49 research outputs found
Variables asociadas al restablecimiento de la función ventricular luego de la revascularización miocárdica
No full textBackground: Myocardial revascularization is the treatment of choice in patients with ischemic systolic dysfunction. Left ventricular ejection fraction (LVEF) constitutes a prognostic factor in these patients, so it is of interest to identify the variables related with left ventricular function improvement. Objective: The aim of this study is to determine the variables associated with improvement of LVEF in patients with ischemic systolic dysfunction undergoing myocardial revascularization. Methods: Patients with LVEF 5% were analyzed. Results: The cohort consisted of 95 patients; 91.6% were men, mean age was 63 years, 40% were diabetic, 27% had previous myocardial infarction and LVEF was 36%±6%. Viability was assessed in 78% of cases. During the immediate postoperative period, 12.6% of patients presented ischemia and 28% low cardiac output. Multivariate analysis revealed that myocardial viability and lack of perioperative ischemia were independent predictors of LVEF improvement. Conclusions: Myocardial viability and absence of perioperative ischemia were associated with improved LVEF during long-term follow-up.Introducción: La revascularización miocárdica es el tratamiento de elección en pacientes con disfunción sistólica isquémica. La presencia de viabilidad miocárdica y otras variables son evaluadas al momento de decidir el tratamiento. Objetivos: Determinar las variables asociadas al restablecimiento de la fracción de eyección y el pronóstico a largo plazo, en pacientes con disfunción ventricular isquémica sometidos a revascularización miocárdica. Materiales y Métodos: Se incluyeron pacientes con FEVI5%). Se realizó seguimiento clínico en busca de eventos cardiovasculares: insuficiencia cardíaca, muerte y eventos combinados. Resultados: Se incluyeron 95 pacientes, 91,6% masculinos, edad media de 63 años, 40% diabéticos, 27% con infarto previo y FEVI media de 36±6%. Se evaluó viabilidad en 78%. Durante el postoperatorio 12% presentaron isquemia perioperatoria y 28% bajo gasto cardíaco. Al seguimiento la tasa de muerte fue del 9,5% e insuficiencia cardíaca del 20%. La viabilidad (OR 0,182; 95% IC 0,057-0,578; p=0,004) y la ausencia de isquemia perioperatoria (OR 0,092; 95% IC 0,012-0,672; p=0,019) fueron predictores independientes de la mejoría de la FEVI. Al analizar el seguimiento según la FEVI post revascularización (Grupo I: no mejoría FEVI; Grupo II: mejoría FEVI) se evidenció menor tasa de eventos a favor del grupo II. El análisis de supervivencia determinó una significativa sobrevida en el grupo II (p=0,026). Conclusiones: La viabilidad y la falta de isquemia durante el perioperatorio se asociaron con mejoría de la FEVI durante postoperatorio alejado. Los pacientes sin mejoría presentan un pronóstico desfavorable al seguimiento
Documento de Consenso sobre terapia antitrombótica en enfermedad coronaria del Comité de Cardiopatía Isquémica de la Federación Argentina de Cardiología
No full textLos pacientes con cardiopatía isquémica se presentan en diferentes escenarios clínicos de la enfermedad
coronaria, desde los síndromes coronarios agudos (con y sin elevación del segmento ST), síndromes coronarios crónicos y situaciones especiales definidas por la co-existencia de ciertos factores de riesgo (diabetes mellitus, enfermedad renal crónica, fibrilación auricular y otras), los cuales pueden requerir de diferentes pautas (o protocolos) de terapia antitrombótica. El objetivo principal de la terapia antitrombótica es el
reducir los eventos isquémicos sin aumentar los riesgos, primordialmente complicaciones hemorrágicas,
asociadas a este tipo de intervención. El objetivo de este artículo es ofrecer una revisión basada en la evidencia más recientes teniendo en cuenta las diferentes situaciones clínicas, así como un cuidadoso análisis del balance de beneficios y riesgos (reducción de eventos y complicaciones hemorrágicas, respectivamente) asociado con la terapia antitrombótica de los pacientes con enfermedad cardiovascular.Fil: Barcudi, Raúl Jesús. Universidad Católica de Córdoba. Clínica Universitaria Reina Fabiola; ArgentinaFil: Bono, Julio. Sanatorio Allende; ArgentinaFil: Ramos, Hugo Roberto. Universidad Nacional de Córdoba; ArgentinaFil: Quiroga Castro, Walter. Instituto Modelo de Cardiología; ArgentinaFil: Muntaner, Juan. Universidad Nacional