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1.
J Cardiothorac Surg ; 19(1): 422, 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38965617

RESUMO

OBJECTIVE: Coronary artery bypass grafting (CABG) is associated with antithrombotic therapy in terms of postoperative adverse events; however, it is still unknown whether the early use of such drugs after CABG is safe and effective. In this study, we aim to evaluate the relationship between different postoperative antithrombotic strategies and in-hospital adverse events in patients undergoing isolated coronary artery bypass grafting surgery. METHODS: This was a single-center, retrospective cohort analysis of patients undergoing isolated CABG due to coronary artery disease (CAD) between 2001 and 2012. Data were extracted from the Medical Information Mart for Intensive Care III database. The patients involved were divided into the ASA (aspirin 81 mg per day only) or DAPT (aspirin plus clopidogrel 75 mg per day) group according to the antiplatelet strategy. Patients were also stratified into subgroups based on the type of anticoagulation. The in-hospital risk of bleeding and adverse events was investigated and compared between groups. Propensity score matching (PSM) was performed to reduce the potential effects of a selection bias. RESULTS: A total of 3274 patients were included in this study, with 2358 in the ASA group and 889 in the DAPT group. Following the PSM, no significant difference was seen in the risk of major bleeding between the two groups according to the PLATO, TIMI or GUSTO criteria. There was no difference in the postoperative mortality. In subgroup analysis, patients given anticoagulant therapy had an increased incidence of bleeding-related events. Multivariable analysis revealed that postoperative anticoagulant therapy and the early use of heparin, but not DAPT, were independent predictors of bleeding-related events. CONCLUSIONS: Postoperative DAPT was not associated with an increased occurrence of bleeding-related events in patients undergoing isolated CABG and appears to be a safe antiplatelet therapy. The addition of anticoagulants to antiplatelet therapy increased the risk of bleeding and should be considered cautiously in clinical practice.


Assuntos
Ponte de Artéria Coronária , Fibrinolíticos , Inibidores da Agregação Plaquetária , Estudos Retrospectivos , Estudos de Coortes , Ponte de Artéria Coronária/efeitos adversos , Período Pós-Operatório , Fibrinolíticos/uso terapêutico , Clopidogrel/uso terapêutico , Aspirina/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Quimioterapia Combinada , Hemorragia/prevenção & controle , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso
3.
J Cardiothorac Surg ; 19(1): 402, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38937841

RESUMO

BACKGROUND: Thoracic endovascular aortic repair (TEVAR) is a minimally invasive technique used to treat type B aortic dissections. Left subclavian artery (LSA) reconstruction is required when treating patients with involvement of LSA. The best antiplatelet therapy after LSA reconstruction is presently uncertain. METHODS: This study retrospectively analyzed 245 type B aortic dissection patients who underwent left subclavian artery revascularization during TEVAR. Out of 245 patients, 159 (64.9%) were in the single antiplatelet therapy (SAPT) group, receiving only aspirin, and 86 (35.1%) were in the dual antiplatelet therapy (DAPT) group, receiving aspirin combined with clopidogrel. During the 6-month follow-up, primary endpoints included hemorrhagic events (general bleeding and hemorrhagic strokes), while secondary endpoints comprised ischemic events (left upper limb ischemia, ischemic stroke, and thrombotic events), as well as death and leakage events. Both univariate and multivariate Cox regression analyses were performed on hemorrhagic and ischemic events, with the Kaplan-Meier method used to generate the survival curve. RESULTS: During the six-month follow-up, the incidence of hemorrhagic events in the DAPT group was higher (8.2% vs. 30.2%, P < 0.001). No significant differences were observed in ischemic events, death, or leakage events among the different antiplatelet treatment schemes. Multivariate Cox regression analysis showed that DAPT (HR: 2.22, 95% CI: 1.07-4.60, P = 0.032) and previous chronic conditions (HR:3.88, 95% CI: 1.24-12.14, P = 0.020) significantly affected the occurrence of hemorrhagic events. Chronic conditions in this study encompassed depression, vitiligo, and cholecystolithiasis. Carotid subclavian bypass (CSB) group (HR:0.29, 95% CI: 0.12-0.68, P = 0.004) and single-branched stent graft (SBSG) group (HR:0.26, 95% CI: 0.13-0.50, P < 0.001) had a lower rate of ischemic events than fenestration TEVAR (F-TEVAR). Survival analysis over 6 months revealed a lower risk of bleeding associated with SAPT during hemorrhagic events (P = 0.043). CONCLUSIONS: In type B aortic dissection patients undergoing LSA blood flow reconstruction after synchronous TEVAR, the bleeding risk significantly decreases with the SAPT regimen, and there is no apparent ischemic compensation within 6 months. Patients with previous chronic conditions have a higher risk of bleeding. The CSB group and SBSG group have less ischemic risk compared to F-TEVAR group.


