RESUMEN
Switching P2Y12 inhibitors is common in clinical practice. However, data on the pharmacodynamic (PD) effects of switching in clinical settings characterized by high platelet reactivity, such as diabetes mellitus (DM), are limited. This is a post-hoc analysis from a prospective, randomized, open-label study conducted in coronary artery disease patients comparing the PD effects of loading dose (LD) and maintenance dose regimens of prasugrel vs ticagrelor according to DM status. A total of 110 patients were enrolled: 42 (38%) with DM and 68 (62%) without DM. All patients were on maintenance dual antiplatelet therapy with aspirin and clopidogrel. PD assessments were performed using whole blood vasodilator-stimulated phosphoprotein (VASP), with results quantified by the platelet reactivity index (PRI), VerifyNow P2Y12 (VN-P2Y12) with results reported as P2Y12 reaction units (PRU), and light transmittance aggregometry (LTA) following 20 and 5 µM adenosine diphosphate stimuli with results reported as maximum platelet aggregation (MPA). PD assessments were performed at baseline (while on clopidogrel), 30 min after LD, 2 h after LD, and 1 week after LD. Overall, platelet reactivity was higher in DM than in non-DM patients while on clopidogrel therapy. After switching to either prasugrel or ticagrelor, platelet reactivity dropped but remained significantly higher among patients with DM at 30 min with all tests (VN-PRU p < 0.01, MPA 20 µM p < 0.01, VASP-PRI p = 0.02) and at 2 h with VN-PRU (p < 0.01) and LTA-MPA 20 µM (p < 0.01) but not with VASP-PRI (p = 0.19). There were no significant differences between prasugrel and ticagrelor both among patients with or without DM, except for lower LTA-MPA 20 at 30 min (p < 0.01) among non-DM patients treated with prasugrel. Patients with DM treated with clopidogrel have higher platelet reactivity compared to patients without DM. Although platelet reactivity markedly reduces to a similar extent after switching to prasugrel or ticagrelor, patients with DM persist with increased platelet reactivity compared to patients without DM.Study registration: ClinicalTrials.gov identifier: NCT01852175.
Asunto(s)
Enfermedad de la Arteria Coronaria , Diabetes Mellitus , Adenosina , Adenosina Difosfato/farmacología , Aspirina/uso terapéutico , Plaquetas , Clopidogrel/farmacología , Clopidogrel/uso terapéutico , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Diabetes Mellitus/tratamiento farmacológico , Humanos , Agregación Plaquetaria , Inhibidores de Agregación Plaquetaria , Pruebas de Función Plaquetaria , Clorhidrato de Prasugrel , Estudios Prospectivos , Ticagrelor/farmacología , Ticagrelor/uso terapéuticoRESUMEN
Low dose enteric-coated aspirin (EC-ASA) is routinely used for secondary cardiovascular event prevention. However, absorption of EC tablets is poor, which can result in subtherapeutic antiplatelet effects. Phospholipid-aspirin liquid filled capsules (PL-ASA) are a novel FDA-approved immediate-release formulation designed to reduce gastrointestinal (GI) injury by limiting direct contact with the stomach lining. We compared the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of PL-ASA versus EC-ASA at a low dose. This randomized, open-label, crossover study assessed PK and PD following a single 81-mg dose of PL-ASA versus EC-ASA under fasting conditions in 36 volunteers without cardiovascular disease between 18 and 75 years of age. Volunteers were randomly assigned 1:1 to either PL-ASA then EC-ASA or vice versa with a minimum 14-day washout. Assessments included PK parameters for acetylsalicylic acid and salicylic acid, platelet aggregation in response to arachidonic acid (AA), and serum thromboxane B2 (TxB2) assessments over 24 h. PL-ASA was rapidly absorbed. PL-ASA reached Tmax 3 h earlier (1.01 vs. 4.00 h, p < 0.0001), with almost double the Cmax (720 vs. 368 ng/mL, p < 0.0001) and overall 44% higher exposure of acetylsalicylic acid (AUC0-t: 601 vs. 416 h*ng/mL, p = 0.0013) compared with EC-ASA. Within 1 h of dosing, PL-ASA achieved significantly lower residual platelet aggregation, which persisted for the full 24 h (median AA-LTA was 47% with PL-ASA vs. 80.5% with EC-ASA; p = 0.0022 at hour-24). Treatment with PL-ASA also resulted in significantly lower serum TxB2 concentrations at each time point compared with EC-ASA (all p-values < 0.05). PL-ASA resulted in faster and more complete aspirin absorption paralleled by more prompt and potent platelet inhibition compared with EC-ASA after a single 81 mg dose. PL-ASA represents an attractive novel aspirin formulation for the secondary prevention of cardiovascular events.Clinical Trial Registration ClinicalTrials.gov identifier: NCT04811625.
Asunto(s)
Aspirina , Inhibidores de Agregación Plaquetaria , Ácido Araquidónico , Aspirina/farmacocinética , Aspirina/farmacología , Cápsulas , Estudios Cruzados , Humanos , Fosfolípidos , Inhibidores de Agregación Plaquetaria/farmacocinética , Inhibidores de Agregación Plaquetaria/farmacología , Estudios Prospectivos , Ácido Salicílico , Comprimidos , Tromboxano B2RESUMEN
Prasugrel and ticagrelor are potent oral platelet P2Y12 inhibitors and are recommended over clopidogrel in patients with acute coronary syndrome (ACS). Oral platelet P2Y12 inhibitors are characterized by varying degrees of pharmacodynamic response profiles as assessed by a variety of commercially available assays. Because of its ease of use, rapid turnaround times and ability to provide results specific to P2Y12 inhibitory effects, VerifyNow has emerged as one of the most commonly utilized platelet function assays. However, reference ranges with VerifyNow have been reported mainly for clopidogrel and there has not yet been any study specifically conducted to provide the expected on treatment reference ranges following administration of prasugrel and ticagrelor. This was a prospective single center investigation conducted in 120 patients with ACS who were treated with prasugrel or ticagrelor as per standard of care. Patients who underwent percutaneous coronary interventions (PCI) were treated with a loading dose of prasugrel (60 mg) or ticagrelor (180 mg), and patients who were on maintenance therapy were taking prasugrel (10 mg qd or 5 mg qd) or ticagrelor (90 mg bid). Platelet function testing was performed using the VerifyNow™ PRUTest™. The overall range of PRUTest values was lower than that observed in studies of patients treated with clopidogrel. The use of a maintenance dose regimen had a wider range of PRUTest values compared to the use of a loading dose for both prasugrel (1-179 vs. 2-128) and ticagrelor (1-196 vs. 1-177). The average PRUTest values in patients on prasugrel and ticagrelor maintenance dosing were 20% and 9% higher those observed in patients treated with a loading dose. PRUTest results following loading dose administration were very similar between drugs, but were 20% higher with prasugrel compared with ticagrelor during maintenance dosing. This study establishes expected PRUTest ranges for patients taking loading and maintenance doses of prasugrel and ticagrelor.Clinical Trial Registration http://www.clinicaltrials.gov Unique Identifier: NCT04492423, registered July 2020 retrospectively registered.
