Pembrolizumab in lung cancer: current evidence and future perspectives.

Pembrolizumab is a humanized monoclonal antibody against PD-1 capable of enhancing antitumor immune activity. The KEYNOTE-001 study showed that pembrolizumab has activity in advanced non-small-cell lung cancer patients and identified programmed death ligand 1 (PD-L1) as a companion test to select patients most likely to benefit from pembrolizumab. Five randomized clinical trials showed the efficacy of pembrolizumab in non-small-cell lung cancer: in second-line setting PD-L1 ≥1% (KEYNOTE-010), in first-line setting PD-L1 ≥50% (KEYNOTE-024 and KEYNOTE-042) and in first-line setting in combination with platinum doublets, any expression of PD-L1 (KEYNOTE-189 and KEYNOTE-407). Future challenges are the identification of the role of pembrolizumab in adjuvant, neoadjuvant, locally advanced disease or oncogene-addicted patients, in combination with radiotherapy or other biological agents.

Gender Differences in Platelet Reactivity in Patients Receiving Dual Antiplatelet Therapy.

BACKGROUND: Cardiovascular risk is still underestimated in women, experiencing higher mortality and worse prognosis after acute cardiovascular events. Gender differences have been reported in thrombotic and hemorrhagic risk during dual antiplatelet therapy (DAPT), thus suggesting a potential variability in platelet reactivity according to sex. The aim of the present study was to assess the role of gender on platelet function and the prevalence of high-on treatment residual platelet reactivity (HRPR) during DAPT in patients with recent acute coronary syndrome or percutaneous coronary revascularization. METHODS: Patients treated with DAPT (ASA and clopidogrel or ticagrelor) were scheduled for platelet function assessment at 30-90 days post-discharge. By whole blood impedance aggregometry, HRPR was considered for ASPI test >862 AU*min (for ASA) and ADP test values ≥417 AU*min (for ADP-antagonists). RESULTS: We included 541 patients on DAPT, 122 (22.6 %) of whom were females. Females were older (p < 0.001), displayed more frequently hypercholesterolemia (p = 0.003), renal failure (p = 0.04), acute presentation (p < 0.001), higher cholesterol levels and platelets count (p < 0.001). Inverse association was demonstrated with smoking (p < 0.001), previous PCI (p = 0.04) and statin use (p = 0.03), creatinine and haemoglobin (p < 0.001). Female gender did not influence mean platelet reactivity or the prevalence of HRPR for ASA (1.7 % vs 1.4 %, OR[95%CI] = 1.14[0.17-4.36], p = 0.99, adjusted OR[95%CI] = 1.54[0.20-11.6], p = 0.68) or ADP-antagonists (26.3 % vs 22.8 %, OR[95%CI] = 1.17[0.52-1.34], p = 0.45, adjusted OR[95%CI] = 1.05[0.59-1.86], p = 0.87). Results did not change when considering separately the 309 patients treated with clopidogrel (34 % vs 31.3 %, OR[95%CI] = 1.13[0.62-2.07], p = 0.76, adjusted OR[95%CI] = 1.35[0.63-2.9], p = 0.44 for females vs males), or patients (n = 232) on ticagrelor (20.4 % vs 11.1 %, OR[95%CI] = 2.27[0.99-5.17], p = 0.06 for females vs males), confirmed after correction for baseline differences (adjusted OR[95%CI] = 1.21[0.28-2.29], p = 0.68). CONCLUSION: In patients receiving dual antiplatelet therapy, gender does not impact on the prevalence of high-on treatment residual platelet reactivity (HRPR) with the major antiplatelet agents ASA, clopidogrel or ticagrelor.

