Antiplatelet efficacy of ticagrelor versus clopidogrel in Mediterranean patients with diabetes mellitus and chronic coronary syndromes: A crossover pharmacodynamic investigation.

Introduction: Patients with diabetes mellitus (DM) have augmented platelet reactivity and diminished responsiveness to clopidogrel. Ticagrelor, a more potent P2Y12 inhibitor, is clinically superior to clopidogrel in acute coronary syndromes, although its role in chronic coronary syndromes (CCS) is still the subject of debate. The aim of this investigation was to compare the pharmacodynamic effectiveness of ticagrelor and clopidogrel in Mediterranean DM patients with CCS. Materials and methods: In this prospective, randomized, crossover study, patients (n = 20) were randomized (1:1) to receive, on top of aspirin therapy, either ticagrelor 180 mg loading dose (LD)/90 mg maintenance dose (MD) b.i.d. or clopidogrel 600 mg LD/75 mg MD o.d. for 1 week in a crossover fashion with a 2-4 week washout period between regimens. Platelet function measurements were performed at 4 timepoints in each period (baseline, 2 h and 24 h after LD, and 1 week), including light transmission aggregometry (LTA, primary endpoint), VASP assay, Multiplate and VerifyNow P2Y12. Results: The ticagrelor LD achieved greater platelet inhibitory effect than clopidogrel LD, assessed with LTA (20 µM ADP as agonist), at 2 h (34.9 ± 3.9% vs. 63.6 ± 3.9%; p < 0.001) and 24 h (39.4 ± 3.5% vs. 52.3 ± 3.8%; p = 0.014). After 1 week of therapy, platelet reactivity was again significantly inferior with ticagrelor compared to clopidogrel (30.7 ± 3.0% vs. 54.3 ± 3.0%; p < 0.001). The results were consistent with the other platelet function assays employed. Conclusion: In Mediterranean patients with DM and CCS, ticagrelor provides a more potent antiplatelet effect than clopidogrel after the LD and during the maintenance phase of therapy. Clinical trial registration: [ClinicalTrials.gov], identifier [NCT02457130].

Association of fractalkine with functional severity of heart failure and impact on clopidogrel efficacy in patients with ischemic heart disease.

INTRODUCTION: Patients with heart failure (HF) display elevated levels of soluble fractalkine, a chemokine involved in inflammation processes, atherosclerosis and platelet activation. Further, fractalkine has been associated with reduced pharmacodynamic (PD) responsiveness to clopidogrel. The aim of this study was to investigate the association of fractalkine with the severity of HF and its impact on platelet activation and clopidogrel response in patients with coronary artery disease (CAD) with and without HF. MATERIALS AND METHODS: This prospective PD study included 116 stable CAD patients on DAPT with aspirin and clopidogrel. Subjects were classified in two groups: patients with HF and reduced (<40%) left ventricular ejection fraction (HFrEF group, n = 56) and patients without HF (no HF group, n = 60). Clinical severity of HF was graded according to NYHA classification. Platelet function assays included vasodilator-stimulated phosphoprotein assay, multiple electrode aggregometry and light transmittance aggregometry. Fractalkine and P-selectin concentrations were determined by ELISA. RESULTS: Fractalkine levels progressively increased with the severity of the disease in the HFrEF group (NYHA I: 471.2 ± 52.4 pg/ml, NYHA II: 500.5 ± 38.4 pg/ml, NYHA III: 638.9 ± 54.3 pg/ml, p for linear trend 0.023). Numerically higher concentrations of fractalkine were observed in the HFrEF group compared to the no HF group with borderline significance (p = 0.052). No significant differences in clopidogrel-induced platelet inhibition according to fractalkine values were observed in any of the groups. CONCLUSIONS: Fractalkine levels were increased in patients with HFrEF and positively associated with the functional severity of the disease. No evident impact of fractalkine on clopidogrel PD efficacy was found.

High and low on-treatment platelet reactivity to P2Y12 inhibitors in a contemporary cohort of acute coronary syndrome patients undergoing percutaneous coronary intervention.

