Evaluation of clopidogrel response variability and identification of the CYP2C19 polymorphism in Mexican patients

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Rodríguez-Granillo" "autores" => array:5 [ 0 => array:2 [ "nombre" => "Macarena" "apellidos" => "de Zan" ] 1 => array:2 [ "nombre" => "Patricia" "apellidos" => "Carrascosa" ] 2 => array:2 [ "nombre" => "Alejandro" "apellidos" => "Deviggiano" ] 3 => array:2 [ "nombre" => "Carlos" "apellidos" => "Capuñay" ] 4 => array:2 [ "nombre" => "Gastón A." "apellidos" => "Rodríguez-Granillo" ] ] ] ] ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1405994016300064?idApp=UINPBA00004N" "url" => "/14059940/0000008600000004/v1_201611090122/S1405994016300064/v1_201611090122/es/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S1405994016300763" "issn" => "14059940" "doi" => "10.1016/j.acmx.2016.09.001" "estado" => "S300" "fechaPublicacion" => "2016-10-01" "aid" => "305" "copyright" => "Instituto Nacional de Cardiología Ignacio Chávez" "documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "sco" "cita" => "Arch Cardiol Mex. 2016;86:295-6" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 2132 "formatos" => array:3 [ "EPUB" => 54 "HTML" => 1759 "PDF" => 319 ] ] "es" => array:10 [ "idiomaDefecto" => true "cabecera" => "Editorial" "titulo" => "Semblanza del Dr. Alfredo de Micheli Serra" "tienePdf" => "es" "tieneTextoCompleto" => "es" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "295" "paginaFinal" => "296" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "A brief portrait of Alfredo de Micheli Serra" ] ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Pedro Iturralde Torres" "autores" => array:1 [ 0 => array:2 [ "nombre" => "Pedro" "apellidos" => "Iturralde Torres" ] ] ] ] ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1405994016300763?idApp=UINPBA00004N" "url" => "/14059940/0000008600000004/v1_201611090122/S1405994016300763/v1_201611090122/es/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "Clinical Research" "titulo" => "Evaluation of clopidogrel response variability and identification of the CYP2C19 polymorphism in Mexican patients" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "297" "paginaFinal" => "304" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Martha Eva Viveros, Carlos Areán, Sergio Gutiérrez, Soledad Vázquez, Mario Humberto Cardiel, Alejandra Taboada, Gissela Marín, Ruben Solorio, Nalley García" "autores" => array:9 [ 0 => array:4 [ "nombre" => "Martha Eva" "apellidos" => "Viveros" "email" => array:1 [ 0 => "marthaevaviveros@yahoo.com.mx" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Carlos" "apellidos" => "Areán" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Sergio" "apellidos" => "Gutiérrez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "Soledad" "apellidos" => "Vázquez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "Mario Humberto" "apellidos" => "Cardiel" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 5 => array:3 [ "nombre" => "Alejandra" "apellidos" => "Taboada" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 6 => array:3 [ "nombre" => "Gissela" "apellidos" => "Marín" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 7 => array:3 [ "nombre" => "Ruben" "apellidos" => "Solorio" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 8 => array:3 [ "nombre" => "Nalley" "apellidos" => "García" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "División de Estudios de Posgrado, Facultad de Ciencias Médicas y Biológicas Dr. Ignacio Chávez, Universidad Michoacana de San Nicolás de Hidalgo, Morelia, Michoacán, Mexico" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Cardiología Intervencionista, Hospital General Dr. Miguel Silva, Morelia, Michoacán, Mexico" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Unidad de Investigación Dr. Mario Alvizouri, Hospital General Dr. Miguel Silva, Morelia, Michoacán, Mexico" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author at: División de Estudios de Posgrado, Facultad de Ciencias Médicas y Biológicas Dr. Ignacio Chávez, Universidad Michoacana de San Nicolás de Hidalgo, Morelia, Michoacán, Mexico, Ave. Rafael Carrillo esq. Dr. Salvador González Herrejón s/n, Col. Cuauhtémoc, Morelia, Michoacán, C.P. 58020, Morelia, Michoacán, Mexico. Tel.: +52 443 299 3159." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Evaluación de la variabilidad en la respuesta a clopidogrel e identificación del polimorfismo CYP2C19 en pacientes mexicanos" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1208 "Ancho" => 2705 "Tamanyo" => 131060 ] ] "descripcion" => array:1 [ "en" => "Basal sample PRI results. Panel A and 24h sample panel B." ] ] ] "textoCompleto" => "IntroductionPlatelets play a central role in the pathogenesis of acute coronary syndromes. Plaque rupture precipitates both the activation and aggregation of platelets with the formation of a thrombus, but this is avoided in patients with acute coronary syndromes as well as in those undergoing percutaneous coronary intervention (PCI) by using antiplatelet drugs to prevent abrupt vessel occlusion. Current guidelines recommend dual therapy with aspirin and P2Y12 antagonists,<a class="elsevierStyleCrossRef" href="#bib0165">1</a> and clopidogrel is the most widely used P2Y12 antagonist. Doses of up to 600mg clopidogrel prior to PCI result in lower platelet aggregation and P-selectin expression with reduced cardiovascular events in patients with non-ST elevation coronary syndromes.<a class="elsevierStyleCrossRef" href="#bib0170">2</a> In recent years, however, resistance to aspirin or clopidogrel has gained importance,<a class="elsevierStyleCrossRef" href="#bib0175">3</a> particularly the presence of a high inter-individual variability of response to the drug.<a class="elsevierStyleCrossRefs" href="#bib0180">4–9</a>The phosphorylation state of vasodilator-stimulated phosphoprotein (VASP) is a specific intracellular marker of residual P2Y12 receptor reactivity in patients treated with P2Y12 blockers, which is currently measured by flow cytometry and has also been correlated with ischemic risk.<a class="elsevierStyleCrossRefs" href="#bib0210">10,11</a> Unlike methods that include ADP-induced aggregation, the VASP phosphorylation assay does not include the contribution of the P2Y1 receptor to the overall response.<a class="elsevierStyleCrossRef" href="#bib0210">10</a> The ratio of dephosphorylated and phosphorylated VASP is a specific measure of P2Y12 activity, which is expressed as the “platelet reactivity index” (PRI).Genetic factors influence the absorption and/or the extent of metabolism of the prodrug clopidogrel to its active metabolite, and this contributes to the observed variability of response. To date, several polymorphisms have been related to high-dose treatment platelet reactivity, with the best established genetic factor being located within the CYP2C19 gene. A single nucleotide mutation (SNP) is associated with a reduction in clopidogrel metabolism and with a slow metabolism phenotype,<a class="elsevierStyleCrossRef" href="#bib0220">12</a> although the frequency of slow metabolizers varies according to the study population. For example, in Asiatic populations, the frequency is as high as 13–23%, compared with 2–5% in Caucasians and 4–6% in African populations.<a class="elsevierStyleCrossRefs" href="#bib0225">13,14</a> The aim of this study was to evaluate platelet response to high-dose clopidogrel and to identify the presence of CYP2C19*2 carriers.MethodsThis descriptive, cross-sectional, observational clinical study was approved by the Institutional Research and Ethics Committee, and all subjects were literate adults who signed an informed consent form. Ninety consecutive patients were enrolled in the study between 2009 and 2012. The cohort consisted of patients with a diagnosis of non-ST acute coronary syndromes, stable angina, or those with a positive ischemia detection test in whom coronary angiography was performed. Exclusion criteria were ST elevation coronary syndromes, use of proton pump inhibitors, hepatic disease, a contraindication to antiplatelet use, and hemorrhagic diathesis. All patients received a 100mg dose of aspirin at the time of the study; a 600mg clopidogrel loading dose was administered 6–8h prior to angiography in all cases. Blood samples were obtained from fasting patients. Basal samples were drawn once arterial access was obtained and a 6F sheath was placed via radial or femoral approach 6–8h after the clopidogrel loading dose. A second sample was obtained by venipuncture 24h after angiography. In all cases, 5mL of blood were discarded from each sample drawn to avoid platelet activation.Angiography and PCIAll patients underwent a diagnostic angiography. Patients undergoing PCI received unfractionated heparin (70UI/kg). Stent placement was performed according to international guidelines,<a class="elsevierStyleCrossRef" href="#bib0235">15</a> and drug-eluted stents or bare metal stents were implanted according to patient requirements. The sheath was removed and anticoagulation was stopped immediately at the end of the procedure in all cases. No GPIIb/IIIa inhibitors were used. A failed PCI was defined as a failure to obtain a residual stenosis <30% after stent placement, or a post-PCI anterograde TIMI 3 flow. All study subjects were followed up after 6 months.VASP phosphorylation analysisThe VASP phosphorylation state was evaluated in all patients within 4h after blood sampling using a standardized flow cytometric assay. Blood samples were collected using 3.8% sodium citrate as an anticoagulant, then incubated with prostaglandin E1 (PGE1) alone or PGE1 plus ADP for 10min, and then fixed in paraformaldehyde for 5min. Cells were permeabilized and labeled with a specific primary monoclonal anti-VASP antibody (clone 16C2) followed by a secondary fluorescein isothiocyanate-labeled polyclonal goat anti-mouse antibody and a platelet reactive marked with PE (anti-CD61PE) according to the manufacturer's instructions of the VASP assay (PLATELET VASP/P2Y12 Biocytex, Marseille, France. The platelet mean fluorescence intensity (MFI) was determined using a flow cytometer (Beckman Coulter Epics Altra). The platelet population was identified by its distribution and at least 20,000 platelet events were analyzed. The platelet reactivity index (PRI) was then calculated from the MFI obtained in the presence of PGE1 alone (PGE1) or PGE1 and ADP simultaneously (PGE1+ADP):<elsevierMultimedia ident="eq0005"></elsevierMultimedia>The ratio is expressed as the percentage of mean platelet reactivity and is inversely proportional to the platelet inhibition obtained with clopidogrel.Determination of polymorphismsGenomic DNA from anticoagulated blood samples was extracted using the phenol-chloroform method, the quality of the obtained DNA was assessed according to standard procedures. The reaction mixture to amplify the sequences of interest containing the CYP2C19*2 polymorphism consists of 25ng of DNA, 10mH pH 9.0 Tris–HCl, 1.0mH MgCl2, 0.2mM of each tryphosphate deoxynucleoside (dATP, dCTP, dGTP, dTTP), 0.5U of Platinum Taq DNA polymerase high fidelity (Gibco-BRL, Life Technologies, Carlsbsad, CA, USA) and 1μM of 5′-CAGAGCTTGGCATATTGTATC-3′ and 5′-GTAAACACACAAAACTAGTCAATG-3′ primers specific for the CYP2C19*2 polymorphism in a final 25μl volume.<a class="elsevierStyleCrossRef" href="#bib0240">16</a> The amplification program was performed as follows: an initial denaturation at 94°C for 5min followed by 35 cycles (consisting of 45s at 94°C, 1min at 60°, and 1min at 72° by cycle) with a final extension of 72°C for 7min. The presence of CYP2C19*2 polymorphism was identified by digesting the amplification product of 316bp with the restriction enzyme Sma I followed by standard 2% agarose gel electrophoresis. We assayed all samples by duplicate. Negative controls were included with every set of amplifications. The presence of an intact 316-bp fragment revealed the AA polymorphism, while a 109- and 207-bp fragment together represented no such polymorphism (GG). In cases where all three fragments were obtained, the patients were classified as heterozygotes (GA). The first amplicons of the CYP2C19 gene positive for GG, AA or GA polymorphism obtained from the samples, were sequenced by Macrogen USA in a Life Tech's AB 3730XL DNA Sequencing analyzer. The sequences were compared in the Gen Bank by the Blast algorithm to found the presence of the SNP and were included as positive controls in subsequent set of amplifications and digestions.Statistical analysisDescriptive statistical analyses were conducted using means and standard deviations for continuous variables. Percentages were applied to categorical variables. Variable distributions were analyzed using the Kolmogorov-Smirnov test, and discrete variables were analyzed with the χ2 test. A two-tailed Student's t-test was used for non-paired continuous variables. Significance was set at an alpha level of 0.05. Analysis was conducted using the statistical package SPSS 18 for Windows (SPSS Inc., Chicago, IL, USA).ResultsNinety patients were included in the study and their demographic, biological, and angiographic characteristics are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. The mean age was 63.2 years, and 78.9% were male. As expected, there was a high incidence of cardiovascular risk factors, with 73.3% having hypertension and 54.4% having diabetes mellitus. The diagnosis on admission was non-ST elevation acute coronary syndromes in 60 individuals (66.7%), stable angina in 24 (26.7%), and silent ischemia in six cases (6.6%). PCI with stent placement was performed in 61 (67.8%) patients and drug-eluted stents were implanted in 36 (60%).