Results from the HEBE III study, a prospective, randomised, multicentre trial performed in seven centres in the Netherlands, suggest that the promising effects of erythropoieitin seen in previous smaller studies cannot be confirmed for the improvement of clinical outcome in patients with a first ST-elevation myocardial infarction.
MI remains a major hazard for millions of patients in Europe. Despite improvements in treatment, the majority still end up with reduced cardiac function, and strategies to improve post-MI cardiac function are strongly needed. One approach, suggested in experimental and smaller clinical studies, is the administration of erythropoietin (EPO), currently used for the treatment of anemia caused by renal disease. The HEBE III study was designed to study the effects of a single intravenous bolus of EPO on clinical outcome in patients with a first ST-elevation MI. The primary endpoint of the trial - as a measure of cardiac function - was left ventricular ejection fraction (LVEF) after six weeks, with secondary endpoints assessed according to infarct size and major adverse cardiovascular events (MACE).
The trial was conducted in 529 randomised STEMI patients and headline results showed that this single IV bolus of EPO did not improve cardiac function. However, patients who received EPO had fewer major cardiac events, such as heart failure, compared with the control group.
The HEBE III trial studied the effect of a single bolus of 60,000 IU epoetin alfa on LVEF. EPO was administered intravenously within three hours after a successful PCI for a first STEMI. The study aimed to find a 3% increase of LVEF in patients treated with EPO compared to standard care. In total, 529 patients were included in the study, in which 263 patients were assigned to the EPO group and 266 to the control group. After six weeks, LVEF was 53% in the EPO group and 52% in the control group, but this 1% difference was too small to be statistically or clinically significant. Furthermore, infarct size, measured by proteins in the blood, was also not significantly different between the two groups. However, in the EPO group, only eight patients suffered a major cardiac adverse event, compared to 19 in the control group.
Commenting on the results, principal investigator Dr Adriaan Voors from the University Medical Center, Groningen, the Netherlands, said: "The promising effects of erythropoieitin in previous smaller studies could not be confirmed in this large clinical trial. The reduction of major cardiac effects is of interest, but, since the study was not primarily designed to reduce cardiac effects, and the numbers are small, we should be careful with its interpretation. Larger clinical trials powered to detect a reduction in hard clinical endpoints should be performed before EPO can be routinely used in patients with an acute heart attack."
29 August 2010
ALPHA OMEGA: Beneficial effect of low doses of n-3 fatty acids only found in sub-groups of post-MI patients
Results from the Alpha Omega Trial, a multicentre, placebo-controlled trial in men and women following myocardial infarction (MI), suggest that low doses of n-3 fatty acids given in the form of enriched margarines do not reduce the overall rate of major cardiovascular events.
Results from the study - in which patients received a 400 mg per day supplement of the fish oil fatty acids EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) and 2 grams of the plant-derived fatty acid alpha-linolenic acid (ALA) via enriched margarines - showed that these supplementary n-3 fatty acids did not reduce major cardiovascular events in the overall patient population. Among sub-groups, there was a borderline significant reduction in major cardiovascular events in women who received ALA, and, in patients with diabetes, n-3 fatty acids were protective against ventricular arrhythmia-related events.
N-3 (or omega-3) fatty acids can be divided in two main classes: EPA and DHA from fish; and ALA from plant foods such as soybean oil and walnuts. "Several intervention studies in cardiac patients have shown that a daily intake of 1-2 grams of EPA + DHA via fish oil capsules reduced mortality from coronary heart disease by 20%," said principal investigator Professor Daan Kromhout from Wageningen University, the Netherlands.
"Epidemiological studies in healthy populations have also suggested that 250 mg EPA + DHA or eating fish once or twice a week can lower the risk of CVD by a similar amount. For ALA, there is less evidence of a cardioprotective effect. We designed the Alpha Omega Trial as a dietary intervention study to examine the effect of low doses of n-3 fatty acids on major cardiovascular events."
A total of 4837 men and women aged 60-80 years were enrolled in the trial. They had all suffered a myocardial infarction approximately four years before the study began. They were randomly assigned to daily use of one of four margarines for 40 months: containing extra EPA + DHA (400 mg/day); ALA (2 g/day); both EPA + DHA and ALA; or placebo. The margarines were similar in taste and appearance for all four treatment groups and were used by the trial participants on bread instead of their regular margarine or butter; compliance and double-blinding were maintained throughout the study period.
