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Comparing the effect of clopidogrel versus ticagrelor on coronary microvascular dysfunction in acute coronary syndrome patients (TIME trial): study protocol for a randomized controlled trial.

ABSTRACT: Although prompt reperfusion treatment restores normal epicardial flow, microvascular dysfunction may persist in some patients with acute coronary syndrome (ACS). Impaired myocardial perfusion is caused by intraluminal platelets, fibrin thrombi and neutrophil plugging; antiplatelet agents play a significant role in terms of protecting against thrombus microembolization. A novel antiplatelet agent, ticagrelor, is a non-thienopyridine, direct P2Y12 blocker that has shown greater, more rapid and more consistent platelet inhibition than clopidogrel. However, the effects of ticagrelor on the prevention of microvascular dysfunction are uncertain. The present study is a comparison between clopidogrel and ticagrelor use for preventing microvascular dysfunction in patients with ST elevation or non-ST elevation myocardial infarction (STEMI or NSTEMI, respectively).The TIME trial is a single-center, randomized, open-label, parallel-arm study designed to demonstrate the superiority of ticagrelor over clopidogrel. A total of 152 patients with a spectrum of STEMI or NSTEMI will undergo prospective random assignment to clopidogrel or ticagrelor (1:1 ratio). The primary endpoint is an index of microcirculatory resistance (IMR) measured after percutaneous coronary intervention (PCI); the secondary endpoint is wall motion score index assessed at 3 months by using echocardiography.The TIME trial is the first study designed to compare the protective effect of clopidogrel and ticagrelor on coronary microvascular dysfunction in patients with STEMI and NSTEMI.ClinicalTrials.gov: NCT02026219. Registration date: 24 December 2013.

SUBMITTER: Park SD

PROVIDER: S-EPMC4031487 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Comparing the effect of clopidogrel versus ticagrelor on coronary microvascular dysfunction in acute coronary syndrome patients (TIME trial): study protocol for a randomized controlled trial.

Park Sang-Don SD Baek Yong-Soo YS Woo Seong-Ill SI Kim Soo-Han SH Shin Sung-Hee SH Kim Dae-Hyeok DH Kwan Jun J Park Keum-Soo KS

Trials 20140501

<h4>Background</h4>Although prompt reperfusion treatment restores normal epicardial flow, microvascular dysfunction may persist in some patients with acute coronary syndrome (ACS). Impaired myocardial perfusion is caused by intraluminal platelets, fibrin thrombi and neutrophil plugging; antiplatelet agents play a significant role in terms of protecting against thrombus microembolization. A novel antiplatelet agent, ticagrelor, is a non-thienopyridine, direct P2Y12 blocker that has shown greater, ...[more]

PMID: 24885437

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Project description:BackgroundPotent P2Y12 inhibitors such as ticagrelor and prasugrel are superior to clopidogrel in acute coronary syndrome (ACS) patients treated with percutaneous coronary intervention (PCI). Whether this benefit extends to a patient population with chronic coronary syndromes (CCS) is unclear.AimsWe sought to compare the safety and efficacy of prasugrel and ticagrelor versus clopidogrel in patients undergoing PCI for CCS.MethodsConsecutive patients undergoing PCI for CCS at a tertiary centre between 2014 and 2019 who were discharged on prasugrel or ticagrelor were compared with those on clopidogrel. The primary endpoint was the composite of death and myocardial infarction (MI), with secondary outcomes including rates of bleeding, stroke, and target vessel revascularisation at 1 year.ResultsOverall, 11,508 patients were included in the study (ticagrelor/prasugrel n=2,860 [24.9%], clopidogrel n=8,648 [75.1%]) with an increasing frequency of potent P2Y12 inhibitor use over the study period (ptrend<0.001). Clopidogrel was used more frequently in patients with multimorbid risk factors, whereas anatomical or procedural complexity was associated with ticagrelor/prasugrel use (left main PCI, bifurcation PCI, number of lesions, rotational atherectomy). No difference in the incidence of death or MI was noted across the groups (ticagrelor/prasugrel vs clopidogrel: 2.7% vs 3.1%, adjusted hazard ratio [adjHR] 0.86, 95% confidence interval [CI]: 0.62-1.17; p=0.33) or secondary outcomes including bleeding (adjHR 0.75, 95% CI: 0.46-1.21; p=0.23) on propensity score stratification analysis. Additionally, no difference in the primary outcome was observed across subgroups, including those undergoing complex PCI.ConclusionsTicagrelor and prasugrel are increasingly used in patients with CCS undergoing PCI with similar 1-year efficacy and safety when compared to clopidogrel. Whether use of these agents can be beneficial in patients undergoing PCI for CCS with a high thrombotic and low bleeding risk warrants further study.

