Cost-effectiveness in unstable economies: the case of sacubitril/valsartan in heart failure with reduced ejection fraction in Argentina.

BACKGROUND: Sacubitril/valsartan (an Angiotensin receptor-neprilysin inhibitor-ARNI) is one of the cornerstones in the management of patients with heart failure with reduced ejection fraction (HFrEF) having demonstrated significant reductions in both mortality and hospitalisations as compared with enalapril. It proved to be a cost-effective treatment in many countries with stable economies. In Argentina, a country with chronic financial instability and a fragmented health care system, the estimation of its cost-effectiveness requires to consider local financial data. OBJECTIVES: To estimate the cost-effectiveness of sacubitril/valsartan in HFrEF in Argentina. METHODS: We populated an Excel-based cost-effectiveness model, previously validated, using inputs from the pivotal phase-3 PARADIGM-HF trial and from local sources. As the main problem to consider was the financial instability, we adopted a differential approach to cost discounting based on the opportunity cost of capital. Thus, a discount rate for costs were set at 31.6%, using the BADLAR rate published by the Central Bank of Argentina. Discount for effects were set at 5% as is the current practice. Costs were expressed in Argentinian pesos (ARS). We used the perspective for both the social security and private payers at a 30-year horizon. The primary analysis was the incremental cost-effectiveness ratio (ICER) versus enalapril, the previous standard of care. Alternative scenarios performed included a 5% cost discount rate and 3 a 5-year horizon (as is usually used). RESULTS: In Argentina the cost-per quality adjusted life-year (QALY) gained for sacubitril/valsartan versus enalapril was 391,158 ARS and 376,665 ARS for a social security and a private payer, respectively, at a 30- year horizon. These ICERs were under the cost- effectiveness threshold of 520,405.79 ARS (1 Gross domestic product (GDP) per capita) suggested by Argentinian health technology assessment bodies. Probabilistic sensitivity analysis showed an acceptability of sacubitril/valsartan as a cost-effective alternative of 86.40% and 88.25% for social security and private payers, respectively. CONCLUSION: Sacubitril/valsartan is a cost-effective treatment in HFrEF using local inputs that considered the financial instability. For both payers considered the cost per QALY gained are under the cost-effectiveness threshold considered.

Estudio TAMARA II. Tabaquismo en médicos de la República Argentina II / The tamara ii trial. smoking among physicians in argentina

background: Smoking is the leading cause of preventable morbidity and death. It is important to know the characteristics of smoking habits among physicians and their attitude toward patients who smoke. Objective: The aim of this study is to investigate the prevalence of smoking among physicians in Argentina, the factors associated with tobacco consumption and their attitude toward their patients who smoke. Methods: An observational cross- sectional study was performed between June and December 2013 in Argentine physicians of dif-ferent specialties. Using a structured survey, the following variables were analyzed: associated cardiovascular risk factors, charac-teristics of tobacco consumption, smoking cessation training and the attitude toward the patient who smokes. results: 3,033 physicians were surveyed, ; 57% were men, and mean age was 41.3±12 years; 19.7% were current smokers and 21.7% were former smokers. The probability of being a smoker was higher among surgeons (OR 1.29) or physicians working at the emergency room (OR 1.41). Undergraduate and postgraduate tobacco cessation training was achieved by 36.6% and 40.8% of physicians, respectively. Young physicians, clinical specialties or private practice were associated with higher level of training. Tobacco cessation counseling was more frequent in physicians with higher level of training than physicians who smoked or surgeons. Former smokers presented higher prevalence of risk factors and cardiovascular events. Family history of smoking habit was more common in former smokers and current smokers. Conclusions: The prevalence of smoking among Argentine physicians is high. Different factors are involved in the probability of smoking, tobacco cessation training or the possibility of medical counseling. Higher level of training in smoking cessation must be provided.

[Diffusion and adoption of health care innovations in cardiology, in Argentina]. / Perfil de difusión y adopción de innovaciones de los cardiólogos en Argentina.

BACKGROUND: Medicine is changing rapidly and diagnostic and therapeutic innovations are common. Not all professionals adopt these innovations in the same way. AIM: To survey the physicians' opinions on adopting innovations in cardiovascular health care, to classify individuals from an innovative to a conservative behavior, and to individualize opinion leaders among them, in order to build a social network of influence. MATERIAL AND METHODS: Between November and December 2008, 765 Argentine cardiologists were surveyed via e-mail in Argentina, to assess the way they adopt and disseminate innovations in cardiovascular health care. RESULTS: The survey was answered by 537 professionals (70.2%). Fifty three percent of respondents were "Early adopters". However, 63 to 79.3% of respondents preferred to wait for a full demonstration of the usefulness of innovation before adopting it. The opinion leaders' distribution adopted a scale-free network pattern, where few leaders had many connections and influence on the whole network. The giant component of the network included 41% of physicians; growth simulation of the network showed that the four most popular leaders influenced over 44% of the giant component. CONCLUSIONS: Among surveyed physicians there was an attitude towards rapid acceptance of innovations in health care. However, when analyzing the direct opinion of physicians, most cases preferred usefulness demonstrated before accepting innovations. The social network including respondents and opinion leaders showed a scale-free topology with a big influence of a few over the whole network.