INTRODUCTION: There is compelling evidence supporting the association between high on-treatment platelet reactivity (HPR) and low on-treatment platelet reactivity (LPR) to clopidogrel with atherothrombotic and bleeding events, respectively. However, it is uncertain if current cutoff values should be used in prasugrel- or ticagrelor-treated subjects. The objective of this analysis was to evaluate the pharmacodynamic (PD) efficacy of P2Y12 antagonists in a contemporary real-world population. MATERIALS AND METHODS: This PD study included 988 patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) and receiving dual therapy with aspirin and a P2Y12 inhibitor (clopidogrel, prasugrel or ticagrelor). Platelet function was assessed at day 1 and day 30 post-PCI by VerifyNow P2Y12 assay, multiple electrode aggregometry and vasodilator-stimulated phosphoprotein (VASP) assay. RESULTS: Clopidogrel-treated patients (n = 324) had greater platelet reactivity than those receiving ticagrelor (n = 469) or prasugrel (n = 195) at both time points (p < 0.001 for all comparisons). No difference between ticagrelor and prasugrel was observed at day 1 with the VerifyNow P2Y12 assay (51.5 ±â€¯2.8 vs. 42.7 ±â€¯3.5 PRUs; p = 0.298), whereas ticagrelor achieved greater platelet inhibition at day 30 (48.1 ±â€¯2.5 vs. 89.2 ±â€¯4.2 PRUs; p < 0.001). Similar results were obtained with the VASP assay. Both prasugrel and ticagrelor had markedly lower HPR rates than clopidogrel and very high rates of LPR at both time points. CONCLUSIONS: Prasugrel and ticagrelor displayed more potent and consistent PD effects than clopidogrel in ACS patients undergoing PCI, with a trend towards greater platelet inhibition with ticagrelor during the maintenance phase of therapy compared to prasugrel.

Hallazgos por IVUS en trombosis de stent tardía y muy tardía. Comparación entre stents metálicos y farmacoactivos / IVUS findings in late and very late stent thrombosis. A comparison between bare-metal and drug-eluting stents

Introducción y objetivos: La trombosis de stent (TS) es una complicación grave tras la angioplastia coronaria, y la ecografía intravascular es una herramienta capaz de discernir las causas. El objetivo es comparar los hallazgos por ecografía intravascular entre stents metálicos (SM) y stents farmacoactivos (SFA) en pacientes con TS tardía (de 31 días a 1 año) o muy tardía (>1año). Métodos: Se incluyó a 114 pacientes (el 45,5% con SM y el 54,5% con SFA) de un total de 250 consecutivos con TS tardía o muy tardía en 7 hospitales españoles. Se realizó una ecografía intravascular, que se analizó posteriormente para detectar la presencia de malaposición, infraexpansión y neoateroesclerosis. Resultados: El tiempo hasta la TS fue de 4,0 años en los SM y 3,4 años en los SFA (p = 0,04). La malaposición fue similar en ambos grupos (el 36,5 frente al 46,8%; p = 0,18), aunque numéricamente menor en los SM con trombosis muy tardía (el 26,6 frente al 48,0%; p = 0,07). La infraexpansión se observó de manera similar en ambos grupos (el 13,5 frente al 11,3%; p = 0,47). La neoateroesclerosis solo se observó en TS muy tardías y fue más prevalente en los SM (22,9%) que en los SFA (6,0%; p = 0,02). A los 2,9 años de seguimiento, las muertes cardiacas eran 0 frente a 6,9% respectivamente (p = 0,06) y las recurrencias de TS se produjeron en el 4,0 frente al 5,2% (p = 0,60). Conclusiones: La malaposición es el hallazgo más frecuente en los pacientes con TS tardía y muy tardía, más prevalente en los SFA con TS muy tardías. Sin embargo, la neoateroesclerosis se observó únicamente en pacientes con TS muy tardías, y principalmente en SM

