Pharmacodynamic Effects of Switching From Ticagrelor to Clopidogrel in Patients With Coronary Artery Disease: Results of the SWAP-4 Study.

BACKGROUND: Switching between different classes of P2Y12 inhibitors, including de-escalation from ticagrelor to clopidogrel, commonly occurs in clinical practice. However, the pharmacodynamic profiles of this strategy have been poorly explored. METHODS: This was a prospective, randomized, open-label study conducted in patients on maintenance dosing (MD) of aspirin (81 mg/d) and clopidogrel (75 mg/d). After a 7-day run-in with ticagrelor (180 mg loading dose [LD] followed by 90 mg twice daily MD), patients (n=80) were randomized into 1 of 4 groups: group A, clopidogrel 600 mg LD 24 hours after the last MD of ticagrelor (C-600 mg-24h); group B, clopidogrel 600 mg LD 12 hours after the last MD of ticagrelor (C-600 mg-12h); group C, clopidogrel 75 mg/d MD 24 hours after the last MD of ticagrelor (C-75 mg-24h); and group D, ticagrelor 90 mg twice daily MD (T-90 mg twice daily). MD of the randomized treatment was maintained for 10±3 days. Pharmacodynamic assessments were performed at baseline, after run-in, and at 2, 24, 48, and 72 hours and 10 days with P2Y12 reaction units by VerifyNow; platelet reactivity index was assessed by vasodilator-stimulated phosphoprotein; and maximal platelet aggregation was determined by light transmittance aggregometry. RESULTS: T-90 mg twice daily led to lower platelet reactivity than any clopidogrel regimen using all assays at all time points. P2Y12 reaction unit levels were similar between the C-600 mg-24h (group A) and the C-75 mg-24h (group C) (P=0.29), including at 48 hours (primary end point; least mean difference, -6.9; 95% confidence interval, -38.1 to 24.3; P=0.66). P2Y12 reaction unit levels were lower with C-600 mg-12h (group B) than with C-75 mg-24h (group C; P=0.024). Maximal platelet aggregation over time was lower with both C-600 mg-24h (group A; P=0.041) and C-600 mg-12h (group B; P=0.028) compared with C-75 mg-24h (group C). Platelet reactivity index profiles paralleled those observed with P2Y12 reaction units. There were no pharmacodynamic differences for all tests between C-600 mg-24h (group A) and C-600 mg-12h (group B). In group C (C-75 mg-24h), platelet reactivity increased compared with baseline as early as 24 hours, reaching statistical significance at 48 and 72 hours and up to 10 days. These pharmacodynamic findings were delayed and blunted in magnitude with the administration of an LD, regardless of the timing of administration. CONCLUSIONS: De-escalation from ticagrelor to clopidogrel therapy is associated with an increase in platelet reactivity. The use of an LD before the initiation of an MD regimen of clopidogrel mitigates these observations, although this is not affected by the timing of its administration after ticagrelor discontinuation. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02287909.

Aerococcus urinae Infective Endocarditis.

Aerococcus urinae is a gram-positive organism frequently found in the urinary tract. It is often mistaken for Streptococcus and Enterococcus based on its appearance. It commonly causes urinary tract infections but has rarely been associated with fatal infective endocarditis and sepsis. We present a case of Aerococcus urinae infective endocarditis and discuss echocardiographic imaging findings and management approach.

Effects of D-allulose on glucose tolerance and insulin response to a standard oral sucrose load: results of a prospective, randomized, crossover study.

INTRODUCTION: Current dietary guidelines recommend limiting sugar intake for the prevention of diabetes mellitus (DM). Reduction in sugar intake may require sugar substitutes. Among these, D-allulose is a non-calorie rare monosaccharide with 70% sweetness of sucrose, which has shown anti-DM effects in Asian populations. However, there is limited data on the effects of D-allulose in other populations, including Westerners. RESEARCH DESIGN AND METHODS: This was a prospective, randomized, double-blind, placebo-controlled, crossover study conducted in 30 subjects without DM. Study participants were given a standard oral (50 g) sucrose load and randomized to placebo or escalating doses of D-allulose (2.5, 5.0, 7.5, 10.0 g). Subjects crossed-over to the alternate study treatment after 7-14 days of wash out. Plasma glucose and insulin levels were measured at five time points: before and at 30, 60, 90 and 120 min after ingestion. RESULTS: D-allulose was associated with a dose-dependent reduction of plasma glucose at 30 min compared with placebo. In particular, glucose was significantly lower with the 7.5 g (mean difference: 11; 95% CI 3 to 19; p=0.005) and 10 g (mean difference: 12; 95% CI 4 to 20; p=0.002) doses. Although glucose was not reduced at the other time points, there was a dose-dependent reduction in glucose excursion compared with placebo, which was significant with the 10 g dose (p=0.023). Accordingly, at 30 min D-allulose was associated with a trend towards lower insulin levels compared with placebo, which was significant with the 10 g dose (mean difference: 14; 95% CI 4 to 25; p=0.006). D-allulose did not reduce insulin at any other time point, but there was a significant dose-dependent reduction in insulin excursion compared with placebo (p=0.028), which was significant with the 10 g dose (p=0.002). CONCLUSIONS: This is the largest study assessing the effects of D-allulose in Westerners demonstrating an early dose-dependent reduction in plasma glucose and insulin levels as well as decreased postprandial glucose and insulin excursion in subjects without DM. These pilot observations set the basis for large-scale investigations to support the anti-DM effects of D-allulose. TRIAL REGISTRATION NUMBER: NCT02714413.