The primary endpoint of the trial, which was completed in November 2009, was major cardiovascular events (MACE) of morbidity and mortality, and cardiac procedures (PCI and CABG). Important secondary endpoints were fatal coronary heart disease and ventricular arrhythmia-related events defined as sudden death, cardiac arrest and cardioverter-defibrillator placement.
"The patients in this trial were very well treated," said Professor Kromhout, "with 98% on antithrombotic agents, 90% on antihypertensive drugs, and 86% on lipid lowering drugs. We found that cardiovascular mortality rate in the study population was only half that expected, probably because of their excellent treatment. This may also be why the rate of major cardiovascular events during follow-up was no lower in the fatty acid groups than in the placebo group.
"However, we did see a 27% borderline significant reduction in primary endpoint in women who received ALA. We also carried out an exploratory analysis in patients with diabetes, and this showed a significant 50% reduction in CHD mortality in patients who received EPA + DHA. For both, EPA + DHA and ALA a similar 50% reduction was observed in the number of arrhythmia-related events in diabetic patients."
Procoralan(R) reduce el riesgo de muerte y hospitalización en pacientes por insuficiencia cardiaca
El mayor estudio de morbi-mortalidad con tratamientos para la insuficiencia cardiaca ha demostrado que añadir el agente reductor específico de la frecuencia cardiaca Procoralan(R) (ivabradina) a la terapia estándar reduce significativamente el riesgo de muerte y hospitalización por insuficiencia cardiaca. (1) Los resultados de este nuevo estudio, SHIFT (Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial), se han presentado hoy en el Congreso Europeo de Cardiología1 celebrado en Estocolmo y se han publicado en The Lancet(2).
SHIFT reclutó a más de 6.500 pacientes de 37 países con insuficiencia cardiaca de moderada a severa y una frecuencia cardiaca de más de 70 lpm que fueron controlados durante una media de 23 meses. Los resultados mostraron que Procoralan(R) reduce el objetivo primario compuesto de muerte cardiovascular u hospitalización por agravamiento de la insuficiencia cardiaca en un 18% (p<0,0001). p="0,014)">
*En función de cada país
"Veinte años después de los inhibidores de la enzima convertidora de angiotensina y diez años después de los betabloqueantes, tenemos ahora un nuevo fármaco que salva vidas disponible para nuestros pacientes", señaló el co-presidente del comité ejecutivo de SHIFT, el profesor Michel Komajda, profesor de Cardiología de la Universidad Pierre et Marie Curie París 6 de Francia.
La insuficiencia cardiaca crónica es un problema común y en aumento que afecta a 15 millones de pacientes en Europa (entre el 2% y el 3% de la población general). La insuficiencia cardiaca dificulta la capacidad del corazón parar bombear sangre correctamente y mantener una circulación suficiente para cubrir las necesidades del organismo. La insuficiencia cardiaca es una importante carga sanitaria y económica, representa el 10% de todos los ingresos hospitalarios y la mitad de los pacientes con insuficiencia cardiaca mueren al cabo de 4 años.
Procoralan(R) es un tratamiento innovador que se utiliza actualmente en pacientes con angina estable ya que alivia los síntomas, la isquemia de miocardio y reduce el riesgo de eventos coronarios. El estudio SHIFT ha demostrado ahora también los beneficios pronósticos de Procoralan(R) en pacientes con insuficiencia cardiaca.
El estudio SHIFT es también el primer estudio que confirma específicamente que, gracias a Procoralan(R), la reducción exclusiva de la frecuencia cardiaca reduce el riesgo de muerte u hospitalización por insuficiencia cardiaca. Este descubrimiento confirma que la frecuencia cardiaca juega un papel clave en la progresión de la enfermedad.
El co-presidente del SHIFT, el profesor Karl Swedberg, de la dirección del Departamento de Emergencia y Medicina Cardiovascular de la Universidad de Gothenburg, Suecia, indicó: "El estudio SHIFT tiene importantes implicaciones para nuestra práctica clínica. Nos indica que tener una frecuencia cardiaca alta es perjudicial para los pacientes con insuficiencia cardiaca. De modo que deberíamos medir rutinariamente la frecuencia cardiaca en todos los pacientes con insuficiencia cardiaca y, si es superior a 70 latidos por minuto, debería considerarse reducirla con Procoralan(R), independientemente del tratamiento de base".