Perfil de difusión y adopción de innovaciones de los cardiólogos en Argentina / Diffusion and adoption of health care innovations in cardiology, in Argentina

Background: Medicine is changing rapidly and diagnostic and therapeutic innovations are common. Not all professionals adopt these innovations in the same way. Aim: To survey the physicians' opinions on adopting innovations in cardiovascular health care, to classify individuals from an innovative to a conservative behavior, and to individualize opinion leaders among them, in order to build a social network of influence. Material and Methods: Between November and December 2008, 765 Argentine cardiologists were surveyed via e-mail in Argentina, to assess the way they adopt and disseminate innovations in cardiovascular health care. Results: The survey was answered by 537professionals (70.2%). Fifty three percent of respondents were "Early adopters". However, 63 to 79.3% of respondents preferred to wait for a full demonstration of the usefulness of innovation before adopting it. The opinion leaders' distribution adopted a scale-free network pattern, where few leaders had many connections and influence on the whole network. The giant component of the network included 41% ofphysicians; growth simulation of the network showed that the four most popular leaders influenced over 44% of the giant component. Conclusions: Among surveyed physicians there was an attitude towards rapid acceptance of innovations in health care. However, when analyzing the direct opinion ofphysicians, most cases preferred usefulness demonstrated before accepting innovations. The social network including respondents and opinion leaders showed a scale-free topology with a big influence of a few over the whole network.

[Patients' preferences for information in health care decision-making]. / Preferencias de los pacientes sobre la información de su enfermedad.

A survey was carried out among patients who concurred to cardiologic services to know how patients preferred to be informed about their health status, and the demographic characteristics associated to these preferences, considering the following items: knowledge about the disease, information about different therapeutic options and decision-making. From 770 people surveyed, 738 (95.8%) answered the form completely. A trend to trust only in the doctor's knowledge to obtain information (81.7%), in wanting to know the options of treatment and express one's point of view (85.9%), and to involve the family in the decisions (63.2%) was observed. 9.6% preferred to receive the minimum necessary information or "to know nothing" about an alleged serious disease. Males tended less to request options and give opinion on the subject (or: 0.64), giving less freedom to family involvement (or: 1.31). people with a lower social and economical level claim fewer options (or: 0.48) and gave less family participation (or = 1.79). Natives from other South American countries had a minor tendency to demand for options and express their thoughts (or: 0.60); and the ones with lower education level trusted less in the doctor's knowledge (or: 1.81), demanded fewer options (or: 0.45) and chose not to know the severity of the disease (or: 0.56). the analysis of the demographical variables allowed to define preferences associated to age, sex, origin, education, religion and health status. In conclusion, although it is imperative to promote the patient's autonomy, individual preferences must be taken into account before informing and compromising the patient in decision-making about his disease.

Preferencias de los pacientes sobre la información de su enfermedad / Patients' preferences for information in health care decision-making

Se realizó una encuesta a pacientes que concurrían a servicios de cardiología para conocer cómo preferían ser informados sobre su estado de salud, y las características sociodemográficas asociadas con estas preferencias, considerando los siguientes ítems: conocimiento sobre la enfermedad, información sobre opciones terapéuticas y toma de decisiones. De 770 encuestados, 738 (95.8%) respondieron completamente el formulario. Se observó una tendencia a confiar sólo en el médico para obtener información (81.7%), a querer conocer las opciones de tratamiento y poder opinar (85.9%) y en menor medida, a la participación de la familia en las decisiones (63.2%). El 9.6% deseaba recibir la información mínima necesaria o "no saber nada" sobre una presunta enfermedad grave. Los varones fueron menos proclives a solicitar opciones y dar opinión (OR: 0.64), dando menos libertad a la participación familiar (OR: 1.31). Los de menor nivel socioeconómico reclamaron menos opciones (OR: 0.48) y dieron menor participación familiar (OR: 1.79). Los provenientes de otros países de Sudamérica tuvieron una menor tendencia a reclamar opciones y manifestar opinión (OR: 0.60); y los de menor nivel educativo confiaron menos en el conocimiento del médico (OR: 1.81), exigieron menos opciones (OR: 0.45) y prefirieron no conocer la gravedad de la enfermedad (OR: 0.56). El análisis de las variables demográficas permitió definir distintas preferencias de información asociadas a la edad, sexo, procedencia, educación, religión y estado de salud. Se concluye que, aunque es imperativo promover la autonomía del paciente, se deben conocer las preferencias individuales antes de informar y comprometer al paciente en el proceso de toma de decisiones sobre su enfermedad.