de Tucumán; ArgentinaFil: Macín, Stella. Universidad Nacional del Nordeste; ArgentinaFil: Zapata, Gerardo. Instituto Cardiovascular de Rosario; ArgentinaFil: Meiriño, Alejandro. Instituto Cardiovascular de Rosario; ArgentinaFil: Hominal, Miguel. Sanatorio Diagnóstico; ArgentinaFil: Mauro, Daniel. Instituto del Corazón San Rafael; ArgentinaFil: Atencio, Lorena. Instituto del Corazón San Rafael; ArgentinaFil: Fernández Murga, Arturo. Instituto de Cardiología; ArgentinaFil: Amoroso, Alejandro. Hospital San Bernardo; ArgentinaFil: Rengel, Esteban. Instituto de Cardiología; ArgentinaFil: Hasbani, Eduardo. Universidad Nacional de Tucumán; ArgentinaFil: Luciardi, Héctor. Universidad Nacional de Tucumán; ArgentinaFil: Zoni, César Rodrigo. Instituto de Cardiología JF Cabral; ArgentinaFil: Onocko, Mariela. Instituto de Cardiología JF Cabral; ArgentinaFil: Caruso, Orlando. Hospital Central de Mendoza; Argentin
Valor pronóstico del tamaño del infarto de miocardio cuantificado mediante SPECT gatillada
No full textObjetivos: Evaluar la utilidad de la cuantificación tamaño de infarto (TI) estimado por gated-SPECT en la predicción de complicaciones cardiovasculares en pacientes con un primer infarto agudo de miocardio (IAM). Material y métodos: Se analizaron los pacientes con IAM con elevación del ST desde 2009 a 2014, excluyéndose aquellos con IAM previo. El cálculo de TI se realizó mediante el software Cedars QPS. Se evaluaron eventos al año: insuficiencia cardíaca, arritmias ventriculares, muerte y la combinación de los tres.Resultados: Se incluyeron 149 pacientes, con edad media de 59±11 años y 81,9% de sexo masculino. El 16,1% eran diabéticos y 9,4% presentaron revascularización previa. El 84,6% ingresaron en Killip y Kimbal A, 43% fueron de territorio anterior y 69,8% fueron reperfundidos. La FEVI por gated-SPECT fue del 51±14%. Se realizó seguimiento clínico en el 95,9% de los casos. Se calculó el punto de corte del TI (curva ROC) para predecir eventos combinados al seguimiento en 22% (Sensibilidad: 92%, Especificidad: 81%, ABC: 0,94) y se dividió a la muestra en dos grupos: grupo I (TI<22%) y grupo II (TI≥22%). La prevalencia de eventos combinados fue mayor en el grupo II (2,1% vs. 50%; p<0,001). Se identificó como única variable predictora de eventos al seguimiento al TI ≥22% (OR 1,978; 95% IC 1,887-1,996; p<0,001). Conclusiones: La cuantificación precoz del TI mediante SPECT es un predictor independiente de riesgo al año que permite establecer una estratificación del riesgo en pacientes con un primer IAM
Iminoboronates as useful scaffolds for tumor-targeting
No full textTese de doutoramento, Farmácia (Química Farmacêutica e Terapêutica), Universidade de Lisboa, Faculdade de Farmácia, 2018Boron has an unique set of chemical and physical properties, since it lies on the borderline between non-metals and metals and is also next to carbon in the periodic table. Boronic acids are trivalent boron compounds with a strong Lewis acid character, therefore they are able to chelate with Lewis base donors through dynamic covalent bonds. These bonds are the ideal tools to construct reversible multicomponent systems, since these ligations can be stable as covalent bonds or reversible as non-covalent bonds, depending on the stimulus applied. Carcinogenesis is classified as a multifaceted biological process and recent therapies are focus in interrupting one or more of these stages by the use of selective multivalent conjugates. Herein, a novel modular platform for the construction of cancer-cell-targeting drug conjugates is described and is based on multifunctional and reversible boronate complexes (B-complexes), which were designed to accommodate bortezomib (Btz), polyethylene glycol (PEG) chains and folate targeting units. These B-complexes revealed to be stable under biocompatible conditions (e.g. t1/2 (72) in human plasma = 60 h), and were hydrolyzed in the presence of glutathione (GSH), leading to intracellular cargo delivery in cancer cells. Small-molecule drug conjugates (SMDCs) 63 and 67 demonstrated a high selectivity for folate-positive MDA-MB-231 cancer cell line and IC50 values in the low nanomolar range. This modular technology was also employed in the construction of responsive and electronically tunable fluorescent boronic acid salicylidenehydrazone (BASHY) complexes, which revealed to have suitable structural and photophysical properties for live cell bioimaging applications. This modular