Red-Fleshed Apples Rich in Anthocyanins and White-Fleshed Apples Modulate the Aorta and Heart Proteome in Hypercholesterolaemic Rats: The AppleCOR Study.

The impact of a red-fleshed apple (RFA) rich in anthocyanins (ACNs), a white-fleshed apple (WFA) without ACNs, and an extract infusion from Aronia fruit (AI) equivalent in dose of cyanidin-3-O-galactoside (main ACN) as RFA was determined by the proteome profile of aorta and heart as key cardiovascular tissues. Hypercholesterolaemic Wistar rats were separated into six groups (n = 6/group; three males and three females) and the proteomic profiles were analyzed using nanoliquid chromatography coupled to mass spectrometry. No adverse events were reported and all products were well tolerated. RFA downregulated C1QB and CFP in aorta and CRP in heart. WFA downregulated C1QB and CFP in aorta and C9 and C3 in aorta and heart, among other proteins. AI downregulated PRKACA, IQGAP1, and HSP90AB1 related to cellular signaling. Thus, both apples showed an anti-inflammatory effect through the complement system, while RFA reduced CRP. Regardless of the ACN content, an apple matrix effect was observed that involved different bioactive components, and inflammatory proteins were reduced.

Phosphoproteomic Analysis and Protein-Protein Interaction of Rat Aorta GJA1 and Rat Heart FKBP1A after Secoiridoid Consumption from Virgin Olive Oil: A Functional Proteomic Approach.

Protein functional interactions could explain the biological response of secoiridoids (SECs), main phenolic compounds in virgin olive oil (VOO). The aim was to assess protein-protein interactions (PPIs) of the aorta gap junction alpha-1 (GJA1) and the heart peptidyl-prolyl cis-trans isomerase (FKBP1A), plus the phosphorylated heart proteome, to describe new molecular pathways in the cardiovascular system in rats using nanoliquid chromatography coupled with mass spectrometry. PPIs modified by SECs and associated with GJA1 in aorta rat tissue were calpain, TUBA1A, and HSPB1. Those associated with FKBP1A in rat heart tissue included SUCLG1, HSPE1, and TNNI3. In the heart, SECs modulated the phosphoproteome through the main canonical pathways PI3K/mTOR signaling (AKT1S1 and GAB2) and gap junction signaling (GAB2 and GJA1). PPIs associated with GJA1 and with FKBP1A, the phosphorylation of GAB2, and the dephosphorylation of GJA1 and AKT1S1 in rat tissues are promising protein targets promoting cardiovascular protection to explain the health benefits of VOO.

Tumor suppressive function of E2F-1 on PTEN-induced serrated colorectal carcinogenesis.

Many human cancers present Phosphatase and tensin homolog (PTEN) deficiency and between 20 and 30% of colorectal tumors show PTEN loss. The transcription factor, E2 promoter binding factor 1 (E2F-1), exhibits tumor promoter or suppressive functions depending on cellular type and tissue context, but its role in the progression and development of colorectal carcinogenesis was largely unknown. Here, using a tamoxifen-inducible PTEN knockout mouse model, we have demonstrated that loss of PTEN leads to the development of colorectal tumorigenesis through the serrated pathway. Next, we studied PTEN loss-driven colorectal lesions in the context of E2F-1 deficiency in vivo. Our results revealed that monoallelic and biallelic absence of E2F-1 led to an increased incidence and progression of serrated tumorigenesis induced by PTEN loss. Finally, we investigated the mechanisms by which double PTEN/E2F-1 deficiency leads to enhanced tumorigenesis. We found that colorectal tumors from PTEN/E2F-1 double knockout mice and the human colorectal carcinoma cell line HT29 with shRNA-mediated downregulation of PTEN and E2F-1 exhibit hyperactivation of the RAS-MAPK pathway, accumulation of DNA damage and resistance to apoptosis. To date, this is the first preclinical study evaluating the effect of genetic deletion of E2F-1 in colorectal malignancies driven by PTEN deficiency. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Hydroxytyrosol and the Colonic Metabolites Derived from Virgin Olive Oil Intake Induce Cell Cycle Arrest and Apoptosis in Colon Cancer Cells.