Asunto(s)
Isquemia Miocárdica , Pruebas de Función Plaquetaria/métodos , Pruebas en el Punto de Atención , Clorhidrato de Prasugrel , Ticagrelor , Relación Dosis-Respuesta a Droga , Monitoreo de Drogas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Isquemia Miocárdica/sangre , Isquemia Miocárdica/diagnóstico , Isquemia Miocárdica/terapia , Evaluación de Procesos y Resultados en Atención de Salud , Intervención Coronaria Percutánea/efectos adversos , Intervención Coronaria Percutánea/métodos , Agregación Plaquetaria/efectos de los fármacos , Clorhidrato de Prasugrel/administración & dosificación , Clorhidrato de Prasugrel/farmacocinética , Estudios Prospectivos , Antagonistas del Receptor Purinérgico P2Y/administración & dosificación , Antagonistas del Receptor Purinérgico P2Y/farmacocinética , Ticagrelor/administración & dosificación , Ticagrelor/farmacocinéticaRESUMEN
BACKGROUND: The platelet inhibitory effects induced by oral P2Y12 receptor antagonists are delayed in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention (P-PCI). In turn, this leads to a gap in platelet inhibition, exposing patients to an increased risk of early thrombotic complications and underscoring the need to define strategies associated with more effective platelet inhibition in the peri-primary percutaneous coronary intervention period. Cangrelor is an intravenous P2Y12 inhibitor with prompt and potent antiplatelet effects. However, to date, there are limited data on the effects of cangrelor used in combination with ticagrelor in patients undergoing primary percutaneous coronary intervention. Moreover, questions have emerged on the potential for drug-drug interactions during the transition from cangrelor to oral P2Y12 inhibitors. METHODS: This was a prospective, randomized, double-blind, placebo-controlled pharmacodynamic study conducted in patients undergoing primary percutaneous coronary intervention (n=50) who were randomized to treatment with either cangrelor or matching placebo (bolus followed by 2-hour infusion). All patients received ticagrelor 180-mg loading dose administered as crushed tablets at the time of cangrelor/placebo bolus administration. Pharmacodynamic analyses were performed at 8 time points. Pharmacodynamic effects were measured as P2Y12 reaction units by VerifyNow and platelet reactivity index by vasodilator-stimulated phosphoprotein. RESULTS: Compared with placebo, cangrelor was associated with reduced P2Y12 reaction units as early as 5 minutes after bolus, which persisted during the entire duration of drug infusion, including at 30 minutes (63 [32-93] versus 214 [183-245]; mean difference, 152 [95% CI, 108-195]; P<0·001; primary end point). Parallel findings were shown with platelet reactivity index. Accordingly, high on-treatment platelet reactivity rates were reduced with cangrelor. After discontinuation of cangrelor/placebo infusion, there were no differences in levels of platelet reactivity between groups, ruling out a drug-drug interaction when cangrelor and ticagrelor are concomitantly administered. CONCLUSIONS: In patients undergoing primary percutaneous coronary intervention, cangrelor is an effective strategy to bridge the gap in platelet inhibition associated with the use of oral P2Y12 inhibition induced by ticagrelor. Ticagrelor can be administered as a crushed formulation concomitantly with cangrelor without any apparent drug-drug interaction. The clinical implications of these pharmacodynamic findings warrant investigation in an adequately powered clinical trial. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03247738.
Asunto(s)
Adenosina Monofosfato/análogos & derivados , Plaquetas/efectos de los fármacos , Intervención Coronaria Percutánea , Inhibidores de Agregación Plaquetaria/administración & dosificación , Antagonistas del Receptor Purinérgico P2Y/administración & dosificación , Infarto del Miocardio con Elevación del ST/terapia , Ticagrelor/administración & dosificación , Adenosina Monofosfato/administración & dosificación , Adenosina Monofosfato/efectos adversos , Anciano , Biomarcadores/sangre , Plaquetas/metabolismo , Moléculas de Adhesión Celular/sangre , Método Doble Ciego , Quimioterapia Combinada , Femenino , Florida , Humanos , Masculino , Proteínas de Microfilamentos/sangre , Persona de Mediana Edad , Intervención Coronaria Percutánea/efectos adversos , Fosfoproteínas/sangre , Inhibidores de Agregación Plaquetaria/efectos adversos , Estudios Prospectivos , Antagonistas del Receptor Purinérgico P2Y/efectos adversos , Receptores Purinérgicos P2Y12/sangre , Infarto del Miocardio con Elevación del ST/sangre , Infarto del Miocardio con Elevación del ST/diagnóstico , Ticagrelor/efectos adversos , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Switching between different classes of P2Y12 inhibitors, including de-escalation from ticagrelor to clopidogrel, commonly occurs in clinical practice. However, the pharmacodynamic profiles of this strategy have been poorly explored. METHODS: This was a prospective, randomized, open-label study conducted in patients on maintenance dosing (MD) of aspirin (81 mg/d) and clopidogrel (75 mg/d). After a 7-day run-in with ticagrelor (180 mg loading dose [LD] followed by 90 mg twice daily MD), patients (n=80) were randomized into 1 of 4 groups: group A, clopidogrel 600 mg LD 24 hours after the last MD of ticagrelor (C-600 mg-24h); group B, clopidogrel 600 mg LD 12 hours after the last MD of ticagrelor (C-600 mg-12h); group C, clopidogrel 75 mg/d MD 24 hours after the last MD of ticagrelor (C-75 mg-24h); and group D, ticagrelor 90 mg twice daily MD (T-90 mg twice daily). MD of the randomized treatment was maintained for 10±3 days. Pharmacodynamic assessments were performed at baseline, after run-in, and at 2, 24, 48, and 72 hours and 10 days with P2Y12 reaction units by VerifyNow; platelet reactivity index was assessed by vasodilator-stimulated phosphoprotein; and maximal platelet aggregation was determined by light transmittance aggregometry. RESULTS: T-90 mg twice daily led to lower platelet reactivity than any clopidogrel regimen using all assays at all time points. P2Y12 reaction unit levels were similar between the C-600 mg-24h (group A) and the C-75 mg-24h (group C) (P=0.29), including at 48 hours (primary end point; least mean difference, -6.9; 95% confidence interval, -38.1 to 24.3; P=0.66). P2Y12 reaction unit levels were lower with C-600 mg-12h (group B) than with C-75 mg-24h (group C; P=0.024). Maximal platelet aggregation over time was lower with both C-600 mg-24h (group A; P=0.041) and C-600 mg-12h (group B; P=0.028) compared with C-75 mg-24h (group C). Platelet reactivity index profiles paralleled those observed with P2Y12 reaction units. There were no pharmacodynamic differences for all tests between C-600 mg-24h (group A) and C-600 mg-12h (group B). In group C (C-75 mg-24h), platelet reactivity increased compared with baseline as early as 24 hours, reaching statistical significance at 48 and 72 hours and up to 10 days. These pharmacodynamic findings were delayed and blunted in magnitude with the administration of an LD, regardless of the timing of administration. CONCLUSIONS: De-escalation from ticagrelor to clopidogrel therapy is associated with an increase in platelet reactivity. The use of an LD before the initiation of an MD regimen of clopidogrel mitigates these observations, although this is not affected by the timing of its administration after ticagrelor discontinuation. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02287909.