approach enabled the straightforward synthesis (yields up to 99 %) of structurally diverse and photostable intramolecular charge-transfer (ICT) dyes, including energy-transfer cassettes (ETCs), that exhibit a polarity-sensitive emission, high quantum yields of up to 0.68 in nonpolar environments, high brightness (up to 121000 M-1.cm-1) and a two-photon-absorption behavior. In terms of bioimaging applications, BASHYs 81a,e were applied in the selective staining of lipid droplets in HeLa cells. Dyes 81a,e and ECT 85 were used to prepare non-cytotoxic and highly fluorescent poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs), which were effectively internalized by bone marrow dendritic cells (BMDC). BASHY-azide 89 was used for the site-selective labelling of Annexin V, which is an apoptosis biomarker. Annexin V-BASHY 92 successfully targeted and detected apoptotic cells maintaining high levels of specific activity.O elemento boro tem propriedades físico-químicas únicas, visto que na tabela periódica se encontra na fronteira entre o grupo dos não-metais e metais e também porque se localiza na posição adjacente ao carbono. Estas propriedades únicas do boro, despertaram o interesse da comunidade científica no desenvolvimento de novas moléculas com este elemento, a fim de ser usadas numa vasta gama de aplicações, tais como medicina, síntese de complexos dinâmicos, entre outras. Os ácidos borónicos são compostos trivalentes de boro com dois grupos hidroxilo e uma unidade alquílica ou arílica. São classificados como ácidos de Lewis fortes, tendo assim a capacidade de formar ligações covalentes dinâmicas com bases de Lewis, que contêm na sua estrutura, álcoois e aminas numa correlação vicinal (1,2) ou hominal (1,3). As ligações covalentes dinâmicas são ideais para a construção de sistemas multivalentes reversíveis, uma vez que as mesmas podem ser estáveis como ligações covalentes ou reversíveis como ligações não covalentes, dependendo do estímulo aplicado. Os sistemas multivalentes dinâmicos podem ser aplicados em diferentes áreas, tais como bioimagem, bioconjugação, terapia do cancro, entre outras. As células cancerígenas emergem a partir de células saudáveis que adquiriram mutações no ADN que não foram reparadas. Esta transformação é atualmente classificada como um processo biológico multifacetado e complexo, e por consequência, as terapias mais recentes para o tratamento do cancro, visam a interrupção do processo de carcinogénese através do uso de conjugados multifuncionais e específicos. Nesta tese de doutoramento é apresentada uma nova abordagem modular para a construção de conjugados multivalentes terapêuticos direcionados para as células cancerígenas. Estes conjugados são baseados em complexos de boro, mantidos por ligações covalentes reversíveis e contêm um agente citotóxico (bortezomib), uma cadeia hidrofílica (polietilenoglicol) e uma unidade de reconhecimento das células cancerígenas (ácido fólico). Estes complexos de boro demonstraram serem estáveis em condições biocompatíveis (ex: tempo de semi-vida do composto 72 em plasma humano = 60 h), no entanto são hidrolisados na presença da glutationa. A distribuição seletiva e libertação dos componentes destes complexos de boro nas células cancerígenas foram comprovadas através de microscopia de fluorescência confocal e foi também proposto um mecanismo para a hidrólise destes complexos de boro induzida pela glutationa com base em dados recolhidos por espectrometria de massa e cálculos teóricos. Esta nova abordagem modular permitiu a construção de conjugados multivalentes 63 e 67, que têm uma elevada seletividade para células cancerígenas MDA-MB-231 (sobre-expressão de receptores para o ácido fólico) com valores de IC50 na região do baixo nanomolar. Esta tecnologia modular foi também utilizada nesta tese de doutoramento na síntese de complexos de boro fluorescentes (BASHYs) com elevada sensibilidade e adaptabilidade em termos das suas propriedades fotofísicas. Os BASHYs foram preparados através da assemblagem modular entre ácidos borónicos e ligandos Schiff-base e revelaram possuir propriedades estruturais e fotofísicas adequadas à aplicação na área da bioimagem em células. Esta metodologia sintética modular permitiu a síntese (rendimentos até 99 %) de diversos BASHYs fotoestáveis que têm uma fluorescência dependente da polaridade, com bons rendimentos quânticos (até 0,68 em ambientes não polares), que possuem um elevado brilho (até 121000 M-1.cm-1) e cujas propriedades fotofísicas permitem a absorção de dois fotões. Relativamente às aplicações de bioimagem em células, BASHYs 81a,e foram utilizados para corar seletivamente gotículas lipídicas nas células HeLa. Sondas fluorescentes 81a,e e 85 foram usadas na preparação de nanopartículas não citotóxicas e fluorescentes que foram efetivamente internalizadas por células dendríticas da medula óssea. BASHY-azida 89 foi utilizada na conjugação com a Anexina V e o conjugado daí resultante (Anexina V-BASHY 92) foi usado com sucesso na marcação seletiva por fluorescência de células apoptóticas