Assuntos
Aneurisma da Aorta Torácica , Dissecção Aórtica , Procedimentos Endovasculares , Inibidores da Agregação Plaquetária , Artéria Subclávia , Humanos , Masculino , Feminino , Estudos Retrospectivos , Inibidores da Agregação Plaquetária/uso terapêutico , Artéria Subclávia/cirurgia , Pessoa de Meia-Idade , Dissecção Aórtica/cirurgia , Procedimentos Endovasculares/métodos , Aneurisma da Aorta Torácica/cirurgia , Idoso , Clopidogrel/uso terapêutico , Aspirina/uso terapêutico , Aspirina/administração & dosagem , Aorta Torácica/cirurgia , Resultado do Tratamento , Implante de Prótese Vascular/métodos , Complicações Pós-Operatórias , Correção Endovascular de Aneurisma
4.
BMC Neurol ; 24(1): 216, 2024 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-38914966

RESUMO

BACKGROUND: Clopidogrel has been the primary choice of antiplatelet in ischemic stroke that inhibits adenosine diphosphate (ADP)-induced platelet aggregation. P-glycoprotein (P-gp) multidrug resistance-1 (MDR1) is a transmembrane efflux transporter in intestinal cells that plays a significant role in clopidogrel absorption, therefore may affect platelet aggregation. P-gp is encoded by the ABCB1 gene. This study aims to evaluate the effect of ABCB1 polymorphism on clopidogrel response variability in ischemic stroke patients and its genotype frequency. METHODS: A cross-sectional study was conducted in ischemic stroke patients who received clopidogrel between 2020 and 2023 in RSUI/RSCM. All subjects were assessed for ABCB1 polymorphisms C3435T and C1236T. Platelet aggregation were measured using VerifyNow PRU. Clopidogrel response variability was classified into unresponsive (> 208 PRU), responsive (95-208 PRU), and bleeding risk (< 95 PRU). RESULTS: 124 subjects enrolled in this study, with 12,9% of subjects classified as non-responsive/resistant, 49,5% as responsive, and 41,9% as bleeding risk. ABCB1 C1236T homozygote wildtype (CC) was associated with 3,76 times higher bleeding risk than other variants (p = 0,008; 95%CI 1,41 - 10,07). Genotype frequency of ABCB1 C3435T homozygote wildtype, heterozygote, and homozygote variants were 35,9%, 43,5% and 16,9%, respectively; while the genotype frequency of ABCB1 C1236T were 17,8%, 39,5%, and 42,7%, respectively. CONCLUSION: ABCB1 C1236T homozygote wildtype was associated with 3,76 times higher bleeding risk than other variants. The most common genotype frequency of ABCB1 C1236T was homozygote variant; while for ABCB1 C3435T was heterozygote.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP , Clopidogrel , AVC Isquêmico , Inibidores da Agregação Plaquetária , Humanos , Clopidogrel/uso terapêutico , Clopidogrel/administração & dosagem , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Estudos Transversais , Masculino , Feminino , Pessoa de Meia-Idade , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/genética , Idoso , Inibidores da Agregação Plaquetária/uso terapêutico , Polimorfismo de Nucleotídeo Único/genética , Genótipo , Agregação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/genética
5.
JACC Cardiovasc Interv ; 17(12): 1413-1421, 2024 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-38842993

RESUMO

BACKGROUND: Whether ticagrelor may reduce periprocedural myocardial necrosis after elective percutaneous coronary intervention (PCI) in patients with and without chronic clopidogrel therapy is unclear. OBJECTIVES: This study sought to compare ticagrelor vs clopidogrel in patients with and without chronic clopidogrel therapy before undergoing elective PCI. METHODS: In this prespecified analysis of the ALPHEUS (Assessment of Loading With the P2Y12 Inhibitor Ticagrelor or Clopidogrel to Halt Ischemic Events in Patients Undergoing Elective Coronary Stenting) trial, patients were defined as clopidogrel(+) and clopidogrel(-) according to the presence and absence of clopidogrel treatment for ≥7 days before PCI, respectively. The primary endpoint was the composite of PCI-related myocardial infarction and major injury as defined by the third and fourth universal definition 48 hours after PCI. RESULTS: A total of 1,882 patients were included, 805 (42.7%) of whom were clopidogrel(+). These patients were older, had more comorbidities, and had more frequent features of complex PCI. The primary endpoint was less frequently present in clopidogrel(-) compared to clopidogrel(+) patients (32.8% vs 40.0%; OR: 0.73; 95% CI: 0.60-0.88), but no significant differences were reported for the risk of death, myocardial infarction, stroke, or transient ischemic attack at 48 hours or 30 days. Ticagrelor did not reduce periprocedural myocardial necrosis or the risk of adverse outcomes, and there was no significant interaction regarding the presence of chronic clopidogrel treatment. CONCLUSIONS: Clopidogrel-naive patients presented less periprocedural complications compared to clopidogrel(+) patients, a difference related to a lower risk profile and less complex PCI. The absence of clopidogrel at baseline did not affect the absence of a difference between ticagrelor and clopidogrel in terms of PCI-related complications supporting the use of clopidogrel as the standard of care in elective PCI in patients with or without chronic clopidogrel treatment.