After the sustained consumption of virgin olive oil (VOO), the unabsorbed native phenols (mainly hydroxytyrosol (HT)) are transformed into its catabolites in the intestine by microbials. The role of these catabolites in preventing colon cancer has not been sufficiently investigated. This work aims to study the antiproliferative and apoptotic activities in colon (Caco-2; HT-29) cancer cell lines of the main catabolites detected in human feces (phenylacetic, phenylpropionic, hydroxyphenylpropionic, and dihydroxyphenylpropionic acids and catechol), after the sustained VOO intake. Additionally, an assessment of the ability of these colonic cells to metabolize the studied compounds was performed. The results showed that HT and phenylacetic and hydroxyphenylpropionic acids produce cell cycle arrest and promote apoptosis. HT-29 cells were more sensitive to phenol treatments than Caco-2. In synthesis, the results of the present study represent a good starting point for understanding the potential apoptotic and antiproliferative effects of VOO phenolic compounds and their colonic metabolites.

Application of dried blood spot cards to determine olive oil phenols (hydroxytyrosol metabolites) in human blood.

In this study, a fast and simple blood sampling and sample pre-treatment method based on the use of the dried blood spot (DBS) cards and ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) for the quantification of olive oil phenolic metabolites in human blood was developed and validated. After validation, the method was applied to determine hydroxytyrosol metabolites in human blood samples after the acute intake of an olive oil phenolic extract. Using the FTA DMPK-A DBS card under optimum conditions, with 20µL as the blood solution volume, 100µL of methanol/Milli-Q water (50/50, v/v) as the extraction solvent and 7 disks punched out from the card, the main hydroxytyrosol metabolites (hydroxytyrosol-3-O-sulphate and hydroxytyrosol acetate sulphate) were identified and quantified. The developed methodology allowed detecting and quantifying the generated metabolites at low µM levels. The proposed method is a significant improvement over existing methods to determine phenolic metabolites circulating in blood and plasma samples, thus making blood sampling possible with the volunteer pricking their own finger, and the subsequent storage of the blood in the DBS cards prior to chromatographic analysis.

Oral intake of genetically engineered high-carotenoid corn ameliorates hepatomegaly and hepatic steatosis in PTEN haploinsufficient mice.

Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease. Here we show that a mouse model of haploinsufficiency in the lipid and protein phosphatase and tensin homolog protein (PTEN(+/-)) exhibits hepatomegaly, increased liver lipogenic gene expression (SREBP-1C and PPARγ) and hepatic lesions analogous to human NAFLD. The livers of PTEN(+/-) mice also contained lower levels of retinoic acid (RA) than normal, similarly to human NAFLD patients. The RA signaling pathway thus offers a novel therapeutic target for the treatment of NAFLD although the impact of nutrition in this context is unclear. We therefore fed PTEN(+/-) mice for 36weeks a diet containing genetically engineered high-carotenoid corn (HCAR) to investigate its potential beneficial effects on the hepatic symptoms of NAFLD. The HCAR diet reduced hepatomegaly and promoted the repartitioning of fatty acids in the liver, away from triacylglycerol storage. At the molecular level, the HCAR diet clearly reduced lipogenic gene expression, boosted catabolism, and increased hepatic RA levels. These results set the stage for human trials to evaluate the use of high-carotenoid foods for the reduction or prevention of steatosis in NAFLD.

Plurality of opinion, scientific discourse and pseudoscience: an in depth analysis of the Séralini et al. study claiming that Roundup™ Ready corn or the herbicide Roundup™ cause cancer in rats.

A recent paper published in the journal Food and Chemical Toxicology presents the results of a long-term toxicity study related to a widely-used commercial herbicide (Roundup™) and a Roundup-tolerant genetically modified variety of maize, concluding that both the herbicide and the maize varieties are toxic. Here we discuss the many errors and inaccuracies in the published article resulting in highly misleading conclusions, whose publication in the scientific literature and in the wider media has caused damage to the credibility of science and researchers in the field. We and many others have criticized the study, and in particular the manner in which the experiments were planned, implemented, analyzed, interpreted and communicated. The study appeared to sweep aside all known benchmarks of scientific good practice and, more importantly, to ignore the minimal standards of scientific and ethical conduct in particular concerning the humane treatment of experimental animals.

Mice fed on a diet enriched with genetically engineered multivitamin corn show no sub-acute toxic effects and no sub-chronic toxicity.

