Mariano Giorgi

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.

Association between LDL-C, Non HDL-C, and Apolipoprotein B Levels with Coronary Plaque Regression

Background Previous reports have inferred a linear relationship between LDL-C and changes in coronary plaque volume (CPV) measured by intravascular ultrasound. However, these publications included a small number of studies and did not explore other lipid markers. Objective To assess the association between changes in lipid markers and regression of CPV using published data. Methods We collected data from the control, placebo and intervention arms in studies that compared the effect of lipidlowering treatments on CPV, and from the placebo and control arms in studies that tested drugs that did not affect lipids. Baseline and final measurements of plaque volume, expressed in mm3, were extracted and the percentage changes after the interventions were calculated. Performing three linear regression analyses, we assessed the relationship between percentage and absolute changes in lipid markers and percentage variations in CPV. Results Twenty-seven studies were selected. Correlations between percentage changes in LDL-C, non-HDL-C, and apolipoprotein B (ApoB) and percentage changes in CPV were moderate (r = 0.48, r = 0.47, and r = 0.44, respectively). Correlations between absolute differences in LDL-C, non‑HDL-C, and ApoB with percentage differences in CPV were stronger (r = 0.57, r = 0.52, and r = 0.79). The linear regression model showed a statistically significant association between a reduction in lipid markers and regression of plaque volume. Conclusion A significant association between changes in different atherogenic particles and regression of CPV was observed. The absolute reduction in ApoB showed the strongest correlation with coronary plaque regression.

Estimation of the cost-effectiveness of apixaban versus vitamin K antagonists in the management of atrial fibrillation in Argentina

Apixaban, a novel oral anticoagulant which has been approved for the prevention of stroke and systemic embolism in non-valvular atrial fibrillation, reduces both ischemic and haemorrhagic stroke and produces fewer bleedings than vitamin K antagonist warfarin. These clinical results lead to a decrease in health care resource utilization and, therefore, have a positive impact on health economics of atrial fibrillation. The cost-effectiveness of apixaban has been assessed in a variety of clinical settings and countries. However, data from emergent markets, as is the case of Argentina, are still scarce.We performed a cost-effectiveness analysis of apixaban versus warfarin in non-valvular atrial fibrillation (NVAF) in patients suitable for oral anticoagulation in Argentina. A Markov-based model including both costs and effects were used to simulate a cohort of patients with NVAF. Local epidemiological, resource utilization and cost data were used and all inputs were validated by a Delphi Panel of local experts. We adopted the payer’s perspective with costs expressed in 2012 US Dollars.The study revealed that apixaban is cost-effective compared with warfarin using a willingness to pay threshold ranging from 1 to 3 per capita Gross Domestic Product (11558 – 34664 USD) with an incremental cost-effectiveness ratio of 786.08 USD per QALY gained. The benefit is primarily a result of the reduction in stroke and bleeding events.The study demonstrates that apixaban is a cost-effective alternative to warfarin in Argentina.

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.

Adaptación para la Argentina y evaluación de las propiedades psicométricas del Cuestionario sobre la Dieta Restrictiva de Sodio en pacientes con insuficiencia cardíaca

espanolIntroduccion: El Cuestionario sobre la Dieta Restrictiva de Sodio [Dietary Sodium Restriction Questionnaire (DSRQ)] estabasado en la teoria del comportamiento planificado. Originalmente desarrollado en ingles, este instrumento, compuesto portres subescalas (en 16 items que evaluan los parametros vinculados con la actitud en relacion con el comportamiento, lanorma subjetiva y el control comportamental percibido), identifica los factores que afectan la adhesion a la dieta hiposodicaen pacientes con insuficiencia cardiaca congestiva (ICC).Objetivos: Realizar la adaptacion transcultural del DSRQ en idioma espanol para su utilizacion en la Argentina y evaluar laspropiedades psicometricas (validez y confiabilidad).Material y metodos: La adaptacion transcultural se realizo con la metodologia recomendada (traduccion, sintesis, revision yretrotraduccion). La validez se determino mediante analisis de forma y factorial de componentes principales con la extraccionde factores y rotacion Varimax. El analisis de la confiabilidad se efectuo mediante el calculo de la consistencia interna (alfade Cronbach) y la correlacion item-total de la escala.Resultados: En la adaptacion transcultural se adaptaron los encabezados y solamente una pregunta tuvo alteraciones semanticasrelevantes. Para el analisis de las propiedades psicometricas se incluyeron 230 pacientes con ICC. La proporcion de datos faltantesfue muy baja (0,20%). En el analisis de componentes principales se extrajeron tres factores. Luego de la rotacion Varimax,los items se agruparon con los factores seleccionados, coincidiendo con las tres subescalas originales. En el analisis item-total,ninguna correlacion mostro un valor EnglishBackground: The Dietary Sodium Restriction Questionnaire (DSRQ) is based on the theory of planned behavior. Originallydeveloped in English, this instrument, consisting of three subscales (divided in 16 items evaluating the parameters associatedwith attitude relative to behavior, the subjective norm and the perceived behavioral control), identifies the factors affectingadherence to low-sodium diet in patients with congestive heart failure (CHF).Objectives: The purpose of this study was to perform the DSRQ transcultural adaptation into Spanish to be used in Argentinaand assess its psychometric properties (validity and reliability).Methods: The transcultural adaptation was done with the recommended methodology (translation, synthesis, revision and backtranslation). Its validity was explored by principal component structure and factor analysis with factor extraction and Varimaxrotation. Reliability was analyzed by internal consistency calculation (Cronbach’s alpha) and the item-total scale correlation.Results: Headlines were adjusted and one question only had relevant semantic changes in the transcultural adaptation. Atotal of 230 CHF patients were included for the psychometric analysis. The proportion of missing data was very low (0.20%).Three factors were extracted from the main component analysis. After Varimax rotation, the items were grouped with theselected factors, matching the three original subscales. In the item-total analysis, no correlation showed a value