Ticagrelor De-escalation Strategy in AMI Patients

Official title

EASTYLE (DE-escAlation Strategy for Optimal Ticagrelor Therapy in Acute MYocardiaL Infarction PatiEnts, Prospective, Multicenter, Randomized) Trial

Overview

DAPT de-escalation strategies to reduce bleeding include de-escalation of DAPT intensity (downgrading from potent P2Y12 inhibitor at conventional doses to either clopidogrel or reduced-dose prasugrel) or abbreviation of DAPT duration. The EASTYLE trial will evaluate a hybrid DAPT de-escalation strategy (reduced-dose ticagrelor, followed by aspirin early discontinuation) in AMI patients, compared with a conventional DAPT strategy.

Detailed description

In ACS patients undergoing percutaneous coronary intervention, conventional dual antiplatelet therapy (DAPT) for patients with acute coronary syndromes undergoing percutaneous coronary intervention comprises aspirin with a potent P2Y12 inhibitor (prasugrel or ticagrelor) for 12 months. Although this approach reduces ischaemic risk, patients are exposed to a substantial risk of bleeding during the stabilized period. Strategies to reduce bleeding include de-escalation of DAPT intensity (downgrading from potent P2Y12 inhibitor at conventional doses to either clopidogrel or reduced-dose prasugrel) or abbreviation of DAPT duration. Abbreviation of DAPT duration after 1-6 months, followed by monotherapy with aspirin or a P2Y12 inhibitor, reduces bleeding without an increase in ischaemic events in patients at high bleeding risk, particularly those without high ischaemic risk. Either strategy requires assessment of the ischaemic and bleeding risks of each individual. Previous clinical and laboratory evidence demonstrates that a conventional-dose of ticagrelor has a potent antiplatelet effect, which appears to have a potential to increase the risk of bleeding during the stabilized period. Adjunctive use of aspirin to P2Y12 inhibitor would be important to protect the risk of thrombotic events in AMI patients, which use has a limited benefit with increased bleeding rate during the the stabilized period.

The EASTYLE trial will evaluate clinical benefit of step-down de-escalation DAPT strategy including downgrading of P2Y12 inhibition (from 90 mg to 60 mg ticagrelor at 1 month post-PCI) and abbreviation of DAPT duration (aspirin discontinuation at 3 months post-PCI), compared with a conventional DAPT strategy in AMI patients. This trial will support that the optimal platelet inhibition would be attenuated over time even in AMI patients. The result will make a big step toward precision medicine in the field of antiplatelet treatment in AMI patients.

Interventions

• Drug De-escalation strategy
  De-escalation strategy indicates conventional DAPT (ticagrelor 90 mg twice daily + aspirin 100 mg once daily) for 1 month, followed by de-escalation DAPT (ticagrelor 60 mg twice daily + aspirin 100 mg once daily) between 1 and 3 months. Between 3 and 12 months, patients will be treated with ticagrelor monotherapy (ticagrelor 60 mg twice daily).
• Drug Conventional strategy
  Conventional stratetgy indicates conventional DAPT including ticagrelor 90 mg twice daily and aspirin 100 mg once daily during 12 months.

Primary outcome measures

• Primary endpoint (NACE) [Time frame: 12 months]

Secondary outcome measures (12)

• Major adverse cardiac and cerebrovascular events (MACCE) [Time frame: 12 months]
• Bleeding events [Time frame: 12 months]
• All-cause death [Time frame: 12 months]
• CV death [Time frame: 12 months]
• MI [Time frame: 12 months]
• Stent thrombosis [Time frame: 12 months]
• Ischemic stroke [Time frame: 12 months]
• Cardiac death, or MI [Time frame: 12 months]
• Cardiac death, MI or stent thrombosis [Time frame: 12 months]
• Cardiovascular death, MI or stroke [Time frame: 12 months]
• TLR [Time frame: 12 months]
• TVR [Time frame: 12 months]

Eligibility criteria

Inclusion criteria

• Diagnosis with acute myocardial infarction.
• Age ≥19 year-old
• Successful PCI with ultrathin bioresorbable polymer sirolimus-eluting stents (Orsiro; Biotronik AG).
• Provision of informed consent.