Multivitamin corn is a novel genetically engineered variety that simultaneously produces high levels of ß-carotene, ascorbate and folate, and therefore has the potential to address simultaneously multiple micronutrient deficiencies caused by the lack of vitamins A, B9 and C in developing country populations. As part of the development process for genetically engineered crops and following European Food Safety Authority (EFSA) recommendations, multivitamin corn must be tested in whole food/feed sub-chronic animal feeding studies to ensure there are no adverse effects, and potential allergens must be identified. We carried out a 28-day toxicity assessment in mice, which showed no short-term sub-acute evidence of diet-related adverse health effects and no difference in clinical markers (food consumption, body weight, organ/tissue weight, haematological and biochemical blood parameters and histopathology) compared to mice fed on a control diet. A subsequent 90-day sub-chronic feeding study again showed no indications of toxicity compared to mice fed on control diets. Our data confirm that diets enriched with multivitamin corn have no adverse effects on mice, do not induce any clinical signs of toxicity and do not contain known allergens.

Rapid methods to determine procyanidins, anthocyanins, theobromine and caffeine in rat tissues by liquid chromatography-tandem mass spectrometry.

Rapid, selective and sensitive methods were developed and validated to determine procyanidins, anthocyanins and alkaloids in different biological tissues, such as liver, brain, the aorta vein and adipose tissue. For this purpose, standards of procyanidins (catechin, epicatechin, and dimer B(2)), anthocyanins (cyanidin-3-glucoside and malvidin-3-glucoside) and alkaloids (theobromine, caffeine and theophylline) were used. The methods included the extraction of homogenized tissues by off-line liquid-solid extraction, and then solid-phase extraction to analyze alkaloids, or microelution solid-phase extraction plate for the analysis of procyanidins and anthocyanins. The eluted extracts were then analyzed by ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry, using a triple quadrupole as the analyzer. The optimum extraction solution was water/methanol/phosphoric acid 4% (94/4.5/1.5, v/v/v). The extraction recoveries were higher than 81% for all the studied compounds in all the tissues, except the anthocyanins, which were between 50 and 65% in the liver and brain. In order to show the applicability of the developed methods, different rat tissues were analyzed to determine the procyanidins, anthocyanins and alkaloids and their generated metabolites. The rats had previously consumed 1g of a grape pomace extract (to analyze procyanidins and anthocyanins) or a cocoa extract (to analyze alkaloids) per kilogram of body weight. Different tissues were extracted 4h after administration of the respective extracts. The analysis of the metabolites revealed a hepatic metabolism of procyanidins. The liver was the tissue which produced a greater accumulation of these metabolites.

Telomerase mRNA expression and immunohistochemical detection as a biomarker of malignant transformation in patients with inflammatory bowel disease

BackgroundInflammatory bowel disease is a premalignant condition for developing colorectal cancer. Since a correlation has been suggested between telomere length, chromosomal instability and neoplastic transformation in this setting, we sought to investigate whether telomerase expression in colorectal mucosa may constitute a biomarker for malignant transformation in patients with inflammatory bowel disease.Patients and methodsForty-seven patients with inflammatory bowel disease with and without cancer or dysplasia were evaluated for human telomerase reverse transcriptase hTERT immunostaining in paraffin-embedded, formalin-fixed colorectal tissues. In addition, hTERT mRNA expression was assessed in fresh frozen specimens from a second set of 35 patients with inflammatory bowel disease at high or low risk for neoplastic transformation.ResultsFive out of 10 patients (50%) with colorectal cancer or high-grade dysplasia exhibited hTERT immunochemical detection in adjacent, non-transformed colonic mucosa. However, this phenomenon was also observed in non-affected mucosa of patients with either long-standing (13 out of 19 patients; 68%) or short duration (13 out of 18 patients; 72%) disease without cancer or dysplasia. On the other hand, hTERT mRNA expression in non-affected colorectal mucosa from patients at high risk for neoplastic transformation due to long-standing disease was higher than in those at low risk (7.42±6.43 vs. 2.87±1.47, respectively; p=0.006).ConclusionsWhereas hTERT immunostaining provides equivocal results, the observation that patients at high risk for colorectal cancer because of long-standing inflammatory bowel disease overexpress hTERT mRNA in non-affected colorectal mucosa suggests its potential usefulness as a biomarker of the risk of malignant transformation(AU)

