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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).
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Significant advancements have shaped the landscape of anticoagulant therapy in the past two decades, including the introduction of direct oral anticoagulants (DOACs), characterized by favorable safety and efficacy profiles and reduced drug-to-drug or food interaction resulting in excellent patient compliance. However, residual concerns still exist with standard-of-care anticoagulant therapy, including the inability to use DOACs in several clinical settings and the need to further reduce the risk of bleeding. Recent improvements in the understanding of the mechanisms behind thrombus formation have led to the awareness that the intrinsic pathway of the coagulation cascade may play an important role in pathological thrombosis, but not in hemostasis. This has represented the rationale for targeting this pathway with factor XI (FXI) inhibitors, with the aim of uncoupling hemostasis and thrombosis. Clinical evidence from patients with FXI deficiency further supports this concept. A number of compounds with different mechanisms of action have been developed to target FXI (i.e., asundexian, abelacimab, Ionis-FXIRx, milvexian, osocimab, and Xisomab 3G). To date, the majority of available trials have not gone beyond completion of phase 2 and results are conflictive making it difficult to appraise the clinical benefit of these compounds in the different clinical settings where they have been tested (i.e., atrial fibrillation, acute ischemic stroke, acute myocardial infarction, end-stage renal disease, total knee arthroplasty). Moreover, the largest phase 3 randomized trial designed to test the efficacy of asundexian over apixaban in patients with atrial fibrillation, the OCEANIC-AF, has been prematurely stopped as a result of the inferior efficacy of asundexian. In this review we discuss the pharmacological properties and available evidence generated thus far for factor XI inhibitors, providing a perspective on the current state of these drugs.
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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).
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Anticoagulantes , Clopidogrel , Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária , Antagonistas do Receptor Purinérgico P2Y , Receptores Purinérgicos P2Y12 , Ticagrelor , Humanos , Intervenção Coronária Percutânea/efeitos adversos , Ticagrelor/efeitos adversos , Ticagrelor/administração & dosagem , Masculino , Estudos Prospectivos , Feminino , Idoso , Pessoa de Meia-Idade , Clopidogrel/administração & dosagem , Clopidogrel/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/efeitos adversos , Administração Oral , Resultado do Tratamento , Fatores de Tempo , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Receptores Purinérgicos P2Y12/efeitos dos fármacos , Receptores Purinérgicos P2Y12/sangue , Testes de Função Plaquetária , Agregação Plaquetária/efeitos dos fármacos , Fosfoproteínas/sangue , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Proteínas dos Microfilamentos/sangue , Proteínas dos Microfilamentos/genética , Doença da Artéria Coronariana/terapia , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Moléculas de Adesão Celular/sangue , Resistência a Medicamentos , Terapia Antiplaquetária Dupla/efeitos adversosRESUMO
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.
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Síndrome Coronariana Aguda , Intervenção Coronária Percutânea , Humanos , Aspirina/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Ticagrelor/uso terapêutico , Rivaroxabana/efeitos adversos , Cloridrato de Prasugrel , Estudos Prospectivos , Adenosina/efeitos adversos , Clopidogrel/uso terapêutico , Síndrome Coronariana Aguda/tratamento farmacológico , Síndrome Coronariana Aguda/etiologia , Difosfato de Adenosina , Antagonistas do Receptor Purinérgico P2Y , Intervenção Coronária Percutânea/efeitos adversosRESUMO
Circulating lipoproteins may interact with platelets, increasing platelet sensitivity to aggregating agonists and their tendency towards activation and thrombus formation. In particular, patients with hypercholesterolemia exhibit a higher degree of platelet reactivity compared to normolipidemic. Moreover, accruing evidence report that lipid-lowering therapies can reduce thrombus formation, particularly in the absence of concomitant antiplatelet therapy. However, the underlying biological mechanism(s) explaining these clinical observations are not completely understood. Baseline platelet reactivity and high on-treatment platelet reactivity while on antiplatelet therapy (e.g., aspirin and clopidogrel) are associated with poor clinical outcomes. Therefore, strategies to reduce baseline platelet reactivity or improve the pharmacodynamic profile of antiplatelet therapies are an unmet clinical need. The potential use of lipid-lowering therapies for optimizing platelet reactivity provides several advantages as there is strong evidence that reducing circulating lipoproteins can improve clinical outcomes, and they may avoid the need for potent antiplatelet therapies that, although more effective, are associated with increased bleeding risk. This review will provide a systematic overview of the effects of lipid-lowering therapy on platelet reactivity in patients treated with and without antiplatelet therapy. We will focus on the potential biological mechanism(s) of action and the effect of statins, ezetimibe, proprotein convertase subtilisin/kexin 9 inhibitors, omega-3 fatty acids, and recombinant high-density lipoprotein on platelet reactivity. Ultimately, we will assess the current gaps in the literature and future perspective in the field.