Exclusion criteria

• Any prior event of hemorrhagic stroke or ICH.
• Active bleeding (e.g., GI bleeding, ICH) or high-risk of serious bleeding.
• Bleeding diathesis or coagulopathy (e.g., hemoglobin ≤ 10 g/dL or platelet count < 100,000/μL, bleeding needing transfusion within 30 days, and so on).
• Allergy to stent metal, contrat media, and antiplatelet regimens.
• Moderate to severe hepatic dysfunction (Child-Pugh class B or C).
• Need for oral anticoagulation therapy.
• Current or potential pregnancy.
• Currently treated with strong CYP3A4 inhibitors.
• Life expectancy <1 year.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

South Korea · 1 center

• DongA University Hospital — Busan

Publications

• Goto S, Huang CH, Park SJ, Emanuelsson H, Kimura T. Ticagrelor vs. clopidogrel in Japanese, Korean and Taiwanese patients with acute coronary syndrome -- randomized, double-blind, phase III PHILO study. Circ J. 2015;79(11):2452-60. doi: 10.1253/circj.CJ-15-0112. Epub 2015 Sep 16. PMID 26376600
• Jin C, Kim MH, Bang J, Serebruany V. A Prospective, Randomized, Open-Label, Blinded, Endpoint Study Exploring Platelet Response to Half-Dose Prasugrel and Ticagrelor in Patients with the Acute Coronary Syndrome: HOPE-TAILOR Study. Cardiology. 2017;138(4):201-206. doi: 10.1159/000478000. Epub 2017 Aug 16. PMID 28810251
• Gorog DA, Ferreiro JL, Ahrens I, Ako J, Geisler T, Halvorsen S, Huber K, Jeong YH, Navarese EP, Rubboli A, Sibbing D, Siller-Matula JM, Storey RF, Tan JWC, Ten Berg JM, Valgimigli M, Vandenbriele C, Lip GYH. De-escalation or abbreviation of dual antiplatelet therapy in acute coronary syndromes and percutaneous coronary intervention: a Consensus Statement from an international expert panel on coron PMID 37474795
• Gorog DA, Jeyalan V, Markides RIL, Navarese EP, Jeong YH, Farag M. Comparison of De-escalation of DAPT Intensity or Duration in East Asian and Western Patients with ACS Undergoing PCI: A Systematic Review and Meta-analysis. Thromb Haemost. 2023 Aug;123(8):773-792. doi: 10.1055/s-0043-57030. Epub 2023 Apr 18. PMID 37072035
• Kang MG, Ahn JH, Kim K, Koh JS, Park JR, Hwang SJ, Park Y, Tantry US, Gurbel PA, Hwang JY, Jeong YH. Prevalence of adverse events during ticagrelor versus clopidogrel treatment and its association with premature discontinuation of dual antiplatelet therapy in East Asian patients with acute coronary syndrome. Front Cardiovasc Med. 2022 Dec 12;9:1053867. doi: 10.3389/fcvm.2022.1053867. eCollection 2 PMID 36578832
• Kubica J, Adamski P, Gorog DA, Kubica A, Jilma B, Budaj A, Siller-Matula JM, Gurbel PA, Alexopoulos D, Badariene J, Dabrowski P, Dudek D, Giannitsis E, Horszczaruk G, Jaguszewski MJ, James S, Jeong YH, Kryjak M, Niezgoda P, Ostrowska M, Patti G, Romanek J, Di Somma S, Specchia G, Tantry U, Gasior M, Tycinska A, Wojakowski W, Buszko K, Gil R, Gruchala M, Kasprzak J, Kleinrok A, Legutko J, Lesiak M, PMID 34622433
• Kim L, Choe JC, Ahn JH, Lee HW, Oh JH, Choi JH, Lee HC, Cha KS, Hong TJ, Jeong YH, Park JS. Temporal Trends of Bleeding Episodes during Half- vs. Standard-Dose Ticagrelor in Acute Coronary Syndrome Patients with Low Platelet Reactivity: A Randomized BLEEDING-ACS Trial. J Clin Med. 2021 Mar 10;10(6):1159. doi: 10.3390/jcm10061159. PMID 33802015
• Kim HK, Tantry US, Smith SC Jr, Jeong MH, Park SJ, Kim MH, Lim DS, Shin ES, Park DW, Huo Y, Chen SL, Bo Z, Goto S, Kimura T, Yasuda S, Chen WJ, Chan M, Aradi D, Geisler T, Gorog DA, Sibbing D, Lip GYH, Angiolillo DJ, Gurbel PA, Jeong YH. The East Asian Paradox: An Updated Position Statement on the Challenges to the Current Antithrombotic Strategy in Patients with Cardiovascular Disease. Thromb Hae PMID 33171520

Identifiers

NCT: NCT04755387 · EASTYLE

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