Asunto(s)
Plaquetas/metabolismo , Clopidogrel , Agregación Plaquetaria/efectos de los fármacos , Ticagrelor , Anciano , Moléculas de Adhesión Celular/sangre , Clopidogrel/administración & dosificación , Clopidogrel/farmacocinética , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Femenino , Humanos , Masculino , Proteínas de Microfilamentos/sangre , Persona de Mediana Edad , Fosfoproteínas/sangre , Pruebas de Función Plaquetaria , Estudios Prospectivos , Ticagrelor/administración & dosificación , Ticagrelor/farmacocinéticaRESUMEN
BACKGROUND: The CYP2C19 nonfunctional genotype reduces clopidogrel effectiveness after percutaneous coronary intervention (PCI). Following clinical implementation of CYP2C19 genotyping at University Florida (UF) Health Shands Hospital in 2012, where genotype results are available approximately 3 days after PCI, testing was expanded to UF Health Jacksonville in 2016 utilizing a rapid genotyping approach. We describe metrics with this latter implementation. METHODS: Patients at UF Health Jacksonville undergoing left heart catheterization with intent to undergo PCI were targeted for genotyping using the Spartan RX™ system. Testing metrics and provider acceptance of testing and response to genotype results were examined, as was antiplatelet therapy over the 6 months following genotyping. RESULTS: In the first year, 931 patients, including 392/505 (78%) total patients undergoing PCI, were genotyped. The median genotype test turnaround time was 96 min. Genotype results were available for 388 (99%) PCI patients prior to discharge. Of 336 genotyped PCI patients alive at discharge and not enrolled in an antiplatelet therapy trial, 1/6 (17%) poor metabolizers (PMs, with two nonfunctional alleles), 38/93 (41%) intermediate metabolizers (IMs, with one nonfunctional allele), and 119/237 (50%) patients without a nonfunctional allele were prescribed clopidogrel (p = 0.110). Clopidogrel use was higher among non-ACS versus ACS patients (78.6% vs. 42.2%, p < 0.001). Six months later, among patients with follow-up data, clopidogrel was prescribed in 0/4 (0%) PMs, 33/65 (51%) IMs, and 115/182 (63%) patients without a nonfunctional allele (p = 0.008 across groups; p = 0.020 for PMs versus those without a nonfunctional allele). CONCLUSION: These data demonstrate that rapid genotyping is clinically feasible at a high volume cardiac catheterization facility and allows informed chronic antiplatelet prescribing, with lower clopidogrel use in PMs at 6 months. Trial registration ClinicalTrials.gov Identifier: NCT02724319; registered March 31, 2016; https://www.clinicaltrials.gov/ct2/show/NCT02724319?term=angiolillo&rank=7.
Asunto(s)
Citocromo P-450 CYP2C19/genética , Técnicas de Genotipaje , Intervención Coronaria Percutánea , Inhibidores de Agregación Plaquetaria/farmacología , Clopidogrel/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad , FenotipoRESUMEN
BACKGROUND: Patients with diabetes mellitus (DM) are at increased risk of atherothrombotic events, underscoring the importance of effective platelet inhibiting therapies. Prasugrel and ticagrelor reduce thrombotic complications to a greater extent than clopidogrel. Subgroup analyses of pivotal clinical trials testing prasugrel and ticagrelor versus clopidogrel showed DM patients to have benefits that were consistent with the overall trial populations, although the magnitude of the ischemic risk reduction appeared to be enhanced with prasugrel. Whether these findings may be attributed to differences in the pharmacodynamic profiles of these drugs in DM patients remains poorly explored and represented the aim of this study. METHODS: In this prospective, randomized, double-blind, double-dummy, crossover pharmacodynamic study, aspirin-treated DM patients (n=50) with coronary artery disease were randomly assigned to receive prasugrel (60 mg loading dose [LD]/10 mg maintenance dose once daily) or ticagrelor (180 mg LD/90 mg maintenance dose twice daily) for 1 week. Pharmacodynamic assessments were conducted using 4 different assays, including VerifyNow P2Y12, vasodilator-stimulated phosphoprotein, light transmittance aggregometry, and Multiplate, which allowed us to explore ADP- and non-ADP-induced (arachidonic acid-, collagen-, thrombin receptor-activating, peptide-induced) platelet signaling pathways. The acute (baseline, 30 minutes, and 2 hours post-LD) and maintenance (1 week) effects of therapy were assessed. The primary end point of the study was the comparison of P2Y12 reaction units determined by VerifyNow P2Y12 at 1 week between prasugrel and ticagrelor. RESULTS: ADP- and non-ADP-induced measures of platelet reactivity reduced significantly with both prasugrel and ticagrelor LD and maintenance dose. P2Y12 reaction units defined by VerifyNow were similar between prasugrel and ticagrelor at 30 minutes and 2 hours post-LD. At 1 week, P2Y12 reaction units were significantly lower with ticagrelor than with prasugrel (52 [32-72] versus 83 [63-103]; least-square means difference: -31; 95% confidence interval, -57 to -4; P=0.022; primary end point). Pharmacodynamic assessments measured by vasodilator-stimulated phosphoprotein, light transmittance aggregometry, and Multiplate were similar between prasugrel and ticagrelor at each time point, including at 1 week. Rates of high on-treatment platelet reactivity were similar between groups with all assays at all time points. CONCLUSIONS: In DM patients with coronary artery disease, ticagrelor exerts similar or greater inhibition of ADP-induced platelet reactivity in comparison with prasugrel in the acute and chronic phases of treatment, whereas the inhibition of measures of non-ADP-induced platelet reactivity was not significantly different between the 2 agents. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01852214.