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>We analyzed platelet function using flow cytometric analysis of VASP phosphorylation in samples 6–8h after a 600-mg bolus of clopidogrel was administered and 24h after the angiographic procedure. The mean PRI value was 53.45±22.48% in the baseline sample and 57.14±23.08% at 24h (p=0.183), with a large inter-individual variability observed in the biological response to clopidogrel (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>, Panels A and B). At 24h, patients with dyslipidemia had a significantly better response to clopidogrel (p=0.030), this was also found in older patients (p=0.050). Lower platelet counts were also associated with a better response to the drug at 24h (p=0.032). No significant results were associated with other variables including body mass index and diabetes (<a class="elsevierStyleCrossRefs" href="#tbl0010">Tables 2 and 3</a>). No hemorrhagic complications were reported.<elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Clopidogrel responseWe found that 36 patients (40%) were good responders, with a VASP-PRI<50% in the baseline sample and 31 (37.8%) at 24h (p=NS); a VASP-PRI greater than 50% (non-responders) was observed in the remaining patients (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>). VAPS-PRI results were further divided into three groups as follows: group 1, VASP-PRI<50%; group 2, VASP-PRI 50–70%; group 3, VASP-PRI>70%. According to this as stated above, 40% of patients were good responders (group 1), the rest of the patients behaved as non-responders, 38% of them had a VASP-PRI 50–70% and 22% had VASP-PRI values greater than 70% (group 3). Dyslipidemia was associated with a significantly better response to the drug at 24h (p=0.017).<elsevierMultimedia ident="tbl0020"></elsevierMultimedia>A change of status of clopidogrel response among the three groups was observed at 24h; nine patients (11%) considered to have a good response in the first sample changed to group 2 (VASP-PRI 50–70%) and six (7.3%) moved to group 3 (VASP-PRI>70%). In group 2 (VASP-PRI 50–70%), 12 patients (14.5%) were good responders at 24h and nearly half of these (12.2%) had VASP-PRI values greater than 70%. Finally, in group 3 (VASP-PRI >70%), only three individuals (3.7%) migrated into group 1 (VASP-PRI <50%) and four (4.9%) into group 2 (VASP-PRI 50–70%). These findings did not follow a normal variation and were statistically significant (p=0.0039; <a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>). Of all patients included in the present study, major adverse cardiac events (MACE) were only observed in four.<elsevierMultimedia ident="tbl0025"></elsevierMultimedia>CYP2C19*2 polymorphism and VASP-PRI analysisDNA was obtained from 51 of the 90 patients, nine (17%) of whom were found to carry the CYP2C19*2 polymorphism. Of these, seven (13.7%) were heterozygotes (GA) and two (3.9%) were homozygous (AA); the remaining 42 patients (82.4%) had the wild-type genotype (GG).When VASP-PRI results were analyzed in this group of patients, we found that the homozygous genotype had a mean VASP-PRI of 62.6% in the baseline sample and a VASP-PRI of 78.3% at 24h (non-responders); these patients did not present MACE at follow-up (<a class="elsevierStyleCrossRef" href="#tbl0030">Table 6</a>). Heterozygote patients (AG) had a mean VASP-PRI of 49.5% in the baseline sample and 60.4% at 24h; finally, patients with the GG genotype showed VASP-PRI mean values of 57.3% and 62.5% in the baseline sample and 24h, respectively (p=NS) (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>, Panels A and B).<elsevierMultimedia ident="tbl0030"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia>DiscussionThe present study was conducted in Mexican Mestizo patients in the central region of Mexico. This population is widely distributed across the country and represents about ninety three percent of the total population, and it is also present in the United States of America, where about the 66 percent of the Hispanic population is from Mexican descent. In Mexico, coronary artery disease is the second cause of death according to national statistics. To date, in this country clopidogrel is the antiplatelet drug must widely used in spite of the newer and more potent antiplatelet drugs. Our results are consistent with several publications that showed a large inter-individual variability. In a previous prospective study of patients undergoing successful coronary artery stenting, a persistent increase in platelet reactivity measured by conventional aggregometry following a 300mg clopidogrel loading dose was demonstrated in some patients, thus a higher loading dose was suggested.<a class="elsevierStyleCrossRef" href="#bib0195">7</a> Similarly, enhanced platelet inhibition was observed during the post-stent period after a 300mg loading dose was given 3–24h prior to stenting, compared with a 75mg dose given at the time of the procedure.<a class="elsevierStyleCrossRef" href="#bib0200">8</a> Studies have also shown that doses of clopidogrel up to 600mg enable a more potent antiplatelet effect to be achieved.<a class="elsevierStyleCrossRef" href="#bib0245">17</a>Moreover, several studies have suggested a link between a low clopidogrel response or persistence of high platelet reactivity after treatment, as assessed by platelet assays, and post-PCI thrombotic events.<a class="elsevierStyleCrossRefs" href="#bib0250">18,19</a> These findings have determined a threshold of platelet reactivity that can be used to predict thrombotic events.<a class="elsevierStyleCrossRefs" href="#bib0260">20,21</a> Prospective studies reported that platelet reactivity above 50% according to the VASP index is associated with MACE after PCI and with stent thrombosis.<a class="elsevierStyleCrossRef" href="#bib0270">22</a> Furthermore, recent trials demonstrated that increased platelet reactivity inhibition results in reduced MACE.<a class="elsevierStyleCrossRef" href="#bib0275">23</a> Bonello et al.<a class="elsevierStyleCrossRef" href="#bib0280">24</a> investigated the impact of a tailored clopidogrel loading dose according to platelet reactivity monitoring for stent thrombosis in patients undergoing nonemergency PCI, and observed a decrease in the primary endpoint without major bleeding complications. Although 60% of our patients presented a VASP-PRI value>50%, we found no significant association with MACE, this could be related to the small sample size and also the percentage of PCI and stenting performed.It is important to note that within groups of responders and non-responders, some patients demonstrated an appropriate response to clopidogrel in the first sample but showed an increased reactivity at 24h in the present study. Similarly, Gurbel et al.<a class="elsevierStyleCrossRef" href="#bib0285">25</a> found that ∼30% of patients were resistant to clopidogrel on days 1 and 5 post-stenting, and 15% were resistant at day 30. Based on these observations, they hypothesized that clopidogrel resistance was related to insufficient active metabolite generation following a 300mg load and a 75mg maintenance dose in selected patients. Further studies were conducted using a 600mg loading dose, and higher platelet inhibition was observed at 24h compared with patients receiving 300mg. However, in the present study, we found that nearly 30% of patients had a VASP-PRI >50% at 24h despite receiving a 600mg loading dose; moreover, patients considered to be good responders at the first sample changed their status to non-responders. This could be related to factors involving clopidogrel pharmacokinetics and deserve further study.Our results showed that 3.9% of patients had the AA genotype, which is higher than the previously reported frequency of 0–1.45% in the Mexican Mestizo groups.<a class="elsevierStyleCrossRef" href="#bib0290">26</a> Although AA frequencies of 3.2% and 1.1% were reported in Mexican-Americans and in Colombian Mestizo individuals, respectively, neither of these studies investigated clopidogrel response.<a class="elsevierStyleCrossRefs" href="#bib0295">27,28</a> The absence of the polymorphism in the present study was not related to lower PRI values; indeed, high platelet reactivity was also found in such individuals, suggesting that the inter-individual response to clopidogrel must be influenced by other factors.Hulot<a class="elsevierStyleCrossRef" href="#bib0305">29</a> previously showed that the presence of the CYP2C19*2 polymorphism was associated with a reduction in clopidogrel metabolism leading to a reduction in its antiplatelet effect. In the present study, homozygous (AA) patients showed higher, albeit non-significant, PRI values compared with heterozygote and wild-type patients. The presence of the CYP2C19*2 SNP in both alleles strongly suggests a poor metabolizer phenotype with reduced clopidogrel response. Heterozygote patients showed a variable behavior, which could be related to the expression of the alleles involved. Some studies not only observed the negative biological effects of the polymorphism but also its association with MACE in patients with PCI and stenting.<a class="elsevierStyleCrossRef" href="#bib0310">30</a> However, the presence of the CYP2C19*2 allele accounts for only 5–15%<a class="elsevierStyleCrossRef" href="#bib0315">31</a> of clopidogrel response heterogeneity; moreover, the meta-analysis by Holmes<a class="elsevierStyleCrossRef" href="#bib0320">32</a> concluded that there is no clinically significant association of the CYP2C19*2 genotype with cardiovascular events. The patients that presented with the AA polymorphism in our study did not develop MACE at the follow-up despite higher levels of VASP-PRI.There are several limitations to our study. First, the sample size is small, which reflects the limited number of patients who agreed to participate, however previous studies have been conducted with a similar number of patients.