Assuntos
Clopidogrel , Infarto do Miocárdio , Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária , Ticagrelor , Humanos , Clopidogrel/efeitos adversos , Clopidogrel/uso terapêutico , Clopidogrel/administração & dosagem , Ticagrelor/efeitos adversos , Ticagrelor/uso terapêutico , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/mortalidade , Feminino , Masculino , Idoso , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/uso terapêutico , Pessoa de Meia-Idade , Resultado do Tratamento , Fatores de Tempo , Fatores de Risco , Infarto do Miocárdio/mortalidade , Doença Crônica , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Necrose , Medição de Risco , Doença da Artéria Coronariana/terapia , Doença da Artéria Coronariana/mortalidade , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/tratamento farmacológico , Stents , Hemorragia/induzido quimicamente
8.
Vet Q ; 44(1): 1-8, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38823415

RESUMO

Dogs that had splenectomy are predisposed to fatal thrombotic conditions, and thrombocytosis is a risk factor for post-splenectomy hypercoagulability. However, in veterinary medicine, there are no specific therapeutic approaches for managing this hypercoagulability. This study aimed to determine the preventive effect of clopidogrel on post-operative hypercoagulability during the first 2 weeks post-splenectomy in dogs with splenic masses. This study included 12 dogs that had splenectomy. Seven dogs received no treatment (group A), and five were treated with clopidogrel (group B). Clopidogrel was loaded at 10 mg/kg on day 2 and continued at 2 mg/kg until day 14. Blood samples were collected on the day of surgery and 2, 7, and 14 days after splenectomy in both groups. In group B, thromboelastography (TEG) was performed on the same days. In group A, there was significant elevation of platelet counts on days 7 (p = 0.007) and 14 (p = 0.001) compared to day 0. In group B, the platelet counts were significantly elevated on day 7 (p = 0.032) but no significant difference was found on day 14 compared to day 0. Platelet counts on day 14 were significantly higher in group A than in group B (p = 0.03). The lower platelet counts were correlated with alterations in TEG parameters, and no significant differences were found in the K and α-angle values at all postoperative assessment points compared to day 0. Our study suggests that clopidogrel may reduce post-operative thrombocytosis and hypercoagulability in dogs that undergo splenectomy for splenic masses.


Assuntos
Clopidogrel , Doenças do Cão , Inibidores da Agregação Plaquetária , Esplenectomia , Tromboelastografia , Trombofilia , Animais , Cães , Esplenectomia/veterinária , Esplenectomia/efeitos adversos , Clopidogrel/uso terapêutico , Doenças do Cão/sangue , Doenças do Cão/cirurgia , Doenças do Cão/tratamento farmacológico , Contagem de Plaquetas/veterinária , Feminino , Masculino , Trombofilia/veterinária , Trombofilia/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Inibidores da Agregação Plaquetária/farmacologia , Tromboelastografia/veterinária , Complicações Pós-Operatórias/veterinária , Complicações Pós-Operatórias/prevenção & controle , Neoplasias Esplênicas/veterinária , Neoplasias Esplênicas/cirurgia , Neoplasias Esplênicas/sangue , Esplenopatias/veterinária , Esplenopatias/cirurgia , Esplenopatias/sangue , Trombocitose/veterinária
9.
Clin Transl Sci ; 17(6): e13862, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38877696

RESUMO

This cohort study aims to assess the connection between cytochrome P450 family 2 subfamily C member 19 (CYP2C19) genotyping, platelet aggregability following oral clopidogrel administration, and the occurrence of postoperative atrial fibrillation (POAF) after off-pump coronary artery bypass graft (CABG) surgery. From May 2017 to November 2022, a total of 258 patients undergoing elective first-time CABG surgery, receiving 100 mg/day oral aspirin and 75 mg/day oral clopidogrel postoperatively, was included for analysis. These patients were categorized based on CYP2C19 genotyping. Platelet aggregability was assessed serially using multiple-electrode aggregometry before CABG, 1 and 5 days after the procedure, and before discharge. The incidences of POAF were compared using the log-rank test for cumulative risk. CYP2C19 genotyping led to categorization into CYP2C19*1*1 (WT group, n = 123) and CYP2C19*2 or *3 (LOF group, n = 135). Baseline characteristics and operative data showed no significant differences between the two groups. The incidence of POAF after CABG was 42.2% in the LOF group, contrasting with 22.8% in the WT group (hazard risk [HR]: 2.061; 95% confidence interval [CI]: 1.347, 3.153; p = 0.0013). Adenosine diphosphate-stimulated platelet aggregation was notably higher in the LOF group compared to the WT group 5 days after CABG (30.4% ± 6.5% vs. 17.9% ± 4.1%, p < 0.001), remaining a similar higher level at hospital discharge (25.6% ± 6.1% vs. 12.2% ± 3.5%, p < 0.001). The presence of CYP2C19 LOF was linked to a higher incidence of POAF and relatively elevated platelet aggregation after CABG surgery under the same oral clopidogrel regimen.


Assuntos
Fibrilação Atrial , Clopidogrel , Ponte de Artéria Coronária , Citocromo P-450 CYP2C19 , Genótipo , Inibidores da Agregação Plaquetária , Agregação Plaquetária , Complicações Pós-Operatórias , Humanos , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Fibrilação Atrial/etiologia , Fibrilação Atrial/genética , Fibrilação Atrial/epidemiologia , Masculino , Feminino , Idoso , Ponte de Artéria Coronária/efeitos adversos , Pessoa de Meia-Idade , Clopidogrel/administração & dosagem , Clopidogrel/efeitos adversos , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/epidemiologia , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/efeitos adversos , Agregação Plaquetária/efeitos dos fármacos , Incidência , Aspirina/administração & dosagem , Aspirina/efeitos adversos
11.
J Am Heart Assoc ; 13(12): e033791, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38874073