Asunto(s)
Adenosina/análogos & derivados , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Complicaciones de la Diabetes/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria , Clorhidrato de Prasugrel , Adenosina/administración & dosificación , Adenosina/farmacocinética , Adolescente , Adulto , Anciano , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/etiología , Estudios Cruzados , Complicaciones de la Diabetes/sangre , Diabetes Mellitus Tipo 2/sangre , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/farmacocinética , Clorhidrato de Prasugrel/administración & dosificación , Clorhidrato de Prasugrel/farmacocinética , Estudios Prospectivos , TicagrelorAsunto(s)
Enfermedades Cardiovasculares , Clopidogrel , Complicaciones de la Diabetes , Procedimientos Quirúrgicos Electivos , Intervención Coronaria Percutánea , Ticagrelor , Adulto , Anciano , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/terapia , Clopidogrel/administración & dosificación , Clopidogrel/farmacocinética , Complicaciones de la Diabetes/sangre , Complicaciones de la Diabetes/terapia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Ticagrelor/administración & dosificación , Ticagrelor/farmacocinéticaRESUMEN
BACKGROUND: To date, there are no data on switching to dual pathway inhibition (DPI) patients who have completed a guideline-recommended dual antiplatelet therapy (DAPT) regimen. OBJECTIVES: To assess the feasibility of switching from DAPT to DPI and to compare the pharmacodynamic (PD) profiles of these treatments. METHODS: This was a prospective, randomized, PD study conducted in 90 patients with chronic coronary syndrome (CCS) on DAPT with aspirin (81 mg/qd) plus a P2Y12 inhibitor (clopidogrel [75 mg/qd; n = 30], ticagrelor [90 mg/bid; n = 30], or prasugrel [10 mg/qd; n = 30]). Patients in each cohort were randomized to maintain DAPT or switch to DPI (aspirin 81 mg/qd plus rivaroxaban 2.5 mg/bid). PD assessments included: VerifyNow P2Y12 reaction units; light transmittance aggregometry following stimuli with adenosine diphosphate (ADP), tissue factor (TF), and a combination of collagen, ADP, and TF (maximum platelet aggregation %); thrombin generation (TG). Assays were performed at baseline and 30 days postrandomization. RESULTS: Switching from DAPT to DPI occurred without major side effects. DAPT was associated with enhanced P2Y12 inhibition, while DPI with reduced TG. Platelet-mediated global thrombogenicity (primary endpoint) showed no differences between DAPT and DPI in the ticagrelor (14.5% [0.0-63.0] vs. 20.0% [0.0-70.0]; p = 0.477) and prasugrel (20.0% [0.0-66.0] vs. 4.0% [0.0-70.0]; p = 0.482), but not clopidogrel (27.0% [0.0-68.0] vs. 53.0% [0.0-81.0]; p = 0.011), cohorts. CONCLUSION: In patients with CCS, switching from different DAPT regimens to DPI was feasible, showing enhanced P2Y12 inhibition with DAPT and reduced TG with DPI, with no differences in platelet-mediated global thrombogenicity between DPI and ticagrelor- and prasugrel-, but not clopidogrel-, based DAPT. CLINICAL TRIAL REGISTRATION: http://www. CLINICALTRIALS: gov Unique Identifier: NCT04006288.
Asunto(s)
Síndrome Coronario Agudo , Intervención Coronaria Percutánea , Humanos , Aspirina/uso terapéutico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Ticagrelor/uso terapéutico , Rivaroxabán/efectos adversos , Clorhidrato de Prasugrel , Estudios Prospectivos , Adenosina/efectos adversos , Clopidogrel/uso terapéutico , Síndrome Coronario Agudo/tratamiento farmacológico , Síndrome Coronario Agudo/etiología , Adenosina Difosfato , Antagonistas del Receptor Purinérgico P2Y , Intervención Coronaria Percutánea/efectos adversosRESUMEN
This prospective ex vivo and in vitro pharmacodynamic (PD)/pharmacokinetic investigation was conducted in patients with diabetes mellitus with (n = 31) and without chronic kidney disease (n = 30). PD assessments included platelet reactivity index, maximum platelet aggregation, and P2Y12 reaction units. Ex vivo pharmacokinetic assessments included plasma levels of clopidogrel and its active metabolite. In vitro PD assessments were conducted on baseline samples incubated with escalating concentrations of clopidogrel and its active metabolite. Among patients with diabetes mellitus treated with clopidogrel, impaired renal function was associated with increased maximum platelet aggregation. This finding could be attributed partially to upregulation of the P2Y12 activity without differences in drug absorption or metabolism. (Impact of Chronic Kidney Disease on Clopidogrel Effects in Diabetes Mellitus; NCT03774394).