<a class="elsevierStyleCrossRefs" href="#bib0195">7,17</a> Second, the patient sample is a heterogeneous mix of those with coronary artery disease, even though we aimed to evaluate the response to a 600mg dose of clopidogrel in all clinical scenarios. Not every patient in the study received a stent and 40% were treated with bare metal stents; such patients may show an improved response to clopidogrel. Third, although VASP analysis is widely accepted, it is an expensive test requiring trained personnel and a flow cytometer, which may limit its widespread use in clinical practice. In conclusion, the response to a 600mg loading dose of clopidogrel showed a wide variability in patients, with 40% responding to the drug according to previously established VASP-PRI cut-off values. Patients that initially responded to this loading dose showed a worsening of such response in the next 24h, although no adverse cardiovascular events were related to this behavior. Of the 51 patients in whom genetic testing was performed, CYP2C19*2 was present in 17%. These data are similar to frequencies found in other populations and ethnic groups, but higher than the one reported in a similar population in Mexico. To our knowledge, this is the first study to evaluate the clopidogrel response using VASP-PRI analysis and correlation with CYP2C19 in Mexican mestizo population.Ethical disclosuresConfidentiality of dataThe authors declare that they have followed the protocols of their work center on the publication of patient data.Protection of human and animal subjectsThe authors declare that no experiments were performed on humans or animals for this study.Right to privacy and informed consentThe authors declare that no patient data appear in this article.FundingAll of the authors acknowledge that this project was financed by the CONACYT grant: CONACYT.SSA.IMSS.ISSSTE S008-2010-142034.Conflict of interestDr. Carlos Areán has served as a consultant and/or speaker for Bristol Myers Squibb, MSD, Elly-Lilly and Bayer receiving less than 3000 USD honorarium. The rest of the authors declare having no competing interests." "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:3 [ "identificador" => "xres753444" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec755794" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres753443" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Método" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec755795" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Angiography and PCI" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "VASP phosphorylation analysis" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Determination of polymorphisms" ] ] ] 6 => array:2 [ "identificador" => "sec0030" "titulo" => "Statistical analysis" ] 7 => array:3 [ "identificador" => "sec0035" "titulo" => "Results" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Clopidogrel response" ] 1 => array:2 [ "identificador" => "sec0045" "titulo" => "CYP2C19*2 polymorphism and VASP-PRI analysis" ] ] ] 8 => array:2 [ "identificador" => "sec0050" "titulo" => "Discussion" ] 9 => array:3 [ "identificador" => "sec0055" "titulo" => "Ethical disclosures" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0060" "titulo" => "Confidentiality of data" ] 1 => array:2 [ "identificador" => "sec0065" "titulo" => "Protection of human and animal subjects" ] 2 => array:2 [ "identificador" => "sec0070" "titulo" => "Right to privacy and informed consent" ] ] ] 10 => array:2 [ "identificador" => "sec0075" "titulo" => "Funding" ] 11 => array:2 [ "identificador" => "sec0080" "titulo" => "Conflict of interest" ] 12 => array:2 [ "identificador" => "xack250521" "titulo" => "Acknowledgement" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-12-10" "fechaAceptado" => "2016-01-28" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec755794" "palabras" => array:6 [ 0 => "VASP analysis" 1 => "Clopidogrel resistance" 2 => "High on treatment platelet reactivity" 3 => "P2Y12" 4 => "CYP2C19*2 polymorphysm" 5 => "Mexico" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec755795" "palabras" => array:6 [ 0 => "Análisis VASP" 1 => "Resistencia a clopidogrel" 2 => "Alta reactividad plaquetaria en tratamiento" 3 => "Receptor P2Y12" 4 => "Polimorfismo CYP2C19*2" 5 => "México" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "ObjectiveDrug inhibition of platelet P2Y12 adenosine diphosphate receptor has reduced the incidence of adverse cardiovascular events after percutaneous coronary interventions. The analysis of the phosphorylation status of vasodilator-stimulated phosphoprotein by flow cytometry has shown a predictive value for adverse events and stent thrombosis. Polymorphisms of CYP2C19 in high risk patients may also relate to adverse cardiovascular events. MethodsNinety patients were enrolled. Patients received a 600mg clopidogrel loading dose. Blood samples were obtained at the time of the procedure and 24h later, platelet reactivity was assessed by vasodilator-stimulated phosphoprotein phosphorylation measurement using flow cytometry. Low response to clopidogrel was defined as a platelet reactivity index≥50%. The presence of CYP2C19*2 was identified with the restriction enzyme SmaI. ResultsMean platelet reactivity index: 53.45±22.48% in the baseline sample and 57.14±23.08% at 24h (p=0.183); 40% of patients behaved as good responders, the rest behaved as non-responders with 38% of patients showing platelet reactivity indexes between 50–70% and 22% showing indexes above 70%. The CYP2C19*2 polymorphism was found in 17% of patients, with a 3.9% AA homozygous genotype carriers. ConclusionResponse to the clopidogrel loading dose showed a wide variability among patients with 40% responding to the drug according to previously established cut-off values. Our results showed that 3.9% of patients show the AA genotype. To our knowledge, this is the first study involving clopidogrel response by flow citometry and genotype typification in Mexican Mestizo population." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "ObjetivoLa inhibición del receptor plaquetario P2Y12 se ha asociado con reducción en incidencia de eventos cardiovasculares mayores en pacientes sometidos a intervenciones coronarias percutáneas. El estudio de la fosfoproteína estimulada por vasodilatadores mediante citometría de flujo tiene valor predictivo para desarrollo de eventos adversos y trombosis del stent. Los polimorfismos del CYP2C19 en pacientes de alto riesgo pueden también asociarse con eventos adversos. Método90 pacientes, dosis de carga de clopidogrel: 600mg. Se obtuvieron muestras de sangre basales y post-24 horas. La reactividad plaquetaria se estudió mediante medición de fosfoproteína estimulada por vasodiatadores por citometría de flujo. Se consideró baja respuesta al clopidogrel un índice de reactividad plaquetaria ≥50%. La presencia del CYP2C19*2 se identificó con enzima de restricción SmaI. ResultadosLa media del índice de reactividad plaquetaria fue: 53.45±22.48% en muestras basales y 57.14±23.08% a 24h (p=0.183); 40% de los pacientes repondieron a clopidogrel, el resto de comportó como no-respondedores, un 38%, mostró índices de reactividad plaquetaria entre 50 -70% y 22%, índices>70%. El polimorfismo CYP2C19*2 se encontró en 17% pacientes, con un 3.9% portadores de genotipo homozigótico AA. ConclusionesLa respuesta a clopidogrel mostró amplia variabilidad entre pacientes, el 40% presentó respuesta de acuerdo con puntos de corte pre establecidos. Un 3.9% de los pacientes presentó genotipo AA. Consideramos que este es el primer estudio realizado en población mestizo-mexicana utilizado citometría de flujo para evaluar la respuesta a clopidogrel así como la tipificación genética de los pacientes." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Método" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "multimedia" => array:9 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1208 "Ancho" => 2705 "Tamanyo" => 131060 ] ] "descripcion" => array:1 [ "en" => "Basal sample PRI results. Panel A and 24h sample panel B." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1050 "Ancho" => 2796 "Tamanyo" => 100494 ] ] "descripcion" => array:1 [ "en" => "CYP2C19 genotype effect on VASP-PRI value. Basal sample panel A and 24h sample panel B." ] ] 2 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "ACS=acute coronary syndromes, NSTEMI=non ST elevation myocardial infarction, UA=unstable angina." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">n=90 \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Male, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">71 (78.9) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Female, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">19 (21.1) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Age (SD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">63.2±9.8 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BMI (kg/m2) (SD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">26.6±3.8 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Smokers, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">52 (61.1) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Dyslipidemia, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">55 (61.1) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hypertensión, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">66 (73.3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Diabetes mellitus, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">49 (54.4) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Family history of CAD, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">42 (46.7) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Platelet count (SD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">223.8±57.6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Percutaneous coronary intervention (stenting), n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">61 (67.8) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ACS (NSTEMI, UA) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">60 (66.7) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Stable angina \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">24 (26.7) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Silent ischemia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 (6.7) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1246836.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Baseline characteristics." ] ] 3 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "SEM=standard error." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">% PRI baseline sample</th><th class="td" title="table-head " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">% PRI 24h</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">n (%) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">SEM \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">P Value \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">n (%) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">SEM \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">P Value \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top">Gender</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Male \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">71 (78.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">53.16±2.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="2" align="char" valign="top">0.894</td><td class="td" title="table-entry " align="char" valign="top">63 (76.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">56.73±2.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="2" align="char" valign="top">0.767</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Female \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">19 (21.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">52.38±5.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">19 (23.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">58.53±5.6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Angiography \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">29 (32.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">51.39±4.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="2" align="char" valign="top">0.642</td><td class="td" title="table-entry " align="char" valign="top">26 (31.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">58.88±4.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="2" align="char" valign="top">0.646</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PCI and stenting \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">61 (67.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">53.75±2.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">56 (68.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">56.34±3.1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="2" align="char" valign="top">0.966</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="2" align="char" valign="top">0.758</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Smokers \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">52 (57.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">52.73±3.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">48 (58.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">57.85±3.2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="2" align="char" valign="top">0.134</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="2" align="char" valign="top">0.030<a class="elsevierStyleCrossRef" href="#tblfn0005">*</a></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Dyslipidemia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">55 (61.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">48.93±3.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">51 (62.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">53.38±3.4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="2" align="char" valign="top">0.964</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="2" align="char" valign="top">0.833</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Diabetes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">49 (54.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">53.09±2.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">46 (56.