Lack of Evidence for Deterioration in Endothelial Function Following Ticagrelor Treatment Cessation.

BACKGROUND: Ticagrelor may exert pleiotropic actions, beyond platelet inhibition, which are possibly adenosine-mediated. It has been suggested that in patients with coronary artery disease (CAD) ticagrelor may influence endothelial function. OBJECTIVE: We aimed to assess the possibility of endothelial function deterioration following ticagrelor treatment cessation. METHODS: This was a prospective, observational study, in stable CAD patients with prior percutaneous coronary intervention (PCI) for acute coronary syndrome manifested 1 year earlier, under ticagrelor maintenance dose (90 mg bid) and due to discontinue ticagrelor. Endothelial function was assessed by Peripheral Arterial Tonometry (EndoPat 2000 system, Itamar Medical, Caesarea, Israel) immediately after receiving the last tablet of ticagrelor (Day 0) and at Day 2 and Day 5 post-ticagrelor cessation. Reactive hyperaemia index (RHI) was calculated by automated software and endothelial dysfunction (ED) was defined as a RHI <1.67. RESULTS: We identified 30 eligible patients with endothelial function assessment pre- and post-ticagrelor cessation (86.7% men, 13.3% with diabetes and 33.3% current smokers; mean age: 63.6±11.5 years). The study's primary endpoint of RHI at Day 5 did not differ significantly compared with RHI at Day 0, 1.69 (1.45-2.23) vs 1.81 (1.59-2.13). ED rate did not differ significantly between Day 5 and Day 0, 40 vs 33.3%, p=0.8, respectively. No differences in RHI or ED rate were observed between Day 2 and Day 0, 1.64 (1.54-2.04) vs 1.8 1(1.59-2.13), p=0.3 and 53.3 vs 33.3%, p=0.2, respectively. In stable CAD patients there is no evidence of deterioration in endothelial function after discontinuing ticagrelor.

Comparison of Ticagrelor Versus Thienopyridine Loading Effect on Fractional Flow Reserve in Patients With Coronary Artery Disease.

Ticagrelor loading dose (LD) increases adenosine plasma levels, which might interfere with fractional flow reserve (FFR) assessment because the latter is based on adenosine-induced hyperemia. In a prospective study, consecutive patients who underwent coronary angiography with at least 1 de novo stenosis >50% and <90% in severity amenable to intervention underwent FFR assessment using intravenous adenosine 140 µg/kg/min for 3 minutes. Patients were subsequently randomized to either ticagrelor 180 mg (n = 38) or control thienopyridine (n = 38) (prasugrel 60 mg [n = 28] or clopidogrel 600 mg [n = 10]), followed by a second FFR assessment of the target lesion 2 hours after drug. Pre-drug, steady hyperemia FFR (sFFR, median, first to third quartiles) was 0.82 (0.75 to 0.88) and 0.81 (0.75 to 0.88), p = 0.9, whereas post-drug, 0.82 (0.72 to 0.87) and 0.79 (0.73 to 0.86), p = 0.5, in thienopyridine and ticagrelor-treated patients, respectively. The primary end point of percent relative change in sFFR between pre- and post-drug periods was greater in ticagrelor- than thienopyridine-treated patients, -1.24 (-5.54 to 0.0) versus -0.51 (-3.68 to 3.21), p = 0.03, respectively. Absolute change in sFFR between pre- and post-drug periods was marginally higher in ticagrelor- than thienopyridine-treated patients -0.01 (-0.04 to 0.0) versus -0.005 (-0.03 to 0.02), p = 0.048, respectively. Reclassification of treatment decision at the sFFR ≤ 0.80 cutoff post-drug occurred in 6 (15.8%) versus 5 (13.2%) of ticagrelor- and thienopyridine-treated patients, respectively. In conclusion, after ticagrelor LD, an absolute and relative reduction in sFFR compared with thienopyridine LD is observed. Administration of ticagrelor should be considered as a potential source, albeit minor, of FFR variability.

Calcium Homeostasis and Kinetics in Heart Failure.