Project description:BackgroundIt is still unknown whether diabetes mellitus (DM) affects the relative safety and efficacy of ticagrelor vs clopidogrel in East Asian patients with acute coronary syndrome (ACS).ObjectivesThe authors sought to assess the safety and efficacy of ticagrelor vs clopidogrel according to the diabetic status of East Asian patients with ACS undergoing invasive management.MethodsThis prespecified analysis of the TICA KOREA (Clinically Significant Bleeding With Ticagrelor Versus Clopidogrel in Korean Patients With Acute Coronary Syndromes Intended for Invasive Management) trial included 800 Korean patients. The primary safety endpoint was clinically significant bleeding (PLATO [Platelet Inhibition and Clinical Outcomes] major or minor bleeding) at 12 months; the efficacy endpoint was major adverse cardiovascular events (cardiovascular death, myocardial infarction, and stroke).ResultsOf 800 patients, 216 (27.0%) had DM. The incidence of clinically significant bleeding within 12 months was significantly higher with ticagrelor than clopidogrel in the nondiabetic group (10.2% vs 4.3%; HR: 2.45; 95% CI: 1.27-4.70; P = 0.007) and tended to be higher in the diabetic group (13.8% vs 8.0%; HR: 1.87; 95% CI: 0.54-4.36; P = 0.15); there was no significant interaction between treatment-arm and DM (P for interaction = 0.64). The incidences of major adverse cardiovascular events were not significantly different after ticagrelor or clopidogrel both in the diabetic group (10.8% vs 6.0%; HR: 1.90; 95% CI: 0.71-5.07; P = 0.20) and in the nondiabetic group (8.5% vs 5.7%; HR: 1.51; 95% CI: 0.81-2.81; P = 0.19) without significant interaction (P-for-interaction = 0.71).ConclusionsIn Korean ACS patients undergoing early invasive management, diabetes status did not affect the relative safety and efficacy of ticagrelor and clopidogrel. (Safety and Efficacy of Ticagrelor Versus Clopidogrel in Asian/Korean Patients With Acute Coronary Syndromes Intended for Invasive Management [TICA KOREA]; NCT02094963).

Project description:BACKGROUND: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. METHODS: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 part of standard care, they are due to switch from DAPT (ASP?+?any P2Y12 blocker) to single antiplatelet treatment with ASP alone after 6-12 months. Patients are randomised to receive either TIC or TIC?+?ASP for 4 weeks. All patients then revert to standard care with ASP alone. Blood samples and clinical data are collected at three study visits: at baseline during treatment with ASP?+?any P2Y12 blocker (visit 1); approximately 4 weeks after visit 1 during treatment with either TIC or TIC?+?ASP (visit 2); and approximately 8 weeks after visit 1 when treatment has reverted to ASP alone (visit 3). The primary outcome is the extent of platelet inhibition, measured by light transmission aggregation, flow cytometry, flow chamber and plasma biomarker tests. The primary analysis will compare the extent of platelet inhibition between the TIC and TIC?+?ASP groups at visit 2, adjusted for baseline platelet reactivity. Secondary analyses will compare the extent of platelet inhibition at visit 2 with that at visit 3. DISCUSSION:This is the first study to compare in detail the extent of platelet inhibition in patients who are receiving TIC compared with TIC?+?ASP. The study findings will complement larger-scale trials of the clinical efficacy and safety of TIC compared to TIC?+?ASP. TRIAL REGISTRATION:ISRCTN registry, identifier ISRCTN84335288 . Registered on 23 June 2014.

Project description:BACKGROUND:The dose and time point for switching from clopidogrel to ticagrelor remain controversial, especially for Chinese acute coronary syndrome (ACS) patients with complicated coronary artery disease (CAD). Hence, the purpose of this study was to further explore the optimal dose and time point for the switching strategy to balance the increase in platelet inhibition and the decrease in adverse events in Chinese ACS patients with complicated CAD managed by percutaneous coronary intervention (PCI). METHODS:From July 2017 to December 2017, the prospective, randomized, open-label study (the SwitcHIng from clopidogrel to ticagrelor study) assigned the eligible Chinese ACS patients with complicated CAD managed by PCI (n = 102) for 90 mg of ticagrelor at 12 h (T-90 mg-12 h), 90 mg of ticagrelor at 24 h (T-90 mg-24h) or 180 mg ticagrelor at 24 h (T-180 mg-24 h) after the last dose of clopidogrel. The primary endpoint was the comparison of maximal platelet aggregation (MPA) values at 2 h after switching strategies among the three groups. In addition, the MPA values at baseline, 8 h and before discharge and the rates of high on-treatment platelet reactivity were evaluated, the incidences of bleeding episodes and dyspnea during hospitalization and at 30-day follow-up in our study were also recorded. The MPA was measured by light transmittance aggregometry in our study. A repeated-measures analysis of variance (ANOVA) model and one-way ANOVA were used to compare data for the primary endpoint. RESULTS:The MPA values were significantly decreased in the T-180 mg-24 h group compared with the T-90 mg-12 h group (P = 0.017) and decreased numerically compared with the T-90 mg-24 h group (P = 0.072) at 2 h. In particular, the MPA values were markedly reduced in the T-90 mg-24 h group compared with the T-90 mg-12 h group at 8 h after switching treatment (P = 0.002). There was no significant difference among the three groups in all bleedings and dyspnea events. CONCLUSIONS:The optimal treatment strategy recommended in this study for Chinese ACS patients with complicated CAD managed by PCI is 180 or 90 mg of ticagrelor at 24 h after the last dose of clopidogrel. In addition, a negative interaction was detected in this study between the overlap for clopidogrel and ticagrelor at 12 h after the last dose of clopidogrel. TRIAL REGISTRATION:ClinicalTrials.gov, NCT03577652; http://clinicaltrials.gov/ct2/show/NCT03577652.

Dataset Information

Comparing the effect of clopidogrel versus ticagrelor on coronary microvascular dysfunction in acute coronary syndrome patients (TIME trial): study protocol for a randomized controlled trial.

Publications

Comparing the effect of clopidogrel versus ticagrelor on coronary microvascular dysfunction in acute coronary syndrome patients (TIME trial): study protocol for a randomized controlled trial.

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