--Diseño del ensayo SHIFT
SHIFT es un estudio aleatorizado, doble ciego que compara Procoralan(R) con placebo en el pronóstico de los pacientes con insuficiencia cardiaca de moderada a severa (más frecuentemente de causa isquémica), fracción de inyección del ventrículo izquierdo disminuida y frecuencia cardiaca superior a 70 lpm. El estudio se diseñó para evaluar si Procoralan(R), puede mejorar los eventos cardiovasculares, los síntomas y la calidad de vida al añadirse a la terapia estándar en pacientes con ICC y disfunción sistólica.
SHIFT es un estudio aleatorizado, doble ciego que compara Procoralan(R) con placebo en el pronóstico de los pacientes con insuficiencia cardiaca de moderada a severa (más frecuentemente de causa isquémica), fracción de inyección del ventrículo izquierdo disminuida y frecuencia cardiaca superior a 70 lpm. El estudio se diseñó para evaluar si Procoralan(R), puede mejorar los eventos cardiovasculares, los síntomas y la calidad de vida al añadirse a la terapia estándar en pacientes con ICC y disfunción sistólica.
Los pacientes recibieron Procoralan(R) o placebo además de su tratamiento estándar para la insuficiencia cardiaca. Estos incluyeron inhibidores ECA y/o ARA II, betabloqueantes, diuréticos y antagonistas de la aldosterona. Un total de 89% de los pacientes en el estudio recibió IECAs y betabloqueantes, y más de la mitad de ellos recibieron al menos un 50% de la dosis objetivo.
SHIFT está patrocinado por Servier, compañía farmacéutica independiente líder en Francia con un largo historial en el desarrollo de fármacos para las enfermedades cardiovasculares, y está coordinado por el comité ejecutivo del SHIFT, un grupo internacional de expertos en insuficiencia cardiaca.
SHIFT está patrocinado por Servier, compañía farmacéutica independiente líder en Francia con un largo historial en el desarrollo de fármacos para las enfermedades cardiovasculares, y está coordinado por el comité ejecutivo del SHIFT, un grupo internacional de expertos en insuficiencia cardiaca.
Procoralan(R) se desarrolló por Servier y está indicado para el tratamiento de la angina estable. Es el primer agente de una nueva clase terapéutica conocida como los inhibidores If selectivos y específicos.
*En función de cada país
New oral potassium binder lowers potassium levels in patients with heart failure and heart failure with chronic kidney disease
Results from a recent phase 2b clinical trial may provide a new approach to managing excess potassium levels in patients with heart failure and heart failure with chronic kidney disease. The PEARL-HF study has shown that a newly developed potassium binder - known as RLY5016 - can help regulate hyperkalemia in such patients, even those receiving aldosterone antagonists.
Hyperkalemia is a serious condition, characterised by elevated potassium levels in the blood (serum potassium), which increases a patient’s risk of cardiac arrhythmia and sudden death. At particular risk are heart failure patients, especially those with an underlying chronic kidney disease being treated with aldosterone antagonists. Although these drugs have shown life-saving benefits in multiple large outcome studies, their use is limited by the occurrence or fear of hyperkalemia
Professor Bertram Pitt from the Division of Cardiovascular Medicine, University of Michigan School of Medicine, USA, who was steering committee chairman of the PEARL-HF (Parallel Evaluation of RLY5016 in Heart Failure), said: “The PEARL-HF trial demonstrates that RLY5016 effectively and safely lowers serum potassium and prevents hyperkalemia in patients with heart failure or heart failure with underlying renal impairment, even those using renin-angiotensin-aldosterone system antagonists. Currently, the risk of hyperkalemia has limited the use of these RAAS inhibitors, which exposes patients to further cardiac risk. These trial data are therefore very significant.”
PEARL-HF was a multicentre, randomised, double-blind, placebo-controlled trial, designed to evaluate the efficacy, safety and tolerability of RLY5016 in the prevention of hyperkalemia in heart failure patients. The study tested a total of 104 patients over four weeks; 55 with a therapeutic dose of RLY5016 and 49 with placebo. Patients with a serum potassium level of 4.3-5.1 mEq/L and chronic kidney disease currently taking one or more heart-failure therapies, or patients with a documented history of hyperkalemia that led to the discontinuation of a heart failure therapy, were also given a daily 25-50 mg dose of the aldosterone antagonist spironolactone.