AntecedentesLa enfermedad intestinal inflamatoria es una condición premaligna para el desarrollo de cáncer colorrectal. Puesto que se ha propuesto la existencia de una correlación entre la longitud de telomero, la inestabilidad cromosómica y la transformación neoplásica en este contexto, nos propusimos investigar si la expresión de la telomerasa en la mucosa colorrectal puede constituir un marcador biológico de transformación neoplásica en pacientes con enfermedad intestinal inflamatoria.Pacientes y métodosSe evaluaron 47 pacientes con enfermedad intestinal inflamatoria, con y sin cáncer o displasia, para inmunotinción de hTERT (transcriptasa inversa de telomerasa humana) en tejidos colorrectales preservados en parafina y fijados con formol. Además, se evaluó la expresión de la ARNm de la hTERT en muestras congeladas procedentes de un segundo grupo de 35 pacientes con enfermedad intestinal inflamatoria clasificados de alto o bajo riesgo de transformación neoplásica.ResultadosCinco de 10 pacientes (50%) con cáncer colorrectal o un grado elevado de displasia presentaban detección inmunoquímica de la hTERT en la mucosa colónica adyacente sin transformación maligna. Sin embargo, este fenómeno también se observó en mucosa no afecta de pacientes que presentaban enfermedad de larga duración (13 de 19 pacientes; 68%) y de corta duración (13 de 18 pacientes; 72%), sin presencia de cáncer ni displasia. Por otro lado, la expresión del ARN de la hTERT en mucosa colorrectal no afecta de pacientes con alto riesgo de transformación neoplásica, debido a enfermedad prolongada, fue mayor que en aquellos con bajo riesgo (7,42±6,43 frente a 2,87±1,47, respectivamente; p=0,006).(..) (AU)

Telomerase mRNA expression and immunohistochemical detection as a biomarker of malignant transformation in patients with inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease is a premalignant condition for developing colorectal cancer. Since a correlation has been suggested between telomere length, chromosomal instability and neoplastic transformation in this setting, we sought to investigate whether telomerase expression in colorectal mucosa may constitute a biomarker for malignant transformation in patients with inflammatory bowel disease. PATIENTS AND METHODS: Forty-seven patients with inflammatory bowel disease with and without cancer or dysplasia were evaluated for human telomerase reverse transcriptase hTERT immunostaining in paraffin-embedded, formalin-fixed colorectal tissues. In addition, hTERT mRNA expression was assessed in fresh frozen specimens from a second set of 35 patients with inflammatory bowel disease at high or low risk for neoplastic transformation. RESULTS: Five out of 10 patients (50%) with colorectal cancer or high-grade dysplasia exhibited hTERT immunochemical detection in adjacent, non-transformed colonic mucosa. However, this phenomenon was also observed in non-affected mucosa of patients with either long-standing (13 out of 19 patients; 68%) or short duration (13 out of 18 patients; 72%) disease without cancer or dysplasia. On the other hand, hTERT mRNA expression in non-affected colorectal mucosa from patients at high risk for neoplastic transformation due to long-standing disease was higher than in those at low risk (7.42+/-6.43 vs. 2.87+/-1.47, respectively; p=0.006). CONCLUSIONS: Whereas hTERT immunostaining provides equivocal results, the observation that patients at high risk for colorectal cancer because of long-standing inflammatory bowel disease overexpress hTERT mRNA in non-affected colorectal mucosa suggests its potential usefulness as a biomarker of the risk of malignant transformation.

Análisis de minimización de costes de fludarabina (Beneflur®) oral vs. vía intravenosa en España / Cost-reduction analysis for oral versus intravenous fludarabine (Beneflur®) in Spain

