Direct Oral Anticoagulants in Special Patient Populations.

Anticoagulants are a cornerstone of treatment in atrial fibrillation. Nowadays, direct oral anticoagulants (DOACs) are extensively used for this condition in developed countries. However, DOAC treatment may be inappropriate in certain patient populations, such as: patients with chronic kidney disease in whom DOAC concentrations may be dangerously elevated; frail elderly patients with an increased risk of falls; patients with significant drug-drug interactions (DDI) affecting either DOAC concentration or effect; patients at the extremes of body mass in whom an "abnormal" volume of distribution may result in inappropriate drug concentrations; patients with recurrent stroke reflecting an unusually high thromboembolic tendency; and, lastly, patients who experience major hemorrhage on an anticoagulant and in whom continued anticoagulation is deemed necessary. Herein we provide a fictional case-based approach to review the recommendations for the use of DOACs in these special patient populations.

Relation between ticagrelor response and levels of circulating reticulated platelets in patients with non-ST elevation acute coronary syndromes.

Antiplatelet responses to clopidogrel and prasugrel are highly variable and subject to significant rates of high on-treatment platelet reactivity (HTPR) after percutaneous coronary intervention (PCI). The proportion of circulating young reticulated platelets (RPs) inversely correlates with responsiveness to both agents. We aimed to determine the relationship between RPs and on-treatment platelet reactivity in ticagrelor-treated patients. Patients with non-ST-elevation acute coronary syndromes (NSTE-ACS) treated with PCI and ticagrelor were tested for platelet reactivity using the VerifyNow P2Y12 assay and multiplate aggregometry. RPs levels were determined using flow cytometry with thiazole orange staining. Tests were performed at 2-4 and 30 days post-PCI. Fifty three patients were included (mean age 62.6 ± 9.8 years, 18.9 % women, 35.8 % diabetes), of which 41 patients (77 %) completed follow-up. Variability in response to ticagrelor was very low according to both assays with no identified cases of HTPR at either time-point. In addition, there were no differences in platelet reactivity, as analyzed by the VerifyNow P2Y12 assay, or in the proportion of RPs between the two time points (p > 0.5). With the multiplate assay, platelet reactivity increased between the two time-points (8.6 ± 6.0 vs. 15.5 ± 11 AU*min; p = 0.0007). There was no significant correlation between RPs and platelet reactivity at both time-points and using both assays (p > 0.5). There were no cases of HTPR up to 30-days post-PCI in patients with NSTE-ACS treated with ticagrelor. In this cohort, no correlation between % RPs and platelet reactivity was observed. Attenuation of RP-induced platelet reactivity as a novel mechanism for ticagrelor's benefit requires further investigation.

Comparison of platelet inhibition by prasugrel versus ticagrelor over time in patients with acute myocardial infarction.

High on-treatment platelet reactivity (HTPR) despite use of P2Y12 antagonists is associated with adverse cardiac events. The long-term variability in response to prasugrel and ticagrelor is unclear. Our aim was to assess residual platelet reactivity (PR) and rates of HTPR during treatment with prasugrel versus ticagrelor in patients with myocardial infarction (MI). 114 patients with MI treated with percutaneous coronary intervention (PCI) were included. Sixty-two patients were treated with prasugrel (mean age 58 ± 8 years, 21 % women, 29 % diabetes), and 52 patients with ticagrelor (mean age 63 ± 9, 19 % women, 37 % diabetes). Patients were tested for PR at 2-4 days and 30 days post-PCI, using the VerifyNow P2Y12 assay and the multiple-electrode aggregometry. Our results show a higher residual PR in patients treated with prasugrel than those treated with ticagrelor (VerifyNow: 65.4 ± 60.6 vs. 26.0 ± 24.2 P2Y12 reaction units, p < 0.001 at 2-4 days, and 67.3 ± 62.5 vs. 21.1 ± 26.1, p < 0.001 at follow-up). HTPR rates were higher in the prasugrel group (8.1-11.3 % vs. none with ticagrelor in the early test, and 8.7-10.9 % vs. none with ticagrelor at follow-up). In conclusion, in patients with MI undergoing PCI, treatment with ticagrelor resulted in greater platelet inhibition and lower HTPR rates compared with prasugrel, up to 30 days after the event.

Circulating reticulated platelets over time in patients with myocardial infarction treated with prasugrel or ticagrelor.

Reticulated platelets (RP) are young, hyperactive platelets that are increased during situations of enhanced platelet turnover such as acute myocardial infarction (AMI). The dynamics of RP levels after AMI is not established. We aimed to characterize the levels of circulating RP over time in patients with AMI. Patients with AMI treated with ticagrelor or prasugrel who underwent percutaneous coronary intervention (PCI) were tested for circulating RP using flow cytometry with Thiazole orange staining at 3 time points at 2-4 days, 30-60 days and 1 year post PCI. Platelet reactivity was assessed using the VerifyNow P2Y12 assay at these time points (results in platelet reactivity units-PRU). Thirty-five patients were included in the study (mean age 62.6 ± 9.1 years, 82.9 % males). Median RP levels were similar at the first and second time points (17.5 %, IQR 25-75: 10.8-22.4 % and 14.9 %, IQR 25-75: 9.7-26.8 %, respectively; p = 0.75). However, RP levels after 1 year were significantly lower as compared to the first and second time points (10.5 % (IQR 25-75: 5.3-18.1 %), p = 0.005 and p = 0.01, respectively). Residual platelet reactivity was very low at all 3 time points (median PRU 25, IQR 25-75: 7-53) and did not change significantly between them (p = 0.66). No significant correlation was found between levels of RP and PRU at any given time point. RP levels of patients with AMI treated with prasugrel or ticagrelor decrease over time after the acute event. However, RP levels over time do not correlate well with residual platelet reactivity.

Response to prasugrel and levels of circulating reticulated platelets in patients with ST-segment elevation myocardial infarction.

OBJECTIVES: The aim of this study was to determine whether response to prasugrel is associated with the proportion of circulating reticulated platelets (RPs) in patients with ST-segment elevation myocardial infarction (STEMI). BACKGROUND: Despite better pharmacodynamic properties and clinical efficacy of prasugrel compared with clopidogrel, antiplatelet responses to prasugrel are not uniform. The mechanism of this variability in response is not clear. RPs, young hyperactive forms, are increased during situations of enhanced platelet turnover. METHODS: Patients with STEMI treated with primary percutaneous intervention (PCI) and prasugrel were tested for platelet reactivity using purinergic receptor P2Y, G-protein coupled, 12 (P2Y12) assay and multiple electrode aggregometry (MEA). RP levels were determined using flow cytometry with thiazole orange staining. Tests were performed at 2 to 4 days and 30 days post-PCI. Platelet function was compared by varying levels of RPs, analyzed as continuous (regression analysis) and categorical (tertiles) variables. RESULTS: Sixty-two patients were included (mean age: 57.5 ± 8 years; 21.2% women; 27.7% diabetes). At the early time point, RP levels were strongly correlated with platelet reactivity when evaluated by the P2Y12 assay (Spearman's correlation coefficient: 0.55 for P2Y12 reaction units, -0.49 for percent inhibition) and MEA (Spearman's: 0.50). The upper tertile of RPs displayed higher platelet reactivity compared with the middle and lower tertiles, according to P2Y12 assay and MEA. Similar results with strong correlations between RP and platelet reactivity were noted at 30 days post-PCI. CONCLUSIONS: The proportion of circulating RPs strongly correlates with response to prasugrel in patients with STEMI treated with PCI. High levels of RPs are associated with increased platelet reactivity despite prasugrel treatment.