The primary endpoint was the measured change from baseline in serum potassium. Efficacy was also evaluated by the proportion of patients with hyperkalemia and the proportion of patients whose spironolactone dose could be increased.
Results showed that RLY5016 significantly reduced the incidence of hyperkalemia compared to the placebo (7% vs. 25%, p=0.015). It also increased the proportion of patients whose spironolactone dose could be increased (91 percent vs. 74 percent, p=0.019). RLY5016 seemed well tolerated by patients, with a withdrawal rate from the study due to an adverse event of 7% (compared to 6% with the placebo), and there were no drug-related serious adverse events.
Hyperkalemia is a serious condition, characterised by elevated potassium levels in the blood (serum potassium), which increases a patient’s risk of cardiac arrhythmia and sudden death. At particular risk are heart failure patients, especially those with an underlying chronic kidney disease being treated with aldosterone antagonists. Although these drugs have shown life-saving benefits in multiple large outcome studies, their use is limited by the occurrence or fear of hyperkalemia
Professor Bertram Pitt from the Division of Cardiovascular Medicine, University of Michigan School of Medicine, USA, who was steering committee chairman of the PEARL-HF (Parallel Evaluation of RLY5016 in Heart Failure), said: “The PEARL-HF trial demonstrates that RLY5016 effectively and safely lowers serum potassium and prevents hyperkalemia in patients with heart failure or heart failure with underlying renal impairment, even those using renin-angiotensin-aldosterone system antagonists. Currently, the risk of hyperkalemia has limited the use of these RAAS inhibitors, which exposes patients to further cardiac risk. These trial data are therefore very significant.”
PEARL-HF was a multicentre, randomised, double-blind, placebo-controlled trial, designed to evaluate the efficacy, safety and tolerability of RLY5016 in the prevention of hyperkalemia in heart failure patients. The study tested a total of 104 patients over four weeks; 55 with a therapeutic dose of RLY5016 and 49 with placebo. Patients with a serum potassium level of 4.3-5.1 mEq/L and chronic kidney disease currently taking one or more heart-failure therapies, or patients with a documented history of hyperkalemia that led to the discontinuation of a heart failure therapy, were also given a daily 25-50 mg dose of the aldosterone antagonist spironolactone.
The primary endpoint was the measured change from baseline in serum potassium. Efficacy was also evaluated by the proportion of patients with hyperkalemia and the proportion of patients whose spironolactone dose could be increased.
Results showed that RLY5016 significantly reduced the incidence of hyperkalemia compared to the placebo (7% vs. 25%, p=0.015). It also increased the proportion of patients whose spironolactone dose could be increased (91 percent vs. 74 percent, p=0.019). RLY5016 seemed well tolerated by patients, with a withdrawal rate from the study due to an adverse event of 7% (compared to 6% with the placebo), and there were no drug-related serious adverse events.
The STAR-heart study: The acute and long-term effect of intracoronary stem cell transplantation in chronic heart failure
Bone marrow stem cell therapy improves ventricular performance, quality of life and survival in patients with chronic heart failure, according to results from the STAR-heart study. Professor Bodo-Eckehard Strauer, from the Cardiology Department, University of Duesseldorf, Germany, said that, although stem cells from bone marrow had been used in several thousand patients as regenerative therapy, there were still many unresolved questions, notably the quantitative amount of improvement in ventricular function, and the long-term effects in chronic heart failure. Both these questions were addressed by the STAR-heart study.
The study comprised 391 patients with chronic heart failure as a result of ischaemic heart disease (following myocardial infarction), with diagnosis defined by a left ventricular ejection fraction (LVEF) of 35% or less. Of these, 191 patients (with a mean NYHA class 3.22) agreed to have intracoronary bone marrow stem cell therapy, which was offered them between 2003 and 2005. The control group (mean NYHA class 3.06) consisted of 200 patients with comparable LVEF who did not have stem cell therapy.
The bone marrow was taken from the patient's iliac crest (at the top of the pelvic bone) and mononuclear cells isolated and identified. The cells were directly infused into the infarct-related artery via an angioplasty balloon catheter. Inflation of the balloon was important to prevent black-flow of the cells and extend the time for the cells to migrate into the infarct area. (Intravenous administration of stem cells allows only a small proportion of cells to reach the infarct region.)