RESUMEN
Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor (clopidogrel, prasugrel, or ticagrelor) is indicated after percutaneous coronary intervention (PCI) to reduce the risk of atherothrombotic events. Approximately 30% of the US population has a CYP2C19 no-function allele that reduces the effectiveness of clopidogrel, but not prasugrel or ticagrelor, after PCI. We have shown improved outcomes with the integration of CYP2C19 genotyping into clinical care to guide the selection of prasugrel or ticagrelor in CYP2C19 no-function allele carriers. However, the influence of patient-specific demographic, clinical, and other genetic factors on outcomes with genotype-guided DAPT has not been defined. In addition, the impact of genotype-guided de-escalation from prasugrel or ticagrelor to clopidogrel in patients without a CYP2C19 no-function allele has not been investigated in a diverse, real-world clinical setting. The Precision Antiplatelet Therapy after Percutaneous Coronary Intervention (Precision PCI) Registry is a multicenter US registry of patients who underwent PCI and clinical CYP2C19 testing. The registry is enrolling a diverse population, assessing atherothrombotic and bleeding events over 12 months, collecting DNA samples, and conducting platelet function testing in a subset of patients. The registry aims to define the influence of African ancestry and other patient-specific factors on clinical outcomes with CYP2C19-guided DAPT, evaluate the safety and effectiveness of CYP2C19-guided DAPT de-escalation following PCI in a real-world setting, and identify additional genetic influences of clopidogrel response after PCI, with the ultimate goal of establishing optimal strategies for individualized antiplatelet therapy that improves outcomes in a diverse, real-world population.
Asunto(s)
Clopidogrel , Citocromo P-450 CYP2C19 , Intervención Coronaria Percutánea , Inhibidores de Agregación Plaquetaria , Clorhidrato de Prasugrel , Medicina de Precisión , Sistema de Registros , Ticagrelor , Humanos , Intervención Coronaria Percutánea/efectos adversos , Citocromo P-450 CYP2C19/genética , Medicina de Precisión/métodos , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/efectos adversos , Clopidogrel/administración & dosificación , Clopidogrel/efectos adversos , Ticagrelor/administración & dosificación , Ticagrelor/uso terapéutico , Clorhidrato de Prasugrel/administración & dosificación , Clorhidrato de Prasugrel/uso terapéutico , Clorhidrato de Prasugrel/efectos adversos , Terapia Antiplaquetaria Doble/métodos , Aspirina/administración & dosificación , Aspirina/efectos adversos , Aspirina/uso terapéutico , Antagonistas del Receptor Purinérgico P2Y/administración & dosificación , Antagonistas del Receptor Purinérgico P2Y/efectos adversos , Antagonistas del Receptor Purinérgico P2Y/uso terapéutico , Hemorragia/inducido químicamente , Hemorragia/prevención & controlRESUMEN
BACKGROUND: Among patients treated with a novel oral anticoagulant (NOAC) undergoing percutaneous coronary intervention (PCI), combination therapy with clopidogrel (ie, known as dual antithrombotic therapy [DAT]) is the treatment of choice. However, there are concerns for individuals with impaired response to clopidogrel. OBJECTIVES: The authors sought to assess the pharmacodynamic (PD) effects of clopidogrel vs low-dose ticagrelor in patients with impaired clopidogrel response assessed by the ABCD-GENE score. METHODS: This was a prospective, randomized PD study of NOAC-treated patients undergoing PCI. Patients with an ABCD-GENE score ≥10 (n = 39), defined as having impaired clopidogrel response, were randomized to low-dose ticagrelor (n = 20; 60 mg twice a day) or clopidogrel (n = 19; 75 mg once a day). Patients with an ABCD-GENE score <10 (n = 42) were treated with clopidogrel (75 mg once a day; control cohort). PD assessments at baseline and 30 days post-randomization (trough and peak) were performed to assess P2Y12 signaling (VerifyNow P2Y12 reaction units [PRU], light transmittance aggregometry, and vasodilator-stimulated phosphoprotein); makers of thrombosis not specific to P2Y12 signaling were also assessed. The primary endpoint was PRU (trough levels) at 30 days. RESULTS: At 30 days, PRU levels were reduced with ticagrelor-based DAT compared with clopidogrel-based DAT at trough (23.0 [Q1-Q3: 3.0-46.0] vs 154.5 [Q1-Q3: 77.5-183.0]; P < 0.001) and peak (6.0 [Q1-Q3: 4.0-14.0] vs 129.0 [Q1-Q3: 66.0-171.0]; P < 0.001). Trough PRU levels in the control arm (104.0 [Q1-Q3: 35.0-167.0]) were higher than ticagrelor-based DAT (P = 0.005) and numerically lower than clopidogrel-based DAT (P = 0.234). Results were consistent by light transmittance aggregometry and vasodilator-stimulated phosphoprotein. Markers measuring other pathways leading to thrombus formation were largely unaffected. CONCLUSIONS: In NOAC-treated patients undergoing PCI with an ABCD-GENE score ≥10, ticagrelor-based DAT using a 60-mg, twice-a-day regimen reduced platelet P2Y12 reactivity compared with clopidogrel-based DAT. (Tailoring P2Y12 Inhibiting Therapy in Patients Requiring Oral Anticoagulation After PCI [SWAP-AC-2]; NCT04483583).
