What is the Optimal Antithrombotic Strategy in Patients With Atrial Fibrillation Undergoing PCI? (WOEST-3)

What is the Optimal Antithrombotic Strategy in Patients With Atrial Fibrillation Having Acute Coronary Syndrome or Undergoing Percutaneous Coronary Intervention?

The optimal antithrombotic management in patients with coronary artery disease (CAD) and concomitant atrial fibrillation (AF) is unknown. AF patients are treated with oral anticoagulation (OAC) to prevent ischemic stroke and systemic embolism and patients undergoing percutaneous coronary intervention (PCI) are treated with dual antiplatelet therapy (DAPT), i.e. aspirin plus P2Y12 inhibitor, to prevent stent thrombosis (ST) and myocardial infarction (MI). Patients with AF undergoing PCI were traditionally treated with triple antithrombotic therapy (TAT, i.e. OAC plus aspirin and P2Y12 inhibitor) to prevent ischemic complications. However, TAT doubles or even triples the risk of major bleeding complications. More recently, several clinical studies demonstrated that omitting aspirin, a strategy known as dual antithrombotic therapy (DAT) is safer compared to TAT with comparable efficacy.

However, pooled evidence from recent meta-analyses suggests that patients treated with DAT are at increased risk of MI and ST. Insights from the AUGUSTUS trial showed that aspirin added to OAC and clopidogrel for 30 days, but not thereafter, resulted in fewer severe ischemic events. This finding emphasizes the relevance of early aspirin administration on ischemic benefit, also reflected in the current ESC guideline. However, because we consider the bleeding risk of TAT unacceptably high, we propose to use a short course of DAPT (omitting OAC for 1 month). There is evidence from the BRIDGE study that a short period of omitting OAC is safe in patients with AF. In this study, these patients are treated with DAPT, which also prevents stroke, albeit not as effective as OAC. This temporary interruption of OAC will allow aspirin treatment in the first month post-PCI where the risk of both bleeding and stent thrombosis is greatest.

The WOEST 3 trial is a multicentre, open-label, randomised controlled trial investigating the safety and efficacy of one month DAPT compared to guideline-directed therapy consisting of OAC and P2Y12 inhibitor combined with aspirin up to 30 days. We hypothesise that the use of short course DAPT is superior in bleeding and non-inferior in preventing ischemic events. The primary safety endpoint is major or clinically relevant non-major bleeding as defined by the ISTH at 6 weeks after PCI. The primary efficacy endpoint is a composite of all-cause death, myocardial infarction, stroke, systemic embolism, or stent thrombosis at 6 weeks after PCI.

Study Overview

• Status: Recruiting
• Conditions: Myocardial Infarction; Coronary Artery Disease; Stroke; Embolism; Atrial Fibrillation; Bleeding; Acute Coronary Syndrome; Atrial Flutter; NSTEMI - Non-ST Segment Elevation MI; Stent Thrombosis; STEMI - ST Elevation Myocardial Infarction
• Intervention / Treatment: Drug: 30-day DAPT; Drug: Guideline-directed therapy

• Study Type: Interventional
• Enrollment (Estimated): 2000
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Ashley Verburg, MD; Phone Number: +31 (0)88 320 0925; Email: as.verburg@antoniusziekenhuis.nl

