Optimal Antithrombotic Therapy for ACS Patients Concomitant With AF and Implanted With New-generation DES (OPTIMA-3, 4)

Optimal Antithrombotic Therapy for Acute Coronary Syndrome Patients Concomitant With Atrial Fibrillation and Implanted With New-generation Drug-eluting Stent: OPTImal Management of Antithrombotic Agents (OPTIMA-3, 4)

It is a multi-center randomized clinical trial (RCT) which will enroll 3746 patients with acute coronary syndrome (ACS) concomitant non-valvular atrial fibrillation (NVAF) and undergoing new generation drug eluting stent (DES) implantation at 70 centers nationwide in China and contains two sub-studies.

In the OPTIMA-3 sub-study, 2274 subjects who choose warfarin as anticoagulant will randomly receive triple antithrombotic therapy (warfarin with targeted INR 2.0-3.0, clopidogrel 75 mg od and aspirin 100 mg od) for 1 month or 6 months in a 1:1 ratio then quit aspirin till 12 months after percutaneous coronary intervention (PCI). The primary endpoint of the OPTIMA-3 is a composite of cardiovascular death, myocardial infarction, ischemic stroke, systemic thromboembolism and unplanned revascularization up to 12 months; the major secondary endpoint is the International Society of Thrombosis and Hemostasis (ISTH) major bleeding or clinically relevant non-major bleeding (CRNMB).

In the OPTIMA-4 sub-study, 1472 subjects who prefer dabigatran will be randomly assigned in a 1:1 ratio to a dual antithrombotic therapy of dabigatran 110 mg twice daily with ticagrelor 90 mg twice daily or with clopidogrel 75 mg od for 12 months after PCI. The primary safety endpoint of the OPTIMA-4 is ISTH major bleeding or CRNMB at 12 months; the primary efficacy endpoint is a composite of cardiovascular death, myocardial infarction, ischemic stroke, systemic thromboembolism and unplanned revascularization.

Other secondary endpoints comprise death (cardiovascular, non- cardiovascular), MI (fatal or non-fatal, Q-wave or non-Q-wave), unplanned revascularization (target or non-target vessel, target or non-target lesion), stent thrombosis (possible, probable, definite), stroke (hemorrhage or ischemic), all bleeding (ISTH and BARC criteria) and net adverse events.

All endpoints will be collected and compared between subgroups and sub-studies during hospitalization and in 1 month (± 7 days), 6 months (± 7 days) and 12 months (± 7 days) for office visits and in 2 weeks (± 7 days), 2 months (± 7 days) and 3 months (± 7 days) for phone call visits.

Study Overview

• Status: Recruiting
• Conditions: Non-valvular Atrial Fibrillation (NVAF); Acute Coronary Syndrome (ACS)
• Intervention / Treatment: Drug: Triple antithrombotic therapy; Drug: Dual antithrombotc therapy-1; Drug: Dual antithrombotc therapy-2

• Study Type: Interventional
• Enrollment (Anticipated): 3746
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Xiaoxuan Gong, MD; Phone Number: +86-18851727059; Email: xiaoxuangong@sina.com

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 210029
      • Recruiting
      • First Affiliated Hospital of Nanjing Medical University
      • Principal Investigator: Chunjian Li, Ph.D
      • Sub-Investigator: Xiaoxuan Gong, MD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• ≥ 18 years;
• ACS patients concomitant non-valvular AF (paroxysmal, persistent and permanent) underwent PCI and new-generation DES implantation;
• CHA2DS2-VASc score ≥ 2;
• Acceptable risk of bleeding at the discretion of the researchers (e.g. HAS-BLED score ≤ 2)
• Consent to participate in the trial

Exclusion Criteria:

• DES implanted in the left main coronary artery
• Cardiogenic shock or Killip III-IV
• STEMI patients with malignant arrhythmias or underwent electrodefibrillation or CPR or with cardiac mechanical complications (heart rupture, ventricular septal perforation, nipple muscle fracture, etc.)
• History of gastrointestinal or intracranial hemorrhage; active bleeding, trauma or major surgery within one month; suspected or diagnosed aortic dissection
• Ischemic stroke with limb dysfunction or dysphasia
• Known allergy or intolerance to the study medications: warfarin, clopidogrel, aspirin, dabigatran, ticagrelor and heparin
• Participating in other ongoing trials
• Planned surgery in 12 months requiring to withdraw the antiplatelet agents
• Planned RFCA or left atrial appendage occlusion in the next 12m
• Abnormal liver or kidney function (ALT ≥ 3 ULN; estimated CrCl < 30 ml/min calculated by Cockcroft-Gault equation); diagnosed liver cirrhosis
• Hematological disease with bleeding tendency; hemoglobin < 100 g/L, platelet count < 100 × 10^9 /L
• Malignancies or life expectancy less than 1 year
• Pregnant (present, suspected, or planned) or lactating woman
• Patients who are taking drugs which may interact with study agents, such as miconazole, ketoconazole, fluconazole, voriconazole, itraconazole, posaconazole, efinaconazole, and rifampicin, etc.
• Patients with any other conditions that may not be suitable to participate in the trial at the discretion of the researchers.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1-month TAT; Randomized experimental group in the OPTIMA-3 substudy; Triple antithrombotic therapy (warfarin with targeted INR 2.0-3.0, clopidogrel 75 mg q.d. and aspirin 100 mg q.d.) for 1 month (30 days) then quit aspirin till 12 months after PCI	Drug: Triple antithrombotic therapy; Including warfarin with targeted INR 2.0-3.0 (Shanghai Xinyi pharma co., LTD, China), aspirin 100 mg q.d. (Bayer, Germany) and clopidogrel 75 mg q.d. (Sanofi, France); Other Names: TAT
Experimental: 6-month TAT; Randomized control group in the OPTIMA-3 substudy; Triple antithrombotic therapy (warfarin with targeted INR 2.0-3.0, clopidogrel 75 mg q.d. and aspirin 100 mg q.d.) for 6 months (180 days）then quit aspirin till 12 months after PCI	Drug: Triple antithrombotic therapy; Including warfarin with targeted INR 2.0-3.0 (Shanghai Xinyi pharma co., LTD, China), aspirin 100 mg q.d. (Bayer, Germany) and clopidogrel 75 mg q.d. (Sanofi, France); Other Names: TAT
Experimental: 12-month DAT-1; Randomized experimental group in the OPTIMA-4 substudy; Dual antithrombotic therapy including dabigatran 110 mg b.i.d. with clopidogrel 75 mg q.d. for 12 months after PCI	Drug: Dual antithrombotc therapy-1; Including dabigatran 110 mg b.i.d. (Boehringer Ingelheim, Germany) plus clopidogrel 75 mg q.d. (Sanofi, France); Other Names: DAT-1
Experimental: 12-month DAT-2; Randomized control group in the OPTIMA-4 substudy; Dual antithrombotic therapy including dabigatran 110 mg b.i.d. with ticagrelor 90 mg b.i.d for 12 months after PCI	Drug: Dual antithrombotc therapy-2; Including dabigatran 110 mg b.i.d. (Boehringer Ingelheim, Germany) plus ticagrelor 90 mg b.i.d. (AstraZeneca, Britain); Other Names: DAT-2

