Clinical trial NCT05955365: Monotherapy With P2Y12 Inhibitors in Patients With Atrial fIbrillation Undergoing Supraflex Stent Implantation
Official title: Monotherapy With a P2Y12 Inhibitor Followed by a Direct-acting Oral Anticoagulant in Patients With ATRial fIbrillation Undergoing suprafleX Cruz Coronary Stent Implantation
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Percutaneous Coronary Intervention (PCI)
Atrial Fibrillation (AF)
Oral Anticoagulation
P2Y12 Inhibitor
Lead sponsor: Insel Gruppe AG, University Hospital Bern
Sponsor class: OTHER
Collaborators: name: Sahajanand Medical Technologies Limited
First posted: 2023-07-21
Enrollment: 3010
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Patients with atrial fibrillation undergoing percutaneous coronary intervention with stent implantation require treatment with different antithrombotic drugs. Oral anticoagulants are prescribed to reduce the risk of stroke associated with atrial fibrillation. Antiplatelet substances are prescribed after stent implantation to reduce the risk of adverse cardiac events such as myocardial infarction or stent thrombosis. Treatment with antithrombotic medications can cause bleeding complications, particularly when these substances are combined.

The currently recommended standard strategy consists of treatment with 3 antithrombotic medications for at least 1 week up to one month, followed by treatment with two of these medications for up to 6-12 months after stent implantation. Thereafter, patients usually receive long-term treatment with only one drug, an anticoagulant.

In the monotherapy group of this study, the investigators will investigate a strategy where only one antithrombotic drug will be used at a time. During the first month after stent implantation, the investigators will prescribe an antiplatelet medication, followed by an oral anticoagulant as monotherapy. This strategy might be associated with fewer bleeding complications, while protecting adequately against thrombotic events.

In this study the investigators would like to investigate whether treatment with a single antithrombotic drug ("monotherapy strategy") is associated with benefits compared to the currently recommended combination therapy of antithrombotic medications ("standard-of-care strategy").

Detailed description: Background:

The optimal antithrombotic treatment following percutaneous coronary intervention (PCI) in patients with atrial fibrillation (AF) requiring long-term oral anticoagulation remains a matter of debate. In particular, the appropriate intensity and duration of antithrombotic strategies to prevent ischemic events, while mitigating the risk of bleeding complications in this high bleeding risk population during the early peri-procedural period (within 30 days) and thereafter (from 30 days to 1 year) following drug-eluting stent implantation remains unclear.

Aim:

The investigators aim to assess the safety and efficacy of a P2Y12 inhibitor monotherapy regimen for 1 month followed by DOAC monotherapy long-term versus current standard of care consisting of triple antithrombotic therapy for up to one month (aspirin, P2Y12 inhibitor and DOAC) followed by dual antithrombotic therapy (P2Y12 inhibitor and DOAC) for 6 to 12 months and DOAC monotherapy thereafter, in AF patients undergoing PCI indicated for treatment with a DOAC after sirolimus-eluting Supraflex Cruz stent implantation and followed for a period of 12 months.

Methodology:

This investigator-initiated, multi-center, randomized, open-label, blinded evaluation, international clinical trial in 3010 AF patients with indication for long-term oral anticoagulation who have undergone successful PCI with Supraflex Cruz sirolimus-eluting biodegradable polymer cobalt chromium stent implantation. The study will be conducted at approximately 150 sites across Europe and Brazil. Patients will be randomized to the antithrombotic monotherapy (experimental antithrombotic strategy) or the standard of care strategy (control group) in a 1:1 ratio. Randomization is stratified by site, acute coronary syndrome (ACS) within the previous 6 months and CHA2DS2-VASc score ≥4. Patients randomized to the antithrombotic monotherapy treatment receive any of the commercially available oral P2Y12 inhibitors (clopidogrel, ticagrelor, prasugrel) and immediately discontinue aspirin and DOAC. After 1 month, the P2Y12 inhibitor will be stopped and treatment with a commercially available DOAC will be initiated for the duration of 11 months. Patients randomized to the standard of care strategy will initiate triple therapy for up to 1 month followed by dual anti-thrombotic therapy (consisting of P2Y12 inhibitor for a minimum of 6 and up to 12 months plus DOAC for at least 12 months).