Iminoboronates as useful scaffolds for tumor-targeting
No full textTese de doutoramento, Farmácia (Química Farmacêutica e Terapêutica), Universidade de Lisboa, Faculdade de Farmácia, 2018Boron has an unique set of chemical and physical properties, since it lies on the borderline between non-metals and metals and is also next to carbon in the periodic table. Boronic acids are trivalent boron compounds with a strong Lewis acid character, therefore they are able to chelate with Lewis base donors through dynamic covalent bonds. These bonds are the ideal tools to construct reversible multicomponent systems, since these ligations can be stable as covalent bonds or reversible as non-covalent bonds, depending on the stimulus applied. Carcinogenesis is classified as a multifaceted biological process and recent therapies are focus in interrupting one or more of these stages by the use of selective multivalent conjugates. Herein, a novel modular platform for the construction of cancer-cell-targeting drug conjugates is described and is based on multifunctional and reversible boronate complexes (B-complexes), which were designed to accommodate bortezomib (Btz), polyethylene glycol (PEG) chains and folate targeting units. These B-complexes revealed to be stable under biocompatible conditions (e.g. t1/2 (72) in human plasma = 60 h), and were hydrolyzed in the presence of glutathione (GSH), leading to intracellular cargo delivery in cancer cells. Small-molecule drug conjugates (SMDCs) 63 and 67 demonstrated a high selectivity for folate-positive MDA-MB-231 cancer cell line and IC50 values in the low nanomolar range. This modular technology was also employed in the construction of responsive and electronically tunable fluorescent boronic acid salicylidenehydrazone (BASHY) complexes, which revealed to have suitable structural and photophysical properties for live cell bioimaging applications. This modular approach enabled the straightforward synthesis (yields up to 99 %) of structurally diverse and photostable intramolecular charge-transfer (ICT) dyes, including energy-transfer cassettes (ETCs), that exhibit a polarity-sensitive emission, high quantum yields of up to 0.68 in nonpolar environments, high brightness (up to 121000 M-1.cm-1) and a two-photon-absorption behavior. In terms of bioimaging applications, BASHYs 81a,e were applied in the selective staining of lipid droplets in HeLa cells. Dyes 81a,e and ECT 85 were used to prepare non-cytotoxic and highly fluorescent poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs), which were effectively internalized by bone marrow dendritic cells (BMDC). BASHY-azide 89 was used for the site-selective labelling of Annexin V, which is an apoptosis biomarker. Annexin V-BASHY 92 successfully targeted and detected apoptotic cells maintaining high levels of specific activity.O elemento boro tem propriedades físico-químicas únicas, visto que na tabela periódica se encontra na fronteira entre o grupo dos não-metais e metais e também porque se localiza na posição adjacente ao carbono. Estas propriedades únicas do boro, despertaram o interesse da comunidade científica no desenvolvimento de novas moléculas com este elemento, a fim de ser usadas numa vasta gama de aplicações, tais como medicina, síntese de complexos dinâmicos, entre outras. Os ácidos borónicos são compostos trivalentes de boro com dois grupos hidroxilo e uma unidade alquílica ou arílica. São classificados como ácidos de Lewis fortes, tendo assim a capacidade de formar ligações covalentes dinâmicas com bases de Lewis, que contêm na sua estrutura, álcoois e aminas numa correlação vicinal (1,2) ou hominal (1,3). As ligações covalentes dinâmicas são ideais para a construção de sistemas multivalentes reversíveis, uma vez que as mesmas podem ser estáveis como ligações covalentes ou reversíveis como