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary endpoint of OPTIMA-3	A composite of cardiovascular death, myocardial infarction, ischemic stroke, systemic thromboembolism and unplanned revascularization	Up to 12 months (± 7 days) after inclusion
Primary safety endpoint of OPTIMA-4	ISTH major bleeding or CRNMB	Up to 12 months (± 7 days) after inclusion
Primary efficacy endpoint of OPTIMA-4	A composite of cardiovascular death, myocardial infarction, ischemic stroke, systemic thromboembolism and unplanned revascularization	Up to 12 months (± 7 days) after inclusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major secondary endpoint of OPTIMA-3	Major bleeding or clinically relevant non-major bleeding assessed by the ISTH definition	Up to 12 months (± 7 days) after inclusion
Other secondary endpoints of OPTIMA-3/4	Death (cardiovascular, non- cardiovascular), MI (fatal or non-fatal, Q-wave or non-Q-wave), unplanned revascularization (target or non-target vessel, target or non-target lesion), stent thrombosis (possible, probable, definite), stroke (hemorrhage or ischemic), all bleeding (ISTH and BARC criteria) and net adverse events	Up to 12 months (± 7 days) after inclusion

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adenosine diphosphate (ADP, final concentration 5 μmol/L) induced platelet aggregation (PLADP)	The PLADP will be detected by light transmission aggregometry (LTA) to reflect platelet function under the treatment of clopidogrel or ticagrelor.	The venous blood will be collected at 7:30 a.m. on the day of discharge and tested within 2 hours.
Arachidonic acid (AA, final concentration 1 mmol/L) induced platelet aggregation (PLAA)	The PLAA will be detected by light transmission aggregometry (LTA) to reflect platelet function under the treatment of aspirin.	The venous blood will be collected at 7:30 a.m. on the day of discharge and tested within 2 hours.
Trough concentration of dabigatran (Cmin)	The trough concentration of dabigatran (Cmin) of dabigatran is to be detected by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS) in OPTIMA-4 trial.	The venous blood will be collected at 0.5 hour before dosing after the patients taking at least 3 days of dabigatran and detected after stored below -80℃ for at most 2 months.
Single nucleotide polymorphisms (SNPs)	The single nucleotide polymorphisms (SNPs) related to the antithrombotic agents used in different groups will be detected as follows: (1) clopidogrel-related SNPs: CYP2C19 (rs12248560, rs28399504, rs41291556, rs4244285, rs4986893, rs5633701, rs72552267, rs72558186); (2) ticagrelor-related SNPs: SLCO1B1 (rs113681054), OATP1B1 (rs4149056), CYP3A4 (rs62471956, rs56324128), UGT2B7 (rs61361928); (3) dabigatran-related SNP: ABCB1 (rs4148738, rs1045642), CES1 (rs8192935).	The venous blood will be collected at any time during hospitalization and detected after stored below -80℃ for at most 5 years.

Collaborators and Investigators

• Sponsor: The First Affiliated Hospital with Nanjing Medical University

Study record dates

Study Major Dates

• Study Start (Actual): February 3, 2018
• Primary Completion (Anticipated): December 31, 2024
• Study Completion (Anticipated): December 31, 2024

Study Registration Dates

• First Submitted: July 25, 2017
• First Submitted That Met QC Criteria: July 26, 2017
• First Posted (Actual): July 31, 2017

Study Record Updates

• Last Update Posted (Actual): April 24, 2023
• Last Update Submitted That Met QC Criteria: April 20, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: antithrombotic therapy; randomized clinical trial (RCT); new generation drug eluting stent (DES)
• Additional Relevant MeSH Terms: Pathologic Processes; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Disease; Arrhythmias, Cardiac; Syndrome; Atrial Fibrillation; Acute Coronary Syndrome
• Other Study ID Numbers: 007

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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