Randomized Double-Blind Assessment of the ONSET and OFFSET of the Antiplatelet Effects of Ticagrelor Versus Clopidogrel in Patients With Stable Coronary Artery Disease: The ONSET/OFFSET Study (original) (raw)

Pharmacodynamic Effects of Switching From Ticagrelor to Clopidogrel in Patients With Coronary Artery Disease: Results of the SWAP (Switching Antiplatelet Therapy)-4 Study

Circulation, 2018

BACKGROUND: Switching between different classes of P2Y 12 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 P2Y 12 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. P2Y 12 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). P2Y 12 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 P2Y 12 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.

Platelet inhibition during ticagrelor monotherapy versus ticagrelor plus aspirin in patients with coronary artery disease (TEMPLATE study): study protocol for a randomised controlled trial

Trials, 2017

Dual antiplatelet therapy (DAPT) with aspirin (ASP) and a P2Y12 blocker is currently standard care after percutaneous coronary intervention (PCI) with stent insertion, and aims to inhibit platelet function in order to prevent stent thrombosis. The P2Y12 blocker ticagrelor (TIC) has greater antiplatelet effect than the previously used members of this class, such as clopidogrel. In healthy volunteers, TIC is sufficient to cause strong platelet inhibition, with little additional effect from ASP. Omission of ASP may improve the safety of antiplatelet regimes by reducing bleeding. However, the effect of single antiplatelet treatment with TIC, compared to DAPT with TIC + ASP, has not been studied in detail in patients with coronary artery disease. To compare TIC with TIC + ASP, we have initiated a single centre, open-label randomised controlled trial (TEMPLATE study) in adults receiving DAPT following PCI with a sample size of 110 patients. Patients are invited to join the study when, as ...

Ticagrelor: a Novel P2Y12 Platelet Receptor Antagonist -A Review of its Properties, Pharmacology and Clinical Usefulness

Blockade of platelet adenosine-diphosphate (ADP) receptors has been established as a key therapeutic strategy in cardiovascular disease. Among the thienopyridines, clopidogrel decreases ischemic outcome in patients who present with acute coronary syndromes and the more potent prasugrel has been demonstrated to be superior to clopidogrel in patients who are scheduled to undergo percutaneous coronary inter-vention. However, the antiplatelet potency is also associated with an increased risk of bleeding complications, and the irreversible ADP receptor antagonism has potential implications especially in the setting of coronary by-pass operation. Ticagrelor is a new reversible antagonist of the P2Y12 receptor, which seems to be more effective and at the same time equally safe to the so far established antiplatelet regimens. This article reviews the current data on this novel compound focusing on its advantageous pharmacology and the clinical results provided by the first phase IIb and III...

Effect of Modifying Anti-platelet Treatment to Ticagrelor in High-Risk Coronary Patients with Low Response to Clopidogrel (MATTIS)

Canadian Journal of Cardiology, 2016

Background: Treatment with clopidogrel is subject to wide variability in response, and high on-treatment platelet reactivity (HTPR) is associated with increased risk of ischemic events. Ticagrelor has been shown to have antiplatelet effects superior to those of clopidogrel, with subsequent reduced clinical ischemic events. However, the efficacy of ticagrelor in high-risk patients with coronary disease who have high ontreatment platelet reactivity (HTPR) with clopidogrel has not been examined. Methods: We recruited 201 patients (mean age, 64 AE 10 years; 20% women) with stable/unstable angina who were receiving clopidogrel treatment and in whom coronary catheterization was planned. Platelet reactivity was tested using VerifyNow P2Y12 assay (Accumetrics, San Diego, CA) (HTPR defined as P2Y12 reaction units [PRU] ! 208). Patients with HTPR were randomized to receive either additional clopidogrel 300 mg or ticagrelor 180 mg before coronary angiography, and persisted with the respective treatment after percutaneous coronary intervention (PCI). The primary end point was the rate of troponin elevation after PCI, and the secondary end point was the change in platelet reactivity 24 hours after PCI. In addition, clinical outcomes at R ESUM E