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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).
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Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária , Humanos , Cloridrato de Prasugrel , Intervenção Coronária Percutânea/efeitos adversos , Estudos Prospectivos , Antagonistas do Receptor Purinérgico P2Y , Testes de Função Plaquetária , Resultado do TratamentoRESUMO
Antiplatelet therapy is the mainstay of pharmacologic treatment to prevent thrombotic or ischemic events in patients with coronary artery disease treated with percutaneous coronary intervention and those treated medically for an acute coronary syndrome. The use of antiplatelet therapy comes at the expense of an increased risk of bleeding complications. Defining the optimal intensity of platelet inhibition according to the clinical presentation of atherosclerotic cardiovascular disease and individual patient factors is a clinical challenge. Modulation of antiplatelet therapy is a medical action that is frequently performed to balance the risk of thrombotic or ischemic events and the risk of bleeding. This aim may be achieved by reducing (ie, de-escalation) or increasing (ie, escalation) the intensity of platelet inhibition by changing the type, dose, or number of antiplatelet drugs. Because de-escalation or escalation can be achieved in different ways, with a number of emerging approaches, confusion arises with terminologies that are often used interchangeably. To address this issue, this Academic Research Consortium collaboration provides an overview and definitions of different strategies of antiplatelet therapy modulation for patients with coronary artery disease, including but not limited to those undergoing percutaneous coronary intervention, and consensus statements on standardized definitions.
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Síndrome Coronariana Aguda , Doença da Artéria Coronariana , Intervenção Coronária Percutânea , Trombose , Humanos , Inibidores da Agregação Plaquetária/efeitos adversos , Doença da Artéria Coronariana/complicações , Hemorragia/etiologia , Plaquetas , Terapia Antiplaquetária Dupla/efeitos adversos , Síndrome Coronariana Aguda/terapia , Trombose/etiologia , Intervenção Coronária Percutânea/efeitos adversos , Resultado do TratamentoRESUMO
Arcobacter spp. is an emerging pathogen that is increasingly recognized as a cause of human infections. Gastrointestinal manifestations are most described in the case report literature. We present a case of the first documented case of Arcobacter spp. isolated in pericardial fluid in an immunocompromised patient with worsening cardiac tamponade that was successfully managed with an urgent pericardiocentesis and ensuing steroids, antibiotics, and a pericardial drain. The patient had a past medical history of HIV, latent syphilis, PCP pneumonia, ESRD, and hypertension, and presented with worsening dyspnea, subjective fever, myalgias, cough, pleuritic chest pain, and pericardial rub. Diagnostic workup revealed a positive COVID-19 PCR test, elevated high-sensitive cardiac troponins, elevated CRP, elevated D-dimer, and elevated creatinine. An ECG revealed diffuse ST-segment elevation, and imaging showed cardiomegaly with pulmonary vascular congestion and diffuse interstitial edema. Urgent TTE showed a large circumferential pericardial effusion with tamponade physiology present. Culture on aerobic blood agar grew Arcobacter spp. of unknown specific species, and blood cultures were also positive for Arcobacter spp. Treatment involved intravenous meropenem for five days, followed by oral ciprofloxacin, low-dose colchicine, and a tapered dose of ibuprofen. Repeat laboratory data and TTE showed complete resolution of the pericardial effusion and improved left ventricular function. This case highlights the potential for Arcobacter spp. to cause severe infections and the importance of considering it as a possible pathogen in patients with atypical presentations.