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">56.67±3.6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="2" align="char" valign="top">0.530</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="2" align="char" valign="top">0.583</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hypertension \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">66 (73.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">53.68±2.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">60 (73.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">56.17±3.0 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1246837.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "*" "nota" => "p<0.05." ] ] ] "descripcion" => array:1 [ "en" => "Patient distribution according to VASP-PRI results (<50% and >50%) baseline and 24h samples." ] ] 4 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "SEM=standard error." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">%PRI baseline \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">% PRI 24h \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">P Value \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">%PRI baseline \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">% PRI 24h \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">P Value \t\t\t\t\t\t\n \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">n (%) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">SEM \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">n (%) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">SEM \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top">Age</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PRI<50% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">35 (38.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">63.17±1.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="2" align="char" valign="middle">0.962</td><td class="td" title="table-entry " align="char" valign="top">30 (36.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">66.87±1.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="2" align="char" valign="middle">0.005<a class="elsevierStyleCrossRef" href="#tblfn0010">*</a></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PRI≥50% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">55 (61.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">63.27±1.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">52 (63.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">60.79±1.2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top">BMI</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PRI<50% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">35 (38.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">26.76±0.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="2" align="char" valign="middle">0.804</td><td class="td" title="table-entry " align="char" valign="top">30 (36.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">27.19±0.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="2" align="char" valign="middle">0.414 (t)</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PRI≥50% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">55 (61.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">26.56±0.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">52 (63.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">26.47±0.5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top">Platelet count</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PRI<50% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">26 (28.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">232.52±13.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="2" align="char" valign="middle">0.323</td><td class="td" title="table-entry " align="char" valign="top">21 (25.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">201.48±12.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="2" align="char" valign="middle">0.032<a class="elsevierStyleCrossRef" href="#tblfn0010">*</a></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PRI≥50% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">38 (42.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">217.91±8.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">36 (43.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">235.85±9.4 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1246838.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "*" "nota" => "p<0.05." ] ] ] "descripcion" => array:1 [ "en" => "VASP-PRI and mean values, age, bodie mass index and platelet count baseline and 24h samples." ] ] 5 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " rowspan="2" align="left" valign="middle" scope="col" style="border-bottom: 2px solid black">VASP-PRI Value</th><th class="td" title="table-head " rowspan="2" align="left" valign="middle" scope="col" style="border-bottom: 2px solid black">Response type</th><th class="td" title="table-head " align="left" valign="top" scope="col">Baseline sample \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">24h Sample \t\t\t\t\t\t\n \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">n (%) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">n (%) \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><50% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Good response \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">36 (40) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">31 (37.8) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">≥50% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Non responders \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">54 (60) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">51 (62.2) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Total \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">90 (100) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">82 (100) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1246834.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Patients Response according to cut off value 50%." ] ] 6 => array:8 [ "identificador" => "tbl0025" "etiqueta" => "Table 5" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at5" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">VASP-PRI 24h</th><th class="td" title="table-head " align="left" valign="top" scope="col">TOTAL \t\t\t\t\t\t\n \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><50% \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">50–70% \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">≥70% \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="6" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top">VASP-PRI Baseline Sample</td><td class="td" title="table-entry " align="left" valign="top"><50% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">15 (18.3%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9 (11.0%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 (7.3%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">30 (36.6%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">50–70% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12 (14.5%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12 (14.6%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10 (12.2%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">34 (41.5%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">≥70% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 (3.7%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 (4.9%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11 (13.4%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">18 (22.0%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">TOTAL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">30 (36.6%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">25 (30.5%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">27 (32.9%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">P=0.039* \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1246839.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Patient distribution on three groups baseline and 24h samples." ] ] 7 => array:8 [ "identificador" => "tbl0030" "etiqueta" => "Table 6" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at6" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Allele \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Phenotype \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Frequency n (%) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">VASP-PRI First Sample± SD \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">VASP-PRI 24h±SD \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">GG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Normal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">42 (82.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">57.3±21.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">62.5±19.7 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">GA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Intermediate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 (13.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">49.5±35.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">60.4±23.5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Slow \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (3.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">62.6±17.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">78.3±0.40 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1246835.png" ] ] ] ] "descripcion" => array:1 [ "en" => "CYP2C19*2 frequency (GA, AA) and VASP-PRI mean values." ] ] 8 => array:5 [ "identificador" => "eq0005" "tipo" => "MULTIMEDIAFORMULA" "mostrarFloat" => false "mostrarDisplay" => true "Formula" => array:5 [ "Matematica" => "PRI %=[(MFI (PGE1)−MFI (PGE1+ADP))/MFI (PGE1)]×100." "Fichero" => "STRIPIN_si1.jpeg" "Tamanyo" => 3306 "Alto" => 14 "Ancho" => 391 ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:32 [ 0 => array:3 [ "identificador" => "bib0165" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction; a report of the A American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction)" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "J.L. Anderson" 1 => "C.D. Adams" 2 => "E.M. Antman" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Circulation" "fecha" => "2007" "volumen" => "116" "paginaInicial" => "148" "paginaFinal" => "304" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0170" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Benefit of a 600mg loading dose of clopidogrel on platelet reactivity and clinical outcomes in patients with non-ST elevation acute coronary syndrome undergoing coronary stenting" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "T. Cuisset" 1 => "C. Frere" 2 => "J. Quilici" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Am Coll Cardiol" "fecha" => "2006" "volumen" => "48" "paginaInicial" => "1339" "paginaFinal" => "1345" ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0175" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Resistance to antiplatelet agents" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "M. Cattaneo" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0049-3848(11)70017-2" "Revista" => array:6 [ "tituloSerie" => "Thromb Res" "fecha" => "2011" "volumen" => "127" "paginaInicial" => "S61" "paginaFinal" => "S63" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21262444" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0180" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Individual variations of platelet inhibition after loading doses of clopidogrel" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "P. Järemo" 1 => "T.L. Lindahl" 2 => "S.G. Fransson" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Intern Med" "fecha" => "2002" "volumen" => "252" "paginaInicial" => "233" "paginaFinal" => "238" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12270003" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0185" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Variability in individual responsiveness to clopidogrel: clinical implications, management and future perspectives" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "D.J. Angiolillo" 1 => "A. Fernandez-Ortíz" 2 => "E. 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Evaluación de la variabilidad en la respuesta a clopidogrel e identificación del polimorfismo CYP2C19 en pacientes mexicanos

Martha Eva Viverosa,

Corresponding author

marthaevaviveros@yahoo.com.mx

Corresponding author at: División de Estudios de Posgrado, Facultad de Ciencias Médicas y Biológicas Dr. Ignacio Chávez, Universidad Michoacana de San Nicolás de Hidalgo, Morelia, Michoacán, Mexico, Ave. Rafael Carrillo esq. Dr. Salvador González Herrejón s/n, Col. Cuauhtémoc, Morelia, Michoacán, C.P. 58020, Morelia, Michoacán, Mexico. Tel.: +52 443 299 3159.

