Amphilimus- vs. zotarolimus-eluting stents in patients with diabetes mellitus and coronary artery disease: the SUGAR trial

Aim: Patients with diabetes mellitus are at high risk of adverse events after percutaneous revascularization, with no differences in outcomes between most contemporary drug-eluting stents. The Cre8 EVO stent releases a formulation of sirolimus with an amphiphilic carrier from laser-dug wells, and has shown clinical benefits in diabetes. We aimed to compare Cre8 EVO stents to Resolute Onyx stents (a contemporary polymer-based zotarolimus-eluting stent) in patients with diabetes. Methods and results: We did an investigator-initiated, randomized, controlled, assessor-blinded trial at 23 sites in Spain. Eligible patients had diabetes and required percutaneous coronary intervention. A total of 1175 patients were randomly assigned (1:1) to receive Cre8 EVO or Resolute Onyx stents. The primary endpoint was target-lesion failure, defined as a composite of cardiac death, target-vessel myocardial infarction, and clinically indicated target-lesion revascularization at 1-year follow-up. The trial had a non-inferiority design with a 4% margin for the primary endpoint. A superiority analysis was planned if non-inferiority was confirmed. There were 106 primary events, 42 (7.2%) in the Cre8 EVO group and 64 (10.9%) in the Resolute Onyx group [hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.44 to 0.96; pnon-inferiority <0.001; psuperiority = 0.030]. Among the secondary endpoints, Cre8 EVO stents had significantly lower rate than Resolute Onyx stents of target-vessel failure (7.5% vs 11.1%, HR 0.67, 95% CI 0.46 to 0.99; p = 0.042). Probable or definite stent thrombosis and all-cause death were not significantly different between groups. Conclusions: In patients with diabetes, Cre8 EVO stents were non-inferior to Resolute Onyx stents with regard to target-lesion failure composite outcome. An exploratory analysis for superiority at 1 year suggests that the Cre8 EVO stents might be superior to Resolute Onyx stents with regard to the same outcome

Rationale and design of the Concordance study between FFR and iFR for the assessment of lesions in the left main coronary artery. The ILITRO-EPIC-07 Trial

Introduction and objectives: Patients with left main coronary artery (LMCA) stenosis have been excluded from the trials that support the non-inferiority of the instantaneous wave-free ratio (iFR) compared to the fractional flow reserve (FFR) in the decision-making process of coronary revascularization. This study proposes to prospectively assess the concordance between the two indices in LMCA lesions and to validate the iFR cut-off value of 0.89 for clinical use. Methods: National, prospective, and observational multicenter registry of 300 consecutive patients with intermediate lesions in the LMCA (angiographic stenosis, 25% to 60%. A pressure gudiewire study and determination of the RFF and the iFR will be performed: in the event of a negative concordant result (FFR > 0.80/iFR > 0.89), no treatment will be performed; in case of a positive concordant result (FFR 0.80/iFR 0.89), an intravascular echocardiography will be performed and revascularization will be delayed if the minimum lumen area is > 6 mm(2). The primary clinical endpoint will be a composite of cardiovascular death, LMCA lesion-related non-fatal infarction or need for revascularization of the LMCA lesion at 12 months. Conclusions: Confirm that an iFR-guided decision-making process in patients with intermediate LMCA stenosis is clinically safe and would have a significant clinical impact. Also, justify its systematic use when prescribing treatment in these potentially high-risk patients

Amphilimus- vs. zotarolimus-eluting stents in patients with diabetes mellitus and coronary artery disease: the SUGAR trial.