RESUMO

BACKGROUND: Cytochrome P450 2C19 (CYP2C19) intermediate and poor metabolizer patients exhibit diminished clopidogrel clinical effectiveness after percutaneous coronary intervention (PCI). However, outcome studies to date have lacked racial diversity. Thus, the impact of CYP2C19 genotype on cardiovascular outcomes in patients treated with clopidogrel who identify as Black or African American remains unclear. METHODS AND RESULTS: Adults among 5 institutions who self-identified as Black or African American, underwent PCI and clinical CYP2C19 genotyping, and were treated with clopidogrel were included. Data were abstracted from health records. Major atherothrombotic (composite of death, myocardial infarction, ischemic stroke, stent thrombosis, or revascularization for unstable angina) and bleeding event rates within 1 year after PCI were compared across CYP2C19 metabolizer groups using multivariable Cox regression adjusted for potential confounders and baseline variables meeting a threshold of P<0.10. The population included 567 Black patients treated with clopidogrel (median age, 62 years; 46% women; 70% with an acute coronary syndrome indication for PCI). Major atherothrombotic events rates were significantly higher among clopidogrel-treated intermediate and poor metabolizers (24 of 125 [19.2%]) versus patients treated with clopidogrel without a no function allele (43 of 442 [9.7%]; 35.1 versus 15.9 events per 100 person-years; adjusted hazard ratio, 2.00 [95% CI, 1.20-3.33], P=0.008). Bleeding event rates were low overall (23 of 567 [4.1%]) and did not differ among the metabolizer groups. CONCLUSIONS: Black patients with CYP2C19 intermediate and poor metabolizer phenotypes who are treated with clopidogrel exhibit increased risk of adverse cardiovascular outcomes after PCI in a real-world clinical setting. Bleeding outcomes should be interpreted cautiously. Prospective studies are needed to determine whether genotype-guided use of prasugrel or ticagrelor in intermediate and poor metabolizers improves outcomes in Black patients undergoing PCI.


Assuntos
Negro ou Afro-Americano , Clopidogrel , Citocromo P-450 CYP2C19 , Hemorragia , Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome Coronariana Aguda/tratamento farmacológico , Síndrome Coronariana Aguda/etnologia , Síndrome Coronariana Aguda/terapia , Negro ou Afro-Americano/genética , Clopidogrel/efeitos adversos , Clopidogrel/uso terapêutico , Doença da Artéria Coronariana/etnologia , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/terapia , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Genótipo , Hemorragia/induzido quimicamente , Hemorragia/genética , Variantes Farmacogenômicos , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/uso terapêutico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Resultado do Tratamento
12.
J Int Med Res ; 52(6): 3000605241258474, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38901839

RESUMO

The gold standard therapy for end-stage heart failure is cardiac transplantation. However, in the face of a donor shortage, a mechanical assist device such as the left ventricular assist device HeartMate 3 (Abbott Laboratories, Abbott Park, IL, USA) serves as bridging therapy to transplantation and/or destination therapy. Current guidelines recommend anticoagulation with a vitamin K antagonist in combination with low-dose aspirin. We herein report a challenging anticoagulation regimen in a patient with a HeartMate 3 in whom systemic anticoagulation with warfarin was not feasible for 4 years because of low compatibility and a rare X-factor deficiency. This is a rare hematological disorder, estimated to affect approximately 1 in every 500,000 to 1,000,000 people in the general population. The patient finally received a modified anticoagulation regimen involving the combination of rivaroxaban and clopidogrel without warfarin. Under this regimen, the patient remained free of thromboembolic complications for 4 years with in situ placement of the left ventricular assist device. This case illustrates that under specific circumstances, long-term absence of warfarin therapy is feasible in patients with a HeartMate 3.


Assuntos
Anticoagulantes , Coração Auxiliar , Tromboembolia , Varfarina , Humanos , Coração Auxiliar/efeitos adversos , Varfarina/uso terapêutico , Varfarina/administração & dosagem , Tromboembolia/etiologia , Tromboembolia/prevenção & controle , Anticoagulantes/uso terapêutico , Anticoagulantes/administração & dosagem , Masculino , Insuficiência Cardíaca/cirurgia , Pessoa de Meia-Idade , Clopidogrel/administração & dosagem , Clopidogrel/uso terapêutico , Clopidogrel/efeitos adversos , Rivaroxabana/administração & dosagem , Rivaroxabana/uso terapêutico , Suspensão de Tratamento
13.
BMC Med Genomics ; 17(1): 166, 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38902747