, Carlos Areánb, Sergio Gutiérreza, Soledad Vázqueza, Mario Humberto Cardielc, Alejandra Taboadaa, Gissela Marína, Ruben Soloriob, Nalley Garcíaa

a División de Estudios de Posgrado, Facultad de Ciencias Médicas y Biológicas Dr. Ignacio Chávez, Universidad Michoacana de San Nicolás de Hidalgo, Morelia, Michoacán, Mexico

b Servicio de Cardiología Intervencionista, Hospital General Dr. Miguel Silva, Morelia, Michoacán, Mexico

c Unidad de Investigación Dr. Mario Alvizouri, Hospital General Dr. Miguel Silva, Morelia, Michoacán, Mexico

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Platelets play a central role in the pathogenesis of acute coronary syndromes&#46; Plaque rupture precipitates both the activation and aggregation of platelets with the formation of a thrombus&#44; but this is avoided in patients with acute coronary syndromes as well as in those undergoing percutaneous coronary intervention &#40;PCI&#41; by using antiplatelet drugs to prevent abrupt vessel occlusion&#46; Current guidelines recommend dual therapy with aspirin and P2Y12 antagonists&#44;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">1</span></a> and clopidogrel is the most widely used P2Y12 antagonist&#46; Doses of up to 600<span class="elsevierStyleHsp" style=""></span>mg clopidogrel prior to PCI result in lower platelet aggregation and P-selectin expression with reduced cardiovascular events in patients with non-ST elevation coronary syndromes&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">2</span></a> In recent years&#44; however&#44; resistance to aspirin or clopidogrel has gained importance&#44;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">3</span></a> particularly the presence of a high inter-individual variability of response to the drug&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">4&#8211;9</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The phosphorylation state of vasodilator-stimulated phosphoprotein &#40;VASP&#41; is a specific intracellular marker of residual P2Y12 receptor reactivity in patients treated with P2Y12 blockers&#44; which is currently measured by flow cytometry and has also been correlated with ischemic risk&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">10&#44;11</span></a> Unlike methods that include ADP-induced aggregation&#44; the VASP phosphorylation assay does not include the contribution of the P2Y1 receptor to the overall response&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">10</span></a> The ratio of dephosphorylated and phosphorylated VASP is a specific measure of P2Y12 activity&#44; which is expressed as the &#8220;platelet reactivity index&#8221; &#40;PRI&#41;&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Genetic factors influence the absorption and&#47;or the extent of metabolism of the prodrug clopidogrel to its active metabolite&#44; and this contributes to the observed variability of response&#46; To date&#44; several polymorphisms have been related to high-dose treatment platelet reactivity&#44; with the best established genetic factor being located within the <span class="elsevierStyleItalic">CYP2C19</span> gene&#46; A single nucleotide mutation &#40;SNP&#41; is associated with a reduction in clopidogrel metabolism and with a slow metabolism phenotype&#44;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">12</span></a> although the frequency of slow metabolizers varies according to the study population&#46; For example&#44; in Asiatic populations&#44; the frequency is as high as 13&#8211;23&#37;&#44; compared with 2&#8211;5&#37; in Caucasians and 4&#8211;6&#37; in African populations&#46;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">13&#44;14</span></a> The aim of this study was to evaluate platelet response to high-dose clopidogrel and to identify the presence of CYP2C19&#42;2 carriers&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods</span><p id="par0020" class="elsevierStylePara elsevierViewall">This descriptive&#44; cross-sectional&#44; observational clinical study was approved by the Institutional Research and Ethics Committee&#44; and all subjects were literate adults who signed an informed consent form&#46; Ninety consecutive patients were enrolled in the study between 2009 and 2012&#46; The cohort consisted of patients with a diagnosis of non-ST acute coronary syndromes&#44; stable angina&#44; or those with a positive ischemia detection test in whom coronary angiography was performed&#46; Exclusion criteria were ST elevation coronary syndromes&#44; use of proton pump inhibitors&#44; hepatic disease&#44; a contraindication to antiplatelet use&#44; and hemorrhagic diathesis&#46; All patients received a 100<span class="elsevierStyleHsp" style=""></span>mg dose of aspirin at the time of the study&#59; a 600<span class="elsevierStyleHsp" style=""></span>mg clopidogrel loading dose was administered 6&#8211;8<span class="elsevierStyleHsp" style=""></span>h prior to angiography in all cases&#46; Blood samples were obtained from fasting patients&#46; Basal samples were drawn once arterial access was obtained and a 6F sheath was placed via radial or femoral approach 6&#8211;8<span class="elsevierStyleHsp" style=""></span>h after the clopidogrel loading dose&#46; A second sample was obtained by venipuncture 24<span class="elsevierStyleHsp" style=""></span>h after angiography&#46; In all cases&#44; 5<span class="elsevierStyleHsp" style=""></span>mL of blood were discarded from each sample drawn to avoid platelet activation&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Angiography and PCI</span><p id="par0025" class="elsevierStylePara elsevierViewall">All patients underwent a diagnostic angiography&#46; Patients undergoing PCI received unfractionated heparin &#40;70<span class="elsevierStyleHsp" style=""></span>UI&#47;kg&#41;&#46; Stent placement was performed according to international guidelines&#44;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">15</span></a> and drug-eluted stents or bare metal stents were implanted according to patient requirements&#46; The sheath was removed and anticoagulation was stopped immediately at the end of the procedure in all cases&#46; No GPIIb&#47;IIIa inhibitors were used&#46; A failed PCI was defined as a failure to obtain a residual stenosis &#60;30&#37; after stent placement&#44; or a post-PCI anterograde TIMI 3 flow&#46; All study subjects were followed up after 6 months&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">VASP phosphorylation analysis</span><p id="par0030" class="elsevierStylePara elsevierViewall">The VASP phosphorylation state was evaluated in all patients within 4<span class="elsevierStyleHsp" style=""></span>h after blood sampling using a standardized flow cytometric assay&#46; Blood samples were collected using 3&#46;8&#37; sodium citrate as an anticoagulant&#44; then incubated with prostaglandin E1 &#40;PGE1&#41; alone or PGE1 plus ADP for 10<span class="elsevierStyleHsp" style=""></span>min&#44; and then fixed in paraformaldehyde for 5<span class="elsevierStyleHsp" style=""></span>min&#46; Cells were permeabilized and labeled with a specific primary monoclonal anti-VASP antibody &#40;clone 16C2&#41; followed by a secondary fluorescein isothiocyanate-labeled polyclonal goat anti-mouse antibody and a platelet reactive marked with PE &#40;anti-CD61PE&#41; according to the manufacturer&#39;s instructions of the VASP assay &#40;PLATELET VASP&#47;P2Y12 Biocytex&#44; Marseille&#44; France&#46; The platelet mean fluorescence intensity &#40;MFI&#41; was determined using a flow cytometer &#40;Beckman Coulter Epics Altra&#41;&#46; The platelet population was identified by its distribution and at least 20&#44;000 platelet events were analyzed&#46; The platelet reactivity index &#40;PRI&#41; was then calculated from the MFI obtained in the presence of PGE1 alone &#40;PGE1&#41; or PGE1 and ADP simultaneously &#40;PGE1<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>ADP&#41;&#58;<elsevierMultimedia ident="eq0005"></elsevierMultimedia></p><p id="par0035" class="elsevierStylePara elsevierViewall">The ratio is expressed as the percentage of mean platelet reactivity and is inversely proportional to the platelet inhibition obtained with clopidogrel&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Determination of polymorphisms</span><p id="par0040" class="elsevierStylePara elsevierViewall">Genomic DNA from anticoagulated blood samples was extracted using the phenol-chloroform method&#44; the quality of the obtained DNA was assessed according to standard procedures&#46; The reaction mixture to amplify the sequences of interest containing the CYP2C19&#42;2 polymorphism consists of 25<span class="elsevierStyleHsp" style=""></span>ng of DNA&#44; 10<span class="elsevierStyleHsp" style=""></span>mH pH 9&#46;0 Tris&#8211;HCl&#44; 1&#46;0<span class="elsevierStyleHsp" style=""></span>mH MgCl<span class="elsevierStyleInf">2</span>&#44; 0&#46;2<span class="elsevierStyleHsp" style=""></span>mM of each tryphosphate deoxynucleoside &#40;dATP&#44; dCTP&#44; dGTP&#44; dTTP&#41;&#44; 0&#46;5<span class="elsevierStyleHsp" style=""></span>U of Platinum Taq DNA polymerase high fidelity &#40;Gibco-BRL&#44; Life Technologies&#44; Carlsbsad&#44; CA&#44; USA&#41; and 1<span class="elsevierStyleHsp" style=""></span>&#956;M of 5&#8242;-CAGAGCTTGGCATATTGTATC-3&#8242; and 5&#8242;-GTAAACACACAAAACTAGTCAATG-3&#8242; primers specific for the CYP2C19&#42;2 polymorphism in a final 25<span class="elsevierStyleHsp" style=""></span>&#956;l volume&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">16</span></a> The amplification program was performed as follows&#58; an initial denaturation at 94<span class="elsevierStyleHsp" style=""></span>&#176;C for 5<span class="elsevierStyleHsp" style=""></span>min followed by 35 cycles &#40;consisting of 45<span class="elsevierStyleHsp" style=""></span>s at 94<span class="elsevierStyleHsp" style=""></span>&#176;C&#44; 1<span class="elsevierStyleHsp" style=""></span>min at 60&#176;&#44; and 1<span class="elsevierStyleHsp" style=""></span>min at 72&#176; by cycle&#41; with a final extension of 72<span class="elsevierStyleHsp" style=""></span>&#176;C for 7<span class="elsevierStyleHsp" style=""></span>min&#46; The presence of CYP2C19&#42;2 polymorphism was identified by digesting the amplification product of 316<span class="elsevierStyleHsp" style=""></span>bp with the restriction enzyme <span class="elsevierStyleItalic">Sma</span> I followed by standard 2&#37; agarose gel electrophoresis&#46; We assayed all samples by duplicate&#46; Negative&#160;controls were included with every set of amplifications&#46; The presence of an intact 316-bp fragment revealed the AA polymorphism&#44; while a 109- and 207-bp fragment together represented no such polymorphism &#40;GG&#41;&#46; In cases where all three fragments were obtained&#44; the patients were classified as heterozygotes &#40;GA&#41;&#46; The first amplicons of the CYP2C19 gene positive for GG&#44; AA or GA polymorphism obtained from the samples&#44; were sequenced by Macrogen USA in a Life Tech&#39;s AB 3730XL DNA Sequencing analyzer&#46; The sequences were compared in the Gen Bank by the Blast algorithm to found the presence of the SNP and were included as positive controls in subsequent set of amplifications and digestions&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Statistical analysis</span><p id="par0045" class="elsevierStylePara elsevierViewall">Descriptive statistical analyses were conducted using means and standard deviations for continuous variables&#46; Percentages were applied to categorical variables&#46; Variable distributions were analyzed using the Kolmogorov-Smirnov test&#44; and discrete variables were analyzed with the &#967;<span class="elsevierStyleSup">2</span> test&#46; A two-tailed Student&#39;s <span class="elsevierStyleItalic">t</span>-test was used for non-paired continuous