AIM: Patients with diabetes mellitus are at high risk of adverse events after percutaneous revascularization, with no differences in outcomes between most contemporary drug-eluting stents. The Cre8 EVO stent releases a formulation of sirolimus with an amphiphilic carrier from laser-dug wells, and has shown clinical benefits in diabetes. We aimed to compare Cre8 EVO stents to Resolute Onyx stents (a contemporary polymer-based zotarolimus-eluting stent) in patients with diabetes. METHODS AND RESULTS: We did an investigator-initiated, randomized, controlled, assessor-blinded trial at 23 sites in Spain. Eligible patients had diabetes and required percutaneous coronary intervention. A total of 1175 patients were randomly assigned (1:1) to receive Cre8 EVO or Resolute Onyx stents. The primary endpoint was target-lesion failure, defined as a composite of cardiac death, target-vessel myocardial infarction, and clinically indicated target-lesion revascularization at 1-year follow-up. The trial had a non-inferiority design with a 4% margin for the primary endpoint. A superiority analysis was planned if non-inferiority was confirmed. There were 106 primary events, 42 (7.2%) in the Cre8 EVO group and 64 (10.9%) in the Resolute Onyx group [hazard ratio (HR): 0.65, 95% confidence interval (CI): 0.44-0.96; Pnon-inferiority < 0.001; Psuperiority = 0.030]. Among the secondary endpoints, Cre8 EVO stents had significantly lower rate than Resolute Onyx stents of target-vessel failure (7.5% vs. 11.1%, HR: 0.67, 95% CI: 0.46-0.99; P = 0.042). Probable or definite stent thrombosis and all-cause death were not significantly different between groups. CONCLUSION: In patients with diabetes, Cre8 EVO stents were non-inferior to Resolute Onyx stents with regard to target-lesion failure composite outcome. An exploratory analysis for superiority at 1 year suggests that the Cre8 EVO stents might be superior to Resolute Onyx stents with regard to the same outcome. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT03321032

Effectiveness of an intervention for improving drug prescription in primary care patients with multimorbidity and polypharmacy:Study protocol of a cluster randomized clinical trial (Multi-PAP project)

This study was funded by the Fondo de Investigaciones Sanitarias ISCIII (Grant Numbers PI15/00276, PI15/00572, PI15/00996), REDISSEC (Project Numbers RD12/0001/0012, RD16/0001/0005), and the European Regional Development Fund ("A way to build Europe").Background: Multimorbidity is associated with negative effects both on people's health and on healthcare systems. A key problem linked to multimorbidity is polypharmacy, which in turn is associated with increased risk of partly preventable adverse effects, including mortality. The Ariadne principles describe a model of care based on a thorough assessment of diseases, treatments (and potential interactions), clinical status, context and preferences of patients with multimorbidity, with the aim of prioritizing and sharing realistic treatment goals that guide an individualized management. The aim of this study is to evaluate the effectiveness of a complex intervention that implements the Ariadne principles in a population of young-old patients with multimorbidity and polypharmacy. The intervention seeks to improve the appropriateness of prescribing in primary care (PC), as measured by the medication appropriateness index (MAI) score at 6 and 12months, as compared with usual care. Methods/Design: Design:pragmatic cluster randomized clinical trial. Unit of randomization: family physician (FP). Unit of analysis: patient. Scope: PC health centres in three autonomous communities: Aragon, Madrid, and Andalusia (Spain). Population: patients aged 65-74years with multimorbidity (≥3 chronic diseases) and polypharmacy (≥5 drugs prescribed in ≥3months). Sample size: n=400 (200 per study arm). Intervention: complex intervention based on the implementation of the Ariadne principles with two components: (1) FP training and (2) FP-patient interview. Outcomes: MAI score, health services use, quality of life (Euroqol 5D-5L), pharmacotherapy and adherence to treatment (Morisky-Green, Haynes-Sackett), and clinical and socio-demographic variables. Statistical analysis: primary outcome is the difference in MAI score between T0 and T1 and corresponding 95% confidence interval. Adjustment for confounding factors will be performed by multilevel analysis. All analyses will be carried out in accordance with the intention-to-treat principle. Discussion: It is essential to provide evidence concerning interventions on PC patients with polypharmacy and multimorbidity, conducted in the context of routine clinical practice, and involving young-old patients with significant potential for preventing negative health outcomes. Trial registration: Clinicaltrials.gov, NCT02866799Publisher PDFPeer reviewe

The First Signal to Initiate Fruit Ripening is Generated in the Cuticle: An Hypothesis

