Dual Antithrombotic Therapy With Dabigatran and Ticagrelor in Patients With ACS and Non-valvular AF Undergoing PCI — ADONIS-PCI  

Atrial Fibrillation Clinical Trial

Official title: Dual Antithrombotic Therapy With Dabigatran and Ticagrelor in Patients With Acute Coronary Syndrome and Non-valvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention (ADONIS-PCI)

Status Recruiting

Clinical Trial Summary

More than 25% of patients referred for diagnostic coronary angiography and percutaneous coronary intervention (PCI) due to acute coronary syndrome (ACS) suffer from non-valvular atrial fibrillation (AF). In this particular setting, balancing between the prevention of thrombosis and the risk of bleeding remains challenging. Oral anticoagulation (OAC) prevents stroke and systemic embolism, but has not been shown to prevent stent thrombosis (ST). Dual antiplatelet therapy (DAPT) reduces the incidence of recurrent ischemic events and ST, but is less effective in reducing the incidence of cardioembolic stroke associated with AF. A common guideline-supported practice is to combine three drugs (OAC, aspirin and clopidogrel) in a triple therapy, which is associated with high annual risk (up to 25%) of major bleeding. Thus, new therapeutic strategies are urgently needed to maintain the efficacy while improving the safety of treatment in patients with AF and ACS undergoing PCI.

This is a prospective, randomized, open-label, blinded-endpoint, non-inferiority trial. 2230 patients with non-valvular AF that had undergone successful PCI due to an ACS within the previous 72 hours will be randomized in 1:1 ratio to receive one of the two treatments: dual therapy with dabigatran (150 mg twice daily or 110 mg twice daily) and ticagrelor (90 mg twice daily for 1 month, followed by 60 mg twice daily up to 12 months), or standard therapy according to current guidelines triple therapy with dabigatran (150 mg b.i.d. or 110 mg b.i.d.) plus clopidogrel (75 mg o.d.) plus aspirin (75 mg o.d.) followed by double therapy depending on the bleeding and ischaemic risk. Study treatment will be continued for 12 months. The primary study end-point is the first major or clinically relevant non-major bleeding event (per ISTH), in a time-to-event analysis. The main secondary end-point is a composite efficacy end-point of thromboembolic events (myocardial infarction, stroke, or systemic embolism), death, or unplanned revascularization (PCI or coronary artery bypass grafting) at 12 months.

We expect that dual antithrombotic therapy including reduced dose ticagrelor and dabigatran is at least non-inferior regarding bleeding risk and ischaemic protection, compared to the standard triple therapy in patients with AF and after ACS, treated with PCI.

Clinical Trial Description

Health problem More than 25% of patients referred for diagnostic coronary angiography and percutaneous coronary intervention (PCI) due to acute coronary syndrome (ACS) suffer from non-valvular atrial fibrillation (AF). In this particular setting, balancing between the prevention of thrombosis and the risk of bleeding remains challenging. Oral anticoagulation (OAC) prevents stroke and systemic embolism but does not prevent stent thrombosis. Dual antiplatelet therapy (DAPT) reduces the incidence of recurrent ischemic events and stent thrombosis but is less effective in reducing the incidence of cardioembolic stroke associated with AF. A common guideline-supported practice is to combine all three drugs (OAC, aspirin, and clopidogrel) in triple therapy, but this approach remains an expert opinion. Moreover, triple therapy is associated with a high annual risk (up to 25%) of major bleeding. Thus, new therapeutic strategies are urgently needed to maintain efficacy while improving treatment safety in patients with AF and ACS undergoing PCI. The investigators hypothesize that dual antithrombotic therapy, including reduced dose ticagrelor (study group, n=1115), is non-inferior regarding bleeding risk and ischaemic protection to the standard triple therapy (control group, n=1115) in patients with AF and treated with PCI due to ACS.

Study population The study's target population is male and female patients aged ≥18 years with non-valvular AF that underwent a successful PCI due to an ACS. AF may be paroxysmal, persistent or permanent but must not be secondary to a reversible disorder such as myocardial infarction, pulmonary embolism, recent surgery, pericarditis, or thyrotoxicosis. ACS may be ST-elevation myocardial infarction (STEMI), non-STEMI (NSTEMI), or unstable angina (UA).

Study design This is a multicentre, prospective, randomized, open-label, blinded endpoint, non-inferiority trial. Within 72 hours post PCI, patients will be randomized in a 1:1 ratio to receive one of the two treatments: dual therapy with ticagrelor (90 mg twice daily for one month, followed by 60 mg twice daily up to 12 months) plus dabigatran (150 mg twice daily or 110 mg twice daily; standard of care) or triple therapy with clopidogrel (75 mg once daily) plus aspirin (75 mg once daily) plus dabigatran (150 mg twice daily or 110 mg twice daily), according to current guidelines. Study treatment will be continued for 12 months.

Endpoints The primary study endpoint is the first major or clinically relevant non-major bleeding event, as defined by the International Society on Thrombosis and Haemostasis (ISTH), in a time-to-event analysis. The main secondary endpoint is a composite efficacy endpoint of thromboembolic events (myocardial infarction, stroke, or systemic embolism), death, or unplanned revascularization (PCI or coronary artery bypass grafting).

Expected results The investigators expect that the off-label regimen of dual antithrombotic therapy, including reduced dose ticagrelor, is at least non-inferior regarding bleeding risk and ischaemic protection, to the standard triple therapy in patients with AF and after ACS, treated with PCI.

Discussion The investigators propose a new off-label treatment regimen which is reduced dose ticagrelor in patients with AF and ACS. The most scientifically valuable points of the proposed project are the first-ever (i) attempt to administer the off-label potent P2Y12 inhibitor (ticagrelor) as a part of dual antiplatelet therapy in patients with AF and ACS and (ii) evaluation of the reduced dose of ticagrelor in the setting of ACS. The three most innovative aspects are: (i) new treatment regimen with a reduced ticagrelor dose in ACS setting, (ii) possibility to introduce the polypill containing ticagrelor and dabigatran to the Polish market, and (iii) potential manufacture of the polypill containing various doses of ticagrelor and dabigatran, depending on the patient's individual ischaemic and bleeding risk. If successful, the proposed study will answer the burning clinical question about the optimal treatment strategy in patients with AF and ACS. ;

Related Conditions & MeSH terms

• Acute Coronary Syndrome
• Antithrombotic Therapy
• Atrial Fibrillation
• Percutaneous Coronary Interventions
• Syndrome

• NCT number: NCT04695106
• Study type: Interventional
• Source: Medical University of Gdansk
• Contact: Milosz Jaguszewski, MD, PhD
• Phone: 791445345
• Email: milosz.jaguszewski@gumed.edu.pl
• Status: Recruiting
• Phase: Phase 4
• Start date: October 25, 2021
• Completion date: March 31, 2026