LANDMARK comparison of early outcomes of newer-generation Myval transcatheter heart valve series with contemporary valves (Sapien and Evolut) in real-world individuals with severe symptomatic native aortic stenosis: a randomised non-inferiority trial

BACKGROUND Transcatheter aortic valve implantation is an established, guideline-endorsed treatment for severe aortic stenosis. Precise sizing of the balloon-expandable Myval transcatheter heart valve (THV) series with the aortic annulus is facilitated by increasing its diameter in 1•5 mm increments, compared with the usual 3 mm increments in valve size. The LANDMARK trial aimed to show non-inferiority of the Myval THV series compared with the contemporary THVs Sapien Series (Edwards Lifesciences, Irvine, CA, USA) or Evolut Series (Medtronic, Minneapolis, MN, USA). METHODS In this prospective, multinational, randomised, open-label, non-inferiority trial across 31 hospitals in 16 countries (Germany, France, Sweden, the Netherlands, Italy, Spain, New Zealand, Portugal, Greece, Hungary, Poland, Slovakia, Slovenia, Croatia, Estonia, and Brazil), 768 participants with severe symptomatic native aortic stenosis were randomly assigned (1:1) to the Myval THV or a contemporary THV. Eligibility was primarily decided by the heart team in accordance with 2021 European Society of Cardiology guidelines. As per the criteria of the third Valve Academic Research Consortium, the primary endpoint at 30 days was a composite of all-cause mortality, all stroke, bleeding (types 3 and 4), acute kidney injury (stages 2­4), major vascular complications, moderate or severe prosthetic valve regurgitation, and conduction system disturbances resulting in a permanent pacemaker implantation. Non-inferiority of the study device was tested in the intention-to-treat population using a non-inferiority margin of 10•44% and assuming an event rate of 26•10%. This trial is registered with ClinicalTrials.gov, NCT04275726, and EudraCT, 2020-000137-40, and is closed to new participants. FINDINGS Between Jan 6, 2021, and Dec 5, 2023, 768 participants with severe symptomatic native aortic stenosis were randomly assigned, 384 to the Myval THV and 384 to a contemporary THV. 369 (48%) participants had their sex recorded as female, and 399 (52%) as male. The mean age of participants was 80•0 years (SD 5•7) for those treated with the Myval THV and 80•4 years (5•4) for those treated with a contemporary THV. Median Society of Thoracic Surgeons scores were the same in both groups (Myval 2•6% [IQR 1•7­4•0] vs contemporary 2•6% [1•7­4•0]). The primary endpoint showed non-inferiority of the Myval (25%) compared with contemporary THV (27%), with a risk difference of ­2•3% (one-sided upper 95% CI 3•8, pnon-inferiority<0•0001). No significant difference was seen in individual components of the primary composite endpoint. INTERPRETATION In individuals with severe symptomatic native aortic stenosis, the Myval THV met its primary endpoint at 30 days.

Comparison of the excretory capacities of erythropoietin and U-74389G concerning serum creatinine levels / Comparación de las capacidades excretoras de eritropoyetina y U-74389G respecto a los niveles de creatinina sérica

Introduction This study compared the excretory effects, the erythropoietin (Epo) and antioxidant drug U-74389G exert on serum creatinine levels through kidneys. 2 preliminary studies were used for this purpose including respectively one drug used in a renal ischemia­reperfusion (IR) protocol of an animal model. The preliminary studies are part of the present work. The subjects were pretreated in preliminary studies but the results of the same subjects were simply compared in the current work. Materials and methods The serum creatinine levels were evaluated at the 60th reperfusion min (for groups A, C and E) and at the 120th reperfusion min (for groups B, D and F) after IR in the 60 rats. Groups A and B received no drugs, rats from groups C and D were administered with Epo, whereas rats from groups E and F were administered with U-74389G. Results The first preliminary study recommended a non-significant excretory effect of Epo (p-value = 0.4430 > 0.05) than placebo for serum creatinine levels. The second preliminary study proved a very significant excretory effect of U-74389G (p-value = 0.0005 < 0.05) than placebo for serum creatinine levels. These 2 studies were co-evaluated since they came from the same experimental setting. The outcome of the co-evaluation was that U-74389G has at least 5-fold significant excretory action (p-value = 0.0000 < 0.05) than Epo for serum creatinine levels. Conclusions The U-74389G presents surprising effective excretory potencies for serum creatinine levels maybe of great importance in hemodialysis patients.

Introducción Este estudio comparó los efectos excretores que la eritropoyetina (Epo) y el fármaco antioxidante U-74389G ejercen sobre los niveles de creatinina sérica a través de los riñones. Se utilizaron 2 estudios preliminares incluyendo, respectivamente, un fármaco utilizado en una rata protocolo de reperfusión de isquemia renal. Los estudios preliminares son parte del presente trabajo. Los sujetos fueron pretratados en estudios preliminares, pero los resultados de los mismos sujetos fueron comparados simplemente en el trabajo actual. Materiales y métodos Se evaluaron los niveles de creatinina sérica en la 60.ª reperfusión en minutos (para los grupos A, C y E) y en la 120.ª reperfusión en minutos (para los grupos B, D y F) después de isquemia renal en las 60 ratas. Los grupos A y B no recibieron fármacos, a las ratas de los grupos C y D se les administró Epo, mientras que las ratas de los grupos E y F se les administró U-74389G. Resultados El primer estudio preliminar recomendó un efecto excretor no significativo de la Epo (valor p = 0,4430 > 0,05) comparado con el placebo para los niveles de creatinina sérica. El segundo estudio preliminar demostró un efecto excretor muy significativo del U-74389G (valor p = 0,0005 < 0,05) comparado con el placebo para los niveles de creatinina sérica. Estos 2 estudios fueron coevaluados, ya que procedían del mismo entorno experimental. El resultado fue que el U-74389G tiene una acción excretora significativa de al menos 5 veces (p = 0,0000 < 0,05) la Epo para los niveles de creatinina sérica. Conclusiones El U-74389G presenta sorprendentes potencias excretoras efectivas para los niveles de creatinina sérica, tal vez de gran importancia en pacientes en hemodiálisis.