Although HF has multiple causes amongst which coronary artery disease, hypertension and non-ischemic dilated cardiomyopathy are the most common, it results in the same final common pathway of neurohormonal activation and multiorgan dysfunction in the context of a salt-avid state. Contemporary pharmacologic HF therapy targets neurohormonal activation at multiple levels with ß- blockers, angiotensin converting enzyme inhibitors, and aldosterone inhibitors, aiming in reversing both its systemic consequences, and the adverse heart remodeling, however is frequently hampered by side effects of the drugs, limiting its benefit. During the last 40 years studies of the gross and molecular aspects of the pathophysiology of HF convincingly converge to the conclusion that deranged calcium (Ca(2+)) handling in the cardiomyocytes plays a cardinal role in HF initiation and progression. The delicate and precise regulation of Ca(2+) cycling i.e. movement into and out of the cell, as well as into and out of the sarcoplasmic reticulum (SR), is finely tuned by numerous macromolecular proteins and regulatory processes like phosphorylation and dephosphorylation, and is severely deranged in HF. The common denominator in this scenario is Ca(2+) depletion of the SR, however loading of cardiomyocytes with Ca(2+) as a result of classic inotropic therapy has proved to be detrimental in the long term. Therefore, the mediator and/or regulatory components of the Ca(2+) cycling apparatus have been the focus of extensive research involving targeted pharmacologic and gene interventions aiming to a restoration of Ca(2+) cycling processes, thus improving inotropy and lucitropy in a more "physiologic" way in the failing myocardium.

Crushed Versus Integral Tablets of Ticagrelor in ST-Segment Elevation Myocardial Infarction Patients: A Randomized Pharmacokinetic/Pharmacodynamic Study.

OBJECTIVE: The objective of this study was to assess the pharmacokinetic and pharmacodynamic behavior of ticagrelor administered either as crushed (in the semi-upright sitting position) or as integral (in the supine position) tablets in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI). METHODS: We randomized 20 patients to ticagrelor 180 mg either as 2 integral tablets administered in the supine position (standard administration) or as 2 tablets crushed and dispersed, administered in the semi-upright sitting position. Blood samples were drawn for pharmacokinetic and pharmacodynamic assessment at randomization (0 h) and at 0.5, 1, 2, and 4 h. RESULTS: At 1 h, ticagrelor plasma exposure and area under the plasma concentration-time curve from time zero to 1 h (AUC1) (co-primary endpoints) were higher in the crushed versus integral tablets group (median 586 vs. 70.1 ng/mL and 234 vs. 24.4 ng·h/mL, respectively), with a ratio of adjusted geometric means (95% confidence interval [CI]) of 12.67 (2.34-68.51) [p = 0.005] and 19.28 (3.51-106.06) [p = 0.002], respectively. Time to maximum plasma concentration was shorter in the crushed versus integral tablets group (median 2 vs. 4 h), with a ratio of adjusted geometric means (95% CI) of 0.69 (0.49-0.97) [p = 0.035]. Parallel findings were observed with AR-C124910XX (active metabolite). Platelet reactivity (VerifyNow(®)) at 1 h was lower with crushed versus standard administration with least squares estimates mean difference (95% CI) of 92 (-158.4 to 26.6) P2Y12 reaction units (p = 0.009). CONCLUSIONS: In patients with STEMI undergoing primary PCI, ticagrelor crushed tablets administered in the semi-upright sitting position seems to lead to a faster-compared with standard administration-absorption, with stronger antiplatelet activity within the first hour. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02046486.

Diabetes mellitus and platelet reactivity in patients under prasugrel or ticagrelor treatment: an observational study.

BACKGROUND: The influence of diabetes mellitus (DM) on platelet reactivity (PR) in prasugrel or ticagrelor treated patients is not well studied. METHODS: In an observational study involving 777 patients with acute coronary syndrome undergoing percutaneous coronary intervention treated by either prasugrel 10 mg od (n = 315) or ticagrelor 90 mg bid (n = 462), platelet function was assessed using the VerifyNow P2Y12 function assay (in PRU) at one month post intrvention. RESULTS: In the overall population, ticagrelor and insulin-treated DM affected PR, with a decrease in log by 0.88 (corresponding to a 58 % decrease in PR) compared to prasugrel-treated patients (p < 0.001), and an increase in log by 0.26 (corresponding to a 30 % increase in PR) compared to non-diabetic patients (p = 0.01), respectively. PR in prasugrel-treated patients differed significantly by DM status: 70.0 (36.3-113.0) in non-diabetic vs 69.0 (44.5-115.3) in non insulin-treated diabetic vs 122.0 (69.0-161.0) in insulin-treated diabetic patients, p for trend = 0.01. No differences were observed in ticagrelor-treated patients. By multivariate analysis, in prasugrel-treated patients insulin-treated DM was the only factor predicting PR, with log of PR increased by 0.42 (corresponding to a 52 % increase in PR) compared to non-diabetic patients (p = 0.001). No factor was found to affect PR in ticagrelor-treated patients. CONCLUSIONS: Patients with insulin-treated DM treated with prasugrel post PCI have higher PR, than patients without DM or non insulin-treated diabetic patients treated with this drug. Ticagrelor treated patients have overall lower PR than patients on prasugrel, independent of DM status or insulin treatment. TRIAL REGISTRATION: Clinical Trials Gov. NCT01774955.