ligações não covalentes, dependendo do estímulo aplicado. Os sistemas multivalentes dinâmicos podem ser aplicados em diferentes áreas, tais como bioimagem, bioconjugação, terapia do cancro, entre outras. As células cancerígenas emergem a partir de células saudáveis que adquiriram mutações no ADN que não foram reparadas. Esta transformação é atualmente classificada como um processo biológico multifacetado e complexo, e por consequência, as terapias mais recentes para o tratamento do cancro, visam a interrupção do processo de carcinogénese através do uso de conjugados multifuncionais e específicos. Nesta tese de doutoramento é apresentada uma nova abordagem modular para a construção de conjugados multivalentes terapêuticos direcionados para as células cancerígenas. Estes conjugados são baseados em complexos de boro, mantidos por ligações covalentes reversíveis e contêm um agente citotóxico (bortezomib), uma cadeia hidrofílica (polietilenoglicol) e uma unidade de reconhecimento das células cancerígenas (ácido fólico). Estes complexos de boro demonstraram serem estáveis em condições biocompatíveis (ex: tempo de semi-vida do composto 72 em plasma humano = 60 h), no entanto são hidrolisados na presença da glutationa. A distribuição seletiva e libertação dos componentes destes complexos de boro nas células cancerígenas foram comprovadas através de microscopia de fluorescência confocal e foi também proposto um mecanismo para a hidrólise destes complexos de boro induzida pela glutationa com base em dados recolhidos por espectrometria de massa e cálculos teóricos. Esta nova abordagem modular permitiu a construção de conjugados multivalentes 63 e 67, que têm uma elevada seletividade para células cancerígenas MDA-MB-231 (sobre-expressão de receptores para o ácido fólico) com valores de IC50 na região do baixo nanomolar. Esta tecnologia modular foi também utilizada nesta tese de doutoramento na síntese de complexos de boro fluorescentes (BASHYs) com elevada sensibilidade e adaptabilidade em termos das suas propriedades fotofísicas. Os BASHYs foram preparados através da assemblagem modular entre ácidos borónicos e ligandos Schiff-base e revelaram possuir propriedades estruturais e fotofísicas adequadas à aplicação na área da bioimagem em células. Esta metodologia sintética modular permitiu a síntese (rendimentos até 99 %) de diversos BASHYs fotoestáveis que têm uma fluorescência dependente da polaridade, com bons rendimentos quânticos (até 0,68 em ambientes não polares), que possuem um elevado brilho (até 121000 M-1.cm-1) e cujas propriedades fotofísicas permitem a absorção de dois fotões. Relativamente às aplicações de bioimagem em células, BASHYs 81a,e foram utilizados para corar seletivamente gotículas lipídicas nas células HeLa. Sondas fluorescentes 81a,e e 85 foram usadas na preparação de nanopartículas não citotóxicas e fluorescentes que foram efetivamente internalizadas por células dendríticas da medula óssea. BASHY-azida 89 foi utilizada na conjugação com a Anexina V e o conjugado daí resultante (Anexina V-BASHY 92) foi usado com sucesso na marcação seletiva por fluorescência de células apoptóticas
Effects of volenrelaxin in worsening heart failure with preserved ejection fraction: a phase 2 randomized trial
No full textRelaxin is a peptide hormone that may decrease circulatory congestion and improve kidney function. In this study, we conducted a double-blind, international, multicenter trial to test whether volenrelaxin, a long-acting form of human relaxin, can improve left atrial (LA) function, reduce congestion and improve kidney function in patients with heart failure and preserved ejection fraction (HFpEF). We randomly assigned patients with New York Heart Association (NYHA) class II–IV HFpEF and recent heart failure (HF) decompensation to 25-mg, 50-mg or 100-mg volenrelaxin or placebo administered subcutaneously once weekly. The primary outcome was the change in LA reservoir strain at 26 weeks, with key secondary endpoints including changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP), estimated glomerular filtration rate (eGFR) and safety. The trial was stopped early by the sponsor because of evidence for worsening congestion after 332 participants had been enrolled (mean age 74 years, 49% women, mean body mass index 30.6 kg m−2, 31.9% NYHA class III–IV). Compared to placebo, 25-mg volenrelaxin improved LA reservoir strain (+3.9%, 95% confidence interval (CI): 1.1–6.6, P = 0.006) but