RESUMO

BACKGROUND: Mediators, genomic and epigenomic characteristics involving in metabolism of arachidonic acid by cyclooxygenase (COX) and lipoxygenase (ALOX) and hepatic activation of clopidogrel have been individually suggested as factors associated with resistance against aspirin and clopidogrel. The present multi-center prospective cohort study evaluated whether the mediators, genomic and epigenomic characteristics participating in arachidonic acid metabolism and clopidogrel activation could be factors that improve the prediction of the aspirin and clopidogrel resistance in addition to cardiovascular risks. METHODS: We enrolled 988 patients with transient ischemic attack and ischemic stroke who were evaluated for a recurrence of ischemic stroke to confirm clinical resistance, and measured aspirin (ARU) and P2Y12 reaction units (PRU) using VerifyNow to assess laboratory resistance 12 weeks after aspirin and clopidogrel administration. We investigated whether mediators, genotypes, and promoter methylation of genes involved in COX and ALOX metabolisms and clopidogrel activation could synergistically improve the prediction of ischemic stroke recurrence and the ARU and PRU levels by integrating to the established cardiovascular risk factors. RESULTS: The logistic model to predict the recurrence used thromboxane A synthase 1 (TXAS1, rs41708) A/A genotype and ALOX12 promoter methylation as independent variables, and, improved sensitivity of recurrence prediction from 3.4% before to 13.8% after adding the mediators, genomic and epigenomic variables to the cardiovascular risks. The linear model we used to predict the ARU level included leukotriene B4, COX2 (rs20417) C/G and thromboxane A2 receptor (rs1131882) A/A genotypes with the addition of COX1 and ALOX15 promoter methylations as variables. The linear PRU prediction model included G/A and prostaglandin I receptor (rs4987262) G/A genotypes, COX2 and TXAS1 promoter methylation, as well as cytochrome P450 2C19*2 (rs4244285) A/A, G/A, and *3 (rs4986893) A/A genotypes as variables. The linear models for predicting ARU (r = 0.291, R2 = 0.033, p < 0.01) and PRU (r = 0.503, R2 = 0.210, p < 0.001) levels had improved prediction performance after adding the genomic and epigenomic variables to the cardiovascular risks. CONCLUSIONS: This study demonstrates that different mediators, genomic and epigenomic characteristics of arachidonic acid metabolism and clopidogrel activation synergistically improved the prediction of the aspirin and clopidogrel resistance together with the cardiovascular risk factors. TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov ; Unique identifier: NCT03823274.


Assuntos
Aspirina , Clopidogrel , Resistência a Medicamentos , Humanos , Clopidogrel/uso terapêutico , Clopidogrel/farmacologia , Masculino , Feminino , Aspirina/uso terapêutico , Aspirina/farmacologia , Resistência a Medicamentos/genética , Pessoa de Meia-Idade , Idoso , Epigenômica , Genômica , Estudos Prospectivos , Inibidores da Agregação Plaquetária/uso terapêutico , Inibidores da Agregação Plaquetária/farmacologia , Metilação de DNA/efeitos dos fármacos
14.
Stroke ; 55(7): 1739-1747, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38860396

RESUMO

BACKGROUND: The atherosclerotic sources of embolism are a significant contributor to embolic stroke of undetermined source (ESUS). However, there is limited evidence for the efficacy of intensive dual antiplatelet therapy for ESUS. We conducted an investigation to determine whether gene-directed dual antiplatelet therapy could reduce the risk of recurrent stroke in patients with ESUS. METHODS: CHANCE-2 (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events-II) was an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial that objectively compared ticagrelor plus aspirin and clopidogrel plus aspirin in patients with minor stroke or transient ischemic attack who carried CYP2C19 loss-of-function alleles in China. All study participants were classified into ESUS and non-ESUS groups for the prespecified exploratory analysis. Cox proportional hazards models were used to assess the interaction of the state of ESUS with the effects of dual antiplatelet therapy with ticagrelor-aspirin versus clopidogrel-aspirin, adjusting for sociodemographic and clinical factors. RESULTS: The subgroup analysis comprised 5796 participants (90.4% of the total 6412 participants) in the CHANCE-2 trial, with a median age of 64.9 years (range, 57.0-71.4 years), of whom 1964 (33.9%) were female. These participants underwent diffusion-weighted imaging as part of the study protocol. After systematic evaluation, 15.2% of patients (881/5796) were deemed to have ESUS. The incidence of stroke recurrence in patients with ESUS was found to be 5.6% in the ticagrelor-aspirin group and 9.2% in the clopidogrel-aspirin group (hazard ratio, 0.57 [95% CI, 0.33-0.99]; P=0.04). In patients without ESUS, the respective incidence rates were 5.6% and 7.5% (hazard ratio, 0.72 [95% CI, 0.58-0.90]; P<0.01). The P value was 0.56 for the treatment × ESUS status interaction effect. CONCLUSIONS: In this prespecified exploratory analysis, ticagrelor with aspirin was superior to clopidogrel with aspirin for preventing stroke at 90 days in patients with acute ischemic stroke or transient ischemic attack who carried CYP2C19 loss-of-function alleles and were classified as ESUS. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04078737.


Assuntos
Aspirina , Clopidogrel , Terapia Antiplaquetária Dupla , AVC Embólico , Inibidores da Agregação Plaquetária , Ticagrelor , Humanos , Pessoa de Meia-Idade , Feminino , Masculino , Inibidores da Agregação Plaquetária/uso terapêutico , Idoso , Clopidogrel/uso terapêutico , Aspirina/uso terapêutico , Ticagrelor/uso terapêutico , Método Duplo-Cego , Terapia Antiplaquetária Dupla/métodos , AVC Embólico/tratamento farmacológico , AVC Embólico/etiologia , Citocromo P-450 CYP2C19/genética , Acidente Vascular Cerebral/tratamento farmacológico
15.
BMC Pharmacol Toxicol ; 25(1): 34, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38845014