A survey was carried out among patients who concurred to cardiologic services to know how patients preferred to be informed about their health status, and the demographic characteristics associated to these preferences, considering the following items: knowledge about the disease, information about different therapeutic options and decision-making. From 770 people surveyed, 738 (95.8%) answered the form completely. A trend to trust only in the doctor's knowledge to obtain information (81.7%), in wanting to know the options of treatment and express one's point of view (85.9%), and to involve the family in the decisions (63.2%) was observed. 9.6% preferred to receive the minimum necessary information or "to know nothing" about an alleged serious disease. Males tended less to request options and give opinion on the subject (OR: 0.64), giving less freedom to family involvement (OR: 1.31). People with a lower social and economical level claim fewer options (OR: 0.48) and gave less family participation (OR = 1.79). Natives from other South American countries had a minor tendency to demand for options and express their thoughts (OR: 0.60); and the ones with lower education level trusted less in the doctor's knowledge (OR: 1.81), demanded fewer options (OR: 0.45) and chose not to know the severity of the disease (OR: 0.56). The analysis of the demographical variables allowed to define preferences associated to age, sex, origin, education, religion and health status. In conclusion, although it is imperative to promote the patient's autonomy, individual preferences must be taken into account before informing and compromising the patient in decision-making about his disease.

Preferencias de los pacientes sobre la información de su enfermedad / Patients preferences for information in health care decision-making

Se realizó una encuesta a pacientes que concurrían a servicios de cardiología para conocer cómo preferían ser informados sobre su estado de salud, y las características sociodemográficas asociadas con estas preferencias, considerando los siguientes ítems: conocimiento sobre la enfermedad, información sobre opciones terapéuticas y toma de decisiones. De 770 encuestados, 738 (95.8%) respondieron completamente el formulario. Se observó una tendencia a confiar sólo en el médico para obtener información (81.7%), a querer conocer las opciones de tratamiento y poder opinar (85.9%) y en menor medida, a la participación de la familia en las decisiones (63.2%). El 9.6% deseaba recibir la información mínima necesaria o "no saber nada" sobre una presunta enfermedad grave. Los varones fueron menos proclives a solicitar opciones y dar opinión (OR: 0.64), dando menos libertad a la participación familiar (OR: 1.31). Los de menor nivel socioeconómico reclamaron menos opciones (OR: 0.48) y dieron menor participación familiar (OR: 1.79). Los provenientes de otros países de Sudamérica tuvieron una menor tendencia a reclamar opciones y manifestar opinión (OR: 0.60); y los de menor nivel educativo confiaron menos en el conocimiento del médico (OR: 1.81), exigieron menos opciones (OR: 0.45) y prefirieron no conocer la gravedad de la enfermedad (OR: 0.56). El análisis de las variables demográficas permitió definir distintas preferencias de información asociadas a la edad, sexo, procedencia, educación, religión y estado de salud. Se concluye que, aunque es imperativo promover la autonomía del paciente, se deben conocer las preferencias individuales antes de informar y comprometer al paciente en el proceso de toma de decisiones sobre su enfermedad.(AU)

A survey was carried out among patients who concurred to cardiologic services to know how patients preferred to be informed about their health status, and the demographic characteristics associated to these preferences, considering the following items: knowledge about the disease, information about different therapeutic options and decision-making. From 770 people surveyed, 738 (95.8%) answered the form completely. A trend to trust only in the doctors knowledge to obtain information (81.7%), in wanting to know the options of treatment and express ones point of view (85.9%), and to involve the family in the decisions (63.2%) was observed. 9.6% preferred to receive the minimum necessary information or "to know nothing" about an alleged serious disease. Males tended less to request options and give opinion on the subject (OR: 0.64), giving less freedom to family involvement (OR: 1.31). People with a lower social and economical level claim fewer options (OR: 0.48) and gave less family participation (OR = 1.79). Natives from other South American countries had a minor tendency to demand for options and express their thoughts (OR: 0.60); and the ones with lower education level trusted less in the doctors knowledge (OR: 1.81), demanded fewer options (OR: 0.45) and chose not to know the severity of the disease (OR: 0.56). The analysis of the demographical variables allowed to define preferences associated to age, sex, origin, education, religion and health status. In conclusion, although it is imperative to promote the patients autonomy, individual preferences must be taken into account before informing and compromising the patient in decision-making about his disease.(AU)

Rivaroxaban in atrial fibrillation.