Acute effect of the antioxidant drug U-74389G on hematocrit levels during hypoxia and reoxygenation injury in rats / Efeito agudo do fármaco antioxidante U-74389G sobre os níveis de hematócrito durante a lesão induzida por hipóxia e reoxigenação em ratos

Aims: This experimental study evaluated the effect of the antioxidant drug U-74389G on hematocrit levels using a rat model of hypoxia and reoxygenation following an established protocol. Methods: Forty rats with a mean weight of 231.875 g were employed in the study. Hematocrit levels were determined at 60 min (groups A and C) and at 120 min (groups B and D) after starting reoxygenation. Groups A and B received no drugs, whereas U-74389G was administered to rats for groups C and D. Results: U-74389G administration significantly increased hematocrit levels by 4.73%±2.25% (p=0.0435). Reoxygenation time increased hematocrit levels non significantly by 3.96%±2.29% (p=0.1025). U-74389G administration combined with reoxygenation time significantly increased hematocrit levels by 3.16%±1.33% (p=0.0196). Conclusions: U-74389G administration, whether it interacted or not with reoxygenation time, significantly increased hematocrit levels in the short term in a rat model of hypoxia and reoxygenation.

Objetivos: Este estudo experimental avaliou o efeito da droga antioxidante U-74389G nos níveis de hematócrito, utilizando um modelo murino de hipóxia e reoxigenação, de acordo com um protocolo estabelecido. Métodos: Quarenta ratos com um peso médio de 231,875 g foram utilizados no estudo. Os níveis de hematócrito foram determinados aos 60 min (grupos A e C) e aos 120 minutos (grupos B e D) após o início da reoxigenação. Os grupos A e B não receberam nenhuma droga, enquanto que a U-74389G foi administrada aos ratos dos Grupos C e D. Resultados: A administração de U-74389G aumentou significativamente os níveis de hematócrito em 4,73%±2,25% (p=0,0435). O tempo de reoxigenação aumentou não significativamente os níveis de hematócrito em 3,96%±2,29% (p=0,1025). Aadministração de U-74389G combinada com o tempo de reoxigenação aumentou significativamente os níveis de hematócrito em 3,16%±1,33 (p=0,0196). Conclusões: A administração de U-74389G, quer interagindo ou não com o tempo de reoxigenação, aumentou significativamente, no curto prazo, os níveis de hematócrito em um modelo murino de hipóxia e reoxigenação.

The effect of erythropoietin on creatine phosphokinase levels during ischemia reperfusion injury in rats / Efecto de la eritropoyetina en niveles de creatine fosfoquinasa durante daño por isquemia reperfusión en ratas

Objective: to examine the effect of erythropoietin testing on rat model and particularly the ischemia reperfusion protocol. Methods: experimental study of 40 rats weighing 247.7 g as average. The beneficial effect or non-effectiveness of the erythroproietin molecule on the blood creatine phosphokinase levels was biochemically studied. It was measured 60 min (groups A and C) and 120 min (groups B and D) after reperfusion with no administration of erythropoietin in groups C and D. Results: Erythropoietin administration significantly increased the creatine phosphokinase levels to 3586.05 IU/L (1873.115 IU/L-5298.985 IU/L;p= 0.0001). This finding was in accordance with the result of paired t-test (p= 0.0001). Reperfusion time significantly increased the CPK levels to 557.35 IU/L (-1513.284 IU/L-2627.984 IU/L; p= 0.5890), also in accordance with paired t-test (p= 0.4661). The interaction of erythropoietin administration and reperfusion time significantly increased the creatine phosphokinase levels to 1988.282 IU/L (918.2646 IU/L-3058.299 IU/L; p= 0.0006). Conclusions: Erythropoietin administration, reperfusion time and their interaction generally increase short-term effects on blood creatine phosphokinase after ischemia reperfusion injury.

Objetivo: examinar el efecto del test de eritropoyetina en un modelo de rata, particularmente el protocolo de isquemia reperfusión. Métodos: estudio experimental en el que se usaron 40 ratas con un peso medio de 247,7 g. Se estudió bioquímicamente el beneficio o el no efecto de la molécula de eritropoyetina en la creatín fosfokinasa sanguínea. Esta se midió en dos momentos: 60 min después de la reperfusión (grupos A y C) y 120 min después de esta (grupos B y D). No se administraron eritropoyetina en los grupos A y B, contrario a los grupos C y D. Resultados: la administración de eritropoyetina aumentó significativamente la creatín fosfokinasa sanguínea a 3586,05 UI/L (1873,115 IU/L-5298,985 UI/L; p= 0,0001), de acuerdo también con el test pareado t-test (p= 0,0001). El tiempo de reperfusión incrementó significativamente la creatín fosfokinasa sanguínea a 557,35 UI/L (-1513,284 UI/L-2627,984 UI/L; p= 0,5890), de acuerdo con el test aplicado t-test (p= 0,4661). La interacción de la administración de eritropoyetina y el tiempo de reperfusión elevó significativamente los niveles de creatín fosfokinasa sanguínea a 1988,282 UI/L (918,2646 IU/L-3058,299 IU/L; p= 0,0006). Conclusión: la administración de eritropoyetina, el tiempo de reperfusión y su interacción, generalmente incrementa los efectos a corto plazo en la creatín fosfokinase sanguínea después del daño por isquemia reperfusión.