Asunto(s)
Anticoagulantes , Clopidogrel , Intervención Coronaria Percutánea , Inhibidores de Agregación Plaquetaria , Antagonistas del Receptor Purinérgico P2Y , Receptores Purinérgicos P2Y12 , Ticagrelor , Humanos , Intervención Coronaria Percutánea/efectos adversos , Ticagrelor/efectos adversos , Ticagrelor/administración & dosificación , Masculino , Estudios Prospectivos , Femenino , Anciano , Persona de Mediana Edad , Clopidogrel/administración & dosificación , Clopidogrel/efectos adversos , Antagonistas del Receptor Purinérgico P2Y/efectos adversos , Antagonistas del Receptor Purinérgico P2Y/administración & dosificación , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/efectos adversos , Administración Oral , Resultado del Tratamiento , Factores de Tiempo , Anticoagulantes/administración & dosificación , Anticoagulantes/efectos adversos , Receptores Purinérgicos P2Y12/efectos de los fármacos , Receptores Purinérgicos P2Y12/sangre , Pruebas de Función Plaquetaria , Agregación Plaquetaria/efectos de los fármacos , Fosfoproteínas/sangre , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Proteínas de Microfilamentos/sangre , Proteínas de Microfilamentos/genética , Enfermedad de la Arteria Coronaria/terapia , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Moléculas de Adhesión Celular/sangre , Resistencia a Medicamentos , Terapia Antiplaquetaria Doble/efectos adversosRESUMEN
BACKGROUND: The discovery of TCF7L2 as a global type 2 diabetes (T2D) gene has sparked investigations to explore the clinical utility of its variants for guiding the development of new diagnostic and therapeutic strategies. However, interpreting the resulting associations into function still remains unclear. Canonical Wnt signaling regulates ß-catenin and its binding with TCF7L2, which in turn is critical for the production of glucagon-like peptide-1 (GLP-1). This study examines the role of a novel frame-shift insertion discovered in a conserved region of WNT16a, and it is proposed that this mutation affects T2D susceptibility in conjunction with gene variants in TCF7L2. RESULTS: Our results predicted that the insertion would convert the upstream open reading frame in the Wnt16a mRNA to an alternative, in-frame translation initiation site, resulting in the prevention of nonsense-mediated decay, leading to a consequent stabilization of the mutated WNT16a message. To examine the role of Wnt16a in the Wnt signaling pathway, DNA and serum samples from 2,034 individuals (48% with T2D) from the Sikh Diabetes Study were used in this investigation. Prevalence of Wnt16a insertion did not differ among T2D cases (33%) and controls (32%). However, there was a 3.2 fold increase in Wnt16a mRNA levels in pancreatic tissues from the insertion carriers and a significant increase (70%, p < 0.0001) in luciferase activity in the constructs carrying the insertion. The expression of TCF7L2 mRNA in pancreas was also elevated (~23-fold) among the insertion carriers (p=0.003). CONCLUSIONS: Our results suggest synergistic effects of WNT16a insertion and the at-risk 'T' allele of TCF7L2 (rs7903146) for elevating the expression of TCF7L2 in human pancreas which may affect the regulation of downstream target genes involved in the development of T2D through Wnt/ß-catenin/TCF7L2 signaling pathway. However, further studies would be needed to mechanistically link the two definitively.
Asunto(s)
Mutación del Sistema de Lectura , Tamización de Portadores Genéticos , Páncreas/metabolismo , Proteína 2 Similar al Factor de Transcripción 7/genética , Proteínas Wnt/genética , Adulto , Anciano , Secuencia de Bases , Estudios de Casos y Controles , Cartilla de ADN , Diabetes Mellitus Tipo 2/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la PolimerasaRESUMEN
BACKGROUND: The impact of intense low-density lipoprotein cholesterol (LDL-C) reduction using a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor on profiles of platelet reactivity has yet to be explored. AIMS: Our aim was to investigate the effects of the PCSK9 inhibitor, evolocumab, on platelet reactivity in patients with atherosclerotic cardiovascular disease (ASCVD) on clopidogrel treatment. METHODS: This was a prospective, randomised, double-blind, placebo-controlled pharmacodynamic study in patients with ASCVD on clopidogrel treatment and with LDL-C levels ≥70 mg/dL despite a maximally tolerated statin dose. Patients were stratified according to levels of platelet reactivity using VerifyNow P2Y12 reactivity units (PRU) into high platelet reactivity (HPR; PRU >208) or normal platelet reactivity (NPR; PRU >85 and ≤208). Each cohort was randomised to receive evolocumab 420 mg or placebo. The primary endpoint was the difference in PRU at 30 days. RESULTS: A total of 84 patients (HPR, n=37 [19 evolocumab vs 18 placebo]; NPR, n=47 [22 evolocumab vs 25 placebo]) were included. Evolocumab significantly reduced LDL-C compared to placebo at 14 (p<0.001) and 30 (p=0.001) days. At 14 days, PRU levels were significantly lower with evolocumab compared to placebo in the HPR (218.2±29.7 vs 246.6±35.2; p=0.017), but not in the NPR cohort (141.2±42.8 vs 148.2±41.7; p=0.578). At 30 days, there were no significant differences in PRU in the HPR (219.3±38.3 vs 240.9±51.8; p=0.161) or NPR (141.5±54.3 vs 158.6±40.8; p=0.229) cohorts. CONCLUSIONS: Compared to placebo, evolocumab in adjunct to statin therapy did not significantly reduce platelet reactivity at 30 days in ASCVD patients on clopidogrel treatment despite intense LDL-C reduction. ClinicalTrials.gov: NCT03096288.
Asunto(s)
Anticolesterolemiantes , Aterosclerosis , Enfermedades Cardiovasculares , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Humanos , Proproteína Convertasa 9 , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , LDL-Colesterol/uso terapéutico , Clopidogrel/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , Enfermedades Cardiovasculares/tratamiento farmacológico , Estudios Prospectivos , Aterosclerosis/tratamiento farmacológico , Resultado del Tratamiento , Método Doble CiegoRESUMEN
BACKGROUND: There are no studies specifically designed to rule out a drug-drug interaction (DDI) when cangrelor is used among patients who have been pretreated with ticagrelor. OBJECTIVES: This study sought to rule out a DDI among cangrelor-treated patients who have been pretreated with ticagrelor. METHODS: In this prospective, randomized, double-blind, placebo-controlled, crossover, pharmacokinetic (PK) and pharmacodynamic (PD) study, patients with coronary artery disease (N = 20) were pretreated with a 180-mg ticagrelor loading dose and after 1 hour randomized to placebo or cangrelor (bolus and infusion for 2 hours). Patients crossed over after 1 to 4 weeks of washout. PK analysis included ticagrelor plasma levels and its active metabolite. PD assessments included VerifyNow P2Y12 reaction units (PRU), light transmittance aggregometry, vasodilator-stimulated phosphoprotein, and Total Thrombus-Formation Analysis System. PK/PD assessments were performed at 7 time points. RESULTS: Compared with placebo, adding cangrelor to patients pretreated with ticagrelor resulted in a significant reduction in PRU at 30 minutes and 1 hour after starting infusion. At 2 hours after stopping cangrelor/placebo infusion, PRU were low and similar in both groups (16.9 vs 12.6; mean difference: 4.3; 95% CI: -28.6 to 37.3), meeting the noninferiority primary endpoint (predefined noninferiority margin 45 PRU). Consistent findings were shown with all PD assays. PK tracked PD findings with no differences between groups in plasma levels of ticagrelor and its metabolite. CONCLUSIONS: Compared with placebo, the use of cangrelor in patients pretreated with ticagrelor results in enhanced platelet inhibition with no differences in PK/PD profiles after discontinuation of drug infusion indicating the absence of a DDI. (PD and PK Profiles of Switching Between Cangrelor and Ticagrelor Following Ticagrelor Pre-treatment [SWAP-5]; NCT04634162).