RESUMO

Antiplatelet therapy is an important factor influencing the postterm patency rate of carotid artery stenting (CAS). Clopidogrel is a platelet aggregation inhibitor mediated by the adenosine diphosphate receptor and is affected by CYP2C19 gene polymorphisms in vivo. When the CYP2C19 gene has a nonfunctional mutation, the activity of the encoded enzyme will be weakened or lost, which directly affects the metabolism of clopidogrel and ultimately weakens its antiplatelet aggregation ability. Therefore, based on network pharmacology, analyzing the influence of CYP2C19 gene polymorphisms on the antiplatelet therapeutic effect of clopidogrel after CAS is highly important for the formulation of individualized clinical drug regimens. The effect of the CYP2C19 gene polymorphism on the antiplatelet aggregation of clopidogrel after CAS was analyzed based on network pharmacology. A total of 100 patients with ischemic cerebrovascular disease who were confirmed by the neurology department and required CAS treatment were studied. CYP2C19 genotyping was performed on all patients via a gene chip. All patients were classified into the wild-type (WT) group (*1/*1), heterozygous mutation (HTM) group (CYP2C19*1/*2, CYP2C19*1/*3), and homozygous mutation (HMM) group (CYP2C19*2/*2, CYP2C19*2/*3, and CYP2C19*3/*3). High-performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS) was used to detect the blood concentration of clopidogrel and the plasma clopidogrel clearance (CL) rate in different groups of patients before and after clopidogrel treatment. The platelet aggregation rate of patients with different genotypes was measured by turbidimetry. The incidences of clopidogrel resistance (CR) and stent thrombosis in different groups after three months of treatment were analyzed. The results showed that among the different CYP2C19 genotypes, patients from the HTM group accounted for the most patients, while patients from the HTM group accounted for the least patients. Similarly, the clopidogrel CL of patients in the HMM group was lower than that of patients in the WT group and HTM group (P < 0.01). The platelet inhibition rate of patients in the HMM group was evidently inferior to that of patients in the WT group and HTM group (P < 0.01). The incidence of CR and stent thrombosis in the WT group was notably lower than that in the HTM and HMM groups (P < 0.01). These results indicate that the CYP2C19 gene can affect CR occurrence and stent thrombosis after CAS by influencing clopidogrel metabolism and platelet count.


Assuntos
Clopidogrel , Citocromo P-450 CYP2C19 , Inibidores da Agregação Plaquetária , Agregação Plaquetária , Stents , Humanos , Citocromo P-450 CYP2C19/genética , Clopidogrel/uso terapêutico , Clopidogrel/farmacologia , Clopidogrel/farmacocinética , Inibidores da Agregação Plaquetária/uso terapêutico , Inibidores da Agregação Plaquetária/farmacologia , Inibidores da Agregação Plaquetária/farmacocinética , Masculino , Feminino , Agregação Plaquetária/efeitos dos fármacos , Idoso , Pessoa de Meia-Idade , Polimorfismo Genético , Ticlopidina/análogos & derivados , Ticlopidina/uso terapêutico , Ticlopidina/farmacologia , Genótipo , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/cirurgia
16.
PLoS One ; 19(6): e0304800, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38924073

RESUMO

BACKGROUND: Despite Antiplatelet therapy (APT), cardiovascular patients undergoing revascularisation remain at high risk for thrombotic events. Individual response to APT varies substantially, resulting in insufficient protection from thrombotic events due to high on-treatment platelet reactivity (HTPR) in ≤40% of patients. Individual variation in platelet response impairs APT guidance on a single patient level. Unfortunately, little is known about individual platelet response to APT over time, timing for accurate residual platelet reactivity measurement, or the optimal test to monitor residual platelet reactivity. AIMS: To investigate residual platelet reactivity variability over time in individual patients undergoing carotid endarterectomy (CEA) treated with clopidogrel. METHODS: Platelet reactivity was determined in patients undergoing CEA in a prospective, single-centre, observational study using the VerifyNow (change in turbidity from ADP-induced binding to fibrinogen-coated beads), the VASP assay (quantification of phosphorylation of vasodilator-stimulated phosphoprotein), and a flow-cytometry-based assay (PACT) at four perioperative time points. Genotyping identified slow (CYP2C19*2 and CYP2C19*3) and fast (CYP2C19*17) metabolisers. RESULTS: Between December 2017 and November 2019, 50 patients undergoing CEA were included. Platelet reactivity measured with the VerifyNow (p = < .001) and VASP (p = .029) changed over time, while the PACT did not. The VerifyNow identified patients changing HTRP status after surgery. The VASP identified patients changing HTPR status after eight weeks (p = .018). CYP2C19 genotyping identified 13 slow metabolisers. CONCLUSION: In patients undergoing CEA, perioperative platelet reactivity measurements fluctuate over time with little agreement between platelet reactivity assays. Consequently, HTPR status of individual patients measured with the VerifyNow and VASP assay changed over time. Therefore, generally used perioperative platelet reactivity measurements seem unreliable for adjusting perioperative APT strategy.


Assuntos
Plaquetas , Clopidogrel , Endarterectomia das Carótidas , Inibidores da Agregação Plaquetária , Humanos , Masculino , Feminino , Idoso , Projetos Piloto , Plaquetas/metabolismo , Estudos Prospectivos , Inibidores da Agregação Plaquetária/uso terapêutico , Inibidores da Agregação Plaquetária/farmacologia , Clopidogrel/uso terapêutico , Testes de Função Plaquetária/métodos , Pessoa de Meia-Idade , Período Perioperatório , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Procedimentos Cirúrgicos Vasculares , Ativação Plaquetária/efeitos dos fármacos , Idoso de 80 Anos ou mais , Moléculas de Adesão Celular/metabolismo , Moléculas de Adesão Celular/sangue , Proteínas dos Microfilamentos/metabolismo , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/sangue
17.
Genes (Basel) ; 15(5)2024 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-38790236