Introducción: Fludarabina ha demostrado su eficacia, seguridad y eficiencia en el tratamiento de la leucemia linfocítica crónica de células B (LLC-B) en diversos estudios internacionales. El objetivo del presente estudio fue realizar un análisis de minimización de costes de 2 formas alternativas de fludarabina (oral e intravenosa) para el tratamiento de la LLC-B en España. Métodos: La existencia de evidencias clínicas sobre la equivalencia terapéutica de las 2 opciones comparadas (fludarabina oral frente a fludarabina intravenosa) llevó a la realización de un análisis de minimización de costes. Se construyó un modelo farmacoeconómico que combinó datos de la bibliografía y la opinión de expertos para determinar el uso de recursos sanitarios asociados al tratamiento, y los costes unitarios se obtuvieron de bases de datos españolas. El análisis consideró 2 perspectivas: a) la del Sistema Nacional de Salud, que incluía sólo los costes directos sanitarios, y b) la perspectiva social, que además de éstos, incluía los costes indirectos derivados de la pérdida de productividad. Resultados: Aunque la forma oral de fludarabina tiene un coste de adquisición mayor que la especialidad farmacéutica genérica de fludarabina intravenosa, los mayores costes de administración de esta última, de uso hospitalario, se tradujeron en unos ahorros totales asociados a fludarabina oral de 1.908 y 1.292 € en monoterapia y tratamiento combinado con ciclofosfamida, respectivamente. La inclusión de los costes indirectos aumentó los ahorros asociados a la forma oral. Conclusiones: El tratamiento de los pacientes con LLC-B con fludarabina oral presenta unos costes menores respecto a fludarabina intravenosa, tanto en monoterapia, como en tratamiento combinado. Diversos análisis de sensibilidad confirmaron estos resultados, en los que se constata que la forma oral de fludarabina debería ser la opción de elección en el tratamiento de la LLC-B en España, salvo que se contraindique (AU)

Introduction: Various international studies have shown that fludarabine is effective, safe, and efficient for treating B-cell chronic lymphocytic leukemia (B-CLL). The purpose of the present study was to carry out a cost-minimization analysis for two alternative forms of fludarabine (oral and intravenous) used to treat B-CLL in Spain. Methods: The presence of clinical evidence about the treatment equivalence of the two options being compared (oral fludarabine vs. intravenous fludarabine) led us to carry out a cost-minimization analysis. A pharmacoeconomic model was constructed to compile data from the literature and experts’ opinions in order to determine the use of health resources associated with the treatment; unit costs were obtained from Spanish databases. The analysis contemplated two perspectives: that of the national health service, which includes only direct health costs, and the social perspective, which also includes the indirect costs that result from loss of productivity. Results: Although fludarabine in its oral form has a higher purchase price than generic intravenous fludarabine does, increased administration costs for the latter, which is used in hospitals, mean that oral fludarabine use produces total savings of €1,908 and €1,292 for single-drug therapy and combined therapy with cyclophosphamide, respectively. Including indirect costs increased the savings associated with the oral form of the drug. Conclusions: In B-CLL patients, treatment with oral fludarabine has a lower cost than treatment with intravenous fludarabine, in both single-drug therapy and combined therapy. Various sensitivity analyses confirmed these results and showed that oral fludarabine should be the treatment of choice for B-CLL in Spain, unless contrain (AU)

[Cost-reduction analysis for oral versus intravenous fludarabine (Beneflur) in Spain]. / Análisis de minimización de costes de fludarabina (Beneflur) oral vs. vía intravenosa en España.

INTRODUCTION: Various international studies have shown that fludarabine is effective, safe, and efficient for treating B-cell chronic lymphocytic leukemia (B-CLL). The purpose of the present study was to carry out a cost-minimization analysis for two alternative forms of fludarabine (oral and intravenous) used to treat B-CLL in Spain. METHODS: The presence of clinical evidence about the treatment equivalence of the two options being compared (oral fludarabine vs. intravenous fludarabine) led us to carry out a cost-minimization analysis. A pharmacoeconomic model was constructed to compile data from the literature and experts' opinions in order to determine the use of health resources associated with the treatment; unit costs were obtained from Spanish databases. The analysis contemplated two perspectives: that of the national health service, which includes only direct health costs, and the social perspective, which also includes the indirect costs that result from loss of productivity. RESULTS: Although fludarabine in its oral form has a higher purchase price than generic intravenous fludarabine does, increased administration costs for the latter, which is used in hospitals, mean that oral fludarabine use produces total savings of euro1,908 and euro1,292 for single-drug therapy and combined therapy with cyclophosphamide, respectively. Including indirect costs increased the savings associated with the oral form of the drug. CONCLUSIONS: In B-CLL patients, treatment with oral fludarabine has a lower cost than treatment with intravenous fludarabine, in both single-drug therapy and combined therapy. Various sensitivity analyses confirmed these results and showed that oral fludarabine should be the treatment of choice for B-CLL in Spain, unless contrain.