did not have effects on this outcome at 50-mg (+1.3%, 95% CI: −1.3 to 3.9, P = 0.332) or 100-mg (+0.9%, 95% CI: −1.8 to 3.6, P = 0.521) doses. At 26 weeks, volenrelaxin (pooling all dosages) increased NT-proBNP levels (+24.5%, 95% CI: 2.0–51.8) and had no significant effect on eGFR (+2.2 ml min−1 1.73 m−2, 95% CI: −1.8 to 6.3). Volenrelaxin was also associated with a non-significant increase in risk for HF hospitalization compared to placebo (hazard ratio = 2.64, 95% CI: 0.93–7.56, P = 0.070), along with signals for an increased number of cardiovascular and renal serious adverse events (odds ratio = 2.52, 95% CI: 0.95–6.68, P = 0.056). In conclusion, despite some evidence for improvement in LA function at a low dose, treatment with this long-acting form of human relaxin was associated with worsening congestion in patients with recently decompensated HFpEF. ClinicalTrials.gov identifier: NCT05592275.<br/
Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND):a double-blind, randomised placebo-controlled trial
No full textBackground: Three different glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular outcomes in people with type 2 diabetes at high cardiovascular risk with high glycated haemoglobin A 1c (HbA 1c) concentrations. We assessed the effect of the GLP-1 receptor agonist dulaglutide on major adverse cardiovascular events when added to the existing antihyperglycaemic regimens of individuals with type 2 diabetes with and without previous cardiovascular disease and a wide range of glycaemic control.Methods: This multicentre, randomised, double-blind, placebo-controlled trial was done at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo. Randomisation was done by a computer-generated random code with stratification by site. All investigators and participants were masked to treatment assignment. Participants were followed up at least every 6 months for incident cardiovascular and other serious clinical outcomes. The primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes), which was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01394952.Findings: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants (mean age 66·2 years [SD 6·5], median HbA 1c 7·2% [IQR 6·6–8·1], 4589 [46·3%] women) were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). During a median follow-up of 5·4 years (IQR 5·1–5·9), the primary composite outcome occurred in 594 (12·0%) participants at an incidence rate of 2·4 per 100 person-years in the dulaglutide group and in 663 (13·4%) participants at an incidence rate of 2·7 per 100 person-years in the placebo group (hazard ratio [HR] 0·88, 95% CI 0·79–0·99; p=0·026). All-cause mortality did not differ between groups (536 [10·8%] in the dulaglutide group vs 592 [12·0%] in the placebo group; HR 0·90, 95% CI 0·80–1·01; p=0·067). 2347 (47·4%) participants assigned to dulaglutide reported a gastrointestinal adverse event during follow-up compared with 1687 (34·1%) participants assigned to placebo (p<0·0001).Interpretation: Dulaglutide could be considered for the management of glycaemic control in middle-aged and older people with type 2 diabetes with either previous cardiovascular disease or cardiovascular risk factors.</p
Lipoprotein(a) and Benefit of PCSK9 Inhibition in Patients With Nominally Controlled LDL Cholesterol
No full textBackground: Guidelines recommend nonstatin lipid-lowering agents in patients at very high risk for major adverse cardiovascular events (MACE) if low-density lipoprotein cholesterol (LDL-C) remains ≥70 mg/dL on maximum tolerated statin treatment. It is uncertain if this approach benefits patients with LDL-C near 70 mg/dL. Lipoprotein(a) levels may influence residual risk. Objectives: In a post hoc analysis of the ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial, the authors evaluated the benefit of adding the proprotein subtilisin/kexin type 9 inhibitor alirocumab to optimized statin treatment in patients with LDL-C levels near 70 mg/dL. Effects were evaluated according to concurrent lipoprotein(a) levels. Methods: ODYSSEY Outcomes compared alirocumab with placebo in 18,924 patients with recent acute coronary syndromes receiving optimized statin treatment. In 4,351 patients (23.0%), screening or randomization LDL-C was 13.7 mg/dL or ≤13.7 mg/dL; corresponding adjusted treatment hazard ratios were 0.82 (95% CI: 0.72-0.92) and 0.89 (95% CI: 0.75-1.06), with Pinteraction = 0.43. Conclusions: In patients with recent acute coronary syndromes and LDL-C near 70 mg/dL on optimized statin therapy, proprotein subtilisin/kexin type 9 inhibition provides incremental clinical benefit only when lipoprotein(a) concentration is at least mildly elevated. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402