Warfarin is the traditional therapeutic option available to manage thromboembolic risk in atrial fibrillation. The hemorrhagic risk with warfarin depends mainly on the international normalized ratio (INR). Data from randomized controlled trials show that patients have a therapeutic INR (2.00-3.00) only 61%-68% of the time while taking warfarin, and this target is sometimes hard to establish. Many compounds have been developed in order to optimize the profile of oral anticoagulants. We focus on one of them, rivaroxaban, comparing it with novel alternatives, ie, dabigatran and apixaban. The indication for rivaroxaban in nonvalvular atrial fibrillation was evaluated in ROCKET-AF (Rivaroxaban-once daily, Oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation). In this trial, rivaroxaban was associated with a 12% reduction in the incidence of the primary endpoint compared with warfarin (hazard ratio 0.88; 95% confidence interval [CI] 0.74-1.03; P < 0.001 for noninferiority and P = 0.12 for superiority). However, patients remained in the therapeutic range for INR only 55% of the time, which is less than that in RE-LY (the Randomized Evaluation of Long-Term Anticoagulation Therapy, 64%) and in the ARISTOTLE trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation, 66%). This shorter time spent in the therapeutic range has been one of the main criticisms of the ROCKET-AF trial, but could actually reflect what happens in real life. In addition, rivaroxaban exhibits good pharmacokinetic and pharmacoeconomic properties. Novel anticoagulants are a viable and commercially available alternative to vitamin K antagonists nowadays for the prevention of thromboembolic complications in atrial fibrillation. Rivaroxaban is an attractive alternative, but the true picture of this novel compound in atrial fibrillation will only become available with more widespread use.

Encuesta sobre el uso de Guías de Práctica Clínica en cardiólogos de Latinoamérica / Survey on Clinical Practice Guidelines Use among Latin American Cardiologists / Survey on Clinical Practice Guidelines Use among Latin American Cardiologist Background

Introducción No obstante el amplio consenso acerca de los beneficios devenidos de la aplicación de Guías de Práctica Clínica (GPC) en la atención de pacientes y de su adopción por cada vez más países, incluso de Latinoamérica, su traslación a la práctica se encuentra por debajo de lo esperado. La falla en la implementación de las GPC está ligada a varios factores, entre los cuales se encuentra la falta de adherencia de los médicos. Objetivos Estimar la tasa de uso de Guías de Práctica Clínica (GPC) y conocer las objeciones a ellas entre cardiólogos latinoamericanos. Material y métodos Se realizó una encuesta anónima por correo electrónico en una muestra aleatoria del 10% de cardiólogos hispanohablantes de la Sociedad Interamericana de Cardiología. Se relevaron datos demográficos, uso de GPC y objeciones respecto de ellas. Entre los supuestos del estudio se consideró que la mayoría respondería positivamente ante la pregunta del uso de GPC; en cambio, se supuso que también manifestarían críticas y limitaciones de las GPC si se les indujera a ello. Resultados De 1.197 encuestados se obtuvo respuesta de 952. El 91,5% refirió que utilizaba GPC; de éstos, el 75,8% (660/871) recurría a GPC extranjeras y locales, mientras que el 24,2% sólo usaba GPC locales. El 58,2% de los encuestados refirió al menos una objeción a la calidad o utilidad de las GPC. Las críticas más comunes fueron que las guías proponían el uso de recursos no disponibles en los lugares de trabajo (11,5%), que recomendaban métodos no pasibles de utilizar por falta de cobertura (9,2%) y que no representaban la realidad de los pacientes asistidos (7,7%). Entre los encuestados que no las utilizaban, el 22,2% refirió que desconocía las últimas GPC. Conclusiones Si bien el uso de GPC es alto, la presencia de objeciones vinculadas a su utilidad constituye una barrera para mejorar la adherencia de los cardiólogos a ellas. Estos datos deben tenerse en cuenta para mejorar la confección, la difusión y la implementación de GPC en Latinoamérica.