Potential significance:

This is the first study investigation the impact of a short course of P2Y12 inhibitor monotherapy up to 1 month, while omitting clopidogrel non-responders, and temporarily omitting OAC, after stent implantation followed by OAC monotherapy in AF patients undergoing PCI. This sequential monotherapy treatment strategy has solid rational and carries potential to balance bleeding against cardiac and cerebral ischemic risks.

Eligibility criteria: Inclusion Criteria:

* Age ≥18 years
* Atrial fibrillation or flutter with an indication for oral anticoagulation using direct-acting oral anticoagulants (DOACs) for ≥12 months
* Successful percutaneous coronary intervention in at least 1 lesion within the previous 7 days with no remaining lesions intended for treatment.
* Free from major adverse events post qualifying PCI, including new onset chest pain suspected to be of ischemic origin, acute or subacute stent thrombosis, new-onset neurological signs or symptoms.
* Written informed consent

Exclusion Criteria:

* Planned staged percutaneous intervention procedure (Patients can be enrolled after complete coronary revascularization with no remaining lesions intended for treatment. Patients who have or develop indication to percutaneous valve intervention can undergo treatment more than 30 days after qualifying PCI.)
* Cardioversion for treatment of atrial fibrillation within 1 month prior to inclusion or planned cardioversion
* AF ablation procedure within 2 months prior to inclusion or planned AF ablation procedure
* Prior mechanical valvular prosthesis implantation
* Deep vein thrombosis/pulmonary embolism, at least moderately severe mitral stenosis or other clinical conditions than atrial fibrillation requiring long-term oral anticoagulation
* Stroke within 1 month prior to randomization
* Hemodynamic instability (persistent systolic blood pressure below 90 mmHg, continuous infusions of catecholamines, clinical signs of hypoperfusion and/or use of percutaneous left ventricular assist devices)
* Uncontrolled severe hypertension with a systolic blood pressure (BP) ≥180 mmHg and/or diastolic BP ≥120 mmHg
* Severe renal impairment with estimated creatinine clearance (CrCL) \<15 mL/min or on dialysis
* Moderate or severe hepatic impairment (Child-Pugh Class B or C) or any hepatic disease associated with coagulopathy
* Any hypersensitivity or contraindications for direct oral anticoagulation or dual antiplatelet therapy with aspirin and a P2Y12 inhibitor
* Any of the following abnormal local laboratory results prior to randomization: platelet count \<50 x109/L or hemoglobin \<8 g/dL
* Known pregnancy or breast-feeding patients
* Life expectancy \<1 year due to other severe non-cardiac disease
* Planned surgery including coronary artery bypass grafting within the next 6 months