Effects of Edoxaban on the Cellular and Protein Phase of Coagulation in Patients with Coronary Artery Disease on Dual Antiplatelet Therapy with Aspirin and Clopidogrel: Results of the EDOX-APT Study.

In patients requiring dual antiplatelet therapy (DAPT) who also have an indication to be treated with oral anticoagulant (OAC) drugs, aspirin withdrawal reduces the risk of bleeding. There is limited data on the pharmacodynamic effects associated with adding a nonvitamin K antagonist OAC on a background of aspirin and a P2Y12 inhibitor as well as dropping aspirin. Seventy-five patients on DAPT (aspirin plus clopidogrel) were randomized to DAPT plus high-dose edoxaban (60 mg once daily, Group A), DAPT plus low-dose edoxaban (30 mg once daily, Group B), or DAPT only (Group C) for 10 ± 2 days (Phase I). Afterwards, Groups A and B interrupted aspirin and maintained clopidogrel plus edoxaban for 10 ± 2 days, while patients in Group C maintained DAPT (Phase II). Platelet aggregation and clot kinetics were assessed at baseline, end of Phase I, and end of Phase II using thrombelastography (TEG), light transmittance aggregometry (LTA), VerifyNow P2Y12, and serum thromboxane-B2. The primary endpoint was the comparison of maximum amplitude (MA) measured by TEG, a measure of clot strength, between patients on DAPT plus high-dose edoxaban and patients on DAPT only. Edoxaban prolonged in a dose-dependent manner speed of thrombin generation (TEG R; Group A: 7.7 [6.8-8.7] vs. Group B: 7.4 [6.4-8.5] vs. Group C: 6.3 [5.7-7.0]; p = 0.05) but did not affect other markers of clot kinetics, including TEG MA (Group A: 63 [61-64] vs. Group B: 65 [63-67] vs. Group C: 64 [63-65]; p = 0.10). After aspirin discontinuation, platelet reactivity assessed by LTA using thrombin receptor activating peptide as agonist increased to a greater extent with low-dose edoxaban. Stopping aspirin did not affect markers of P2Y12 reactivity and had no or marginal effects on clot kinetics, but increased markers sensitive to cyclooxygenase-1 blockade.

Effects of Methylnaltrexone on Ticagrelor-Induced Antiplatelet Effects in Coronary Artery Disease Patients Treated With Morphine.