Study Locations

• Belgium
  • Aalst, Belgium
    • Recruiting
    • ASZ Aalst
    • Contact: Rosseel
  • Antwerpen, Belgium
    • Recruiting
    • UZ Antwerpen
    • Contact: Vandendriessche
  • Bonheiden, Belgium
    • Recruiting
    • Imelda Ziekenhuis
    • Contact: Dewilde
  • Brussel, Belgium
    • Recruiting
    • UZ Brussel
    • Contact: Vandeloo
  • Genk, Belgium
    • Recruiting
    • Ziekenhuis Oost-Limburg
    • Contact: Ferdinande
  • Gent, Belgium
    • Recruiting
    • AZ Maria Middelares Gent
    • Contact: Cornelis
  • Ieper, Belgium
    • Not yet recruiting
    • Jan Yperman
    • Contact: De Keyser
  • Kortrijk, Belgium
    • Recruiting
    • AZ Groeninge
    • Contact: van mieghem, MD PhD
  • Leuven, Belgium
    • Recruiting
    • UZ Leuven
    • Contact: Adriaenssens
  • Roeselare, Belgium
    • Recruiting
    • AZ Delta
    • Contact: Dujardin
• Netherlands
  • Alkmaar, Netherlands
    • Recruiting
    • Noordwest Ziekenhuisgroep
    • Contact: Heestermans
  • Amsterdam, Netherlands
    • Recruiting
    • Amsterdam UMC
    • Contact: Simao Henriques, MD PhD
  • Amsterdam, Netherlands
    • Recruiting
    • OLVG
    • Contact: Vink
  • Den Haag, Netherlands
    • Recruiting
    • Hagaziekenhuis
    • Contact: Schotborgh
  • Eindhoven, Netherlands
    • Recruiting
    • Catharina Ziekenhuis
    • Contact: Vlaar
  • Emmen, Netherlands
    • Recruiting
    • Treant zorggroep
    • Contact: Ruifrok
  • Heerlen, Netherlands
    • Not yet recruiting
    • Zuyderland ziekenhuis
    • Contact: Van 't hof
  • Hilversum, Netherlands
    • Recruiting
    • Tergooi MC
    • Contact: Plomp
  • Nieuwegein, Netherlands
    • Recruiting
    • St. Antonius Hospital
    • Contact: Jurrien ten berg, MD PhD
  • Tilburg, Netherlands
    • Recruiting
    • Elisabeth TweeSteden Ziekenhuis
    • Contact: Magro

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients ≥ 18 years
2. Undergoing successful PCI (either ACS or elective PCI)
3. History of or newly diagnosed (<72 hours after PCI/ACS) atrial fibrillation or flutter with a long-term (≥ 1 year) indication for OAC

Exclusion Criteria:

1. Contra indication to edoxaban, aspirin or all P2Y12 inhibitors
2. Current indication for OAC besides atrial fibrillation/flutter (e.g. venous thromboembolism)
3. <12 months after any stroke
4. CHADSVASc score ≥7
5. Moderate to severe mitral valve stenosis (AVA ≤1.5 cm2)
6. Mechanical heart valve prosthesis
7. Intracardiac thrombus or apical aneurysm requiring OAC
8. Poor LV function (LVEF <30%) with proven slow-flow
9. History of intracranial haemorrhage
10. Active bleeding on randomization
11. History of intraocular, spinal, retroperitoneal, or traumatic intra-articular bleeding, unless the causative factor has been permanently resolved
12. Recent (<1 month) gastrointestinal haemorrhage, unless the causative factor has been permanently resolved.
13. Known coagulopathy
14. Severe anaemia requiring blood transfusion or thrombocytopenia <50 × 109/L
15. BMI >40 or bariatric surgery
16. Kidney failure (eGFR <15)
17. Active liver disease (ALT, ASP, AP >3x ULN or active hepatitis A, B or C)
18. Active malignancy excluding non-melanoma skin cancer
19. Life expectancy <1 year
20. Pregnancy or breast-feeding women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: First month DAPT; 30-day DAPT (aspirin + P2Y12 inhibitor). After 30 days all patients will be treated with edoxaban and P2Y12 inhibitor. Selection of P2Y12 inhibitor is at the discretion of the treating physician, depending on both bleeding and ischemic risk. Dosage of aspirin and P2Y12 inhibitor is according to local guidelines. NOAC of choice will be edoxaban. Patients will be treated with the recommended dose of 60mg once daily or the reduced dose of 30mg once daily.	Drug: 30-day DAPT; DAPT (aspirin + P2Y12 inhibitor) during the first 30 days following PCI. After 30 days, all patients will be treated with edoxaban and a P2Y12 inhibitor.
Active Comparator: Guideline-directed therapy; Standard guideline-directed therapy (edoxaban + P2Y12 inhibitor, aspirin limited to in-hospital use or up to 30 days in selected high-risk patients). After 30 days all patients will be treated with edoxaban and P2Y12 inhibitor. Selection of P2Y12 inhibitor is at the discretion of the treating physician, depending on both bleeding and ischemic risk. Dosage of aspirin and P2Y12 inhibitor is according to local guidelines. NOAC of choice will be edoxaban. Patients will be treated with the recommended dose of 60mg once daily or the reduced dose of 30mg once daily.	Drug: Guideline-directed therapy; Guideline-directed therapy (edoxaban + P2Y12 inhibitor, aspirin limited to in-hospital use or up to 30 days in selected high-risk patients)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary safety endpoint	Major or clinically relevant non-major bleeding as defined by the International Society of Thrombosis and Haemostasis	6 weeks
Primary efficacy endpoint	Composite of all-cause death, myocardial infarction, stroke, systemic embolism, or stent thrombosis	6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bleeding complications	Major or clinically relevant non-major bleeding as defined by the International Society of Thrombosis and Haemostasis	6 months
Thrombotic complications	Composite of all-cause death, myocardial infarction, stroke, systemic embolism, or stent thrombosis	6 months
Net clinical benefit	Composite of major bleeding, myocardial infarction, stroke, systemic embolism all-cause death and stent thrombosis	6 weeks, 3 months, 6 months
Clinical symptom severity	CCS grade	6 weeks, 3 months, 6 months
All-cause death	All-cause death as defined by ARC-2 and SCTI	6 weeks, 3 months, 6 months
Myocardial infarction	Myocardial infarction as defined by the 4th Universal Definition of Myocardial Infarction	6 weeks, 3 months, 6 months
Stroke	Stroke as defined by VARC-2 definitions	6 weeks, 3 months, 6 months
Systemic embolism	Systemic embolism according to ENTRUST-AF PCI definition	6 weeks, 3 months, 6 months
Stent thrombosis	Stent thrombosis as defined by ARC-2	6 weeks, 3 months, 6 months
Major bleeding	Major bleeding as defined by BARC 3 or 5	6 weeks, 3 months, 6 months
Clinically relevant non-major bleeding	CRNM as defined by BARC 2	6 weeks, 3 months, 6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of life as assessed by the EuroQol-5D-5L questionnaire	EuroQol-5D-5L questionnaire	6 weeks, 3 months, 6 months