variables&#46; Significance was set at an alpha level of 0&#46;05&#46; Analysis was conducted using the statistical package SPSS 18 for Windows &#40;SPSS Inc&#46;&#44; Chicago&#44; IL&#44; USA&#41;&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Results</span><p id="par0050" class="elsevierStylePara elsevierViewall">Ninety patients were included in the study and their demographic&#44; biological&#44; and angiographic characteristics are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; The mean age was 63&#46;2 years&#44; and 78&#46;9&#37; were male&#46; As expected&#44; there was a high incidence of cardiovascular risk factors&#44; with 73&#46;3&#37; having hypertension and 54&#46;4&#37; having diabetes mellitus&#46; The diagnosis on admission was non-ST elevation acute coronary syndromes in 60 individuals &#40;66&#46;7&#37;&#41;&#44; stable angina in 24 &#40;26&#46;7&#37;&#41;&#44; and silent ischemia in six cases &#40;6&#46;6&#37;&#41;&#46; PCI with stent placement was performed in 61 &#40;67&#46;8&#37;&#41; patients and drug-eluted stents were implanted in 36 &#40;60&#37;&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">We analyzed platelet function using flow cytometric analysis of VASP phosphorylation in samples 6&#8211;8<span class="elsevierStyleHsp" style=""></span>h after a 600-mg bolus of clopidogrel was administered and 24<span class="elsevierStyleHsp" style=""></span>h after the angiographic procedure&#46; The mean PRI value was 53&#46;45<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>22&#46;48&#37; in the baseline sample and 57&#46;14<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>23&#46;08&#37; at 24<span class="elsevierStyleHsp" style=""></span>h &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;183&#41;&#44; with a large inter-individual variability observed in the biological response to clopidogrel &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#44; Panels A and B&#41;&#46; At 24<span class="elsevierStyleHsp" style=""></span>h&#44; patients with dyslipidemia had a significantly better response to clopidogrel &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;030&#41;&#44; this was also found in older patients &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;050&#41;&#46; Lower platelet counts were also associated with a better response to the drug at 24<span class="elsevierStyleHsp" style=""></span>h &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;032&#41;&#46; No significant results were associated with other variables including body mass index and diabetes &#40;<a class="elsevierStyleCrossRefs" href="#tbl0010">Tables 2 and 3</a>&#41;&#46; No hemorrhagic complications were reported&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Clopidogrel response</span><p id="par0060" class="elsevierStylePara elsevierViewall">We found that 36 patients &#40;40&#37;&#41; were good responders&#44; with a VASP-PRI<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>50&#37; in the baseline sample and 31 &#40;37&#46;8&#37;&#41; at 24<span class="elsevierStyleHsp" style=""></span>h &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>NS&#41;&#59; a VASP-PRI greater than 50&#37; &#40;non-responders&#41; was observed in the remaining patients &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46; VAPS-PRI results were further divided into three groups as follows&#58; group 1&#44; VASP-PRI<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>50&#37;&#59; group 2&#44; VASP-PRI 50&#8211;70&#37;&#59; group 3&#44; VASP-PRI<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>70&#37;&#46; According to this as stated above&#44; 40&#37; of patients were good responders &#40;group 1&#41;&#44; the rest of the patients behaved as non-responders&#44; 38&#37; of them had a VASP-PRI 50&#8211;70&#37; and 22&#37; had VASP-PRI values greater than 70&#37; &#40;group 3&#41;&#46; Dyslipidemia was associated with a significantly better response to the drug at 24<span class="elsevierStyleHsp" style=""></span>h &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;017&#41;&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">A change of status of clopidogrel response among the three groups was observed at 24<span class="elsevierStyleHsp" style=""></span>h&#59; nine patients &#40;11&#37;&#41; considered to have a good response in the first sample changed to group 2 &#40;VASP-PRI 50&#8211;70&#37;&#41; and six &#40;7&#46;3&#37;&#41; moved to group 3 &#40;VASP-PRI<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>70&#37;&#41;&#46; In group 2 &#40;VASP-PRI 50&#8211;70&#37;&#41;&#44; 12 patients &#40;14&#46;5&#37;&#41; were good responders at 24<span class="elsevierStyleHsp" style=""></span>h and nearly half of these &#40;12&#46;2&#37;&#41; had VASP-PRI values greater than 70&#37;&#46; Finally&#44; in group 3 &#40;VASP-PRI &#62;70&#37;&#41;&#44; only three individuals &#40;3&#46;7&#37;&#41; migrated into group 1 &#40;VASP-PRI &#60;50&#37;&#41; and four &#40;4&#46;9&#37;&#41; into group 2 &#40;VASP-PRI 50&#8211;70&#37;&#41;&#46; These findings did not follow a normal variation and were statistically significant &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0039&#59; <a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>&#41;&#46; Of all patients included in the present study&#44; major adverse cardiac events &#40;MACE&#41; were only observed in four&#46;</p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">CYP2C19&#42;2 polymorphism and VASP-PRI analysis</span><p id="par0070" class="elsevierStylePara elsevierViewall">DNA was obtained from 51 of the 90 patients&#44; nine &#40;17&#37;&#41; of whom were found to carry the CYP2C19&#42;2 polymorphism&#46; Of these&#44; seven &#40;13&#46;7&#37;&#41; were heterozygotes &#40;GA&#41; and two &#40;3&#46;9&#37;&#41; were homozygous &#40;AA&#41;&#59; the remaining 42 patients &#40;82&#46;4&#37;&#41; had the wild-type genotype &#40;GG&#41;&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">When VASP-PRI results were analyzed in this group of patients&#44; we found that the homozygous genotype had a mean VASP-PRI of 62&#46;6&#37; in the baseline sample and a VASP-PRI of 78&#46;3&#37; at 24<span class="elsevierStyleHsp" style=""></span>h &#40;non-responders&#41;&#59; these patients did not present MACE at follow-up &#40;<a class="elsevierStyleCrossRef" href="#tbl0030">Table 6</a>&#41;&#46; Heterozygote patients &#40;AG&#41; had a mean VASP-PRI of 49&#46;5&#37; in the baseline sample and 60&#46;4&#37; at 24<span class="elsevierStyleHsp" style=""></span>h&#59; finally&#44; patients with the GG genotype showed VASP-PRI mean values of 57&#46;3&#37; and 62&#46;5&#37; in the baseline sample and 24<span class="elsevierStyleHsp" style=""></span>h&#44; respectively &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>NS&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#44; Panels A and B&#41;&#46;</p><elsevierMultimedia ident="tbl0030"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Discussion</span><p id="par0080" class="elsevierStylePara elsevierViewall">The present study was conducted in Mexican Mestizo patients in the central region of Mexico&#46; This population is widely distributed across the country and represents about ninety three percent of the total population&#44; and it is also present in the United States of America&#44; where about the 66 percent of the Hispanic population is from Mexican descent&#46; In Mexico&#44; coronary artery disease is the second cause of death according to national statistics&#46; To date&#44; in this country clopidogrel is the antiplatelet drug must widely used in spite of the newer and more potent antiplatelet drugs&#46; Our results are consistent with several publications that showed a large inter-individual variability&#46; In a previous prospective study of patients undergoing successful coronary artery stenting&#44; a persistent increase in platelet reactivity measured by conventional aggregometry following a 300<span class="elsevierStyleHsp" style=""></span>mg clopidogrel loading dose was demonstrated in some patients&#44; thus a higher loading dose was suggested&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">7</span></a> Similarly&#44; enhanced platelet inhibition was observed during the post-stent period after a 300<span class="elsevierStyleHsp" style=""></span>mg loading dose was given 3&#8211;24<span class="elsevierStyleHsp" style=""></span>h prior to stenting&#44; compared with a 75<span class="elsevierStyleHsp" style=""></span>mg dose given at the time of the procedure&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">8</span></a> Studies have also shown that doses of clopidogrel up to 600<span class="elsevierStyleHsp" style=""></span>mg enable a more potent antiplatelet effect to be achieved&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">17</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Moreover&#44; several studies have suggested a link between a low clopidogrel response or persistence of high platelet reactivity after treatment&#44; as assessed by platelet assays&#44; and post-PCI thrombotic events&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">18&#44;19</span></a> These findings have determined a threshold of platelet reactivity that can be used to predict thrombotic events&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">20&#44;21</span></a> Prospective studies reported that platelet reactivity above 50&#37; according to the VASP index is associated with MACE after PCI and with stent thrombosis&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">22</span></a> Furthermore&#44; recent trials demonstrated that increased platelet reactivity inhibition results in reduced MACE&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">23</span></a> Bonello et al&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">24</span></a> investigated the impact of a tailored clopidogrel loading dose according to platelet reactivity monitoring for stent thrombosis in patients undergoing nonemergency PCI&#44; and observed a decrease in the primary endpoint without major bleeding complications&#46; Although 60&#37; of our patients presented a VASP-PRI value<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>50&#37;&#44; we found no significant association with MACE&#44; this could be related to the small sample size and also the percentage of PCI and stenting performed&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">It is important to note that within groups of responders and non-responders&#44; some patients demonstrated an appropriate response to clopidogrel in the first sample but showed an increased reactivity at 24<span class="elsevierStyleHsp" style=""></span>h in the present study&#46; Similarly&#44; Gurbel et al&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">25</span></a> found that &#8764;30&#37; of patients were resistant to clopidogrel on days 1 and 5 post-stenting&#44; and 15&#37; were resistant at day 30&#46; Based on these observations&#44; they hypothesized that clopidogrel resistance was related to insufficient active metabolite generation following a 300<span class="elsevierStyleHsp" style=""></span>mg load and a 75<span class="elsevierStyleHsp" style=""></span>mg maintenance dose in selected patients&#46; Further studies were conducted using a 600<span class="elsevierStyleHsp" style=""></span>mg loading dose&#44; and higher platelet inhibition was observed at 24<span class="elsevierStyleHsp" style=""></span>h compared with patients receiving 300<span class="elsevierStyleHsp" style=""></span>mg&#46; However&#44; in the present study&#44; we found that nearly 30&#37; of patients had a VASP-PRI &#62;50&#37; at 24<span class="elsevierStyleHsp" style=""></span>h despite receiving a 600<span class="elsevierStyleHsp" style=""></span>mg loading dose&#59; moreover&#44; patients considered to be good responders at the first sample changed their status to