The paradigm that has prevailed for a long time sustains that ethylene is the first signal that initiates fruit ripening. However, in this manuscript, we present the hypothesis that a signal generated from the cuticle induces the synthesis of ethylene, and therefore, it is the initial signal that triggers the fruit-ripening phenomena. Among the experimental evidence supporting the hypothesis, we can mention that cuticle components released during the plant pathogenic attack can induce the synthesis of ethylene in plants. Also, it has been found that in fungi, a cuticle component can activate a transcription factor by phosphorylation, which induces the transcription of a gene encoding a cutinase. Besides, studies with plant tissues experiencing a high rate of cell expansion have shown that there is a careful synchronization between the demand of cuticle components and biosynthesis, which suggests that the plant cell can sense the moment in which the fruit would stop growing by cell expansion, and initiate the ripening phenomena. In this chapter, experimental evidences supporting the physiological role of the fruit cuticle in the fruit ripening phenomena will be presented and reviewed with the goal to show a possible role of the fruit cuticle in the onset of fruit ripening

Justificación y diseño del estudio Concordancia entre RFF e iFR en lesiones del tronco común.: Estudio iLITRO-EPIC-07

Introduction and objectives: Patients with left main coronary artery (LMCA) stenosis have been excluded from the trials that support the non-inferiority of the instantaneous wave-free ratio (iFR) compared to the fractional flow reserve (FFR) in the decision-making process of coronary revascularization. This study proposes to prospectively assess the concordance between the two indices in LMCA lesions and to validate the iFR cut-off value of 0.89 for clinical use. Methods: National, prospective, and observational multicenter registry of 300 consecutive patients with intermediate lesions in the LMCA (angiographic stenosis, 25% to 60%. A pressure gudiewire study and determination of the RFF and the iFR will be performed: in the event of a negative concordant result (FFR > 0.80/iFR > 0.89), no treatment will be performed; in case of a positive concordant result (FFR ≤ 0.80/iFR ≤ 0.89), revascularization will be performed; In the event of a discordant result (FFR> 0.80/iFR ≤ 0.89 or FFR ≤ 0.80/iFR> 0.89), an intravascular echocardiography will be performed and revascularization will be delayed if the minimum lumen area is > 6 mm2. The primary clinical endpoint will be a composite of cardiovascular death, LMCA lesion-related non-fatal infarction or need for revascularization of the LMCA lesion at 12 months. Conclusions: Confirm that an iFR-guided decision-making process in patients with intermediate LMCA stenosis is clinically safe and would have a significant clinical impact. Also, justify its systematic use when prescribing treatment in these potentially high-risk patients. Registered at ClinicalTrials.gov ( Identifier: NCT03767621).Introducción y objetivos: Los pacientes con estenosis en el tronco coronario izquierdo (TCI) han sido excluidos de los ensayos que apoyan la no inferioridad del cociente de presiones en el índice diastólico instantáneo sin ondas (iFR) respecto a la reserva fraccional de flujo (RFF) en la toma de decisiones sobre revascularización coronaria. El presente estudio propone valorar de manera prospectiva la concordancia entre los dos índices en lesiones del TCI y validar el valor de corte del iFR de 0,89 para su uso clínico. Métodos: Registro multicéntrico nacional, prospectivo, observacional, con la inclusión de 300 pacientes consecutivos con lesiones intermedias (estenosis angiográfica 25-60%) en el TCI. Se realizará un estudio con guía de presión y determinación de RFF e iFR. En caso de resultado concordante negativo (RFF > 0,80 / iFR > 0,89), no se realizará tratamiento; en caso de resultado concordante positivo (RFF ≤ 0,80 / iFR ≤ 0,89), se realizará revascularización; en caso de resultado discordante (RFF > 0,80 / iFR ≤ 0,89 o RFF ≤ 0,80 / iFR > 0,89), se realizará estudio con ecocardiografía intravascular y se considerará diferir la revascularización si el área luminal mínima es > 6 mm2. El criterio de valoración clínico primario será la incidencia del combinado de muerte cardiovascular, infarto no mortal relacionado con la lesión del TCI o necesidad de revascularización de la lesión del TCI a los 12 meses. Conclusiones: La demostración de la seguridad clínica en la toma de decisiones del iFR en pacientes con lesiones intermedias en el TCI tendría un impacto clínico importante y justificaría su uso sistemático para la decisión del tratamiento en estos pacientes de potencial alto riesgo. Registrado en ClinicalTrials.gov (identificador: NCT03767621)

Impact of diabetes in patients waiting for invasive cardiac procedures during COVID-19 pandemic