Collaborators and Investigators

• Sponsor: St. Antonius Hospital
• Collaborators: Daiichi Sankyo, Inc.
• Investigators: Principal Investigator: Jurriën M ten Berg, Prof, MD, St. Antonius Hospital

Study record dates

Study Major Dates

• Study Start (Actual): January 11, 2023
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: June 16, 2020
• First Submitted That Met QC Criteria: June 16, 2020
• First Posted (Actual): June 18, 2020

Study Record Updates

• Last Update Posted (Estimated): December 15, 2023
• Last Update Submitted That Met QC Criteria: December 14, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Stroke; Atrial Fibrillation; Coronary artery disease; Thrombosis; Percutaneous coronary intervention; Bleeding; Acute Coronary Syndrome; Myocardial Infarction; Stent Thrombosis; Dual Therapy; Oral Anticoagulant; Atrial Flutter; Systemic Embolism; Antithrombotic Therapy; Triple Therapy; STEMI - ST Elevation Myocardial Infarction; NSTEMI - Non-ST Segment Elevation MI; NOAC - Novel Oral Anticoagulant; DOAC - Direct Oral Anticoagulant; DAPT - Dual Antiplatelet Therapy
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Disease; Embolism and Thrombosis; Arrhythmias, Cardiac; Myocardial Infarction; Infarction; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Syndrome; ST Elevation Myocardial Infarction; Embolism; Atrial Fibrillation; Thrombosis; Acute Coronary Syndrome; Atrial Flutter
• Other Study ID Numbers: NL81102.100.22; 2022-001298-30 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Will individual participant data be available? Yes

What data in particular will be shared? Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices).

What other documents will be available? Study Protocol, informed consent form, clinical study report

When will data be available (start and end dates)? Within 1 year following article publication. End date to be determined.

With whom? Researchers who provide a methodologically sound proposal.

For what types of analyses? To achieve aims in the approved proposal.

By what mechanism will data be made available? Proposals should be directed to as.verburg@antoniusziekenhuis.nl. To gain access, data requestors will need to sign a data access agreement.

• IPD Sharing Time Frame: Within 1 year following article publication. End date to be determined.
• IPD Sharing Access Criteria: Researchers who provide a methodologically sound proposal.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No