RESUMO

A recently discovered haplotype-CYP2C:TG-determines the ultrarapid metabolism of several CYP2C19 substrates. The platelet inhibitor clopidogrel requires CYP2C19-mediated activation: the risk of ischemic events is increased in patients with a poor (PM) or intermediate (IM) CYP2C19 metabolizer phenotype (vs. normal, NM; rapid, RM; or ultrarapid, UM). We investigated whether the CYP2C:TG haplotype affected efficacy/bleeding risk in clopidogrel-treated patients. Adults (n = 283) treated with clopidogrel over 3-6 months were classified by CYP2C19 phenotype based on the CYP2C19*2*17 genotype, and based on the CYP2C19/CYP2C cluster genotype, and regarding carriage of the CYP2:TG haplotype, and were balanced on a number of covariates across the levels of phenotypes/haplotype carriage. Overall, 45 (15.9%) patients experienced ischemic events, and 49 (17.3%) experienced bleedings. By either classification, the incidence of ischemic events was similarly numerically higher in PM/IM patients (21.6%, 21.8%, respectively) than in mutually similar NM, RM, and UM patients (13.2-14.8%), whereas the incidence of bleeding events was numerically lower (13.1% vs. 16.6-20.5%). The incidence of ischemic events was similar in CYP2C:TG carries and non-carries (14.1% vs. 16.1%), whereas the incidence of bleedings appeared mildly lower in the former (14.9% vs. 20.1%). We observed no signal to suggest a major effect of the CYP2C19/CYP2C cluster genotype or CYP2C:TG haplotype on the clinical efficacy/safety of clopidogrel.


Assuntos
Clopidogrel , Citocromo P-450 CYP2C19 , Haplótipos , Hemorragia , Inibidores da Agregação Plaquetária , Humanos , Clopidogrel/efeitos adversos , Clopidogrel/uso terapêutico , Masculino , Feminino , Citocromo P-450 CYP2C19/genética , Hemorragia/induzido quimicamente , Hemorragia/genética , Idoso , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/uso terapêutico , Genótipo , Ticlopidina/análogos & derivados , Ticlopidina/efeitos adversos , Ticlopidina/uso terapêutico
18.
Clin Neurol Neurosurg ; 242: 108326, 2024 07.
Artigo em Inglês | MEDLINE | ID: mdl-38772278

RESUMO

OBJECTIVES: 1.To explore the incidence of concurrent gouty arthritis (GA) during hospitalization in patients with different subtypes of acute stroke. 2.To investigate disparities in acute cerebral infarction patients with coexisting GA undergoing various antiplatelet strategies. MATERIALS AND METHODS: Data from acute stroke patients admitted to the Affiliated Panyu Central Hospital of Guangzhou Medical University, from January 2019 to December 2021, underwent screening. The incidence of GA in acute stroke patients of various subtypes were analyzed. Subsequently, we divided cerebral infarction cases into three cohorts based on distinct antiplatelet therapies: the aspirin group, the dual antiplatelet therapy group (DAPT,aspirin plus clopidogrel), and the clopidogrel group. Investigate disparities in acute cerebral infarction patients with coexisting GA undergoing various antiplatelet strategies. RESULTS: A total of 12,381 patients with acute stroke were screened in this study. The incidence of GA in various subtypes of acute stroke was as follows: cerebral infarction (3.56 %, n = 9890), TIA (1.81 %, n = 443), cerebral hemorrhag (0.64 %, n = 1713), and SAH (0.30 %, n = 335). The incidence of GA in patients with ischemic stroke is higher than that of hemorrhagic stroke (χ2 = 49.258, p<0.001). No significant differences were observed in the incidence of GA among three different antiplatelet therapy groups. But there was marginal statistical difference in the incidence of GA between the aspirin group and the DAPT group (P = 0.051), as well as between the clopidogrel group and the DAPT group (P = 0.059). CONCLUSIONS: The incidence of GA in patients with ischemic stroke is higher than that of hemorrhagic stroke. No significant differences were observed in the incidence of GA in acute cerebral infarction across various antiplatelet Strategies. The marginal statistical difference in the incidence of GA between the single antiplatelet group and the DAPT group requires further investigation.


Assuntos
Artrite Gotosa , Aspirina , Infarto Cerebral , Clopidogrel , Hospitalização , Inibidores da Agregação Plaquetária , Humanos , Masculino , Inibidores da Agregação Plaquetária/uso terapêutico , Feminino , Pessoa de Meia-Idade , Infarto Cerebral/epidemiologia , Incidência , Idoso , Artrite Gotosa/epidemiologia , Aspirina/uso terapêutico , Clopidogrel/uso terapêutico , Terapia Antiplaquetária Dupla/métodos , Idoso de 80 Anos ou mais
19.
J Am Heart Assoc ; 13(9): e034414, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38700032