Background: During COVID-19 pandemic, elective invasive cardiac procedures (ICP) have been frequently cancelled or postponed. Consequences may be more evident in patients with diabetes. Objectives: The objective was to identify the peculiarities of patients with DM among those in whom ICP were cancelled or postponed due to the COVID-19 pandemic, as well as to identify subgroups in which the influence of DM has higher impact on the clinical outcome. Methods: We included 2,158 patients in whom an elective ICP was cancelled or postponed during COVID-19 pandemic in 37 hospitals in Spain. Among them, 700 (32.4%) were diabetics. Patients with and without diabetes were compared. Results: Patients with diabetes were older and had a higher prevalence of other cardiovascular risk factors, previous cardiovascular history and co-morbidities. Diabetics had a higher mortality (3.0% vs. 1.0%; p = 0.001) and cardiovascular mortality (1.9% vs. 0.4%; p = 0.001). Differences were especially important in patients with valvular heart disease (mortality 6.9% vs 1.7% [p < 0.001] and cardiovascular mortality 4.9% vs 0.9% [p = 0.002] in patients with and without diabetes, respectively). In the multivariable analysis, diabetes remained as an independent risk factor both for overall and cardiovascular mortality. No significant interaction was found with other clinical variables. Conclusion: Among patients in whom an elective invasive cardiac procedure is cancelled or postponed during COVID-19 pandemic, mortality and cardiovascular mortality is higher in patients with diabetes, irrespectively on other clinical conditions. These procedures should not be cancelled in patients with diabetes

Consequences of canceling elective invasive cardiac procedures during Covid-19 outbreak.

During COVID-19 pandemic in Spain, elective procedures were canceled or postponed, mainly due to health care systems overwhelming. The objective of this study was to evaluate the consequences of interrupting invasive procedures in patients with chronic cardiac diseases due to the COVID-19 outbreak in Spain. The study population is comprised of 2,158 patients that were pending on elective cardiac invasive procedures in 37 hospitals in Spain on the 14th of March 2020, when a state of alarm and subsequent lockdown was declared in Spain due to the COVID-19 pandemic. These patients were followed-up until April 31th. Out of the 2,158 patients, 36 (1.7%) died. Mortality was significantly higher in patients pending on structural procedures (4.5% vs. 0.8%, respectively; p 80 year-old (5.1% vs. 0.7%, p II (3.8% vs. 1.2%, p = .001), and CCS > II (4.2% vs. 1.4%, p = .013), whereas was it was significantly lower in smokers (0.5% vs. 1.9%, p = .013). Multivariable analysis identified age > 80, diabetes, renal failure and CCS > II as independent predictors for mortality. Mortality at 45 days during COVID-19 outbreak in patients with chronic cardiovascular diseases included in a waiting list due to cancellation of invasive elective procedures was 1.7%. Some clinical characteristics may be of help in patient selection for being promptly treated when similar situations happen in the future

Evolución temporal en el tratamiento transcatéter de la estenosis aórtica: análisis del registro español de TAVI