Asunto(s)
Enfermedad de la Arteria Coronaria , Humanos , Ticagrelor , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria , Estudios Prospectivos , Resultado del Tratamiento , Plaquetas/metabolismo , Antagonistas del Receptor Purinérgico P2Y , Pruebas de Función PlaquetariaRESUMEN
BACKGROUND: A drug-drug interaction (DDI) may occur when transitioning from intravenous P2Y12 inhibition with cangrelor to oral P2Y12 inhibition with prasugrel. However, this has never been tested in patients undergoing percutaneous coronary intervention (PCI). OBJECTIVES: This study sought to rule out a DDI when cangrelor and prasugrel are concomitantly administered in PCI patients. METHODS: SWAP-6 (Switching Antiplatelet-6) was a prospective, randomized, 3-arm, open-label pharmacokinetic (PK) and pharmacodynamic (PD) study. Patients (N = 77) were randomized to 1) prasugrel only at the start of PCI, 2) cangrelor plus prasugrel concomitantly at the start of PCI, or 3) cangrelor at the start of PCI plus prasugrel at the end of infusion. Cangrelor infusion was maintained for 2 hours. PK/PD assessments were performed at baseline and 6 time points postrandomization. The primary endpoint was noninferiority in VerifyNow (Werfen) P2Y12 reaction units measured at 4 hours after randomization between cangrelor plus prasugrel concomitantly administered vs prasugrel only. PK assessments included plasma levels of the active metabolite of prasugrel. RESULTS: Compared with prasugrel, cangrelor further enhances P2Y12 inhibitory effects. At 4 hours postrandomization, P2Y12 reaction unit levels were significantly lower with prasugrel only compared to cangrelor and prasugrel concomitantly administered (least squares means difference = 130; 95% CI: 85-176), failing to meet the prespecified noninferiority margin. Findings were corroborated by multiple PD assays. The active metabolite of prasugrel levels were not affected by concomitant administration of cangrelor and were low at the end of cangrelor infusion. CONCLUSIONS: In patients undergoing PCI, concomitant administration of prasugrel with cangrelor leads to a marked increase in platelet reactivity after stopping cangrelor infusion, supporting the presence of a DDI. (Switching Antiplatelet Therapy-6 [SWAP-6]; NCT04668144).
Asunto(s)
Intervención Coronaria Percutánea , Inhibidores de Agregación Plaquetaria , Humanos , Clorhidrato de Prasugrel , Intervención Coronaria Percutánea/efectos adversos , Estudios Prospectivos , Antagonistas del Receptor Purinérgico P2Y , Pruebas de Función Plaquetaria , Resultado del TratamientoRESUMEN
BACKGROUND: The role of cholesteryl ester transfer protein (CETP) in the metabolism of high-density lipoprotein cholesterol (HDL-C) is well studied but still controversial. More recently, genome-wide association studies and meta-analyses reported the association of a promoter variant (rs3764261) with HDL-C in Caucasians and other ethnic groups. In this study, we have examined the role of genetic variation in the promoter region of CETP with HDL-C, CETP activity, coronary artery disease (CAD), CAD risk factors, and the interaction of genetic factors with environment in a unique diabetic cohort of Asian Indian Sikhs. METHODS AND RESULTS: We genotyped four variants; three tagging single nucleotide polymorphisms from promoter (rs3764261, rs12447924, rs4783961) and one intronic variant (rs708272 Taq1B) on 2431 individuals from the Sikh Diabetes study. Two variants (rs3764261 and rs708272) exhibited a strong association with HDL-C in both normoglycemic controls (ß=0.12; P=9.35×10 for rs3764261; ß=0.10, P=0.002 for rs708272) and diabetic cases (ß=0.07, P=0.016 for rs3764261; ß=0.08, P=0.005 for rs708272) with increased levels among minor homozygous 'AA' carriers. In addition, the same 'A' allele carriers in rs3764261 showed a significant decrease in systolic blood pressure (ß=-0.08, P=0.002) in normoglycemic controls. Haplotype analysis of rs3764261, rs12447924, rs4783961, and rs708272 further revealed a significant association of 'ATAA' haplotype with an increased HDL-C (ß=2.71, P=6.38×10) and 'CTAG' haplotype with decreased HDL-C levels (ß=-1.78, P=2.5×10). Although there was no direct association of CETP activity and CETP polymorphisms, low CETP activity was associated with an increased risk to CAD (age, BMI, and sex-adjusted odds ratio=2.2; 95% confidence interval: 1.4-3.4; P=0.001) in this study. Our data revealed a strong interaction of rs3764261 and rs708272 for affecting the association between CETP activity and HDL-C levels (P=2.2×10 and P=4.4×10, respectively). CONCLUSION: Our results, in conjunction with earlier reports confirm low CETP activity to be associated with higher CAD risk. Although there was no direct association of CETP activity with CETP polymorphisms, our findings revealed a significant interaction between CETP variants and CETP activity for affecting HDL-C levels. These results urge a deeper evaluation of the individual genetic variation in the CETP before implementing pharmaceutical intervention of blocking CETP for preventing CAD events.