There is a broad consensus about the benefits of applying Clinical Practice Guidelines (CPGs) as a standard of care and most countries, even in Latin America; however, the applicability of CPGs to medical practice is lower than expected. The failure in the implementation of CPGs is due to several factors, including physicians' lack of adherence. Objectives To estimate the utilization rate of CPGs and to know the objections of Latin American cardiologists against them. Material and Methods We conducted an anonymous email survey among 10% of the Spanish-speaking members of the Interamerican Society of Cardiology that were randomly selected. The questions included demographic data, use of CPGs and objections to use them. We assumed that most of the respondents would make a positive answer when asked about the use CPGs; yet, we also assumed that they would criticize and comment the limitations of CPGs if they were induced to do so. Results The survey was responded by 952 of the 1197 cardiologists selected. The utilization rate of CPGs was 91.5%; 75.8% (660/871) used foreign and local guidelines, while 24.2% only used local CPGs. 58.2% of survey respondents had at least one objection to the quality or usefulness of CPGs. The most common complaints were that the guidelines proposed the use of resources that were not always available (11.5%), recommended impractical strategies due to lack of medical coverage (9.2%) and did not represent the patients in real practice (7.7%). Among those who did not use CPGs, 22.2% did not know the last guidelines published. Conclusions Although the utilization of CPGs is high, the objections about their usefulness constitute a barrier to improve the adherence of cardiologists to use them. These data should be considered to improve the production, diffusion and implementation of CPGs in Latin America.

Encuesta sobre el uso de Guías de Práctica Clínica en cardiólogos de Latinoamérica / Survey on Clinical Practice Guidelines Use among Latin American Cardiologists / Survey on Clinical Practice Guidelines Use among Latin American Cardiologist Background

Introducción No obstante el amplio consenso acerca de los beneficios devenidos de la aplicación de Guías de Práctica Clínica (GPC) en la atención de pacientes y de su adopción por cada vez más países, incluso de Latinoamérica, su traslación a la práctica se encuentra por debajo de lo esperado. La falla en la implementación de las GPC está ligada a varios factores, entre los cuales se encuentra la falta de adherencia de los médicos. Objetivos Estimar la tasa de uso de Guías de Práctica Clínica (GPC) y conocer las objeciones a ellas entre cardiólogos latinoamericanos. Material y métodos Se realizó una encuesta anónima por correo electrónico en una muestra aleatoria del 10% de cardiólogos hispanohablantes de la Sociedad Interamericana de Cardiología. Se relevaron datos demográficos, uso de GPC y objeciones respecto de ellas. Entre los supuestos del estudio se consideró que la mayoría respondería positivamente ante la pregunta del uso de GPC; en cambio, se supuso que también manifestarían críticas y limitaciones de las GPC si se les indujera a ello. Resultados De 1.197 encuestados se obtuvo respuesta de 952. El 91,5% refirió que utilizaba GPC; de éstos, el 75,8% (660/871) recurría a GPC extranjeras y locales, mientras que el 24,2% sólo usaba GPC locales. El 58,2% de los encuestados refirió al menos una objeción a la calidad o utilidad de las GPC. Las críticas más comunes fueron que las guías proponían el uso de recursos no disponibles en los lugares de trabajo (11,5%), que recomendaban métodos no pasibles de utilizar por falta de cobertura (9,2%) y que no representaban la realidad de los pacientes asistidos (7,7%). Entre los encuestados que no las utilizaban, el 22,2% refirió que desconocía las últimas GPC. Conclusiones Si bien el uso de GPC es alto, la presencia de objeciones vinculadas a su utilidad constituye una barrera para mejorar la adherencia de los cardiólogos a ellas. Estos datos deben tenerse en cuenta para mejorar la confección, la difusión y la implementación de GPC en Latinoamérica.(AU)

There is a broad consensus about the benefits of applying Clinical Practice Guidelines (CPGs) as a standard of care and most countries, even in Latin America; however, the applicability of CPGs to medical practice is lower than expected. The failure in the implementation of CPGs is due to several factors, including physicians lack of adherence. Objectives To estimate the utilization rate of CPGs and to know the objections of Latin American cardiologists against them. Material and Methods We conducted an anonymous email survey among 10% of the Spanish-speaking members of the Interamerican Society of Cardiology that were randomly selected. The questions included demographic data, use of CPGs and objections to use them. We assumed that most of the respondents would make a positive answer when asked about the use CPGs; yet, we also assumed that they would criticize and comment the limitations of CPGs if they were induced to do so. Results The survey was responded by 952 of the 1197 cardiologists selected. The utilization rate of CPGs was 91.5%; 75.8% (660/871) used foreign and local guidelines, while 24.2% only used local CPGs. 58.2% of survey respondents had at least one objection to the quality or usefulness of CPGs. The most common complaints were that the guidelines proposed the use of resources that were not always available (11.5%), recommended impractical strategies due to lack of medical coverage (9.2%) and did not represent the patients in real practice (7.7%). Among those who did not use CPGs, 22.2% did not know the last guidelines published. Conclusions Although the utilization of CPGs is high, the objections about their usefulness constitute a barrier to improve the adherence of cardiologists to use them. These data should be considered to improve the production, diffusion and implementation of CPGs in Latin America.(AU)

The production of articles on cardiology from Latin America in Medline indexed journals.