Primary outcomes:
measure: The number of participants with a major adverse cardiac or cerebral events (MACCE), defined as the composite of death from any cause, myocardial infarction, stroke or non-central nervous system (non-CNS) systemic embolism
timeFrame: 12 months
measure: The number of participants with a major or clinically relevant non-major bleeding (MCB), defined according to the International Society of Thrombosis and Haemostasis (ISTH) criteria
timeFrame: 12 months
Secondary outcomes:
measure: The incidence of MACCE or MCB
timeFrame: 12 months
measure: The incidence of MACCE or MCB
timeFrame: 15 months
measure: The number of participants with a composite of death from cardiovascular causes, myocardial infarction or stroke
timeFrame: 12 months
measure: The number of participants with a composite of death from cardiovascular causes, myocardial infarction or stroke
timeFrame: 15 months
measure: The number of participants with a composite of death from cardiovascular causes, myocardial infarction, stroke or non-CNS systemic embolism
timeFrame: 12 months
measure: The number of participants with a composite of death from cardiovascular causes, myocardial infarction, stroke or non-CNS systemic embolism
timeFrame: 15 months
measure: The number of participants died from cardiovascular or non-cardiovascular causes
timeFrame: 12 months
measure: The number of participants died from cardiovascular or non-cardiovascular causes
timeFrame: 15 months
measure: The number of participants with a composite of stroke and non-CNS systemic embolism
timeFrame: 12 months
measure: The number of participants with a composite of stroke and non-CNS systemic embolism
timeFrame: 15 months
measure: The number of participants with any stroke (including ischemic, hemorrhagic and unknown types)
timeFrame: 12 months
measure: The number of participants with any stroke (including ischemic, hemorrhagic and unknown types)
timeFrame: 15 months
measure: The number of participants with an ischaemic stroke
timeFrame: 12 months
measure: The number of participants with an ischaemic stroke
timeFrame: 15 months
measure: The number of participants with a hemorrhagic stroke
timeFrame: 12 months
measure: The number of participants with a hemorrhagic stroke
timeFrame: 15 months
measure: The number of participants with a transient ischemic attack
timeFrame: 12 months
measure: The number of participants with a transient ischemic attack
timeFrame: 15 months
measure: The number of participants with a composite of definite or probable stent thrombosis
timeFrame: 12 months
measure: The number of participants with a composite of definite or probable stent thrombosis
timeFrame: 15 months
measure: The number of participants with a definite stent thrombosis
timeFrame: 12 months
measure: The number of participants with a definite stent thrombosis
timeFrame: 15 months
measure: The number of participants with a hospitalization
timeFrame: 12 months
measure: The number of participants with a hospitalization
timeFrame: 15 months
measure: The number of participants with a composite of death or hospitalization
timeFrame: 12 months
measure: The number of participants with a composite of death or hospitalization
timeFrame: 15 months
measure: The number of participants with any target lesion revascularization
timeFrame: 12 months
measure: The number of participants with any target lesion revascularization
timeFrame: 15 months
measure: The number of participants with any target vessel revascularization
timeFrame: 12 months
measure: The number of participants with any target vessel revascularization
timeFrame: 15 months
measure: The number of participants with any revascularization
timeFrame: 12 months
measure: The number of participants with any revascularization
timeFrame: 15 months
measure: The number of all bleeding events, also adjudicated according to Bleeding Academic Research Consortium, Thrombolysis in Myocardial Infarction or Global Use of Strategies to Open Occluded Coronary Arteries scales
timeFrame: 12 months
measure: The number of all bleeding events, also adjudicated according to Bleeding Academic Research Consortium, Thrombolysis in Myocardial Infarction or Global Use of Strategies to Open Occluded Coronary Arteries scales
timeFrame: 15 months
measure: Transfusion rates both in patients with and/or without clinically detected overt bleeding
timeFrame: 12 months
measure: Transfusion rates both in patients with and/or without clinically detected overt bleeding
timeFrame: 15 months
measure: The number of participants with a major adverse cardiac or cerebral events (MACCE), defined as the composite of death from any cause, myocardial infarction, stroke or non-central nervous system (non-CNS) systemic embolism
timeFrame: 15 months
Other outcomes:
Locations:
city: Hasselt
country: Belgium
facility: Hartcentrum Hasselt
city: Nîmes
country: France
facility: CHU Nîmes
city: Frankfurt am Main
country: Germany
facility: Universitätsklinikum Frankfurt/Main
city: Friedrichshafen
country: Germany
facility: Klinikum Friedrichshafen
city: Catania
country: Italy
facility: Ospedale Ferrarotto
state: Catania CT
city: Milano
country: Italy
facility: IRCCS Humanitas
state: Rozzano
city: Amsterdam
country: Netherlands
facility: UMC public
city: Poznań
country: Poland
facility: Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu
city: Santander
country: Spain
facility: Hospital Universitario Marques de Valdecilla
city: Lugano
country: Switzerland
facility: Cardiocentro Ticino Institute
state: Ticino
city: Basel
country: Switzerland
facility: Universitätsspital Basel
city: Bern
country: Switzerland
facility: Inselspital, Bern University Hospital, Department of Cardiology
city: Geneva
country: Switzerland
facility: Hôpitaux Universitaires de Genève
city: Zürich
country: Switzerland
facility: University Hospital Zürich
city: London
country: United Kingdom
facility: Imperial College London
Study officials:
affiliation: Bern University Hospital, Department of Cardiology
name: Stephan Windecker, Prof
role: PRINCIPAL_INVESTIGATOR
affiliation: Cardiocentro Ticino Institute
name: Marco Valgimigli, Prof
role: PRINCIPAL_INVESTIGATOR
References: