferente: el dabigatrán (un inhibidor de la trombina), el rivaroxabán y el apixabán (inhibidores del factor Xa). En esta revisión se analizan las características y los resultados de los tres estudios. En todos se ha demostrado algún beneficio clínico sobre la warfarina y en su conjunto ofrecen una alternativa superior a los antagonistas de la vitamina K en la prevención de ictus y embolias sistémicas en una gran proporción de pacientes con fibrilación auricular no valvular. La utilización de estos nuevos fármacos anticoagulantes debería iniciarse ya, sin olvidar que, al ser fármacos anticoagulantes, siempre existe el riesgo de hemorragia, por lo que la selección y la educación de los enfermos son obligatorias (AU)
For 50 years, vitamin K inhibitors have been the only oral anticoagulants available for long-term use in the prevention of embolism in patients with atrial fibrillation. Recently, three studies of antithrombotic drugs with different mechanisms of action have been completed and reported: one involved the thrombin inhibitor dabigatran and two involved the factor-Xa inhibitors rivaroxaban and apixaban. This review describes the designs and results of the three studies. All demonstrated that the new drugs had some clinical advantage over warfarin and, taken together, they offer a better alternative to the use of vitamin K antagonists for preventing stroke and systematic embolism in a large proportion of patients with nonvalvular atrial fibrillation. These new anticoagulant drugs should already be in clinical use. However, it should be remembered that, as with all anticoagulants, there is always a risk of bleeding. Accordingly, it is essential that patients are carefully selected and provided with adequate information (AU)