INTRODUCTION: Latin America has dramatically increased the number of articles Publisher from 1995 to 2002, but the individual contribution of each country appears to be very unequal. OBJECTIVES: To analyze the production of articles on Cardiology research published in Latin American countries in the past years in international journals. METHODS: A bibliography search was carried out throughout PubMed in regards to biomedical articles in general and on Cardiology in particular, corresponding to the period 1987-2006. RESULTS: A total of 106,871 biomedical articles was identified, and 11,416 on Cardiology published between 1997 and 2006 by Latin American countries. This corresponds to 10.6% of articles on cardiovascular disease over the total. Brazil, Mexico and Argentina contributed with 80% of the publications in Latin America in the same period. The magnitude of growth since 1987 was between 5.9- and 15-fold for these countries. In regards to Brazil, since 1998 a significant increased number of publications was noted compared to Mexico and Argentina (P=0.0001). The impact factor of the journals where each country published during 2006 showed that it was in average higher in the publications from Chile and Argentina compared to Brazil and Mexico (P<0.001). CONCLUSIONS: The scientific production in Cardiology from Latin America shows dramatic differences among the countries, and Brazil, Mexico, and Argentina alone provide 80% of the publications. Brazil seems to have led the region for 20 years, especially since 1998. From the quality of the articles point of view, considering the impact factor, Chile and Argentina appear to be better positioned.

The production of articles on cardiology from Latin America in Medline indexed journals / La producción de artículos cardiológicos latinoamericanos indizados en Medline

Introduction: Latin America has dramatically increased the number of articles published from 1995 to 2002, but the individual contribution of each country appears to be very unequal. Objectives: To analyze the production of articles on Cardiology research published in Latin American countries in the past years in international journals. Methods: A bibliography search was carried out throughout PubMed in regards to biomedical articles in general and on Cardiology in particular, corresponding to the period 1987 - 2006. Results: A total of 106 871 biomedical articles was identified, and 11 416 on Cardiology published between 1997 and 2006 by Latin American countries. This corresponds to 10.6% of articles on cardiovascular disease over the total. Brazil, Mexico and Argentina contributed with 80% of the publications in Latin America in the same period. The magnitude of growth since 1987 was between 5.9- and 15-fold for these countries. In regards to Brazil, since 1998 a significant increased number of publications was noted compared to Mexico and Argentina (P = 0.0001). The impact factor of the journals where each country published during 2006 showed that it was in average higher in the publications from Chile and Argentina compared to Brazil and Mexico (P <0.001). Conclusions: The scientific production in Cardiology from Latin America shows dramatic differences among the countries, and Brazil, Mexico, and Argentina alone provide 80% of the publications. Brazil seems to have led the region for 20 years, especially since 1998. From the quality of the articles point of view, considering the impact factor, Chile and Argentina appear to be better positioned.

Introducción: La estimación de la producción científica en enfermedades cardiovasculares indica que América Latina incrementó el número de artículos publicados desde 1995 hasta 2002, pero la contribución individual de cada país parece ser desigual. Objetivo: Analizar la producción de artículos de investigación cardiológica publicados por los países latinoamericanos en revistas internacionales. Métodos: Se realizó una búsqueda bibliográfica en PubMed de artículos biomédicos y cardiológicos. Correspondientes al periodo de 1987 a 2006. Resultados: Se identificaron 106 871 artículos biomédicos y 11 416 cardiológicos (10.6%) publicados entre 1997 y 2006 por países latinoamericanos. En orden de importancia, Brasil, México y Argentina contribuyeron con 80% de las publicaciones. La magnitud del crecimiento de los artículos cardiológicos desde 1987 estuvo entre 5.9 y 15 veces para estos tres países. En Brasil se observó a partir de 1998, un aumento significativo del número de publicaciones con respecto a México y Argentina (P = 0.0001). El factor de impacto de las revistas en que publicaron sus artículos cardiológicos cada país durante 2006 mostró que éste fue en promedio superior en las publicaciones de Chile y Argentina con respecto a Brasil y México (P <0.001). Conclusiones: La producción científica cardiológica de América Latina tiene marcadas diferencias entre los países, y solamente Brasil, México y Argentina aportan 80% de lo publicado. Brasil lidera la región desde hace 20 años; en cuanto al factor de impacto, Chile y Argentina parecen estar mejor posicionados. Esta información serviría para conocer la situación individual de cada país y para establecer políticas de promoción científica.