With haemodynamic assessments taking place between three months and five years after the bone marrow cell therapy, there was a significant improvement in LVEF, cardiac index, exercise capacity, oxygen uptake, and LV contractility. Moreover, the beneficial effects of the bone marrow cell therapy seen at the first three-month evaluation were continued at 12 and 60 months - while in controls there was deterioration in LV performance.
Importantly, there was a significant decrease in long-term mortality in the stem-cell treated patients compared with the control group. Within a median follow-up time of 4.6 years, seven patients died in the bone marrow cell-treated group, equivalent to an average mortality rate of 0.75% per year. In the control group the average mortality rate was 3.68% per year (32 patients died within a median follow-up time of 4.87 years).
Commenting on the outcome, Professor Strauer said: "Despite progress in its medical treatment, heart failure is still a growing public health problem, with a high rate of cardiovascular complications and mortality. First-line treatment of chronic heart failure mainly aims to prevent the deterioration of heart function, which has often started following myocardial infarction. "Nevertheless, these conventional treatments for heart failure resulting from MI do not attempt to correct the underlying cause, which is usually the loss of functional myocardial tissue - and prognosis remains poor. That's why in these particular cases there is a need for strategies aimed at regeneration and tissue repair.
"Our study suggests that, when administered as an alternative or in addition to conventional therapy, bone marrow cell therapy can improve quality of life, increase ventricular performance, and increase survival. Intracoronary therapy has been shown to be effective in acute myocardial infarction, and the STAR-heart study now indicates its efficacy in chronic heart failure."
The study comprised 391 patients with chronic heart failure as a result of ischaemic heart disease (following myocardial infarction), with diagnosis defined by a left ventricular ejection fraction (LVEF) of 35% or less. Of these, 191 patients (with a mean NYHA class 3.22) agreed to have intracoronary bone marrow stem cell therapy, which was offered them between 2003 and 2005. The control group (mean NYHA class 3.06) consisted of 200 patients with comparable LVEF who did not have stem cell therapy.
The bone marrow was taken from the patient's iliac crest (at the top of the pelvic bone) and mononuclear cells isolated and identified. The cells were directly infused into the infarct-related artery via an angioplasty balloon catheter. Inflation of the balloon was important to prevent black-flow of the cells and extend the time for the cells to migrate into the infarct area. (Intravenous administration of stem cells allows only a small proportion of cells to reach the infarct region.)
With haemodynamic assessments taking place between three months and five years after the bone marrow cell therapy, there was a significant improvement in LVEF, cardiac index, exercise capacity, oxygen uptake, and LV contractility. Moreover, the beneficial effects of the bone marrow cell therapy seen at the first three-month evaluation were continued at 12 and 60 months - while in controls there was deterioration in LV performance.
Importantly, there was a significant decrease in long-term mortality in the stem-cell treated patients compared with the control group. Within a median follow-up time of 4.6 years, seven patients died in the bone marrow cell-treated group, equivalent to an average mortality rate of 0.75% per year. In the control group the average mortality rate was 3.68% per year (32 patients died within a median follow-up time of 4.87 years).
Commenting on the outcome, Professor Strauer said: "Despite progress in its medical treatment, heart failure is still a growing public health problem, with a high rate of cardiovascular complications and mortality. First-line treatment of chronic heart failure mainly aims to prevent the deterioration of heart function, which has often started following myocardial infarction. "Nevertheless, these conventional treatments for heart failure resulting from MI do not attempt to correct the underlying cause, which is usually the loss of functional myocardial tissue - and prognosis remains poor. That's why in these particular cases there is a need for strategies aimed at regeneration and tissue repair.
"Our study suggests that, when administered as an alternative or in addition to conventional therapy, bone marrow cell therapy can improve quality of life, increase ventricular performance, and increase survival. Intracoronary therapy has been shown to be effective in acute myocardial infarction, and the STAR-heart study now indicates its efficacy in chronic heart failure."