OBJECTIVES: The aim of this study was to assess if intravenous methylnaltrexone can counteract the effects of morphine on the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of ticagrelor. BACKGROUND: Morphine delays the onset of action of oral P2Y12 receptor inhibitors, including ticagrelor, by inhibiting gastric emptying and leading to delayed drug absorption. Methylnaltrexone is a peripheral opioid receptor antagonist that has the potential to prevent opioid-induced peripherally mediated side effects (e.g., gastric emptying inhibition) without affecting analgesia. METHODS: In this prospective, randomized, double-blind, placebo-controlled, crossover study, aspirin-treated patients with stable coronary artery disease (n = 30) were randomized to receive methylnaltrexone (0.3 mg/kg intravenous) or matching placebo. After methylnaltrexone or placebo administration, all patients received morphine (5 mg intravenous). This was followed 15 min later by a 180-mg loading dose of ticagrelor. Patients crossed over to the alternative study treatment after 7 ± 2 days of washout. PK and PD assessments were performed at 12 time points (6 pre- and 6 post-crossover). PK analysis included measurement of plasma levels of ticagrelor and its major active metabolite (AR-C124910XX). PD assessments included VerifyNow P2Y12, light transmittance aggregometry, and vasodilator-stimulated phosphoprotein. RESULTS: Only marginal changes in plasma levels of ticagrelor (and its major active metabolite) were observed with ticagrelor: maximum plasma concentration and area under the plasma concentration versus time curve from time 0 to the last measurable concentration were 38% and 30% higher, respectively, in patients receiving methylnaltrexone compared with those receiving placebo, but no differences in time to maximum plasma concentration were observed. There were no differences in P2Y12 reaction units by VerifyNow P2Y12 between groups at each time point, including 2 h (the primary endpoint; p = 0.261). Similarly, there were no differences in PD markers assessed by light transmittance aggregometry and vasodilator-stimulated phosphoprotein. CONCLUSIONS: In patients with coronary artery disease receiving morphine, intravenous administration of the peripheral opioid receptor antagonist methylnaltrexone leads to only marginal changes in plasma levels of ticagrelor and its major metabolite, without affecting levels of platelet reactivity. (Effect of Methylnaltrexone on the PK/PD Profiles of Ticagrelor in Patients Treated With Morphine; NCT02403830).

Pharmacodynamic Effects of Vorapaxar in Patients With and Without Diabetes Mellitus: Results of the OPTIMUS-5 Study.

Vorapaxar reduces thrombotic cardiovascular events at the expense of increased bleeding. However, the differential pharmacodynamic (PD) effects of vorapaxar according to diabetes mellitus (DM) status are unknown. Moreover, although withdrawal of aspirin has emerged as a bleeding reduction strategy, the PD effects of stopping aspirin in patients treated with vorapaxar also are unknown. In this prospective PD investigation, vorapaxar was associated with reduced platelet-mediated thrombogenicity without affecting clot kinetics irrespective of DM status. However, platelet-mediated thrombogenicity increased after aspirin withdrawal, particularly among patients with DM. (Optimizing anti-Platelet Therapy In diabetes MellitUS-5 Study [OPTIMUS-5]; NCT02548650).

Diabetes and antiplatelet therapy: from bench to bedside.

Diabetes mellitus (DM) is a metabolic disorder associated with accelerated atherogenesis and an increased risk of atherothrombotic complications. Multiple mechanisms contribute to the pro-thrombotic status which characterizes DM patients underscoring the importance of antiplatelet therapies used for secondary prevention in these patients. For many years, dual antiplatelet therapy (DAPT) with aspirin and the P2Y12 inhibitor clopidogrel has represented the mainstay of treatment following an acute coronary syndrome (ACS) or in patients undergoing percutaneous coronary interventions (PCI). Although DAPT reduces the incidence of atherothrombotic recurrences, these rates remain high in DM patients underscoring the need for more efficacious therapies. Oral platelet P2Y12 receptor inhibitors with enhanced potency, such as prasugrel and ticagrelor, as well as antiplatelet therapies such as vorapaxar inhibiting the thrombin-mediated platelet signaling pathway, constitute treatment opportunities for patients with DM and have shown to be associated with a greater reduction in ischemic recurrences, albeit at the cost of more bleeding. This article reviews currently available antiplatelet agents and delivers an update on the advances and drawbacks of these agents used for secondary prevention in DM patients experiencing an ACS or undergoing PCI.

Role of genetic testing in patients undergoing percutaneous coronary intervention.

INTRODUCTION: Variability in individual response profiles to antiplatelet therapy, in particular clopidogrel, is a well-established phenomenon. Genetic variations of the cytochrome P450 (CYP) 2C19 enzyme, a key determinant in clopidogrel metabolism, have been associated with clopidogrel response profiles. Moreover, the presence of a CYP2C19 loss-of-function allele is associated with an increased risk of atherothrombotic events among clopidogrel-treated patients undergoing percutaneous coronary interventions (PCI), prompting studies evaluating the use of genetic tests to identify patients who may be potential candidates for alternative platelet P2Y12 receptor inhibiting therapies (prasugrel or ticagrelor). Areas covered: The present manuscript provides an overview of genetic factors associated with response profiles to platelet P2Y12 receptor inhibitors and their clinical implications, as well as the most recent developments and future considerations on the role of genetic testing in patients undergoing PCI. Expert commentary: The availability of more user-friendly genetic tests has contributed towards the development of many ongoing clinical trials and personalized medicine programs for patients undergoing PCI. Results of pilot investigations have shown promising results, which however need to be confirmed in larger-scale studies to support the routine use of genetic testing as a strategy to personalize antiplatelet therapy and improve clinical outcomes.

