Personalized Vs. Standard Duration of Dual Antiplatelet Therapy and New-generation Polymer-Free vs- Biodegradable-Polymer DES

Study Overview
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Brief Summary
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New-generation metallic drug-eluting stents represent the standard of care among patients undergoing percutaneous coronary intervention (PCI). Currently, few data are available as regards to the safety and efficacy of the Cre8 amphilimus-eluting stent (Cre8 AES, Alvimedica, Instanbul, Turkey) in comparison with the biodegradable polymer everolimus-eluting stent (Synergy EES, Boston Scientific, Marlborough, MA, USA). Results from randomized trials and meta-analyses consistently indicate that prolonged dual antiplatelet therapy (DAPT) after PCI reduces ischemic events, but invariably conveys an excess of clinically relevant bleeding, which is proportional to the duration of treatment. It has been estimated, indeed, that for every non-fatal ischemic event avoided with prolonged DAPT, two or more clinically relevant bleeding events have to be expected. Given the trade-off between benefits and risks and the lack of mortality benefit in favor of prolonged DAPT, expert consensus suggests that DAPT duration should be individualized based on ischemic versus bleeding risks. At this regard, the DAPT score has been recently proposed as standardized tool to identify patients who derive benefit or lack from a prolonged course of DAPT. However, a prospective assessment of the DAPT score is lacking and whether a personalized duration of DAPT based on the DAPT score improves the net clinical benefit remains unknown. The objective of the study is to compared the safety and the efficacy of the Cre8 AES with the Synergy EES and a personalized DAPT duration based on the DAPT score with a standard DAPT duration among patients undergoing PCI.

Detailed Description
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The objective of the trial is: i) to evaluate the efficacy and safety of the Cre8 AES vs. the Synergy EES in a broadly unselected patient population with coronary artery disease undergoing PCI; ii) to compare the safety and efficacy of a personalized DAPT duration (3-, 6-, or 24-month) guided by the application of the DAPT score with a standard DAPT duration (12-month) after PCI. In particular, the objectives of the trial are to test the following hypothesis: The Cre8 AES is non-inferior to the Synergy EES with regards to a device-oriented composite endpoint (DOCE) at 1-year follow-up. A personalized DAPT duration based on the DAPT score is superior to a standard DAPT duration with regards to a net adverse clinical endpoint (NACE) at 2-year follow-up. This is a prospective, randomized, multicenter, investigator-initiated, assessor-blind trial to be conducted at interventional cardiology centers in Italy. Patients undergoing PCI will be randomized in a 2-by-2 randomization fashion to undergo PCI with the Cre8 AES or Synergy EES and to receive a personalized or standard DAPT duration. All patients will be followed at 3-, 6-, 12- and 24-month after PCI for clinical endpoints. Use of experimental and control DES: Both the study stent (Cre8 AES) and the control stent (Synergy EES) will be used according to their indications for use. The randomly assigned stent is not expected to have an influence on the conduct of the procedure that will take place according to the routine practice. Eligible patients will undergo PCI as per local protocol, according to current guidelines of the European Society of Cardiology on myocardial revascularization. The technique of PCI (vascular access route, choice of the vascular sheath diameter, choice of the diagnostic and guiding catheters sizes and shapes, choice of the coronary guidewire) will be left to the discretion of the operator as per standard individual and local practice. The operator will choose the appropriate length and diameter of the stents to be implanted by visual estimate or quantitative coronary angiography as per local practice. The Cre8 AES and the Synergy EES systems are commercially available and all sizes may be used for the study. DAPT duration according to randomization: DAPT duration in patients randomized to personalized DAPT regimen: In patients that are randomized to a personalized DAPT and have a low DAPT score (<2), DAPT duration is recommended for 3 months in case of stable coronary artery disease at the time of the index procedure or for 6 months in case of acute coronary syndrome at the time of the index procedure. A low dose of aspirin (75 to 162 mg daily) will be administered throughout the course of the study. In patients that are randomized to a personalized DAPT and have a high DAPT score (≥2), DAPT duration is recommended for 24 months. Changes in the dose or in the type of P2Y12 receptor inhibitor (clopidogrel, prasugrel, or ticagrelor) are allowed during the course of the study. A low dose of aspirin (75 to 162 mg daily) will be administered throughout the course of the study. At 12-month, patients on treatment with prasugrel or ticagrelor should continue the same P2Y12 receptor inhibitor. In this specific scenario, it is preferable to continue with the same P2Y12 receptor inhibitor (prasugrel 10 mg daily or ticagrelor 90 mg daily) or to switch to a low-dose regimen of ticagrelor (60 mg twice daily) if clinically indicated or to switch to clopidogrel (75 mg daily). DAPT regimen in patients in patients randomized to a standard DAPT duration: In patients that are randomized to a standard DAPT duration, oral P2Y12 inhibitors (clopidogrel, prasugrel, or ticagrelor) should be administered for 12-month. A low dose of aspirin (75 to 162 mg daily) will be administered throughout the course of the study.