non-responders&#46; This could be related to factors involving clopidogrel pharmacokinetics and deserve further study&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Our results showed that 3&#46;9&#37; of patients had the AA genotype&#44; which is higher than the previously reported frequency of 0&#8211;1&#46;45&#37; in the Mexican Mestizo groups&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">26</span></a> Although AA frequencies of 3&#46;2&#37; and 1&#46;1&#37; were reported in Mexican-Americans and in Colombian Mestizo individuals&#44; respectively&#44; neither of these studies investigated clopidogrel response&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">27&#44;28</span></a> The absence of the polymorphism in the present study was not related to lower PRI values&#59; indeed&#44; high platelet reactivity was also found in such individuals&#44; suggesting that the inter-individual response to clopidogrel must be influenced by other factors&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Hulot<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">29</span></a> previously showed that the presence of the CYP2C19&#42;2 polymorphism was associated with a reduction in clopidogrel metabolism leading to a reduction in its antiplatelet effect&#46; In the present study&#44; homozygous &#40;AA&#41; patients showed higher&#44; albeit non-significant&#44; PRI values compared with heterozygote and wild-type patients&#46; The presence of the CYP2C19&#42;2 SNP in both alleles strongly suggests a poor metabolizer phenotype with reduced clopidogrel response&#46; Heterozygote patients showed a variable behavior&#44; which could be related to the expression of the alleles involved&#46; Some studies not only observed the negative biological effects of the polymorphism but also its association with MACE in patients with PCI and stenting&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">30</span></a> However&#44; the presence of the CYP2C19&#42;2 allele accounts for only 5&#8211;15&#37;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">31</span></a> of clopidogrel response heterogeneity&#59; moreover&#44; the meta-analysis by Holmes<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">32</span></a> concluded that there is no clinically significant association of the CYP2C19&#42;2 genotype with cardiovascular events&#46; The patients that presented with the AA polymorphism in our study did not develop MACE at the follow-up despite higher levels of VASP-PRI&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">There are several limitations to our study&#46; First&#44; the sample size is small&#44; which reflects the limited number of patients who agreed to participate&#44; however previous studies have been conducted with a similar number of patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">7&#44;17</span></a> Second&#44; the patient sample is a heterogeneous mix of those with coronary artery disease&#44; even though we aimed to evaluate the response to a 600<span class="elsevierStyleHsp" style=""></span>mg dose of clopidogrel in all clinical scenarios&#46; Not every patient in the study received a stent and 40&#37; were treated with bare metal stents&#59; such patients may show an improved response to clopidogrel&#46; Third&#44; although VASP analysis is widely accepted&#44; it is an expensive test requiring trained personnel and a flow cytometer&#44; which may limit its widespread use in clinical practice&#46; In conclusion&#44; the response to a 600<span class="elsevierStyleHsp" style=""></span>mg loading dose of clopidogrel showed a wide variability in patients&#44; with 40&#37; responding to the drug according to previously established VASP-PRI cut-off values&#46; Patients that initially responded to this loading dose showed a worsening of such response in the next 24<span class="elsevierStyleHsp" style=""></span>h&#44; although no adverse cardiovascular events were related to this behavior&#46; Of the 51 patients in whom genetic testing was performed&#44; CYP2C19&#42;2 was present in 17&#37;&#46; These data are similar to frequencies found in other populations and ethnic groups&#44; but higher than the one reported in a similar population in Mexico&#46; To our knowledge&#44; this is the first study to evaluate the clopidogrel response using VASP-PRI analysis and correlation with CYP2C19 in Mexican mestizo population&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Ethical disclosures</span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Confidentiality of data</span><p id="par0110" class="elsevierStylePara elsevierViewall">The authors declare that they have followed the protocols of their work center on the publication of patient data&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Protection of human and animal subjects</span><p id="par0115" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this study&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Right to privacy and informed consent</span><p id="par0120" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article&#46;</p></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Funding</span><p id="par0125" class="elsevierStylePara elsevierViewall">All of the authors acknowledge that this project was financed by the <span class="elsevierStyleGrantSponsor" id="gs1">CONACYT</span> grant&#58; CONACYT&#46;SSA&#46;IMSS&#46;ISSSTE <span class="elsevierStyleGrantNumber" refid="gs1">S008-2010-142034</span>&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Conflict of interest</span><p id="par0130" class="elsevierStylePara elsevierViewall">Dr&#46; Carlos Are&#225;n has served as a consultant and&#47;or speaker for Bristol Myers Squibb&#44; MSD&#44; Elly-Lilly and Bayer receiving less than 3000 USD honorarium&#46; The rest of the authors declare having no competing interests&#46;</p></span></span>"
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              "titulo" => "Clopidogrel response"
            ]
            1 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "CYP2C19&#42;2 polymorphism and VASP-PRI analysis"
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          "identificador" => "sec0050"
          "titulo" => "Discussion"
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        9 => array:3 [
          "identificador" => "sec0055"
          "titulo" => "Ethical disclosures"
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            0 => array:2 [
              "identificador" => "sec0060"
              "titulo" => "Confidentiality of data"
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            1 => array:2 [
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              "titulo" => "Protection of human and animal subjects"
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              "titulo" => "Right to privacy and informed consent"
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          "titulo" => "Funding"
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          "identificador" => "sec0080"
          "titulo" => "Conflict of interest"
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        12 => array:2 [
          "identificador" => "xack250521"
          "titulo" => "Acknowledgement"
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          "titulo" => "References"
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      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2015-12-10"
    "fechaAceptado" => "2016-01-28"
    "PalabrasClave" => array:2 [
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec755794"
          "palabras" => array:6 [
            0 => "VASP analysis"
            1 => "Clopidogrel resistance"
            2 => "High on treatment platelet reactivity"
            3 => "P2Y12"
            4 => "CYP2C19&#42;2 polymorphysm"
            5 => "Mexico"
          ]
        ]
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      "es" => array:1 [
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          "identificador" => "xpalclavsec755795"
          "palabras" => array:6 [
            0 => "An&#225;lisis VASP"
            1 => "Resistencia a clopidogrel"
            2 => "Alta reactividad plaquetaria en tratamiento"
            3 => "Receptor P2Y12"
            4 => "Polimorfismo CYP2C19&#42;2"
            5 => "M&#233;xico"
          ]
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      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Drug inhibition of platelet P2Y12 adenosine diphosphate receptor has reduced the incidence of adverse cardiovascular events after percutaneous coronary interventions&#46; The analysis of the phosphorylation status of vasodilator-stimulated phosphoprotein by flow cytometry has shown a predictive value for adverse events and stent thrombosis&#46; Polymorphisms of CYP2C19 in high risk patients may also relate to adverse cardiovascular events&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Ninety patients were enrolled&#46; Patients received a 600<span class="elsevierStyleHsp" style=""></span>mg clopidogrel loading dose&#46; Blood samples were obtained at the time of the procedure and 24<span class="elsevierStyleHsp" style=""></span>h later&#44; platelet reactivity was assessed by vasodilator-stimulated phosphoprotein phosphorylation measurement using flow cytometry&#46; Low response to clopidogrel was defined as a platelet reactivity index<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>50&#37;&#46; The presence of CYP2C19&#42;2 was identified with the restriction enzyme <span class="elsevierStyleItalic">Sma</span>I&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Mean platelet reactivity index&#58; 53&#46;45<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>22&#46;48&#37; in the baseline sample and 57&#46;14<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>23&#46;08&#37; at 24<span class="elsevierStyleHsp" style=""></span>h &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;183&#41;&#59; 40&#37; of patients behaved as good responders&#44; the rest behaved as non-responders with 38&#37; of patients showing platelet reactivity indexes between 50&#8211;70&#37; and 22&#37; showing indexes above 70&#37;&#46; The CYP2C19&#42;2 polymorphism was found in 17&#37; of patients&#44; with a 3&#46;9&#37; AA homozygous genotype carriers&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Response to the clopidogrel loading dose showed a wide variability among patients with 40&#37; responding to the drug according to previously established cut-off values&#46; Our results showed that 3&#46;9&#37; of patients show the AA genotype&#46; To our knowledge&#44; this is the first study involving clopidogrel response by flow citometry and genotype typification in Mexican Mestizo population&#46;</p></span>"
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            "titulo" => "Methods"
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            "titulo" => "Results"
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            "titulo" => "Conclusion"