Introduction and objectives: This study primary endpoint was to present the in-hospital all-cause mortality of the Spanish TAVI registry from its inception until 2018. Secondary endpoints included other in-hospital clinical events, 30-day all-cause mortality, and an assessment of the time trend of this registry. Methods: All consecutive patients included in the Spanish TAVI registry were analyzed. In this time-based analysis, the population was been divided into patients treated before 2014 (cohort A: 2009-2013) and patients treated between 2014 and 2018 (cohort B). Results: From August 2007 to June 2018, 7180 patients were included. The mean age was 81.2 ± 6.5 years and 53% were women. The logistic EuroSCORE was 12% (8-20). Transfemoral access was used in 89%. In-hospital and 30-day all-cause mortality was 4.7% and 5.7%, respectively. On the time-based analyses during the hospital stay, the rate of myocardial infarction, stroke, need for pacemakers, tamponade, coronary obstruction, and vascular complications was similar between both groups. However, cohort B showed less need for conversion to surgery and malapposition of the valve. Also, the implant success rate increased from 93% to 96% (P < .001). In-hospital and 30-day all-cause mortality was significantly lower in cohort B, ([OR, 0.65; IC95%, 0.48-0.86; P = .003] and [OR, 0.71; IC95%, 0.54-0.92; P = .002], respectively). Conclusions: The time trend analysis of the Spanish TAVI registry showed a change in the patients’ clinical profile and an improvement in the in-hospital clinical outcomes and 30-day all-cause mortality in patients treated more recently.Introducción y objetivos: El objetivo primario de este estudio fue presentar la mortalidad total intrahospitalaria del registro español de implante percutáneo de válvula aórtica (TAVI) desde su inicio hasta el año 2018, y como objetivos secundarios otros eventos clínicos intrahospitalarios, la mortalidad total a los 30 días y la evaluación de cuál ha sido la evolución temporal de este registro. Métodos: Fueron analizados todos los pacientes consecutivos incluidos en el registro español de TAVI. En este análisis temporal se dividió la población en pacientes tratados antes de 2014 (cohorte A: 2009-2013) y pacientes tratados entre los años 2014 y 2018 (cohorte B). Resultados: Desde agosto de 2007 hasta junio de 2018 se incluyeron 7.180 pacientes. La edad media fue de 81,2 ± 6,5 años y el 53% eran mujeres. El EuroSCORE logístico fue del 12% (8-20). Se utilizó un acceso transfemoral en el 89%. La mortalidad total intrahospitalaria fue del 4,7% y a los 30 días fue del 5,7%. En el análisis temporal durante la fase hospitalaria, las tasas de infarto, accidente cerebrovascular, necesidad de marcapasos, taponamiento, obstrucción coronaria y complicaciones vasculares fueron similares en ambos grupos. Sin embargo, en la cohorte B se observó una reducción de la necesidad de conversión a cirugía y de mala posición de la válvula, y además la tasa de éxito del implante fue mayor (93 frente a 96%; p < 0,001). La mortalidad por cualquier causa ajustada tanto intrahospitalaria como a los 30 días, fue significativamente menor en la cohorte B (odds ratio [OR] = 0,65; intervalo de confianza del 95% [IC95%], 0,48-0,86; p = 0,003; y OR = 0,71; IC95%, 0,54-0,92; p = 0,002, respectivamente). Conclusiones: En el análisis temporal del registro español de TAVI se observan un cambio en el perfil clínico de los pacientes y una mejora en la evolución clínica tanto intrahospitalaria como a los 30 días en los pacientes tratados en los últimos años

Impacto de la COVID-19 en el tratamiento del infarto agudo de miocardio con elevación del segmento ST. La experiencia Española

The COVID-19 outbreak has had an unclear impact on the treatment and outcomes of patients with ST-segment elevation myocardial infarction (STEMI). The aim of this study was to assess changes in STEMI management during the COVID-19 outbreak. Using a multicenter, nationwide, retrospective, observational registry of consecutive patients who were managed in 75 specific STEMI care centers in Spain, we compared patient and procedural characteristics and in-hospital outcomes in 2 different cohorts with 30-day follow-up according to whether the patients had been treated before or after COVID-19. Suspected STEMI patients treated in STEMI networks decreased by 27.6% and patients with confirmed STEMI fell from 1305 to 1009 (22.7%). There were no differences in reperfusion strategy (> 94% treated with primary percutaneous coronary intervention in both cohorts). Patients treated with primary percutaneous coronary intervention during the COVID-19 outbreak had a longer ischemic time (233 [150-375] vs 200 [140-332] minutes, P < .001) but showed no differences in the time from first medical contact to reperfusion. In-hospital mortality was higher during COVID-19 (7.5% vs 5.1%; unadjusted OR, 1.50; 95%CI, 1.07-2.11; P < .001); this association remained after adjustment for confounders (risk-adjusted OR, 1.88; 95%CI, 1.12-3.14; P = .017). In the 2020 cohort, there was a 6.3% incidence of confirmed SARS-CoV-2 infection during hospitalization. The number of STEMI patients treated during the current COVID-19 outbreak fell vs the previous year and there was an increase in the median time from symptom onset to reperfusion and a significant 2-fold increase in the rate of in-hospital mortality. No changes in reperfusion strategy were detected, with primary percutaneous coronary intervention performed for the vast majority of patients. The co-existence of STEMI and SARS-CoV-2 infection was relatively infrequent.S