[Cost-effectiveness of the addition of acarbose to the treatment of patients with type-2 diabetes in Spain]. / Coste-efectividad de la adición de acarbosa al tratamiento de pacientes con diabetes tipo 2 en España.

OBJECTIVES: To assess the cost-effectiveness of the addition of acarbose to existing treatment in patients with type 2 diabetes mellitus (DM2) in Spain. METHODS: The CORE Diabetes Model (a published and validated computer simulation model) was used to project long-term clinical and cost outcomes in DM2. Transition probabilities and risk adjustments were derived from published sources. Treatment effects and baseline cohort characteristics were based on a meta-analysis. Direct costs were retrieved from published sources and projected over patient lifetimes from the perspective of the Spanish National Health Service. Costs and clinical benefits were discounted at 3% per year. Sensitivity analyses were performed. RESULTS: Acarbose treatment was associated with improved life expectancy (0.23 years) and quality-adjusted life years (QALY) (0.21 years). Direct costs were on average euro 468 per patient more expensive with acarbose than with placebo. The incremental cost-effectiveness ratios were euro 2,002 per life year gained and euro 2,199 per QALY gained. An acceptability curve showed that with a willingness to pay euro 20,000, which is generally accepted to represent very good value for money, acarbose treatment was associated with a 93.5% probability of being cost-effective. CONCLUSIONS: This long-term economic study showed that the addition of acarbose to existing therapy for DM2 was associated with improvements in life expectancy and QALYs in these patients.

Coste-efectividad de la adición de acarbosa al tratamiento de pacientes con diabetes tipo 2 en España / Cost-effectiveness of the addition of acarbose to the treatment of patients with type-2 diabetes in Spain

Objetivos: Evaluar el coste-efectividad de la adición de acarbosa al tratamiento de pacientes con diabetes mellitus tipo 2 (DM2) en España. Métodos: Se utilizó el CORE Diabetes Model (modelo de simulación informática publicado y validado) para proyectar a largo plazo los resultados clínicos y de costes de la DM2. Las probabilidades de transición y los riesgos se obtuvieron de distintas publicaciones. Los efectos del tratamiento y las características basales de la cohorte se obtuvieron de un metaanálisis. Los costes directos se extrajeron de diversas publicaciones y se proyectaron a lo largo de la vida de los pacientes bajo la perspectiva del Sistema Nacional de Salud de España. Los costes y beneficios fueron descontados en un 3% anual. Se realizaron análisis de sensibilidad. Resultados: El tratamiento con acarbosa se asoció con mejoras en la esperanza de vida (0,23 años) y en los años de vida ajustados por calidad (AVAC) (0,21 años). Los costes directos fueron en promedio, por paciente, de 468 € más caros con acarbosa que con placebo. La razón de coste-efectividad incremental fue de 2.002 €/año de vida ganado y de 2.199 €/AVAC ganado. La curva de aceptabilidad mostró que con una disponibilidad a pagar de 20.000 €, generalmente aceptada como muy buen valor monetario, el tratamiento con acarbosa se asoció con una probabilidad del 93,5% de ser coste-efectiva. Conclusiones: Este estudio económico a largo plazo mostró que la adición de acarbosa al tratamiento de pacientes con DM2 produjo mejoras en la esperanza de vida y en los AVAC de estos pacientes

Objectives: To assess the cost-effectiveness of the addition of acarbose to existing treatment in patients with type 2 diabetes mellitus (DM2) in Spain. Methods: The CORE Diabetes Model (a published and validated computer simulation model) was used to project long-term clinical and cost outcomes in DM2. Transition probabilities and risk adjustments were derived from published sources. Treatment effects and baseline cohort characteristics were based on a meta-analysis. Direct costs were retrieved from published sources and projected over patient lifetimes from the perspective of the Spanish National Health Service. Costs and clinical benefits were discounted at 3% per year. Sensitivity analyses were performed. Results: Acarbose treatment was associated with improved life expectancy (0.23 years) and quality-adjusted life years (QALY) (0.21 years). Direct costs were on average € 468 per patient more expensive with acarbose than with placebo. The incremental cost-effectiveness ratios were € 2,002 per life year gained and € 2,199 per QALY gained. An acceptability curve showed that with a willingness to pay € 20,000, which is generally accepted to represent very good value for money, acarbose treatment was associated with a 93.5% probability of being cost-effective. Conclusions: This long-term economic study showed that the addition of acarbose to existing therapy for DM2 was associated with improvements in life expectancy and QALYs in these patients