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      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La inhibici&#243;n del receptor plaquetario P2Y12 se ha asociado con reducci&#243;n en incidencia de eventos cardiovasculares mayores en pacientes sometidos a intervenciones coronarias percut&#225;neas&#46; El estudio de la fosfoprote&#237;na estimulada por vasodilatadores mediante citometr&#237;a de flujo tiene valor predictivo para desarrollo de eventos adversos y trombosis del stent&#46; Los polimorfismos del CYP2C19 en pacientes de alto riesgo pueden tambi&#233;n asociarse con eventos adversos&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todo</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">90 pacientes&#44; dosis de carga de clopidogrel&#58; 600<span class="elsevierStyleHsp" style=""></span>mg&#46; Se obtuvieron muestras de sangre basales y post-24 horas&#46; La reactividad plaquetaria se estudi&#243; mediante medici&#243;n de fosfoprote&#237;na estimulada por vasodiatadores por citometr&#237;a de flujo&#46; Se consider&#243; baja respuesta al clopidogrel un &#237;ndice de reactividad plaquetaria &#8805;50&#37;&#46; La presencia del CYP2C19&#42;2 se identific&#243; con enzima de restricci&#243;n <span class="elsevierStyleItalic">Sma</span>I&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">La media del &#237;ndice de reactividad plaquetaria fue&#58; 53&#46;45<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>22&#46;48&#37; en muestras basales y 57&#46;14<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>23&#46;08&#37; a 24<span class="elsevierStyleHsp" style=""></span>h &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;183&#41;&#59; 40&#37; de los pacientes repondieron a clopidogrel&#44; el resto de comport&#243; como no-respondedores&#44; un 38&#37;&#44; mostr&#243; &#237;ndices de reactividad plaquetaria entre 50 -70&#37; y 22&#37;&#44; &#237;ndices<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>70&#37;&#46; El polimorfismo CYP2C19&#42;2 se encontr&#243; en 17&#37; pacientes&#44; con un 3&#46;9&#37; portadores de genotipo homozig&#243;tico AA&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La respuesta a clopidogrel mostr&#243; amplia variabilidad entre pacientes&#44; el 40&#37; present&#243; respuesta de acuerdo con puntos de corte pre establecidos&#46; Un 3&#46;9&#37; de los pacientes present&#243; genotipo AA&#46; Consideramos que este es el primer estudio realizado en poblaci&#243;n mestizo-mexicana utilizado citometr&#237;a de flujo para evaluar la respuesta a clopidogrel as&#237; como la tipificaci&#243;n gen&#233;tica de los pacientes&#46;</p></span>"
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          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">ACS<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>acute coronary syndromes&#44; NSTEMI<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>non ST elevation myocardial infarction&#44; UA<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>unstable angina&#46;</p>"
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BMI &#40;kg&#47;m<span class="elsevierStyleSup">2</span>&#41; &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">26&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Smokers&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">52 &#40;61&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Dyslipidemia&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">55 &#40;61&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hypertensi&#243;n&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">66 &#40;73&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top">Gender</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">71 &#40;78&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">53&#46;16<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="char" valign="top">0&#46;894</td><td class="td" title="table-entry  " align="char" valign="top">63 &#40;76&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">56&#46;73<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="char" valign="top">0&#46;767</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">19 &#40;21&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">52&#46;38<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">19 &#40;23&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">58&#46;53<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Angiography&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">29 &#40;32&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">51&#46;39<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="char" valign="top">0&#46;642</td><td class="td" title="table-entry  " align="char" valign="top">26 &#40;31&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">58&#46;88<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="char" valign="top">0&#46;646</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>PCI and stenting&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">61 &#40;67&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">53&#46;75<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">56 &#40;68&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">56&#46;34<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="char" valign="top">0&#46;966</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="char" valign="top">0&#46;758</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Smokers&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">52&#46;73<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">48 &#40;58&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">57&#46;85<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="char" valign="top">0&#46;134</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="char" valign="top">0&#46;030<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;</span></a></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Dyslipidemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">55 &#40;61&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">48&#46;93<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">51 &#40;62&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">53&#46;38<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="char" valign="top">0&#46;964</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="char" valign="top">0&#46;833</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Diabetes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">49 &#40;54&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">53&#46;09<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">46 &#40;56&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">56&#46;67<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="char" valign="top">0&#46;530</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="char" valign="top">0&#46;583</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Hypertension&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">66 &#40;73&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">53&#46;68<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">60 &#40;73&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">56&#46;17<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;0&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">63&#46;17<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="char" valign="middle">0&#46;962</td><td class="td" title="table-entry  " align="char" valign="top">30 &#40;36&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">66&#46;87<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="char" valign="middle">0&#46;005<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">&#42;</span></a></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>PRI<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>50&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">63&#46;27<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;4&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">60&#46;79<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">26&#46;76<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;6&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">27&#46;19<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;7&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">26&#46;56<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">52 &#40;63&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">26&#46;47<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top">Platelet count</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>PRI<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>50&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">26 &#40;28&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="char" valign="middle">0&#46;323</td><td class="td" title="table-entry  " align="char" valign="top">21 &#40;25&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="char" valign="middle">0&#46;032<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">&#42;</span></a></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>PRI<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>50&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">235&#46;85<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>9&#46;4&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6 &#40;7&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                      "titulo" => "ACC&#47;AHA 2007 guidelines for the management of patients with unstable angina&#47;non ST-elevation myocardial infarction&#59; a report of the A American College of Cardiology&#47;American Heart Association Task Force on Practice Guidelines &#40;Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina&#47;Non ST-Elevation Myocardial Infarction&#41;"
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                        "fecha" => "2007"
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                        "paginaInicial" => "148"
                        "paginaFinal" => "304"
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                      "titulo" => "Benefit of a 600mg loading dose of clopidogrel on platelet reactivity and clinical outcomes in patients with non-ST elevation acute coronary syndrome undergoing coronary stenting"
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                        0 => array:2 [
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                          "autores" => array:3 [
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Article information

ISSN: 14059940
Original language: English

DOI:10.1016/j.acmx.2016.01.007

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	3	1	4
2024 October	40	3	43
2024 September	38	6	44
2024 August	39	4	43
2024 July	30	3	33
2024 June	18	1	19
2024 May	49	4	53
2024 April	37	21	58
2024 March	30	6	36
2024 February	25	4	29
2024 January	39	3	42
2023 December	29	8	37
2023 November	19	9	28
2023 October	37	8	45
2023 September	42	7	49
2023 August	33	7	40
2023 July	21	9	30
2023 June	33	6	39
2023 May	36	13	49
2023 April	20	0	20
2023 March	31	6	37
2023 February	15	4	19
2023 January	18	4	22
2022 December	25	7	32
2022 November	18	16	34
2022 October	15	18	33
2022 September	17	21	38
2022 August	21	17	38
2022 July	17	7	24
2022 June	18	8	26
2022 May	24	9	33
2022 April	13	14	27
2022 March	14	9	23
2022 February	26	11	37
2022 January	35	5	40
2021 December	10	17	27
2021 November	17	13	30
2021 October	26	14	40
2021 September	18	15	33
2021 August	17	6	23
2021 July	9	14	23
2021 June	20	8	28
2021 May	29	10	39
2021 April	59	21	80
2021 March	17	3	20
2021 February	24	11	35
2021 January	20	13	33
2020 December	13	11	24
2020 November	18	2	20
2020 October	11	5	16
2020 September	13	19	32
2020 August	32	37	69
2020 July	18	14	32
2020 June	22	16	38
2020 May	30	11	41
2020 April	15	1	16
2020 March	19	5	24
2020 February	10	11	21
2020 January	17	13	30
2019 December	24	4	28
2019 November	5	15	20
2019 October	20	5	25
2019 September	15	12	27
2019 August	26	12	38
2019 July	29	9	38
2019 June	32	31	63
2019 May	117	54	171
2019 April	56	10	66
2019 March	14	7	21
2019 February	17	16	33
2019 January	13	10	23
2018 December	11	12	23
2018 November	15	5	20
2018 October	23	23	46
2018 September	25	9	34
2018 August	16	4	20
2018 July	8	4	12
2018 June	9	1	10
2018 May	10	4	14
2018 April	21	9	30
2018 March	12	3	15
2018 February	7	2	9
2018 January	17	1	18
2017 December	15	6	21
2017 November	14	1	15
2017 October	19	11	30
2017 September	20	4	24
2017 August	8	12	20
2017 July	17	2	19
2017 June	21	8	29
2017 May	23	8	31
2017 April	25	47	72
2017 March	28	39	67
2017 February	43	8	51
2017 January	46	11	57
2016 December	46	16	62
2016 November	65	25	90
2016 October	8	10	18
2016 September	9	5	14
2016 August	5	9	14
2016 July	1	5	6

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