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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)

Primary Purpose

MYOCARDIAL INFARCTION

Status

Not yet recruiting

Phase

Phase 3

Locations

France

Study Type

Interventional

Intervention

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

About this trial

This is an interventional other trial for MYOCARDIAL INFARCTION focused on measuring Acute Coronary Syndrome, High Bleeding Risk, Antiplatelet Therapy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Hopital Pitié Salpetrière

Arms of the Study

Arm 1

Arm 2

Arm Type

No Intervention

Other

Arm Label

Control arm

Intervention arm

Arm Description

Standard of Care : Systematic de-escalation to a high potency antiplatelet single therapy

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

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

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

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

Full Information

NCT ID

NCT05577988

First Posted

October 10, 2022

Last Updated

January 10, 2023

Sponsor

Assistance Publique - Hôpitaux de Paris

Collaborators

Fonds de Dotation ACTION

1. Study Identification

Unique Protocol Identification Number

NCT05577988

Brief Title

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

Acronym

ADEN

Official Title

Study Type

Interventional

2. Study Status

Record Verification Date

October 2022

Overall Recruitment Status

Not yet recruiting

Study Start Date

April 2023 (Anticipated)

Primary Completion Date

December 2025 (Anticipated)

Study Completion Date

January 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Assistance Publique - Hôpitaux de Paris

Collaborators

Fonds de Dotation ACTION

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

MYOCARDIAL INFARCTION

Keywords

Acute Coronary Syndrome, High Bleeding Risk, Antiplatelet Therapy

7. Study Design

Primary Purpose

Other

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Model Description

National, multicentre, comparative, controlled, randomized, open label trial using the PROBE study design (Prospective Randomized Open Blinded End-point)

Masking

Outcomes Assessor

Masking Description

Members of the Endpoint Adjudication Committee (AEC) are blinded to randomization group, treatments and characteristics. The Committee will assess all endpoints according to the definitions stated in the protocol. This will be a blinded evaluation. Clinical endpoint adjudication will be performed using blinded source data that are provided by CRAs to the committee.

Allocation

Randomized

Enrollment

2468 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Control arm

Arm Type

No Intervention

Arm Description

Standard of Care : Systematic de-escalation to a high potency antiplatelet single therapy

Arm Title

Intervention arm

Arm Type

Other

Arm Description

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

Intervention Type

Other

Intervention Name(s)

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

Intervention Description

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.

Primary Outcome Measure Information:

Title

Rate of combinated major and minor bleeding events (BARC 2 to 5 BARC)

Description

Time Frame

From randomization (1-3months after inclusion) to 1year after inclusion

Secondary Outcome Measure Information:

Title

Rate of major adverse cardiovascular events

Description

Time Frame

From randomization to de-escalation (1-3months) to 1year

Title

Rate of major bleeding events

Description

Time Frame

randomization to de-escalation (1-3months) to 1year

Title

Rate of minor bleeding events

Description

Time Frame

randomization to de-escalation (1-3months) to 1year

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Michel ZEITOUNI, MD,PhD

Phone

33142165535

michel.zeitouni@aphp.fr

First Name & Middle Initial & Last Name or Official Title & Degree

Delphine BRUGIER, PhD

Phone

33142162918

delphine.brugier-ext@aphp.fr

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Michel ZEITOUNI, MD, PhD

Organizational Affiliation

Assistance Publique - Hôpitaux de Paris

Official's Role

Study Chair

Facility Information:

Facility Name

Hopital Pitié Salpetrière

City

Paris

State/Province

IDF

ZIP/Postal Code

75013

Country

France

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Michel MD ZEITOUNI, MD,PhD

Phone

33142165535

michel.zeitouni@aphp.fr

First Name & Middle Initial & Last Name & Degree

Delphine BRUGIER, PhD

Phone

33142162918

delphine.brugier-ext@aphp.fr

12. IPD Sharing Statement

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