[Health economic evaluation of low-dose acetylsalicylic acid in the primary prevention of cardiovascular disease]. / Evaluación económica del tratamiento con ácido acetilsalicílico en dosis bajas en la prevención primaria de enfermedades cardiovasculares.

INTRODUCTION AND OBJECTIVES: Low-dose aspirin is standard treatment for patients with a history of cardiovascular disease. Its use in primary prevention is more controversial. However, recent studies also support the use of aspirin in high-risk individuals with no history of cardiovascular disease. This study investigated the health economic implications of using low-dose aspirin in the primary prevention of cardiovascular disease in Spain. METHODS: A model was developed to predict the cost-effectiveness of low-dose aspirin in the primary prevention of cardiovascular disease over a period of 10 years. The direct costs used were those of the Spanish National Health Service (NHS). Results were expressed as cost per life-year gained and per quality-adjusted life-year gained. RESULTS: Administering low-dose aspirin to an individual with a 10-year risk of coronary heart disease > or =15% resulted in an average net saving of e 797 (95% CI, e 263-1331) over the 10-year period, with savings starting in the first year. For an annual risk > or =0.24%, this form of treatment would reduce NHS costs. Treating all at-risk individuals in the Spanish population with aspirin would save e 26.5 million from the healthcare budget, starting in the first year. CONCLUSIONS: Administering low-dose aspirin to individuals with a 10-year risk of coronary heart disease > or =15% would result in significant cost savings for the Spanish NHS. Sensitivity analysis confirmed the robustness of these findings.

Evaluación económica del tratamiento con ácido acetilsalicílico en dosis bajas en la prevención primaria de enfermedades cardiovasculares / Health Economic Evaluation of Low-Dose Acetylsalicylic Acid in the Primary Prevention of Cardiovascular Disease

Introducción y objetivos. El ácido acetilsalicílico (AAS) en dosis bajas es un tratamiento estándar en pacientes con antecedentes de enfermedades cardiovasculares (ECV); se discute su empleo en prevención primaria. Recientes estudios apoyan su uso en personas de alto riesgo y sin antecedentes de ECV. Se evaluó la repercusión económica del uso de AAS en la prevención primaria de ECV en España. Métodos. Se desarrolló un modelo para estimar la relación coste/efectividad del tratamiento con AAS a dosis bajas en la prevención primaria de ECV a los 10 años. Se estudiaron los costes directos desde la perspectiva del Sistema Nacional de Salud (SNS) español. Los resultados se expresaron como coste por años de vida ganados y por años de vida ajustados por calidad. Resultados. La administración de AAS en dosis bajas a personas con riesgo de enfermedad coronaria (EC) ≥ 15% a los 10 años produce un ahorro neto medio de 797 euros (intervalo de confianza [IC] del 95%, 263-1.331 euros), que empieza el primer año. A partir de un riesgo anual ≥ 0,24%, este tratamiento ahorra costes al SNS. El tratamiento con AAS a toda la población española con riesgo produciría un ahorro de 26,5 millones de euros en servicios sanitarios desde el primer año. Conclusiones. El tratamiento con AAS en dosis bajas de individuos con riesgo de EC ≥ 15% a los 10 años produciría un ahorro de costes significativo al SNS. Los análisis de sensibilidad prueban la robustez de los resultados (AU)