RESUMO

BACKGROUND: Over the past decade, major society guidelines have recommended the use of newer P2Y12 inhibitors over clopidogrel for those undergoing percutaneous coronary intervention for acute coronary syndrome. It is unclear what impact these recommendations had on clinical practice. METHODS AND RESULTS: All percutaneous coronary intervention procedures (n=534 210) for acute coronary syndrome in England and Wales (April 1, 2010, to March 31, 2022) were retrospectively analyzed, stratified by choice of preprocedural P2Y12 inhibitor (clopidogrel, ticagrelor, and prasugrel). Multivariable logistic regression models were used to examine odds ratios of receipt of ticagrelor and prasugrel (versus clopidogrel) over time, and predictors of their receipt. Overall, there was a significant increase in receipt of newer P2Y12 inhibitors from 2010 to 2020 (2022 versus 2010: ticagrelor odds ratio, 8.12 [95% CI, 7.67-8.60]; prasugrel odds ratio, 6.14 [95% CI, 5.53-6.81]), more so in ST-segment-elevation myocardial infarction than non-ST-segment-elevation acute coronary syndrome indication. The most significant increase in odds of receipt of prasugrel was observed between 2020 and 2022 (P<0.001), following a decline/plateau in its use in earlier years (2011-2019). In contrast, the odds of receipt of ticagrelor significantly increased in earlier years (2012-2017, Ptrend<0.001), after which the trend was stable (Ptrend=0.093). CONCLUSIONS: Over a 13-year-period, there has been a significant increase in use of newer P2Y12 inhibitors, although uptake of prasugrel use remained significantly lower than ticagrelor. Earlier society guidelines (pre-2017) were associated with the highest rates of ticagrelor use for non-ST-segment-elevation acute coronary syndrome and ST-segment-elevation myocardial infarction cases while the ISAR-REACT 5 (Prospective, Randomized Trial of Ticagrelor Versus Prasugrel in Patients With Acute Coronary Syndrome) trial and later society guidelines were associated with higher prasugrel use, mainly for ST-segment-elevation myocardial infarction indication.


Assuntos
Síndrome Coronariana Aguda , Clopidogrel , Intervenção Coronária Percutânea , Guias de Prática Clínica como Assunto , Cloridrato de Prasugrel , Antagonistas do Receptor Purinérgico P2Y , Ticagrelor , Humanos , Síndrome Coronariana Aguda/tratamento farmacológico , Síndrome Coronariana Aguda/cirurgia , Síndrome Coronariana Aguda/terapia , Intervenção Coronária Percutânea/tendências , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Masculino , Feminino , Ticagrelor/uso terapêutico , Cloridrato de Prasugrel/uso terapêutico , Idoso , Pessoa de Meia-Idade , Estudos Retrospectivos , País de Gales , Clopidogrel/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Padrões de Prática Médica/tendências , Inglaterra , Fidelidade a Diretrizes/tendências , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Infarto do Miocárdio sem Supradesnível do Segmento ST/tratamento farmacológico , Infarto do Miocárdio sem Supradesnível do Segmento ST/cirurgia , Infarto do Miocárdio sem Supradesnível do Segmento ST/terapia , Fatores de Tempo , Resultado do Tratamento
20.
J Am Heart Assoc ; 13(10): e032248, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38761068

RESUMO

BACKGROUND: Carriers of CYP2C19 loss-of-function alleles have increased adverse events after percutaneous coronary intervention, but limited data are available for older patients. We aimed to evaluate the prognostic impact of CYP2C19 genotypes on clinical outcomes in older patients after percutaneous coronary intervention. METHODS AND RESULTS: The study included 1201 older patients (aged ≥75 years) who underwent percutaneous coronary intervention and received clopidogrel-based dual antiplatelet therapy in South Korea. Patients were grouped on the basis of CYP2C19 genotypes. The primary outcome was 3-year major adverse cardiac events, defined as a composite of cardiac death, myocardial infarction, and stent thrombosis. Older patients were grouped into 3 groups: normal metabolizer (36.6%), intermediate metabolizer (48.1%), and poor metabolizer (15.2%). The occurrence of the primary outcome was significantly different among the groups (3.1, 7.0, and 6.2% in the normal metabolizer, intermediate metabolizer, and poor metabolizer groups, respectively; P=0.02). The incidence rate of all-cause death at 3 years was greater in the intermediate metabolizer and poor metabolizer groups (8.1% and 9.2%, respectively) compared with that in the normal metabolizer group (3.5%, P=0.03) without significant differences in major bleeding. In the multivariable analysis, the intermediate metabolizer and poor metabolizer groups were independent predictors of 3-year clinical outcomes. CONCLUSIONS: In older patients, the presence of any CYP2C19 loss-of-function allele was found to be predictive of a higher incidence of major adverse cardiac events within 3 years following percutaneous coronary intervention. This finding suggests a need for further investigation into an optimal antiplatelet strategy for older patients. REGISTRATION: URL: https://clinicaltrials.gov. Identifier: NCT04734028.


Assuntos
Clopidogrel , Citocromo P-450 CYP2C19 , Genótipo , Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária , Humanos , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Intervenção Coronária Percutânea/efeitos adversos , Masculino , Feminino , Idoso , Inibidores da Agregação Plaquetária/farmacocinética , Inibidores da Agregação Plaquetária/uso terapêutico , Inibidores da Agregação Plaquetária/efeitos adversos , República da Coreia/epidemiologia , Clopidogrel/farmacocinética , Clopidogrel/uso terapêutico , Clopidogrel/efeitos adversos , Idoso de 80 Anos ou mais , Prognóstico , Resultado do Tratamento , Fatores de Tempo , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/cirurgia , Doença da Artéria Coronariana/mortalidade , Doença da Artéria Coronariana/terapia , Fatores de Risco , Terapia Antiplaquetária Dupla/efeitos adversos , Medição de Risco , Fatores Etários , Infarto do Miocárdio/genética , Infarto do Miocárdio/epidemiologia , Variantes Farmacogenômicos
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