Clinical trial NCT05577988: 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
Official 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: MYOCARDIAL INFARCTION
Keywords: Acute Coronary Syndrome
High Bleeding Risk
Antiplatelet Therapy
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Fonds de Dotation ACTION
First posted: 2022-10-13
Enrollment: 2468
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: National, multicentre, comparative, controlled, randomized, open label trial using the PROBE study design (Prospective Randomized Open Blinded End-point)
Primary purpose: OTHER

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.

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

Primary outcomes:
measure: Rate of combinated major and minor bleeding events (BARC 2 to 5 BARC)
timeFrame: From randomization (1-3months after inclusion) to 1year after inclusion
Secondary outcomes:
measure: Rate of major adverse cardiovascular events
timeFrame: From randomization to de-escalation (1-3months) to 1year
measure: Rate of major bleeding events
timeFrame: randomization to de-escalation (1-3months) to 1year
measure: Rate of minor bleeding events
timeFrame: randomization to de-escalation (1-3months) to 1year
Other outcomes:
Locations:
city: Paris
country: France
facility: Hopital Pitié Salpetrière
state: IDF
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Michel ZEITOUNI, MD, PhD
role: STUDY_CHAIR
References: