Assessment of an Early De-Escalation to a Low-potency Single Antiplatelet Therapy Guided by Genetics Versus a Systematic High-Potency Single Antiplatelet Therapy to Neutralize Bleeding Complications in Patients With High Bleeding Risk Beyond One Month After an Acute Coronary Syndrome (ADEN)

Patients who suffered from acute coronary syndrome (ACS) are usually treated with a long-term dual antiplatelet therapy (DAPT) to reduce stent thrombosis and recurrent ischemic event. Nonetheless, recent important data have demonstrated the efficacy of a short term DAPT and an early single antiplatelet therapy in high bleeding and ischemic risk patients.

The bleeding risk is associated with a significant mortality. This risk is especially high in patients treated with potent P2Y12 inhibitors like ticagrelor or prasugrel after an ACS.

As a result of the abounding data regarding the safety of an early single antiplatelet therapy with high potency antiplatelet therapy (ticagrelor or prasugrel), it is likely that such strategy will soon be implemented in the guidelines.

The benefits of these high-potency P2Y12 inhibitors over clopidogrel mostly occur in patients with genetic polymorphisms of CYP2Y12 associated with a loss of function in clopidogrel metabolism.

Furthermore, the anti-ischemic benefit of potent P2Y12 inhibitors over clopidogrel occurs early, while excess bleeding events often arise during chronic treatment.

Our hypothesis is that a systematic and rapid genetic screening of CYP2C90 *2 or *17 polymorphism to guide an early single therapy with low potency antiplatelet (aspirin or clopidogrel) could lead to less bleeding events with a consistent efficacy towards cardiac events compared with high potency antiplatelet therapies (prasugrel or ticagrelor) in high bleeding risk patients treated for ACS.

Study Overview

• Status: Not yet recruiting
• Conditions: MYOCARDIAL INFARCTION
• Intervention / Treatment: Other: single-antiplatelet with a low-potency antiplatelet (aspirin or clopidogrel) guided by genetic testing.

Detailed Description

Multicenter, randomized, open label trial using the PROBE study design. Randomization 1 to 3 months (preferably 1, considering the HBR) after ACS into 2 parallel arms. Stratification: according to revascularization status (PCI or no PCI), genotype (loss of function, fast metabolization, none) and center.

Control arm: stop aspirin for a single antiplatelet therapy with a high-potency antiplatelet (ticagrelor or prasugrel).

Intervention arm: single-antiplatelet with a low-potency antiplatelet (aspirin or clopidogrel) guided by genetic testing.

• Study Type: Interventional
• Enrollment (Estimated): 2468
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Michel ZEITOUNI, MD,PhD; Phone Number: 33142165535; Email: michel.zeitouni@aphp.fr
• Study Contact Backup: Name: Delphine BRUGIER, PhD; Phone Number: 33142162918; Email: delphine.brugier-ext@aphp.fr

Study Locations

• France
  • IDF
    • Paris, IDF, France, 75013
      • Hôpital Pitié Salpêtrière
      • Contact: Delphine BRUGIER, PhD; Phone Number: 33142162918; Email: delphine.brugier-ext@aphp.fr
      • Contact: Michel MD ZEITOUNI, MD,PhD; Phone Number: 33142165535; Email: michel.zeitouni@aphp.fr

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Being 18-year-old or older
• Admission for type 1 acute myocardial infarction (STEMI or NSTEMI)
• Bedside genetic testing for clopidogrel resistance that can be performed during hospital stay for ACS (oral swab kit with result within 1 hour)
• Treated with aspirin and ticagrelor, or aspirin and prasugrel at the screening phase and at the randomization visit.

• High bleeding risk as defined by the Consensus Document From the Academic Research Consortium for High Bleeding Risk (at least one criterion) :

  • Age ≥75 years old.
  • Baseline haemoglobin <11 g/dl (or anaemia requiring transfusion during the 4 weeks prior to randomization).
  • Chronic Kidney Disease with estimated glomerular filtration rate ≤ 30 ml/min.
  • Thrombocytopenia with platelet count < 100 x 109 / L
  • Chronic bleeding diatheses: inherited or acquired conditions known to be associated with increased bleeding risk such as platelet dysfunction, von Willebrand disease (prevalence of 1%-2% in the general population), inherited or acquired clotting factor deficiencies (including factors VII, VIII [hemophilia A], IX [hemophilia B], and XI), or acquired antibodies to clotting factors, among others.
  • Cirrhosis with portal hypertension.
  • PCI after major traumatism or surgery.
  • Any documented stroke in the last 12 months.
  • Hospital admission for bleeding or transfusion within last 6 months.
  • Nonskin cancer diagnosed or treated ≤3 years.
  • Planned daily nonsteroidal anti-inflammatory drugs (other than aspirin) or steroids for ≥30 days after PCI.
• patient affiliated to a social security system
• signed informed consent form
• For women of childbearing potential, an effective contraception method must be used up to the visit V3

Exclusion Criteria:

• Enrolled in another clinical trial except non interventional studies
• Any prior documented intracerebral bleed
• Contra-indication, known allergy or expected interactions with clopidogrel. Baseline treatment (at screening) should not include an antiplatelet therapy for which a contra-indication, known allergy or expected interactions is known (example history of stroke and use of prasugrel, or concomitant use of ticagrelor and ritonavir)
• Patients on concomitant treatment with an anticoagulant agent (Vitamin-K antagonists or novel oral anticoagulants such as rivaroxaban, dabigatran or apixaban)
• Planned surgery within 12 coming months
• Patient under guardianship or curatorship
• Pregnancy or breastfeeding
• Inability to sign the informed consent form

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control arm; Standard of Care : Systematic de-escalation to a high potency antiplatelet single therapy
Other: Intervention arm; single-antiplatelet with a low-potency antiplatelet (aspirin or clopidogrel) guided by genetic testing.	Other: single-antiplatelet with a low-potency antiplatelet (aspirin or clopidogrel) guided by genetic testing.; Individuals without genetic loss of function to metabolize clopidogrel: stop DAPT and switch to a single antiplatelet therapy by clopidogrel.; Individuals with genetic loss of function to metabolize clopidogrel (*2/*3, 1/*3, *2/*2, *1/*2): stop potent P2Y12 inhibitor and treat with a single antiplatelet therapy by aspirin.; Individuals with fast metabolization of clopidogrel (*1/*17 or *17/*17): stop potent P2Y12 inhibitor and treat with a single antiplatelet therapy by aspirin.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of combinated major and minor bleeding events (BARC 2 to 5 BARC)	the occurrence of major or minor bleeding events between randomization to one of the de-escalation strategies and 1 year after index ACS defined according to the Bleeding Academic Research Consortium (BARC) classification as type 2 to 5	From randomization (1-3months after inclusion) to 1year after inclusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of major adverse cardiovascular events	major adverse cardiovascular events defined as follow and in the following hierarchical order: Death or myocardial infarction or stroke or stent thrombosis (key secondary); Death or Myocardial infarction	From randomization to de-escalation (1-3months) to 1year
Rate of major bleeding events	the occurrence of major bleeding events between randomization to one of the de-escalation strategies and 1 year after index ACS defined according to the Bleeding Academic Research Consortium (BARC) classification	randomization to de-escalation (1-3months) to 1year
Rate of minor bleeding events	the occurrence of minor bleeding events between randomization to one of the de-escalation strategies and 1 year after index ACS defined according to the Bleeding Academic Research Consortium (BARC) classification	randomization to de-escalation (1-3months) to 1year

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Fonds de Dotation ACTION
• Investigators: Study Chair: Michel ZEITOUNI, MD, PhD, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2024
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): January 1, 2026

Study Registration Dates

• First Submitted: October 10, 2022
• First Submitted That Met QC Criteria: October 10, 2022
• First Posted (Actual): October 13, 2022

Study Record Updates

• Last Update Posted (Actual): April 5, 2024
• Last Update Submitted That Met QC Criteria: April 4, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: High Bleeding Risk; Acute Coronary Syndrome; Antiplatelet Therapy
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Myocardial Infarction; Infarction; Hemorrhage; Acute Coronary Syndrome; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Aspirin; Clopidogrel
• Other Study ID Numbers: APHP211027; 20-0570 PHRC (Other Identifier: DGOS)

Drug and device information, study documents

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