Optimal cutoff for the evaluation of insulin resistance through triglyceride-glucose index: A cross-sectional study in a Venezuelan population.

Background: Insulin resistance (IR) evaluation is a fundamental goal in clinical and epidemiological research. However, the most widely used methods are difficult to apply to populations with low incomes. The triglyceride-glucose index (TGI) emerges as an alternative to use in daily clinical practice. Therefore the objective of this study was to determine an optimal cutoff point for the TGI in an adult population from Maracaibo, Venezuela. Methods: This is a sub-study of Maracaibo City Metabolic Syndrome Prevalence Study, a descriptive, cross-sectional study with random and multi-stage sampling. For this analysis, 2004 individuals of both genders ≥18 years old with basal insulin determination and triglycerides < 500 mg/dl were evaluated.. A reference population was selected according to clinical and metabolic criteria to plot ROC Curves specific for gender and age groups to determine the optimal cutoff point according to sensitivity and specificity.The TGI was calculated according to the equation: ln [Fasting triglyceride (mg / dl) x Fasting glucose (mg / dl)] / 2. Results: The TGI in the general population was 4.6±0.3 (male: 4.66±0.34 vs. female: 4.56±0.33, p=8.93x10 -10). The optimal cutoff point was 4.49, with a sensitivity of 82.6% and specificity of 82.1% (AUC=0.889, 95% CI: 0.854-0.924). There were no significant differences in the predictive capacity of the index when evaluated according to gender and age groups. Those individuals with TGI≥4.5 had higher HOMA2-IR averages than those with TGI <4.5 (2.48 vs 1.74, respectively, p<0.001). Conclusions: The TGI is a measure of interest to identify IR in the general population. We propose a single cutoff point of 4.5 to classify individuals with IR. Future studies should evaluate the predictive capacity of this index to determine atypical metabolic phenotypes, type 2 diabetes mellitus and even cardiovascular risk in our population.

Epicardial Fat: Physiological, Pathological, and Therapeutic Implications.

Epicardial fat is closely related to blood supply vessels, both anatomically and functionally, which is why any change in this adipose tissue's behavior is considered a potential risk factor for cardiovascular disease development. When proinflammatory adipokines are released from the epicardial fat, this can lead to a decrease in insulin sensitivity, low adiponectin production, and an increased proliferation of vascular smooth muscle cells. These adipokines move from one compartment to another by either transcellular passing or diffusion, thus having the ability to regulate cardiac muscle activity, a phenomenon called vasocrine regulation. The participation of these adipokines generates a state of persistent vasoconstriction, increased stiffness, and weakening of the coronary wall, consequently contributing to the formation of atherosclerotic plaques. Therefore, epicardial adipose tissue thickening should be considered a risk factor in the development of cardiovascular disease, a potential therapeutic target for cardiovascular pathology and a molecular point of contact for "endocrine-cardiology."

Importance of high triglycerides levels between novel coronary risk factors / Importancia de niveles elevados de triglicéridos entre los factores de riesgo coronario nuevos

Abstract Introduction: The analysis of new cardiovascular risk factors is under an extensive debate in the cardiology and metabolic research fields. Objective: To determine the main factors that contribute to the classification of individuals with higher coronary risk in the adult population from Maracaibo, Venezuela. Methods: A descriptive, cross-sectional study with multistage random sampling in 1379 individuals belonging to the Maracaibo City Metabolic Syndrome Prevalence Study (MMSPS) was performed. They were classified according to the coronary risk by Framingham-Wilson equation adapted to our population. The association between various risk factors was evaluated by ordinal logistic regression models. Results: 1,379 subjects (females 55.9%; n = 771) were evaluated, 66.2% (n = 913) were classified with low coronary risk. In univariate ((2 = 112.35; p < 0.00001) and multivariate analysis [OR: 3.98 (2.39-6.63); p < 0.01], the main factors associated to be classified as the highest risk category were hypertriglyceridemia. Conclusion: There are several factors that should be included in predictive models use worldwide. The most important in our population were dyslipidemia such as hypertriglyceridemia, hyperlipoproteinemia (a) and insulin resistance.