Pharmacogenomics and adverse drug reactions: the case of statins.

INTRODUCTION: The use of genomics to predict adverse drug reactions (ADRs) has been the subject of much research over the last decade. Concerns about the muscular safety of statins, a highly prescribed group of drugs, are partially related to their high exposure. Many studies have identified a variety of genetic markers related to statin-induced myopathy. However, only polymorphisms in the SLCO1B1 gene (which encodes the carrier responsible for the hepatic uptake of statins, which, in turn, contributes to the regulation of plasma levels of SLCO1B1) were strongly associated with statin-induced muscular adverse effects. These was found to be most prominent for simvastatin. The strength of these findings relies on the use of modern genetic approaches, such as well-designed, case-controlled and genome-wide association studies. Nevertheless, the clinical use of this information is far from known at present and needs to be evaluated. AREAS COVERED: The links between genetic polymorphisms (i.e., SLCO1B1 gene) and statin-induced muscle ADRs and the methodological issues involved in the establishment of such an association are explored. EXPERT OPINION: Despite there being a statin-gene association for myopathy, in the case of some statins the usefulness of this information still needs to be proven.

Beyond efficacy: pharmacokinetic differences between clopidogrel, prasugrel and ticagrelor.

INTRODUCTION: Clinical nonresponse to clopidogrel has been associated with variability in response. This has led to the development of other P2Y12 receptor inhibitors, such as prasugrel and ticagrelor, with different pharmacokinetic characteristics that influence their pharmacodynamics. AREAS COVERED: Clopidogrel response variability is attributable to its complex pharmacokinetics and is vulnerable to genetic polymorphisms in genes involved in absorption, metabolism and drug-drug interactions (i.e., proton pump inhibitors). Prasugrel which has a simpler metabolism, leading to greater bioavailability, seems to be less affected by genetic or drug-drug interactions and achieves a greater antiplatelet effect. Ticagrelor is the most novel compound approved with a simpler metabolism. Both prasugrel and ticagrelor reached their antiplatelet effect faster and to a much greater extent than clopidogrel. All these differences observed in kinetics explain, to some degree, the efficacy and safety profile observed in clinical trials for these molecules associated with other antiplatelet agents (aspirin, gpIIb/IIIa inhibitors) and anticoagulants. EXPERT OPINION: Clopidogrel is still the best standard of care. However, the pharmacokinetic advantages of both prasugrel and ticagrelor allow clinicians to center patient management by selecting the best drug for the appropriate subject.

Changing anticoagulant paradigms for atrial fibrillation: dabigatran, apixaban and rivaroxaban.

INTRODUCTION: Vitamin K antagonists (VKAs) are the main therapeutic agents used to prevent embolic events in patients with atrial fibrillation (AF). Despite their proven efficacy, VKAs are underused and have several limitations. In recent years, there has been great interest in the development of new oral anticoagulants with a more efficient pharmacological profile, first tested in venous thromboembolism prevention and later in AF. AREAS COVERED: The authors review the pharmacological differences between dabigatran, rivaroxaban and apixaban, and potential subgroups of patients in whom these new drugs would constitute a possible alternative to VKA therapy. Pharmacodynamic and pharmacokinetic data from each compound are analyzed in respect to their potential use in AF. This article provides an exhaustive review of the current status of this topic and the controversies still regarding each drug. EXPERT OPINION: Apixaban and rivaroxaban are under evaluation for thromboembolic prevention in AF; dabigatran was recently approved for this indication. Therefore, it is important to know the characteristics of these drugs as a potential alternative to VKAs.

Nonresponders to clopidogrel: pharmacokinetics and interactions involved.

IMPORTANCE OF THE FIELD: The use of clopidogrel and aspirin has become standard therapy in patients with acute coronary syndromes and stent implantation. However, concern arises because about 25% of subjects are nonresponders to clopidogrel. This nonresponsiveness is associated with a threefold increase in adverse outcomes. Clopidogrel resistance is multifactorial, but genetic polymorphisms in clopidogrel's metabolic activation (e.g., cytochrome P450 2C19) and drug-drug interactions at this level (e.g., between proton pump inhibitors (PPIs) and clopidogrel) are both associated with decreased clopidogrel efficacy. Despite all PPIs being potent inhibitors of CYP2C19, evidence about their clinical impact is controversial. AREAS COVERED IN THIS REVIEW: Pharmacogenomic and pharmacokinetic aspects of clopidogrel nonresponsiveness were considered in detail. WHAT THE READER WILL GAIN: The reader will gain an exhaustive review of the current state of the controversial issues regarding genetic polymorphisms and drug-drug interactions affecting clopidogrel efficacy. TAKE HOME MESSAGE: It is important to consider clopidogrel resistance in some patients and establish strategies to handle this problem (e.g., genotyping, platelet aggregability tests, new antiplatelet drugs). The combined use of PPIs and clopidogrel is at present regulated by the FDA and EMEA; however, the risk/benefit balance should be made for each patient individually.