Tratamiento antiagregante de muy corta duración tras la ICP y nuevos SLF: metanálisis de 5 estudios aleatorizados / Very short dual antiplatelet therapy after PCI and new DES: a meta-analysis of 5 randomized trials

Introducción y objetivos La interrupción muy precoz (entre 1 y 3 meses) del tratamiento antiagregante plaquetario doble (TAPD), ha aparecido recientemente en el intervencionismo percutáneo con la nueva generación de stents liberadores de fármacos. El objetivo del presente metanálisis fue evaluar el impacto pronóstico de los diferentes regímenes de doble terapia antiagregante corta o muy corta, comparada con la clásica durante 12 meses en pacientes tratados con intervencionismo coronario percutáneo con un stent liberador de fármacos (SLF) de nueva generación. Métodos Se buscaron ensayos clínicos aleatorizados en la literatura y en las principales sesiones científicas. El objetivo primario de eficacia fue la mortalidad y el objetivo primario de seguridad fueron las hemorragias mayores. Un análisis pre-especificado se realizó de acuerdo con el antiagregante elegido a largo plazo. Resultados Se incluyeron 5 ensayos clínicos aleatorizados con un total de 30.621 pacientes; entre los cuales, un 49,97% fueron aleatorizados a una TAPD muy corta (1-3 meses), seguidos de ácido acetilsalicílico o P2Y12I en monoterapia. Una TAPD más corta redujo significativamente el ratio de hemorragias mayores (2 frente a 3,1%, OR=0,62; IC95%, 0,46-0,84; p=0,002; phet=0,02), aunque no se observó un impacto significativo en la mortalidad (1,3 frente a 2%, OR=0,97; IC95%, 0,73-1,29; p=0,84; phet=0,18). La reducción de eventos como las hemorragias fue incluso más significativa en los ensayos aleatorizados en los que los pacientes estaban libres de eventos en el momento de la suspensión de la DAT. La aparición de infarto agudo de miocardio y la trombosis del stent fue similar en ambas estrategias (TAPD muy corta frente a TAPD clásica de 12 meses). Conclusiones Basándonos en el actual metanálisis, un periodo muy breve (1-3 meses) de TAPD se asocia con una reducción significativa de hemorragia mayor en comparación con la terapia clásica de 12 meses... (AU)

Introduction and objectives Very early (1-3 months) discontinuation of dual antiplatelet therapy (DAPT) has been recently proposed in percutaneous coronary interventions with modern drug-eluting stents (DES), with contrasting results. The aim of the present meta-analysis was to evaluate the prognostic impact of very short DAPT regimens vs the standard 12-month regimen in patients undergoing percutaneous coronary intervention with new DES. Methods Literature and main scientific session abstracts were searched for randomized clinical trials (RCT). The primary efficacy endpoint was mortality, and the primary safety endpoint was major bleeding events. A prespecified analysis was conducted according to the long-term antiplatelet agent. Results We included 5 RCTs, with a total of 30 621 patients; 49.97% were randomized to very short (1-3 months) DAPT, followed by aspirin or P2Y12I monotherapy. Shorter DAPT duration significantly reduced the rate of major bleeding (2% vs 3.1%, OR, 0.62; 95%CI, 0.46-0.84; P=.002; Phet=.02), but did not significantly condition overall mortality (1.3% vs 2%, OR, 0.97; 95%CI, 0.73-1.29; P=.84; Phet=.18). The reduction in bleeding events was even more significant in trials randomizing event-free patients at the time of DAPT discontinuation. The occurrence of myocardial infarction and stent thrombosis was similar between shorter vs standard 12-month DAPT. Conclusions Based on the current meta-analysis, a very short (1-3 months) period is associated with a significant reduction in major bleeding compared with the standard 12-month therapy, with no increase in major ischemic events and comparable survival. (AU)

Relationship between glycoprotein IIIa platelet receptor gene polymorphism and coronary artery disease.

Glycoprotein IIb/IIIa (GP IIb/IIIa) is a key receptor for platelet aggregation and adhesion. We investigated whether a single-nucleotide polymorphism of GP IIIa subunit (Leu33Pro-PlA(1)/PlA(2) allele) is associated with the extent of coronary artery disease (CAD) in a consecutive cohort of 1518 patients undergoing coronary angiography. Significant CAD was defined as at least a stenosis >50% and severe CAD as left main disease and/or trivessel disease. Additionally, carotid intima-media thickness (cIMT) was evaluated in 339 patients. The PlA(2) allele was observed in 458 (30.2%) patients and associated with hypercholesterolemia (P = .03). No difference was observed in the prevalence of CAD (72.6% vs 70.1%, P = .29; adjusted odds ratio, OR [95% confidence interval, CI] = 0.85 [0.67-1.08], P = .19) and severe CAD (27.5% vs 26.5%, adjusted OR [95% CI] = 0.93 [0.72-1.19], P = .55). Furthermore, Leu33Pro polymorphism did not affect cIMT and the prevalence of carotid plaques. Therefore, this polymorphism cannot be regarded as a risk factor for coronary or carotid atherosclerosis.