28 August 2010
El tabaquismo aumenta el riesgo de depresión en la juventud
El tabaquismo incrementa los síntomas de depresión en los adolescentes, sobre todo en los que fuman para combatir la tristeza, según ha descubierto un grupo de investigadores de la Universidad de Toronto y la de Montreal, en Canadá, a través de un estudio publicado en 'Addictive Behaviors', cuyos resultados son parte del trabajo titulado 'Dependencia de la Nicotina en Adolescentes' (NDIT, por sus siglas en inglés), que desarrolla a largo plazo el Centro de Investigaciones del Hospital Universitario de Montreal.
Según el investigador principal de este estudio, Michael Chaiton, profesor de la Unidad Ontario de Investigación en Tabaco de la Universidad de Toronto, "este estudio observacional es uno de los pocos que examina los beneficios emocionales percibidos de fumar en los adolescentes".
"Aunque los cigarrillos parecen tener efectos similares a una 'automedicación' o mejorar el humor, a largo plazo hemos visto adolescentes que emperezaron a fumar que registran mayores síntomas de depresión", añade.
Como parte de un estudio mayor, unos 662 adolescentes de instituto rellenaron un cuestionario de unas 20 preguntas sobre su consumo de cigarrillos y cómo les afecta al humor. Los institutos fueron seleccionados para conseguir una mezcla de participantes franceses e ingleses, procedentes de centros rurales y urbanos y situados en barrios con niveles socioeconómicos bajo, medio y alto.
Los adolescentes fueron divididos en tres grupos: el de los que nunca habían fumado, los fumadores que aseguraron no usar el tabaco para 'automedicación' y mejorar su estado físico o anímico, y aquellos fumadores que reconocieron que fumaban para sentirse mejor.
Los síntomas de depresión fueron medidos utilizando una escala en la que se preguntaba con qué frecuencia los participantes se sentían demasiado cansados para hacer cosas; tenían problemas para irse a dormir o para permanecer despiertos; se sentían infelices, tristes o deprimidos; se sentían desesperanzados sobre su futuro; nerviosos o tensos, y demasiado preocupados por algún motivo.
Según el investigador principal de este estudio, Michael Chaiton, profesor de la Unidad Ontario de Investigación en Tabaco de la Universidad de Toronto, "este estudio observacional es uno de los pocos que examina los beneficios emocionales percibidos de fumar en los adolescentes".
"Aunque los cigarrillos parecen tener efectos similares a una 'automedicación' o mejorar el humor, a largo plazo hemos visto adolescentes que emperezaron a fumar que registran mayores síntomas de depresión", añade.
Como parte de un estudio mayor, unos 662 adolescentes de instituto rellenaron un cuestionario de unas 20 preguntas sobre su consumo de cigarrillos y cómo les afecta al humor. Los institutos fueron seleccionados para conseguir una mezcla de participantes franceses e ingleses, procedentes de centros rurales y urbanos y situados en barrios con niveles socioeconómicos bajo, medio y alto.
Los adolescentes fueron divididos en tres grupos: el de los que nunca habían fumado, los fumadores que aseguraron no usar el tabaco para 'automedicación' y mejorar su estado físico o anímico, y aquellos fumadores que reconocieron que fumaban para sentirse mejor.
Los síntomas de depresión fueron medidos utilizando una escala en la que se preguntaba con qué frecuencia los participantes se sentían demasiado cansados para hacer cosas; tenían problemas para irse a dormir o para permanecer despiertos; se sentían infelices, tristes o deprimidos; se sentían desesperanzados sobre su futuro; nerviosos o tensos, y demasiado preocupados por algún motivo.
"Los fumadores que utilizaban los cigarrillos como método para mejorar su humor tenían un mayor riesgo de sufrir más síntomas depresivos que aquellos adolescentes que nunca habían fumado", explicó la coautora del estudio Jennifer O'Loughlin, profesor del Departamento de Medicina Social y Preventiva de la Universidad de Montreal y del Centro de Investigaciones del Hospital Universitario de Montreal. "Nuestro estudio descubrió que los adolescentes fumadores que aseguraron conseguir beneficios emocionales de fumar corrían un mayor riesgo de desarrollar síntomas depresivos", señala.
La asociación entre depresión y tabaquismo se daba sobre todo entre los adolescentes que fumaban para sentirse mejor. "Es importante destacar que los síntomas depresivos eran mayores entre los adolescentes que reconocieron conseguir beneficios emocionales de fumar después de iniciarse en el hábito", recalca Chaiton.
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