QT interval prolongation: preclinical and clinical testing arrhythmogenesis in drugs and regulatory implications.

The assessment about the proarrhythmic risk associated with a particular drug is a major requirement for drugs under development, since many drugs have been withdrawn from market or got under strict pharmacological vigilance because of such a risk. Predicting the development of a life-threatening arrhythmia is a hard task but, in the case of TdP ("Torsades de Pointes"), there are some useful markers. Among them, the prolongation of the QT interval and its heart rate correction (QTc) are the most remarkable. Actually, QT prolongation is considered the surrogate marker of TdP from the clinical and regulatory standpoint. ICH E14 provides recommendations to sponsors concerning the design, conduct, analysis, and interpretation of clinical studies to assess the potential of a drug to delay cardiac repolarization. The regulatory information about preclinical safety evaluation is contained in ICH S7B. Both guidelines have been a matter of intense debate. False negative and false positive results have been found within the preclinical and clinical field. There still are grey areas in which further research would be necessary. Improvement of tools that may contribute to complement the data from the human ether-a-go-go-related gene HERG channel and QT/QTc studies, such as concentration-QT relationship (CQT) studies and other innovative techniques, will be more than welcome.

Expectativas de los estudiantes de medicina de la Universidad de Buenos Aires sobre su práctica profesional / Medical students' attitudes regarding professional practice

Aunque la elección de la carrera de medicina por los jóvenes implica algún grado de conocimiento de las condiciones laborales actuales del médico, las expectativas de los estudiantes de medicina con respecto a su práctica profesional futura rara vez han sido estudiadas en la Argentina. El objetivo fue recabar información sobre las expectativas que tienen los estudiantes de medicina próximos a graduarse, con respecto a su práctica profesional futura. Entre septiembre y diciembre de 2008 se encuestaron 125 estudiantes que cursaban el Internado Anual Rotatorio. Por medio de una encuesta anónima se recolectó información sobre las expectativas que tenían con respecto a su futura práctica profesional. Respondieron la encuesta 82.4% (103/125) de los encuestados. El 98.0% (101/103) expresó que deseaba ingresar a un programa de residencias. Con respecto a la elección de la especialidad, pediatría y psiquiatría fueron preferentes entre las mujeres (27% vs. 8%, p = 0.029 y 27% vs. 3%, p = 0.004), mientras que traumatología fue preponderante entre los varones (18% vs. 2%, p = 0.019). La mediana de ingresos esperados a 5 años fue $4.000 (mínimo: $1.500, máximo: $10.000), a 10 años $7.000 (mínimo: $3,000, máximo: $20.000) y a 20 años $10.000 (mínimo: $3 000, máximo: $30.000), según valores ajustados a diciembre de 2008 ($3.0 = US$ 1.0). En conclusión, las especialidades elegidas parecen depender del proceso de feminización de la carrera; mientras que los ingresos esperados podrían exceder la verdadera renta actual de los médicos. Se destaca la intención de participar en la docencia y el escaso interés por la investigación.

Although the choice to study medicine implies some knowledge of the current working situation of practitioners, medical students' expectations regarding their future professional practice have been rarely investigated in Argentina. The aim of this work was to collect data about the expectations of senior medical students regarding their future professional practice. One hundred and twenty-five senior medical students were surveyed between September and December 2008. By using an anonymous survey, information regarding the expectations about their future professional practice was collected. The survey was answered by 82.4% (103/125) of the students and 98.0% (101/103) expressed their desire to enter a residence programme. Regarding specialty, pediatrics and psychiatry were the most chosen by women (27% vs. 8%, p=0.029 and 27% vs. 3%, p=0.004), and orthopedic surgery was the predominant choice in men (18% vs. 2%, p=0.019). Median of expected income at 5 years post graduation was $ 4.000 (minimum: $1,500, maximum: $10.000), at 10 years $7.000 (minimum: $3.000, maximum: $ 20.000) and at 20 years $10.000 (minimum: $3.000, maximum: $30 000), according to money value adjusted to December 2008 ($3.0 = US$ 1.0). In conclusion, chosen specialties seem to be dependent on the increasing number of female students, the expected income would exceed the current remuneration of physicians. Noterworthy finding out the students' willingness to be involved in teaching and the less interest in research.