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

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.

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.

Eligibility Criteria:
Inclusion Criteria:

* Male and female patients aged ≥18 years'
* Patients with new-onset or pre-existing non-valvular AF that have been receiving oral anticoagulant treatment with dabigatran for at least 48 hours or were treatment naïve prior to PCI. AF may be paroxysmal, persistent or permanent, but must not be secondary to a reversible disorder such as MI, pulmonary embolism, recent surgery, pericarditis or thyrotoxicosis unless long-term treatment with an OAC is anticipated.
* Patients presenting with ACS that had undergone a successful PCI with drug-eluting stent (DES) implantation within the previous 72 hours. ACS may be ST-elevation myocardial infarction (STEMI), non-STEMI (NSTEMI), or unstable angina (UA). Successful treatment with PCI is defined as achievement of \<30% residual diameter stenosis of the target lesion assessed by visual inspection or quantitative coronary angiography and no in-hospital major adverse cardiac events (AMI or repeat coronary revascularisation of the target lesion). For ACS patients with ST-segment elevation, persistent ST-segment elevation of at least 0.1 mV in at least two contiguous leads or a new left bundle-branch block should be present. For ACS patients without ST-segment elevation, at least two of the following three criteria should be met: (i) ST-segment changes on electrocardiography, indicating ischemia; (ii) a positive test of a biomarker, indicating myocardial necrosis; or (iii) one of several risk factors (age ≥60 years; previous myocardial infarction or coronary artery bypass grafting; coronary artery disease with stenosis of ≥50% in at least two vessels; previous ischemic stroke, transient ischemic attack, carotid stenosis of at least 50%, or cerebral revascularization; diabetes mellitus; peripheral arterial disease; chronic renal dysfunction, defined as a creatinine clearance of \<60 ml per minute per 1.73 m2 of body surface area).
* The patient must be able to give informed consent in accordance with ICH GCP guidelines and local legislation and/or regulations.

Exclusion Criteria:

* Mechanical or biological heart valve prosthesis;
* PCI with bare-metal stent insertion;
* Unsuccessful PCI (\>30% residual stenosis of the target lesion);
* Cardiogenic shock during current hospitalization;
* Adverse bleeding or ischaemic event during current hospitalization;
* Anaemia (haemoglobin \<10 g/dL) or thrombocytopenia (platelet count \<100 x109/L) at screening,
* Severe renal impairment (creatinine clearance \<30mL/min (estimated CrCl calculated by Cockcroft-Gault equation) at screening;
* Active liver disease at screening, as indicated by at least one of the following: persistent alanine aminotransferase (ALT) or aspartate transaminase (AST) \>3-fold upper limit of normal (ULN), known active hepatitis C, known active hepatitis B, known active hepatitis A;
* Use of fibrinolytic agents within 24 hours of screening;
* Gastrointestinal bleeding within 1 month prior to screening unless, in the opinion of the Investigator, the cause has been permanently eliminated (e.g., by surgery);
* Major bleeding episode (reduction in the hemoglobin level of at least 2 g/dL, transfusion of at least two units of blood, or symptomatic bleeding in a critical area or organ), including life-threatening bleeding episode (symptomatic intracranial bleeding, bleeding with a decrease in the hemoglobin level of at least 5 g/dL or bleeding requiring transfusion of at least 4 units of blood or inotropic agents or necessitating surgery) within 1 month prior to screening;
* Stroke within 1 month prior to screening;
* Major surgery within 1 month prior to screening;
* Malignancy or radiation therapy within 6 months prior to screening unless, in the opinion of the Investigator, the estimated life expectancy is greater than 36 months;
* History of intraocular, spinal, retroperitoneal, or traumatic intra-articular bleeding unless the causative factor has been permanently eliminated or repaired;
* Hemorrhagic disorder or bleeding diathesis (e.g. von Willebrand disease, hemophilia A or B or other hereditary bleeding disorder, history of spontaneous intra-articular bleeding, history of prolonged bleeding after surgery/intervention);
* Past an organ transplant or patient on the waiting list for organ transplant;
* Need for continued treatment with systemic ketoconazole, itraconazole, posaconazole, cyclosporine, tacrolimus, dronedarone, rifampicin, phenytoin, carbamazepine, St. John's Wort or any cytotoxic/myelosuppressive therapy.
* Need for continued treatment with non-steroidal anti-inflammatory drugs (NSAIDs);
* Pre-menopausal women (last menstruation ≤1 year prior to screening) who: sre pregnant or breastfeeding or are not surgically sterile or are of childbearing potential and not practicing two acceptable methods of birth control, or do not plan to continue practicing an acceptable method of birth control throughout the trial. Acceptable methods of birth control are oral or parenteral (patch, injection, implant) hormonal contraception, which has been used continuously for at least one month prior to the first dose of study medication, intrauterine device or intrauterine system, double-barrier method of contraception (condom and occlusive cap or condom and spermicidal agent), male sterilization and complete sexual abstinence (if acceptable by local authorities). Periodic abstinence is not an acceptable method of contraception.
* Known allergy to dabigatran, ticagrelor, clopidogrel, aspirin, or to the excipients used for the tables of the drugs;
* Contraindications, in the Investigator's opinion to dabigatran, ticagrelor, clopidogrel, or aspirin;
* Participation in another trial with an investigational drug or device within the past 30 days preceding the screening visit (patients participating in an observational study only will not be excluded);
* Patients who are not willing or able to comply with the protocol requirements or considered unreliable by the Investigator concerning the requirements for follow-up during the study and/or compliance with study drug administration, who have a life expectancy less than the expected duration of the trial due to concomitant disease, or who have any condition which in the opinion of the Investigator, would not allow safe participation in the study (e.g., drug addiction, alcohol abuse).