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Antiplatelet agents are among the most frequently used medications in cardiovascular medicine. Although in patients with atherosclerotic disease manifestations, in particular those treated by percutaneous coronary intervention, antiplatelet agents are beneficial for the prevention of ischemic events, they inevitably increase the risk of bleeding. Furthermore, 5-15% of patients treated by percutaneous coronary intervention may need a surgical procedure within 2 years, creating challenges to safe and effective antiplatelet drug management. Importantly, major spontaneous or procedural-related bleedings are associated with increased hospital admission, length, costs, and poor prognosis. Although the effects of other antithrombotic therapies, such as direct oral anticoagulants, can be reversed by approved specific agents, there are no approved reversal agents for any antiplatelet drugs. The fact that many antiplatelet agents, such as aspirin and thienopyridines (i.e., clopidogrel and prasugrel), bind irreversibly to their targets represents a challenge for the development of a drug-specific reversal agent. In contrast, ticagrelor is a non-thienopyridine with a plasma half-life of 7-9 h that reversely binds the P2Y12 receptor producing potent signaling blockage. In 2015, bentracimab (also known as PB2452 or MEDI2452), a neutralizing monoclonal antibody fragment that binds free plasma ticagrelor and its major active metabolite, was identified. This systematic overview provides a comprehensive summary of the drug development program of bentracimab, focusing on its pharmacodynamic, pharmacokinetic, and safety profiles.
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Síndrome Coronariana Aguda , Intervenção Coronária Percutânea , Humanos , Síndrome Coronariana Aguda/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Clopidogrel , Hemorragia/induzido quimicamente , Inibidores da Agregação Plaquetária/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , TicagrelorRESUMO
BACKGROUND: Phase II randomized controlled trials (RCTs) on factor(F)XI inhibitors have shown promising results but they were burdened by low statistical power for clinical outcomes. METHODS: We performed a systematic review and meta-analysis of RCT comparing FXI inhibitors versus other anticoagulants (enoxaparin or direct oral anticoagulants, DOACs) or versus placebo on top of antiplatelet therapy. RESULTS: Eight RCTs testing FXI inhibitors (ISIS 416858, osocimab, abelacimab, milvexian, asundexian) and enrolling 9,216 patients were included. Compared with enoxaparin, FXI inhibitors were associated with reduced any-bleeding (risk ratio [RR]: 0.49, 95% confidence interval [CI]: 0.31-0.77), no difference in major bleeding (RR: 0.96, 95% CI: 0.41-2.28), and reduced trial-defined efficacy endpoint (RR: 0.62, 95% CI: 0.49-0.79), the latter driven by the high-dose regimens. Compared with DOACs, FXI inhibitors were associated with a trend toward reduced any-bleeding (RR: 0.66, 95% CI: 0.31-1.38) and no difference in major bleeding (RR: 1.03, 95% CI: 0.22-4.78) or in trial-defined efficacy endpoint (RR: 1.23, 95% CI: 0.88-1.70). Compared with placebo, FXI inhibitors were associated with increased any-bleeding (RR: 1.25, 95% CI: 1.08-1.43) and a trend toward increased major bleeding (RR: 1.21, 95% CI: 0.75-1.93), both driven by high-dose regimens, with no difference in trial-defined efficacy endpoint (RR: 1.02, 95% CI: 0.92-1.13). CONCLUSION: Results of this meta-analysis on FXI inhibitors suggest increased safety and efficacy compared with enoxaparin and modest increased safety compared with DOACs. The use of FXI inhibitors in adjunct to antiplatelet therapy versus placebo appears to be associated with a dose-dependent increase in bleeding without any difference in efficacy. STUDY REGISTRATION: This study is registered in PROSPERO (CRD42022367706).