Resumen Introducción: El análisis de nuevos factores de riesgo cardiovascular constituye un tema de amplio debate en la investigación cardio-metabólica. Objetivo: Determinar los principales factores que contribuyen a la clasificación de sujetos en las categorías de mayor riesgo coronario en individuos adultos de la ciudad de Maracaibo, Venezuela. Métodos: Estudio descriptivo, trasversal con muestreo aleatorio multietapas en 1.379 individuos pertenecientes al Estudio de Prevalencia de Síndrome Metabólico de la Ciudad de Maracaibo (EPSMM). Estos fueron clasificaron de acuerdo con el riesgo coronario mediante la fórmula Framingham-Wilson adaptada para nuestra población. Se evaluó la asociación entre diversos factores de riesgo mediante un modelo de regresión logística ordinal. Resultados: Se evaluaron 1.379 sujetos (mujeres: 55,9%; n = 771), de los cuales un 66,2% (n = 913) fueron clasificados en riesgo coronario bajo. Tanto en el contexto univariante ((2 = 112,35; p < 0,00001) como multivariante [OR: 3,98 (2,39-6,63); p < 0,01] el principal factor asociado para ser clasificado en las categorías de riesgo más elevado fue la hipertrigliceridemia. Conclusión: Existen numerosos factores que deberían ser incluidos en los modelos de predicción empleados en el mundo, en cuyo caso las dislipidemias: hipertrigliceridemia, hiperlipoproteinemia (a), e insulinorresistencia son las más importantes en nuestra población.

Punto de corte para el índice de adiposidad visceral en una población venezolana: resultados del Estudio de prevalencia de síndrome metabólico de Maracaibo / Optimal cutoff for visceral adiposity index in a Venezuelan population: Results from the Maracaibo City Metabolic Syndrome Prevalence Study

Aim: Visceral obesity is one of the most intensely researched cardiometabolic risk factors in recent years; nonetheless, its accurate assessment remains a challenge in regions were socioeconomic conditions hinder the widespread use of diagnostic methods for this purpose, such as imaging tests. In this setting, Visceral Adiposity Index (VAI) may be a useful tool. Thus, the objective of this study was to determine the VAI cutoff in adult population from Maracaibo City, Venezuela. Methods: This is a descriptive, cross-sectional study with multi-staged sampling; 2026 subjects of both genders aged ≥18 years were selected from this database and had their VAI calculated. In order to determine VAI cutoffs, subsamples of metabolically healthy and sick individuals were determined, with 599 and 286 subjects, respectively. Gender-specific and general ROC curves were plotted in order to identify the most suitable cutoff according to sensitivity and specificity. Results: Median VAI in the selected sample was 1.67 (0.97-2.78). The optimal cutoff was determined to be 1.91, with 70.3% sensitivity, 70.3% specificity [AUC = 0.777 (0.745-0.808)]. No differences were found between genders. Analysis by age revealed VAI to have greater predictive power among subjects aged < 30 years (cutoff: 1.53), 78.6% sensitivity, 72.8% specificity [AUC = 0.797 (0.709-0.884)]. Conclusion: We suggest a VAI cutoff of 1.9 for define dysfunctional adiposity in our population, with age being an important factor in the epidemiologic behavior of this variable, particularly in younger individuals.

Objetivo: La obesidad central es uno de los factores de riesgo cardiometabólicos emergente más evaluado durante los últimos años, sin embargo, su medición de forma precisa resulta un reto en aquellas poblaciones cuyas condiciones económicas dificultan la realización de métodos diagnósticos complejos, como pruebas de imagen. Por ello el objetivo de este estudio es determinar el punto de corte del índice de adiposidad visceral (VAI) en sujetos adultos de la ciudad de Maracaibo, Venezuela. Métodos: Se seleccionó a 2.026 individuos de ambos sexos, mayores de 18 años, de la base de datos del Estudio de prevalencia de síndrome metabólico en la ciudad de Maracaibo, un estudio descriptivo, transversal, con muestreo multietápico. El VAI se calculó para cada sexo y para la estimación del punto corte se seleccionó a 599 sujetos sanos y 286 enfermos, realizándose curvas COR para identificar el mejor valor de acuerdo con la sensibilidad y la especificidad. Resultados: El promedio de VAI en la muestra seleccionada fue 1,67 (0,97-2,78). El punto de corte fue 1,91 (70,3% de sensibilidad y 70,3% de especificidad) con AUC = 0,777 (0,745-0,808), sin diferencias en el punto de corte según sexo. En el análisis por grupos etarios la mayor capacidad predictiva fue para el grupo < 30 años con AUC = 0,797 (0,709-0,884), con un punto de corte de 1,53 (78,6% de sensibilidad y 72,8% de especificidad). Conclusión: El punto de corte indicado para VAI en nuestra población es de 1,9; considerando la edad como un factor importante en su comportamiento, especialmente en los grupos más jóvenes.