Elevated homocysteine and the risk of contrast-induced nephropathy: a cohort study.

Contrast-induced nephropathy (CIN) is a common complication in patients with impaired kidney function undergoing coronary angiography/angioplasty. We evaluated whether elevated homocysteine (known to be associated with free radical generation and oxidative stress) increases the risk of CIN. Patients (n = 876) with creatinine clearance <60 mL/min undergoing coronary angiography or percutaneous coronary intervention (PCI) were divided into tertiles of homocysteine levels. Contrast-induced nephropathy was defined as ≥0.5 mg/dL or ≥25% creatinine increase 24 to 48 hours post-PCI. A significant relationship was observed between homocysteine levels and the risk of CIN (P = .033), confirmed after correction for baseline confounding factors, adjusted odds ratio, OR (95% confidence interval, [CI]) = 1.68 (1.09-2.59), P = .019. This association was also significant applying the new definition of contrast-induced acute kidney injury (11.9% in group 1, 10.4% in group 2, and 22.8% in group 3; P < .001), adjusted OR (95% CI) = 1.96 (1.3-2.95), P = .001. Future studies are needed to confirm our findings and to define the role of homocysteine in CIN.

High-density lipoproteins and coronary artery disease: a single-center cohort study.

Our goal was to estimate the role of high-density lipoprotein cholesterol (HDL-C) in predicting the prevalence and extent of coronary artery disease (CAD) in 3280 patients undergoing coronary angiography. Predictors of lower HDL levels (<32 mg/dL) were male gender (P < .001), diabetes mellitus (P = .03), renal failure (P = .01), higher low-density lipoprotein and total cholesterol (P < .001, respectively), triglycerides (P < .001), and white blood cells (P < .001), aging (P < .001), previous myocardial infarction (P = .02) and hemoglobin (P < .001), treatment with angiotensin-receptor blockers (P < .001), and statins (P = .002). The HDL-C levels were significantly inversely associated with prevalence of CAD (P < .001, adjusted odds ratio [OR] [95% confidence interval, CI] = 1.35 [1.25-1.45], P < .001), and HDL-C <44 mg/dL was best the predictive value of the risk of CAD, (adjusted OR [95%CI] = 1.61 [1.24-2.1], P < .001). We found significant association between HDL-C and the risk of CAD; a value <44 mg/dL was the best cutoff in the prediction of CAD.

Tratamiento antitrombótico tras implante percutáneo de válvula aórtica: grandes lagunas para una cuestión de extrema importancia. Respuesta / Antithrombotic therapy after percutaneous aortic valve implantation: large gaps for a matter of extreme importance. Response

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Antiagregación doble frente a simple, con o sin anticoagulación, tras reemplazo percutáneo de válvula aórtica: comparación indirecta y metanálisis / Dual versus single antiplatelet regimen with or without anticoagulation in transcatheter aortic valve replacement: indirect comparison and meta-analysis