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Enoxaparina , Fator XI , Humanos , Inibidores da Agregação Plaquetária , AnticoagulantesRESUMO
Ticagrelor has multiple indications, including for some patients with chronic coronary syndromes (CCS) at high risk of ischaemic events. Body mass can potentially affect pharmacodynamics (PD) and pharmacokinetics (PK). We investigated the influence of body mass (range 53-172 kg, 20.8-46.9 kg/m2) on PD/PK in 221 CCS patients receiving ticagrelor 60 mg or 90 mg twice-daily (BD) during two randomised-controlled trials. Correlations between body weight (BW) or body mass index (BMI) and PD/PK measurements obtained during maintenance treatment at trough ('pre-dose') and peak effect ('post-dose') were assessed. BW and BMI correlated with P2Y12 reactivity units at pre-dose (e.g. BW:R = 0.26, p = 0.008) but not post-dose timepoints. BW affected ticagrelor active metabolite (TAM) levels (e.g. 60 mg BD, post-dose:R = -0.39, p < 0.0001) and there was evidence of an inverse power law relationship between BW and TAM-to-ticagrelor ratio. PK with ticagrelor 60 mg correlated significantly with BMI. BW and BMI did not affect the chance of high platelet reactivity, which remained very low across the whole cohort. There was no difference in PRU between the two doses of ticagrelor within each weight or BMI group. Body mass has modest effects on the PK/PD response to ticagrelor in patients with CCS but currently-used regimens appear adequate across the range of BW/BMI studied.
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Agregação Plaquetária , Antagonistas do Receptor Purinérgico P2Y , Humanos , Ticagrelor/efeitos adversos , Índice de Massa Corporal , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Adenosina/efeitos adversos , Plaquetas , Peso Corporal , Inibidores da Agregação Plaquetária/efeitos adversos , Resultado do TratamentoRESUMO
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.
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Anticolesterolemiantes , Aterosclerose , Doenças Cardiovasculares , Inibidores de Hidroximetilglutaril-CoA Redutases , Humanos , Pró-Proteína Convertase 9 , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , LDL-Colesterol/uso terapêutico , Clopidogrel/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/efeitos adversos , Doenças Cardiovasculares/tratamento farmacológico , Estudos Prospectivos , Aterosclerose/tratamento farmacológico , Resultado do Tratamento , Método Duplo-CegoRESUMO
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).
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Doença da Artéria Coronariana , Humanos , Ticagrelor , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/tratamento farmacológico , Inibidores da Agregação Plaquetária , Estudos Prospectivos , Resultado do Tratamento , Plaquetas/metabolismo , Antagonistas do Receptor Purinérgico P2Y , Testes de Função PlaquetáriaRESUMO
INTRODUCTION: The persistence of elevated rates of ischemic recurrences despite the use of antiplatelet therapy among patients with atherosclerotic disease together with the understanding of the pivotal role of coagulation in the thrombo-inflammatory processes involved in the pathogenesis of atherosclerosis and its complications has fostered the development of treatments targeting both platelets and coagulation, a strategy known as dual-pathway inhibition (DPI). AREAS COVERED: In this review we discuss the recent advancements in the understanding of the interplay between coagulation, platelets and inflammation involved in the pathophysiology of atherosclerosis and atherothrombosis, as the rationale for the implementation of a DPI strategy. We also discuss the available pharmacodynamic (PD) evidence and clinical implications with the use of DPI in patients with atherosclerotic disease. EXPERT OPINION: The implementation of a DPI by adding the so-called 'vascular dose of rivaroxaban' (i.e. 2.5 mg bis in die), on top of antiplatelet therapy has consistently been associated with reduced levels of thrombin generation in PD studies and with reduced ischemic event rates at the cost of increased bleeding compared to antiplatelet therapy alone. Further research is warranted to best define patients in whom a DPI regimen has the best safety and efficacy profile.
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Aterosclerose , Inibidores da Agregação Plaquetária , Humanos , Inibidores da Agregação Plaquetária/efeitos adversos , Aspirina , Aterosclerose/complicações , Hemorragia/induzido quimicamente , Rivaroxabana , Quimioterapia CombinadaRESUMO
Dual antiplatelet therapy (DAPT) represents the standard of care for patients undergoing percutaneous coronary intervention (PCI). Increasing evidence indicates that a "one-size-fits-all" approach with the use of a standard DAPT regimen for all patients undergoing PCI could lead to either suboptimal efficacy or prohibitively high bleeding in specific cohorts of patients. Moreover, the broad interindividual variability in response to P2Y12 inhibitors can impact outcomes and resource utilization. Among the strategies proposed to provide a more balanced trade-off between bleeding and ischemic events at a single patient level, a guided selection of P2Y12 inhibitors, by using platelet function or genetic testing, has shown promising results. In this review, we provide a focused summary of the rationale and evidence on the use of platelet function and genetic testing-guided antiplatelet therapy, and we explore the implications for their use in the modern setting of patients undergoing PCI.