Asunto(s)
Proteínas de Transferencia de Ésteres de Colesterol/sangre , Proteínas de Transferencia de Ésteres de Colesterol/genética , Enfermedad de la Arteria Coronaria/genética , Diabetes Mellitus Tipo 2/metabolismo , Variación Genética , Anciano , Pueblo Asiatico , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , HDL-Colesterol/sangre , HDL-Colesterol/genética , Estudios de Cohortes , Enfermedad de la Arteria Coronaria/etnología , Diabetes Mellitus Tipo 2/genética , Femenino , Estudio de Asociación del Genoma Completo , Humanos , India , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Factores de RiesgoRESUMEN
AIM: Inhibition of thrombin-mediated signaling processes using a vascular dose of rivaroxaban in adjunct to antiplatelet therapy, known as dual-pathway inhibition (DPI), reduces atherothrombotic events in patients with stable atherosclerotic disease. However, there are limited data on the pharmacodynamic (PD) effects of this strategy and how it compares to standard dual antiplatelet therapy (DAPT). METHODS AND RESULTS: This investigation was conducted in selected cohorts of patients (n = 40) with stable atherosclerotic disease-enrolled within a larger prospective, open-label, parallel-group PD study-who were treated with either aspirin plus clopidogrel (DAPT), aspirin plus rivaroxaban 2.5 mg/bid (DPI), or DAPT plus rivaroxaban 2.5 mg/bid. Multiple PD assays providing a comprehensive assessment of markers of thrombosis were used. PD endpoints included platelet-mediated global thrombogenicity measured by light transmittance aggregometry (LTA) following stimuli with CATF (collagen-related peptide + adenosine diphosphate [ADP] + tissue factor [TF]), markers of P2Y12 reactivity, markers of platelet aggregation using LTA following several stimuli (arachidonic acid, ADP, collagen, TF, and thrombin receptor-activating peptide [TRAP]), thrombin generation, and thrombus formation. There was no difference in platelet-mediated global thrombogenicity between groups. Rivaroxaban significantly reduced thrombin generation and was associated with a trend toward reduced TF-induced platelet aggregation. Clopidogrel-based treatments reduced markers of P2Y12 signaling and TRAP-induced platelet aggregation. There were no differences between groups on markers of cyclooxygenase-1-mediated activity. CONCLUSION: Compared with DAPT, DPI does not result in any differences in platelet-mediated global thrombogenicity, but reduces thrombin generation. These PD observations suggest that modulating thrombin generation-by means of factor Xa inhibition-in adjunct to antiplatelet therapy provides effective antithrombotic effects, supporting the efficacy and safety findings of a DPI strategy observed in clinical trials.
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Aterosclerosis , Trombosis , Adenosina Difosfato/farmacología , Aspirina , Aterosclerosis/tratamiento farmacológico , Plaquetas , Clopidogrel/farmacología , Humanos , Agregación Plaquetaria , Inhibidores de Agregación Plaquetaria , Estudios Prospectivos , Rivaroxabán , Trombina/farmacología , Trombosis/tratamiento farmacológicoRESUMEN
AIMS: Dual pathway inhibition (DPI) by adding a vascular dose of rivaroxaban to a single antiplatelet agent has emerged as a promising antithrombotic strategy. However, in most studies the antiplatelet agent of choice used in adjunct to a vascular dose of rivaroxaban was aspirin, and data on a P2Y12 inhibitor and how this DPI regimen compares with standard dual antiplatelet therapy (DAPT) are limited. METHODS AND RESULTS: This investigation was a substudy analysis conducted in selected cohorts of patients with stable atherosclerotic disease enrolled from a larger prospective, open-label, parallel-group pharmacodynamic (PD) study. We analysed data from 40 patients treated with either clopidogrel- or ticagrelor-based DAPT first, and clopidogrel- or ticagrelor-based DPI thereafter. PD measures explored key pathways involved in thrombus formation and included markers of (1) P2Y12 reactivity, (2) platelet-mediated global thrombogenicity, (3) cyclooxygenase-1 activity, (4) thrombin receptor-activating peptide (TRAP)-induced platelet aggregation, (5) tissue factor (TF)-induced platelet aggregation, and (6) thrombin generation. Compared with DAPT, on a background of the same P2Y12 inhibitor (clopidogrel or ticagrelor), DPI was associated with reduced thrombin generation, increased markers of cyclooxygenase-1 activity and TRAP-induced platelet aggregation, and no differences in markers of P2Y12 signalling, platelet-mediated global thrombogenicity, and TF-induced platelet aggregation. In an analysis according to P2Y12 inhibitor type, ticagrelor reduced markers of platelet-mediated global thrombogenicity, P2Y12 signalling, and rates of high platelet reactivity compared with clopidogrel. CONCLUSION: Compared with DAPT with aspirin and a P2Y12 inhibitor, the use of a P2Y12 inhibitor in adjunct to a vascular dose of rivaroxaban as part of a DPI strategy is associated with similar effects on platelet-mediated global thrombogenicity but reduced thrombin generation. A DPI strategy with ticagrelor is associated with enhanced antithrombotic efficacy, the clinical implications of which warrant larger scale investigations. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03718429.
Asunto(s)
Aspirina , Inhibidores de Agregación Plaquetaria , Clopidogrel/efectos adversos , Ciclooxigenasa 1 , Fibrinolíticos/uso terapéutico , Humanos , Péptidos , Estudios Prospectivos , Receptores de Trombina , Rivaroxabán/efectos adversos , Trombina , Tromboplastina , Ticagrelor/efectos adversosRESUMEN
AIMS: Patients with diabetes mellitus (DM) and chronic kidney disease (CKD) are at increased risk of atherothrombotic events. Ticagrelor reduces ischaemic events compared to clopidogrel, with the greatest risk reduction in patients with both DM and CKD. How CKD status affects the pharmacodynamic (PD) and pharmacokinetic (PK) profiles of different ticagrelor maintenance dose regimens in patients with DM is unknown. METHODS AND RESULTS: In this randomized, crossover study, patients with DM on treatment with dual antiplatelet therapy (aspirin and clopidogrel) were stratified according to CKD status and randomized to ticagrelor 90 or 60 mg bid. PK/PD assessments were performed at baseline, after 7-10 days of ticagrelor (peak and trough), and after 7-10 days of alternative ticagrelor regimen (peak and trough). PK assessments included plasma concentrations of ticagrelor and its major metabolite. PD assessments included vasodilator-stimulated phosphoprotein (VASP)-platelet reactivity index (PRI), VerifyNow P2Y12, and light transmittance aggregometry (LTA). A total of 92 patients with DM (CKD, n = 44; non-CKD, n = 48) were randomized. Levels of platelet reactivity were lower with the 90 mg compared with the 60 mg ticagrelor dose, which was statistically significant in non-CKD but not in CKD patients for most PD measures. There were no significant differences in the primary endpoint (trough levels of VASP-PRI following ticagrelor 90 mg dosing) between cohorts (31 ± 20 vs. 25 ± 14; P = 0.105). VerifyNow and LTA provided similar findings. PK assessments tracked PD profiles showing increased plasma concentrations of ticagrelor and its major metabolite in CKD compared to non-CKD patients. CONCLUSION: In patients with DM, although ticagrelor maintenance dose regimens (60 and 90 mg) yield potent P2Y12 inhibition, levels of platelet reactivity tended to be higher and subject to broader variability in non-CKD compared with CKD patients. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov Unique Identifier: NCT02539160.