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

NCT04695106 | Recruiting Phase 4

• 2 other identifiers: NBK 182/1/20202020-004887-24
• Study Type: interventional
• Target: 2,230
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

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

Keywords

Atrial Fibrillation; Acute Coronary Syndrome; Dabigatran; Ticagrelor; Antithrombotic therapy

Outcome Measures

Primary Outcomes (1)

• Primary safety endpoint - first major or clinically relevant non-major bleeding event, as defined by the ISTH

  First major or clinically relevant non-major bleeding event, as defined by the International Society on Thrombosis and Haemostasis (ISTH)

  24 months

Secondary Outcomes (2)

• Secondary efficacy endpoint - thromboembolic events or death or unplanned revascularization; individual thromboembolic events; definite stent thrombosis

  24 months

• Secondary safety endpoint - major bleeding events; clinically relevant non-major bleeding events; clinically relevant bleeding; minor and total bleeding; intracranial hemorrhage

  24 months

Study Arms (2)

Study population

EXPERIMENTAL

In the study group (both STEMI and NSTE-ACS), aspirin will be discontinued, and ticagrelor will be started at a loading dose of 180 mg, irrespective of timing and dosing of clopidogrel, and continued at a maintenance dose of 90 mg twice daily for 1 month, followed by 60 mg twice daily up to 12 months. Dabigatran will be used as a standard-of-care. Lower dose dabigatran (110 mg twice daily) will be used in patients ≥80 years of age and will be considered in patients (i) 75-80 years of age, (ii) with creatinine clearance 30-50 ml/min, (iii) at high risk of bleeding (HAS-BLED ≥ 3), (iv) at high-risk of gastrointestinal bleeding (with esophagitis, gastritis, gastroesophageal reflux disease), and (v) treated with verapamil, in accordance with the guidelines.

Drug: Ticagrelor; Drug: Dabigatran Etexilate

Control group

ACTIVE COMPARATOR

In the control group, aspirin and clopidogrel will be continued depending on the diagnosis (STEMI or NSTE-ACS) and bleeding risk. In patients with STEMI, aspirin will be discontinued after 1-6 months, according to a balance between the estimated risk of recurrent coronary events and bleeding. In patients at high bleeding risk aspirin will be discontinued after 1 month. Subsequently, all patients will be treated with clopidogrel and dabigatran up to 12 months. In the NSTE-ACS group, aspirin will be used up to 1 week (in-hospital period), extendable up to one month in patients at high ischaemic risk. Dual therapy will be continued up to 12 months with the possibility of shortening for patients at high bleeding risk. Dabigatran will be used as a standard-of-care (as above).

Drug: Dabigatran Etexilate; Drug: Aspirin; Drug: Clopidogrel

Interventions

Ticagrelor DRUG

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.

Also known as: Brilique

Study population

Dabigatran Etexilate DRUG

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

Also known as: Pradaxa

Control group; Study population

Aspirin DRUG

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

Control group

Clopidogrel DRUG

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

Control group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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;

Sponsors & Collaborators

• Medical University of Gdansk: lead
• Medical University of Warsaw: collaborator
• Nicolaus Copernicus University: collaborator
• National Institute of Cardiology, Warsaw, Poland: collaborator
• Military Institute od Medicine National Research Institute: collaborator
• Bielanski Hospital: collaborator
• Medical University of Silesia: collaborator
• Poznan University of Medical Sciences: collaborator
• University of Opole, Poland: collaborator
• Medical University of Łódź: collaborator
• Voivodeship Hospital, Kielce, Poland: collaborator
• Voivode Specialist Hospital in Olsztyn, Poland: collaborator
• Medical University of Lublin: collaborator
• Pomeranian Medical University Szczecin: collaborator
• Central Clinical Hospital of the Ministry of Internal Affairs and Administration, Warsaw, Poland: collaborator

Study Sites (1)

Cardiac lntensive Care Unit, First Department of Cardiology, University Clinical Centre in Gdańsk

Gdansk, Pomeranian Voivodeship, 80-214, Poland

RECRUITING

MeSH Terms

Conditions

Atrial Fibrillation; Acute Coronary Syndrome

Interventions

Ticagrelor; Dabigatran; Aspirin; Clopidogrel

Condition Hierarchy (Ancestors)

Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Myocardial Ischemia; Vascular Diseases

Intervention Hierarchy (Ancestors)

Adenosine; Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Pyridines; Heterocyclic Compounds, 1-Ring; Benzimidazoles; Salicylates; Hydroxybenzoates; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Ticlopidine; Thienopyridines; Thiophenes; Sulfur Compounds

Study Officials

• Magdalena Leszczyńska-Wiloch, PhD

  Department of Non-Commercial Clinical Research, Medical University of Gdansk

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Miłosz Jaguszewski, MD, PhD

CONTACT

791445345; milosz.jaguszewski@gumed.edu.pl

Natasza Gilis-Malinowska, MD, PhD

CONTACT

791445345; n.gilis@gumed.edu.pl

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: November 25, 2020
• First Posted: January 5, 2021
• Study Start: October 25, 2021
• Primary Completion: March 1, 2024
• Study Completion: March 31, 2026
• Last Updated: November 4, 2021

Record last verified: 2021-10

Data Sharing

• IPD Sharing: Will not share

Locations

PL (1)