Introduction and objectives: Stent thrombosis (ST) is a life-threatening complication after stent implantation. Intravascular ultrasound is able to discern most causes of ST. The aim of this study was to compare intravascular ultrasound findings between bare-metal stents (BMS) and drug-eluting stents (DES) in patients with late (31 days to 1 year) or very late ST (> 1 year). Methods: Of 250 consecutive patients with late or very late ST in 7 Spanish institutions, 114 patients (45.5% BMS and 54.5% DES) were imaged with intravascular ultrasound. Off-line intravascular ultrasound analysis was performed to assess malapposition, underexpansion, and neoatherosclerosis. Results: The median time from stent implantation to ST was 4.0 years with BMS and 3.4 years with DES (P = .04). Isolated malapposition was similarly observed in both groups (36.5% vs 46.8%; P = .18) but was numerically lower with BMS (26.6% vs 48.0%; P = .07) in patients with very late ST. Isolated underexpansion was similarly observed in both groups (13.5% vs 11.3%; P = .47). Isolated neoatherosclerosis occurred only in patients with very late ST and was more prevalent with BMS (22.9%) than with DES (6.0%); P = .02. At 2.9 years' follow-up, there were 0% and 6.9% cardiac deaths, respectively (P = .06) and recurrent ST occurred in 4.0% and 5.2% of patients, respectively (P = .60). Conclusions: Malapposition was the most common finding in patients with late and very late ST and is more prevalent with DES in very late ST. In contrast, neoatherosclerosis was exclusively observed in patients with very late ST and mainly with BMS

Impact of acute exacerbations on platelet reactivity in chronic obstructive pulmonary disease patients.

Background: A higher risk of atherothrombotic cardiovascular events, which are platelet-driven processes, has been described during acute exacerbations of chronic obstructive pulmonary disease (AECOPD). However, the relevance of platelet reactivity during AECOPD and whether this is affected by antiplatelet agents are not fully elucidated to date. This study aimed to evaluate whether platelet reactivity is augmented during an exacerbation in COPD patients with and without antiplatelet therapy and its association with systemic inflammatory parameters. Materials and methods: Prospective, observational, ex vivo investigation was conducted in consecutive patients suffering an exacerbation of COPD. Platelet reactivity was assessed during AECOPD and at stable state. Platelet function assays included: 1) vasodilator-stimulated phosphoprotein assay expressed as P2Y12 reactivity index (PRI), 2) multiple electrode aggregometry and 3) optical aggregometry. Systemic inflammatory parameters such as leukocyte count, interleukin-6 and fibrinogen were also assessed. Results: Higher platelet reactivity was observed during AECOPD compared to stability measured by vasodilator-stimulated phosphoprotein (PRI: 75.2%±1.9% vs 68.8%±2.4%, p=0.001). This augmented platelet aggregability was also observed in the subset of patients on antiplatelet therapy (PRI: 72.8%±3.1% vs 61.7%±7.5%, p=0.071). Consistent findings were observed with all other platelet function tests. Patients with greater enhancement of inflammatory markers during AECOPD were more likely to present a higher increase in platelet reactivity. Conclusion: Platelet reactivity is increased during AECOPD, which may contribute to the augmented cardiovascular risk of these patients. Additionally, the increase in platelet reactivity might be associated with an increment in inflammatory markers during exacerbations.

IVUS Findings in Late and Very Late Stent Thrombosis. A Comparison Between Bare-metal and Drug-eluting Stents.

INTRODUCTION AND OBJECTIVES: Stent thrombosis (ST) is a life-threatening complication after stent implantation. Intravascular ultrasound is able to discern most causes of ST. The aim of this study was to compare intravascular ultrasound findings between bare-metal stents (BMS) and drug-eluting stents (DES) in patients with late (31 days to 1 year) or very late ST (> 1 year). METHODS: Of 250 consecutive patients with late or very late ST in 7 Spanish institutions, 114 patients (45.5% BMS and 54.5% DES) were imaged with intravascular ultrasound. Off-line intravascular ultrasound analysis was performed to assess malapposition, underexpansion, and neoatherosclerosis. RESULTS: The median time from stent implantation to ST was 4.0 years with BMS and 3.4 years with DES (P = .04). Isolated malapposition was similarly observed in both groups (36.5% vs 46.8%; P = .18) but was numerically lower with BMS (26.6% vs 48.0%; P = .07) in patients with very late ST. Isolated underexpansion was similarly observed in both groups (13.5% vs 11.3%; P = .47). Isolated neoatherosclerosis occurred only in patients with very late ST and was more prevalent with BMS (22.9%) than with DES (6.0%); P = .02. At 2.9 years' follow-up, there were 0% and 6.9% cardiac deaths, respectively (P = .06) and recurrent ST occurred in 4.0% and 5.2% of patients, respectively (P = .60). CONCLUSIONS: Malapposition was the most common finding in patients with late and very late ST and is more prevalent with DES in very late ST. In contrast, neoatherosclerosis was exclusively observed in patients with very late ST and mainly with BMS.