Introducción y objetivos. La estrategia antitrombótica más adecuada tras el reemplazo percutáneo de válvula aórtica (RPVA) es incierta, de manera que actualmente se recomienda de manera empírica el tratamiento antiagregante plaquetario doble (TAPD). El objetivo del presente metanálisis es valorar la seguridad y la efectividad del TAPD en pacientes sometidos a RPVA. Métodos. Se incluyeron estudios que compararon diferentes estrategias antitrombóticas tras el RPVA. La variable de resultado primaria fue mortalidad total a los 30 días. Resultados. Se incluyeron 9 estudios, 5 de ellos compararon el TAPD con el ácido acetilsalicílico como único antiagregante y 4, el TAPD con un tratamiento antiagregante plaquetario único (TAPU) junto con anticoagulación oral. De un total de 7.991 pacientes, el 72% estaba en TAPD. La mediana de seguimiento fue de 3,5 meses. Se observó menos mortalidad entre los pacientes en TAPD (el 12,2 frente al 14,4%; OR = 0,81; IC95%, 0,70-0,93; p = 0,003; phet = 0,93), con beneficio cuando se comparó con ácido acetilsalicílico en monoterapia (OR = 0,80; IC95%, 0,69-0,93; p = 0,004; phet = 0,60) y sin beneficio estadísticamente significativo cuando se comparó con la estrategia combinada de TAPU junto con anticoagulación oral (OR = 0,86; IC95%, 0,55-1,35; p = 0,51; phet = 0,97). Una tendencia similar se observó respecto al ictus (OR = 0,83; IC95%, 0,63-1,10; p = 0,20; phet = 0,67), sin incremento de la tasa de hemorragias mayores (OR = 1,69; IC95%, 0,86-3,31; p = 0,13; phet < 0,0001). Mediante el método de análisis de comparación indirecta, no se documentó beneficio en las tasas de supervivencia total, ictus y hemorragias mayores con la adición de anticoagulación oral. Conclusiones. Los resultados de este metanálisis muestran una reducción de la mortalidad y un beneficio discreto en la tasa de ictus, sin un aumento de la de hemorragias mayores, con el TAPD respecto al tratamiento con un único antiagregante tras el RPVA. La adición de anticoagulación oral al ácido acetilsalicílico no obtuvo mayor beneficio respecto al TAPD o al TAPU (AU)

Introduction and objectives. There is uncertainty on the correct management of antithrombotic therapies after transcatheter aortic valve replacement (TAVR), with dual antiplatelet therapy (DAPT) being currently recommended on an empirical basis. The aim of the present meta-analysis was to assess the safety and effectiveness of DAPT in patients undergoing TAVR. Methods. Studies comparing different antithrombotic regimens after TAVR were included. The primary endpoint was 30-day overall mortality. Results. We included 9 studies, 5 comparing DAPT with aspirin monotherapy and 4 comparing DAPT with monoantiplatelet therapy (MAPT) + oral anticoagulation. Among 7991 patients, 72% were on DAPT. The median follow-up was 3.5 months. Mortality was significantly lower in the DAPT group (12.2% vs 14.4%; OR, 0.81; 95%CI, 0.70-0.93; P = .003; Phet = .93), with similar benefits compared with aspirin monotherapy (OR, 0.80; 95%CI, 0.69-0.93; P = .004; Phet = .60), which were not statistically significant when compared with MAPT + oral anticoagulation (OR, 0.86; 95%CI, 0.55-1.35; P = .51; Phet = .97). A similar trend for DAPT was observed for stroke (OR, 0.83 95%CI, 0.63-1.10; P = .20; Phet = .67), with no increase in the rate of major bleedings (OR, 1.69; 95%CI, 0.86-3.31; P = .13; Phet< .0001). On indirect comparison analysis, no benefit in survival, stroke, or bleedings was identified for additional oral anticoagulation. Conclusions. The present meta-analysis supports the use of DAPT after TAVR, reducing mortality and offering slight benefits in stroke, with no increase in major bleedings compared with MAPT. The strategy of aspirin + oral anticoagulation did not provide significant benefits compared with MAPT or DAPT (AU)

Bivalirudina frente a heparina no fraccionada en síndromes coronarios agudos: un metanálisis actualizado de ensayos aleatorizados / Bivalirudin versus unfractionated heparin in acute coronary syndromes: An updated meta-analysis of randomized trials