Effects of alirocumab on cardiovascular and metabolic outcomes after acute coronary syndrome in patients with or without diabetes: a prespecified analysis of the ODYSSEY OUTCOMES randomised controlled trial
No full textBackground: After acute coronary syndrome, diabetes conveys an excess risk of ischaemic cardiovascular events. A reduction in mean LDL cholesterol to 1·4–1·8 mmol/L with ezetimibe or statins reduces cardiovascular events in patients with an acute coronary syndrome and diabetes. However, the efficacy and safety of further reduction in LDL cholesterol with an inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) after acute coronary syndrome is unknown. We aimed to explore this issue in a prespecified analysis of the ODYSSEY OUTCOMES trial of the PCSK9 inhibitor alirocumab, assessing its effects on cardiovascular outcomes by baseline glycaemic status, while also assessing its effects on glycaemic measures including risk of new-onset diabetes. Methods: ODYSSEY OUTCOMES was a randomised, double-blind, placebo-controlled trial, done at 1315 sites in 57 countries, that compared alirocumab with placebo in patients who had been admitted to hospital with an acute coronary syndrome (myocardial infarction or unstable angina) 1–12 months before randomisation and who had raised concentrations of atherogenic lipoproteins despite use of high-intensity statins. Patients were randomly assigned (1:1) to receive alirocumab or placebo every 2 weeks; randomisation was stratified by country and was done centrally with an interactive voice-response or web-response system. Alirocumab was titrated to target LDL cholesterol concentrations of 0·65–1·30 mmol/L. In this prespecified analysis, we investigated the effect of alirocumab on cardiovascular events by glycaemic status at baseline (diabetes, prediabetes, or normoglycaemia)—defined on the basis of patient history, review of medical records, or baseline HbA1c or fasting serum glucose—and risk of new-onset diabetes among those without diabetes at baseline. The primary endpoint was a composite of death from coronary heart disease, non-fatal myocardial infarction, fatal or non-fatal ischaemic stroke, or unstable angina requiring hospital admission. ODYSSEY OUTCOMES is registered with ClinicalTrials.gov, number NCT01663402. Findings: At study baseline, 5444 patients (28·8%) had diabetes, 8246 (43·6%) had prediabetes, and 5234 (27·7%) had normoglycaemia. There were no significant differences across glycaemic categories in median LDL cholesterol at baseline (2·20–2·28 mmol/L), after 4 months' treatment with alirocumab (0·80 mmol/L), or after 4 months' treatment with placebo (2·25–2·28 mmol/L). In the placebo group, the incidence of the primary endpoint over a median of 2·8 years was greater in patients with diabetes (16·4%) than in those with prediabetes (9·2%) or normoglycaemia (8·5%); hazard ratio (HR) for diabetes versus normoglycaemia 2·09 (95% CI 1·78–2·46, p<0·0001) and for diabetes versus prediabetes 1·90 (1·65–2·17, p<0·0001). Alirocumab resulted in similar relative reductions in the incidence of the primary endpoint in each glycaemic category, but a greater absolute reduction in the incidence of the primary endpoint in patients with diabetes (2·3%, 95% CI 0·4 to 4·2) than in those with prediabetes (1·2%, 0·0 to 2·4) or normoglycaemia (1·2%, −0·3 to 2·7; absolute risk reduction pinteraction=0·0019). Among patients without diabetes at baseline, 676 (10·1%) developed diabetes in the placebo group, compared with 648 (9·6%) in the alirocumab group; alirocumab did not increase the risk of new-onset diabetes (HR 1·00, 95% CI 0·89–1·11). HRs were 0·97 (95% CI 0·87–1·09) for patients with prediabetes and 1·30 (95% CI 0·93–1·81) for those with normoglycaemia (pinteraction=0·11). Interpretation: After a recent acute coronary syndrome, alirocumab treatment targeting an LDL cholesterol concentration of 0·65–1·30 mmol/L produced about twice the absolute reduction in cardiovascular events among patients with diabetes as in those without diabetes. Alirocumab treatment did not increase the risk of new-onset diabetes. Funding: Sanofi and Regeneron Pharmaceuticals