Assuntos
Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária , Humanos , Inibidores da Agregação Plaquetária/efeitos adversos , Intervenção Coronária Percutânea/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Terapia Antiplaquetária Dupla/efeitos adversos , Hemorragia/induzido quimicamente , Testes Genéticos , Resultado do TratamentoRESUMO
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.
Assuntos
Doença da Artéria Coronariana , Diabetes Mellitus , Adenosina , Difosfato de Adenosina/farmacologia , Aspirina/uso terapêutico , Plaquetas , Clopidogrel/farmacologia , Clopidogrel/uso terapêutico , Doença da Artéria Coronariana/tratamento farmacológico , Diabetes Mellitus/tratamento farmacológico , Humanos , Agregação Plaquetária , Inibidores da Agregação Plaquetária , Testes de Função Plaquetária , Cloridrato de Prasugrel , Estudos Prospectivos , Ticagrelor/farmacologia , Ticagrelor/uso terapêuticoRESUMO
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.
Assuntos
Aspirina , Inibidores da Agregação Plaquetária , Ácido Araquidônico , Aspirina/farmacocinética , Aspirina/farmacologia , Cápsulas , Estudos Cross-Over , Humanos , Fosfolipídeos , Inibidores da Agregação Plaquetária/farmacocinética , Inibidores da Agregação Plaquetária/farmacologia , Estudos Prospectivos , Ácido Salicílico , Comprimidos , Tromboxano B2RESUMO
Precision medicine is a medical model that proposes the customization of medical treatments to the individual patient, as opposed to a one-drug-fits-all model. Such a "personalized medicine" approach has been widely adopted in several medical fields, such as cancer medicine, but the implementation of precision medicine in cardiovascular medicine has not been similarly straightforward. Because pharmacogenomics plays an important role in the safety and efficacy of cardiovascular drug therapy, there has been a great interest in the use of tools aiming at personalizing antiplatelet therapy. Moreover, antiplatelet therapy is essential for the treatment of cardiovascular patients to reduce the risk of thrombotic complications, particularly those undergoing percutaneous coronary intervention, but it is inevitably associated with increased bleeding risk. In this review, the authors discuss the rationale, summarize the evidence and discuss the current and future directions for the personalization of antiplatelet treatment regimens in patients undergoing percutaneous coronary intervention.
Assuntos
Cardiologia , Intervenção Coronária Percutânea , Hemorragia/induzido quimicamente , Hemorragia/tratamento farmacológico , Hemorragia/genética , Humanos , Intervenção Coronária Percutânea/efeitos adversos , Inibidores da Agregação Plaquetária/efeitos adversos , Medicina de Precisão , Resultado do TratamentoRESUMO
For 20 years, dual antiplatelet therapy (DAPT), consisting of the combination of aspirin and a platelet P2Y12 receptor inhibitor, has been the gold standard of antithrombotic pharmacology after percutaneous coronary intervention (PCI). In the past 5 years, several investigations have challenged this paradigm by testing the efficacy and safety of P2Y12 inhibitor monotherapy (that is, without aspirin) following a short course of DAPT. Collectively, these studies suggested a reduction in the risk of major bleeding and no significant increase in thrombotic or ischaemic events compared with guideline-recommended DAPT. Current recommendations are evolving to inform clinical practice on the ideal candidates for P2Y12 inhibitor monotherapy after PCI. Generalizing the results of studies of P2Y12 inhibitor monotherapy requires a thorough understanding of their design, populations, interventions, comparators and results. In this Review, we provide an up-to-date overview on the use of P2Y12 inhibitor monotherapy after PCI, including supporting pharmacodynamic and clinical evidence, practical recommendations and future directions.