Introducción y objetivos: Se han presentado datos contradictorios respecto al uso de bivalirudina como estrategia de anticoagulación durante las intervenciones coronarias percutáneas, puesto que aporta beneficios teóricos en cuanto a las complicaciones hemorrágicas, pero preocupa el posible aumento del riesgo de trombosis del stent. Se realizó un metanálisis actualizado para evaluar la eficacia y la seguridad de la bivalirudina comparada con la heparina no fraccionada en pacientes sometidos a intervenciones percutáneas por síndromes coronarios agudos. Métodos: Se realizó una búsqueda de artículos en la literatura médica y en actas de reuniones científicas importantes. El objetivo principal de eficacia fue la mortalidad total a 30 días. Los objetivos secundarios fueron evaluar trombosis del stent y hemorragias mayores. Se llevó a cabo un análisis preespecificado según la forma de presentación clínica. Resultados: Se incluyeron 12 ensayos aleatorizados con un total de 32.746 pacientes (el 52,5% asignados aleatoriamente a bivalirudina). La mortalidad fue del 1,8%, sin que se apreciaran diferencias entre la bivalirudina y la heparina (odds ratio = 0,91; intervalo de confianza del 95%, 0,77-1,08; p = 0,28; p para la heterogeneidad = 0,41). Se obtuvieron resultados similares en los pacientes con infarto de miocardio sin y con elevación del segmento ST. Se observó una tasa de trombosis del stent significativamente superior con bivalirudina (odds ratio = 1,42; intervalo de confianza del 95%, 1,09-1,83; p = 0,008; p para la heterogeneidad = 0,09). La bivalirudina se asoció a una reducción significativa de la tasa de hemorragias mayores (odds ratio = 0,60; intervalo de confianza del 95%, 0,54-0,75; p < 0,00001; p para la heterogeneidad < 0,0001) que, sin embargo, estaba relacionada con la diferencia existente en el uso de inhibidores de la glucoproteína IIb/IIIa (r = -0,02 [-0,033 a -0,0032]; p = 0,02) y no se tradujo en un efecto favorable en supervivencia. Conclusiones: En pacientes sometidos a intervenciones coronarias percutáneas, la bivalirudina, comparada con la heparina, no se asoció a una reducción de la mortalidad, pero sí a un aumento de trombosis del stent. La reducción de las complicaciones hemorrágicas observada con el uso de bivalirudina no se tradujo en un efecto beneficioso en la supervivencia, en cambio estuvo influida por una diferencia en el uso de inhibidores de la glucoproteína IIb/IIIa (AU)

Introduction and objectives: Contrasting data have been reported on bivalirudin as an anticoagulation strategy during percutaneous coronary interventions, offering theoretical benefits on bleeding complications but raising concerns on a potential increase in the risk of stent thrombosis. We performed an updated meta-analysis to evaluate the efficacy and safety of bivalirudin compared with unfractionated heparin in patients undergoing percutaneous interventions for acute coronary syndromes. Methods: Literature archives and main scientific sessions were scanned. The primary efficacy endpoint was 30-day overalmortality. Secondary endpoints were stent thrombosis and major bleeding. A prespecified analysis was conducted according to clinical presentation. Results: Twelve randomized trials were included, involving 32 746 patients (52.5% randomized to bivalirudin). Death occurred in 1.8% of the patients, with no differences between bivalirudin and heparin (odds ratio = 0.91; 95% confidence interval, 0.77-1.08; P = .28; P for heterogeneity = .41). Similar results were obtained for patients with non—ST-segment elevation and in ST-segment elevation myocardial infarction. A significantly higher rate of stent thrombosis was observed with bivalirudin (odds ratio = 1.42; 95% confidence interval, 1.09-1.83; P = .008; P for heterogeneity = .09). Bivalirudin was associated with a significant reduction in the rate of major bleeding (odds ratio = 0.60; 95% confidence interval, 0.54-0.75; P < .00001; P for heterogeneity < .0001), which, however, was related to the differential use of glycoprotein IIb/IIIa inhibitors (r = −0.02 [−0.033 to -0.0032]; P = .02) and did not translate into survival benefits. Conclusions: In patients undergoing percutaneous coronary interventions, bivalirudin is not associated with a reduction in mortality compared with heparin but does increase stent thrombosis. The reduction in bleeding complications observed with bivalirudin does not translate into survival benefits but is rather influenced by a differential use of glycoprotein IIb/IIIa inhibitors (AU)

¡Retrasar el tratamiento equivale a negarlo! / Treatment delayed is treatment denied!

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