Role of New Antiplatelet Drugs on Cardiovascular Disease: Update on Cangrelor.

Dual therapy with a P2Y12 receptor antagonist in addition to aspirin is the antiplatelet treatment of choice in patients with acute coronary syndromes or undergoing percutaneous coronary intervention (PCI). However, available oral P2Y12 antagonists have several limitations, mostly due to their pharmacological profile, which can affect outcomes in certain clinical settings. Cangrelor is an intravenous, direct-acting, potent P2Y12 inhibitor with rapid onset and offset of action, which has been recently approved for clinical use in patients undergoing PCI. In clinical trials, cangrelor has demonstrated greater efficacy than clopidogrel with a favorable safety profile among PCI patients not receiving pretreatment with oral P2Y12 antagonists. However, its definitive role in contemporary practice is yet to be determined. This review aims to provide a comprehensive overview of the current status of knowledge on cangrelor, focusing on its pharmacological properties, clinical development, and the potential applications of this newly available agent.

Impact of mild hypothermia on platelet responsiveness to aspirin and clopidogrel: an in vitro pharmacodynamic investigation.

UNLABELLED: The combination of percutaneous coronary intervention (PCI) and therapeutic hypothermia in comatose patients after cardiac arrest due to an acute coronary syndrome has been reported to be safe and effective. However, recent investigations suggest that hypothermia may be associated with impaired response to clopidogrel and greater risk of thrombotic complications after PCI. This investigation aimed to evaluate the effect of hypothermia on the pharmacodynamic response of aspirin and clopidogrel in patients (n = 20) with ST elevation myocardial infarction undergoing primary PCI. Higher platelet reactivity (ADP stimulus) was observed in samples incubated at 33 °C compared with those at 37 °C (multiple electrode aggregometry, 235.2 ± 31.4 AU×min vs. 181.9 ± 30.2 AU×min, p < 0.001; VerifyNow P2Y12, 172.9 ± 20.3 PRU vs. 151.0 ± 19.3 PRU, p = 0.004). Numerically greater rates of clopidogrel poor responsiveness were also observed at 33 °C. No differences were seen in aspirin responsiveness. In conclusion, mild hypothermia was associated with reduced clopidogrel-mediated platelet inhibition with no impact on aspirin effects. CLINICAL RELEVANCE: Mild therapeutic hypothermia is associated with impaired response to clopidogrel therapy, which might contribute to increase the risk of thrombotic events in ACS comatose patients undergoing PCI.

Clopidogrel pretreatment in primary percutaneous coronary intervention: prevalence of high on-treatment platelet reactivity and impact on preprocedural patency of the infarct-related artery.

To date, there is limited data on levels of platelet inhibition achieved in patients with ST-elevation myocardial infarction (STEMI) who are loaded with clopidogrel and aspirin (ASA) prior to undergoing primary percutaneous coronary intervention (P-PCI). The aim of this investigation was to evaluate the percentage of STEMI patients with high on-treatment platelet reactivity (HPR) to clopidogrel at the time of initiating P-PCI and its association with the initial patency of the infarct-related artery (IRA). This prospective pharmacodynamic study included 50 STEMI patients, previously naïve to oral antiplatelet agents, who received 500-mg ASA and 600-mg clopidogrel loading doses prior to P-PCI. Platelet function assessment was performed at the beginning of the procedure using various assays, including VerifyNow™ system (primary endpoint), light transmission aggregometry and multiple electrode aggregometry. The percentage of patients with suboptimal response to clopidogrel and ASA assessed with the VerifyNow™ system was 88.0% and 28.6%, respectively. Similar results were obtained with the other assays used. A higher percentage of patients with initial patency of the IRA was observed among those patients without HPR compared with those with HPR to clopidogrel (66.7% vs 15.9%; p=0.013), while no differences were observed regarding postprocedural angiographic or electrocardiographic outcomes. In conclusion, this study shows that a high percentage of STEMI patients have inadequate levels of clopidogrel-induced and, to a lesser extent, aspirin-mediated platelet inhibition when starting a P-PCI procedure, and suggests that a poor response to clopidogrel might be associated with impaired initial TIMI flow in the IRA.