Official Title
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Randomized 2x2 Factorial Trial Comparing the Cre8 Amphilimus-sirolimus Eluting Stent vs. the Synergy Everolimus-eluting Stent and a Personalized vs. Standard Duration of Dual Antiplatelet Therapy in All-comers Patients Undergoing Percutaneous Coronary Intervention

Conditions
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Coronary Artery Disease, Acute Coronary Syndrome, Chronic Coronary Syndrome, Myocardial Infarction

Intervention / Treatment
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* Device: Percutaneous coronary intervention with implantation of amphilimus-eluting stents for coronary artery disease.
* Device: Percutaneous coronary intervention with implantation of everolimus-eluting stents for coronary artery disease.
* Drug: Personalized DAPT duration
* Drug: Standard DAPT duration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years; Clinical evidence of coronary artery disease requiring PCI with DES implantation; Any coronary lesion sized 2.25-4.5 mm by visual estimation. Exclusion Criteria: Inability to provide informed consent; Active bleeding requiring medical attention (BARC ≥2); Need for chronic oral anticoagulant therapy; Planned surgery within 3 months; Known hypersensitivity or allergy to aspirin or any P2Y12 receptor inhibitor (clopidogrel, prasugrel, ticagrelor), heparin, contrast agent, or any DES-components; Previous treatment with bioresorbable vascular scaffolds; Participation in another study that has not reached the primary endpoint; A life expectancy of less than 24 months; Female of childbearing potential; Under judicial protection, tutorship or curatorship.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: 2-by-2 randomization
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Cre8 AES and personalized DAPT duration<br>Percutaneous coronary intervention with implantation of a Cre8 amphilimus- eluting stent for coronary artery disease. Personalized duration of dual antiplatelet therapy for 3-, 6-, or 24-month after percutaneous coronary intervention based on the DAPT score. | Device: Percutaneous coronary intervention with implantation of amphilimus-eluting stents for coronary artery disease.<br>* Implantation of polymer-free, amphilimus-eluting, drug-eluting stents<br>* Other names: Cre8 AES;Drug: Personalized DAPT duration<br>* Duration of dual antiplatelet therapy according to DAPT score for 3- or 6- months in patients with low DAPT score (stable CAD or ACS, respectively) or for 24-months in patients with high DAPT score<br>|
| Other: Cre8 AES and standard DAPT duration<br>Percutaneous coronary intervention with implantation of a Cre8 amphilimus- eluting stent for coronary artery disease. Standard duration of dual antiplatelet therapy for 12-month after percutaneous coronary intervention. | Device: Percutaneous coronary intervention with implantation of amphilimus-eluting stents for coronary artery disease.<br>* Implantation of polymer-free, amphilimus-eluting, drug-eluting stents<br>* Other names: Cre8 AES;Drug: Standard DAPT duration<br>* Duration of dual antiplatelet therapy for 12 months.<br>|
| Other: Synergy EES and personalized DAPT duration<br>Percutaneous coronary intervention with implantation of a Synergy everolimus-eluting stent for coronary artery disease. Personalized duration of dual antiplatelet therapy for 3-, 6-, or 24-month after percutaneous coronary intervention based on the DAPT score. | Device: Percutaneous coronary intervention with implantation of everolimus-eluting stents for coronary artery disease.<br>* Implantation of biodegradable-polymer, everolimus-eluting, drug-eluting stents<br>* Other names: Synergy EES;Drug: Personalized DAPT duration<br>* Duration of dual antiplatelet therapy according to DAPT score for 3- or 6- months in patients with low DAPT score (stable CAD or ACS, respectively) or for 24-months in patients with high DAPT score<br>|
| Other: Synergy EES and standard DAPT duration<br>Percutaneous coronary intervention with implantation of a Synergy everolimus-eluting stent for coronary artery disease. Standard duration of dual antiplatelet therapy for 12-month after percutaneous coronary intervention. | Device: Percutaneous coronary intervention with implantation of everolimus-eluting stents for coronary artery disease.<br>* Implantation of biodegradable-polymer, everolimus-eluting, drug-eluting stents<br>* Other names: Synergy EES;Drug: Standard DAPT duration<br>* Duration of dual antiplatelet therapy for 12 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Device-oriented composite endpoint (DOCE) for the comparison between the Cre8 AES and the Synergy EES. | The composite of cardiovascular death, myocardial infarction not clearly attributable to a non-target vessel, or clinically-driven target-lesion revascularization. | 12 months | 
| Number of Participants with Net adverse clinical endpoint (NACE) for the comparison between a personalized and standard DAPT duration. | The composite of all-cause death, any myocardial infarction, stroke, urgent target-vessel revascularization, or BARC type 2 to 5 bleeding at 24-month follow-up. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with All-cause death |  | 12- and 24-month | 
| Number of Participants with Death from cardiovascular causes |  | 12- and 24-month | 
| Number of Participants with Myocardial infarction |  | 12- and 24-month | 
| Number of Participants with Stroke |  | 12- and 24-month | 
| Number of Participants with Clinically-driven target-lesion revascularization |  | 12- and 24-month | 
| Number of Participants with Definite or probable stent thrombosis |  | 12- and 24-month | 
| Number of Participants with Definite stent thrombosis |  | 12- and 24-month | 
| Number of Participants with Any revascularization |  | 12- and 24-month | 
| Number of Participants with Clinically-driven target-vessel revascularization |  | 12- and 24-month | 
| Number of Participants with Urgent target-vessel revascularization |  | 12- and 24-month | 
| Number of Participants with Urgent non-target-vessel revascularization |  | 12- and 24-month | 
| Number of Participants with Any target-lesion revascularization |  | 12- and 24-month | 
| Number of Participants with Any target-vessel revascularization |  | 12- and 24-month | 
| Number of Participants with Bleeding events | Bleeding events according to the BARC, TIMI and GUSTO classification | 12- and 24-month |