Introduction and objectives. Low-dose aspirin is standard treatment for patients with a history of cardiovascular disease. Its use in primary prevention is more controversial. However, recent studies also support the use of aspirin in high-risk individuals with no history of cardiovascular disease. This study investigated the health economic implications of using low-dose aspirin in the primary prevention of cardiovascular disease in Spain. Methods. A model was developed to predict the cost- effectiveness of low-dose aspirin in the primary prevention of cardiovascular disease over a period of 10 years. The direct costs used were those of the Spanish National Health Service (NHS). Results were expressed as cost per life-year gained and per quality-adjusted life- year gained. Results. Administering low-dose aspirin to an individual with a 10-year risk of coronary heart disease ≥15% resulted in an average net saving of e 797 (95% CI, e 263-1331) over the 10-year period, with savings starting in the first year. For an annual risk ≥0.24%, this form of treatment would reduce NHS costs. Treating all at-risk individuals in the Spanish population with aspirin would save e 26.5 million from the healthcare budget, starting in the first year. Conclusions. Administering low-dose aspirin to individuals with a 10-year risk of coronary heart disease ≥15% would result in significant cost savings for the Spanish NHS. Sensitivity analysis confirmed the robustness of these findings (AU)

[Economic evaluation of the treatment with aspirin plus esomeprazole compared to clopidogrel in gastrointestinal bleeding prevention]. / Evaluación económica del tratamiento con ácido acetilsalicílico más esomeprazol comparado con clopidogrel en la prevención de la hemorragia gastrointestinal.

OBJECTIVE: To evaluate the use of aspirin plus esomeprazole vs. clopidogrel in the prevention of gastrointestinal bleeding. METHODS: We performed a cost-effectiveness analysis (two-branch decision tree: aspirin plus esomeprazole or clopidogrel) of prevention of gastrointestinal bleeding over a 2-year period, as well as sensitivity analyses. RESULTS: The total cost of aspirin plus esomeprazole treatment (2,865 Euro/patient free of hemorrhage) was lower than that of clopidogrel (2,965 Euro). Aspirin treatment was dominant. The combination continued to be dominant in all sensitivity analyses. When esomeprazole 40 mg was substituted by omeprazole 40 mg, the cost of combination therapy decreased to 1,934 Euro/prevented hemorrhage. CONCLUSIONS: The association of esomeprazole and aspirin is more cost-effective than clopidogrel in preventing gastrointestinal bleeding. Aspirin plus omeprazole was even more cost-effective.

Evaluación económica del tratamiento con ácido acetilsalicílico más esomeprazol comparado con clopidogrel en la prevención de la hemorragia gastrointestinal / Economic evaluation of the treatment of aspirin plus esomeprazole compared to clopidogrel in gastrointestinal bleeding prevention

Objetivo: Evaluar la eficiencia del ácido acetilsalicílico (AAS) más esomeprazol frente a clopidogrel en la prevención de la hemorragia gastrointestinal. Métodos: Análisis coste-efectividad (árbol de decisión de 2 ramas: AAS más esomeprazol y clopidogrel) respecto a la evitación de casos de hemorragia gastrointestinal en 2 años, y análisis de sensibilidad. Resultados: El coste total del tratamiento con AAS más esomeprazol (2.865 S por paciente libre de hemorragia) fue inferior al clopidogrel (2.965 S). El tratamiento con AAS resultó dominante. En todos los análisis de sensibilidad la combinación siguió siendo dominante. Al sustituir esomeprazol 40 mg por omeprazol 40 mg, el coste del tratamiento combinado descendió hasta 1.934S/por episodio evitado. Conclusiones: La asociación de esomeprazol y AAS es más coste-efectiva que clopidogrel en la prevención de la hemorragia gastrointestinal. La combinación con omeprazol resulta aún más coste-efectiva

Objective: To evaluate the use of aspirin plus esomeprazole vs. clopidogrel in the prevention of gastrointestinal bleeding. Methods: We performed a cost-effectiveness analysis (two-branch decision tree: aspirin plus esomeprazole or clopidogrel) of prevention of gastrointestinal bleeding over a 2-year period, as well as sensitivity analyses. Results: The total cost of aspirin plus esomeprazole treatment (2,865S/patient free of hemorrhage) was lower than that of clopidogrel (2,965S). Aspirin treatment was dominant. The combination continued to be dominant in all sensitivity analyses. When esomeprazole 40 mg was substituted by omeprazole 40 mg, the cost of combination therapy decreased to 1,934 S/prevented hemorrhage. Conclusions: The association of esomeprazole and aspirin is more cost-effective than clopidogrel in preventing gastrointestinal bleeding. Aspirin plus omeprazole was even more cost-effective