Ticagrelor Versus Prasugrel in Acute Coronary Syndrome Patients with High on Clopidogrel Treatment Platelet Reactivity Post Pci: A Pharmacodynamic Study

Journal of the American College of Cardiology, 2012

The study aimed to compare the antiplatelet action of ticagrelor with prasugrel in acute coronary syndrome (ACS) patients with high on-treatment platelet reactivity (HTPR) while on clopidogrel after percutaneous coronary intervention (PCI). Background Newer P2Y12 inhibitors like prasugrel and ticagrelor provide stronger platelet inhibition compared with clopidogrel. Both agents are efficacious in patients with HTPR while on clopidogrel, but direct comparison between them has not yet been reported. Methods In a prospective, single-center, single-blind study, 44 (of 139 screened, 31.7%) ACS patients with HTPR while on clopidogrel 24 h post-PCI were randomized to either ticagrelor 90 mg twice daily or prasugrel 10 mg once daily for 15 days with a crossover directly to the alternate treatment for another 15 days. HTPR was defined as platelet reactivity units (PRU) Ն235 as assessed by the VerifyNow P2Y12 function assay. Results The primary endpoint of platelet reactivity at the end of the 2 treatment periods was lower for ticagrelor (32.9 PRU, 95% confidence interval [CI]: 18.7 to 47.2) compared with prasugrel (101.3 PRU, 95% CI: 86.8 to 115.7) with a least squares mean difference of-68.3 PRU (95% CI:-88.6 to-48.1; p Ͻ 0.001). The secondary endpoint of HTPR rate was 0% for ticagrelor and 2.4% for prasugrel (1 of 42, p ϭ 0.5). No patient exhibited a major bleeding event at either treatment group. Conclusions In patients with ACS exhibiting HTPR while on clopidogrel 24 h post-PCI, ticagrelor produces a significantly higher platelet inhibition compared with prasugrel.

Ticagrelor as an Alternative Antiplatelet Therapy in Cardiac Patients Non-Sensitive to Aspirin

Medicina, 2020

Background and Objectives: Aspirin (acetylsalicylic acid—ASA) is a first-line antiplatelet therapy provided to patients with coronary artery disease (CAD). However, it has been demonstrated that 20–30% of these patients are non-sensitive to their ASA therapy. ASA non-sensitivity is a phenomenon where low-dose ASA (81–325 mg) does not completely inhibit arachidonic-acid-induced platelet aggregation, putting patients at risk of adverse cardio-thrombotic events. Ticagrelor is a P2Y12 receptor inhibitor and alternative antiplatelet that has been approved to reduce the risk of stroke, myocardial infarction, and overall cardiovascular-related death. In this study, we aimed to identify ASA non-sensitive patients and evaluate if they would be sensitive to ticagrelor. Materials and Methods: For this pilot study, thirty-eight patients with CAD taking 81 mg ASA were recruited. Blood samples were collected from each patient and platelet rich plasma (PRP) from each sample was isolated. Light-tra...

Administration of a Loading Dose Has No Additive Effect on Platelet Aggregation During the Switch From Ongoing Clopidogrel Treatment to Ticagrelor in Patients With Acute Coronary Syndrome

Circulation: Cardiovascular Interventions, 2014

Background— Ticagrelor outperforms clopidogrel in preventing cardiovascular events in acute coronary syndrome. Despite the inclusion of a loading dose in the Platelet Inhibition and Patient Outcomes (PLATO) trial for all patients randomized to ticagrelor, it may not be necessary in patients receiving ongoing clopidogrel therapy. The aim of the present study was to assess whether a ticagrelor loading dose is associated with a further platelet inhibition during the switch from clopidogrel to ticagrelor in patients with acute coronary syndrome receiving ongoing antiplatelet treatment. Methods and Results— Fifty patients with acute coronary syndrome receiving aspirin and clopidogrel treatment were randomly assigned to a starting dose of ticagrelor (group 1, 90 mg; group 2, 180 mg). Platelet aggregation was measured using multiple electrode aggregometry and standard light transmission aggregometry just before the switch and at 2, 6, 24, and 72 hours. No relevant difference in platelet ag...