OPTImal Management of Antithrombotic Agents: OPTIMA-2 Trial

Sponsor

The First Affiliated Hospital with Nanjing Medical University (Other)

Overall Status

Completed

CT.gov ID

NCT01955200

Collaborator

National Natural Science Foundation of China (Other)

1,724

Enrollment

Location

Arms

49.8

Actual Duration (Months)

34.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

High on-treatment platelet reactivity (HOPR) is associated with increased risk of cardiovascular events in patients undergoing percutaneous coronary intervention (PCI). We sought to investigate the efficacy and safety of 1-month intensified antiplatelet therapies in post-PCI patients with HOPR.

Condition or Disease	Intervention/Treatment	Phase
Coronary Artery Disease	Drug: Clopidogrel Drug: Cilostazol Drug: Ticagrelor Drug: Clopidogrel Drug: Clopidogrel	Phase 4

Detailed Description

OPTImal Management of Antithrombotic agents: OPTIMA-2 trial

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor is the foundation antiplatelet therapy in patients undergoing percutaneous coronary intervention (PCI). Clopidogrel is the most commonly used P2Y12 receptor inhibitor worldwide because it is effective and inexpensive1. High on-treatment platelet reactivity (HOPR) occurs in as many as one-third of patients treated with standard dose clopidogrel (75mg once daily), and is associated with an increased risk of major adverse cardiovascular events (MACE).

Various approaches have been tested to overcome HOPR in patients treated with aspirin and clopidogrel, including higher doses of clopidogrel; the addition of cilostazol; and replacement of clopidogrel with prasugrel; however, the results of these intensified treatments were controversial, and a more potent P2Y12 receptor inhibitor, ticagrelor has never been studied in this scenario.

TOPIC study showed that short-term (i.e. 1-month) intensification of antiplatelet treatment might be sufficient to achieve optimal outcomes. Similarly, TROPICAL ACS showed that guided de-escalation of antiplatelet treatment with clopidogrel was non-inferior to the treatment with prasugrel at 1 year after PCI in terms of net clinical benefit, which suggests that routinely long-term intensification of antiplatelet treatment is not required for all PCI patients.

Accordingly we performed a randomized trial to test the hypothesis that in patients with HOPR intensification of antiplatelet therapy with double dose clopidogrel, the addition of cilostazol, or replacement of clopidogrel with ticagrelor for 1 month followed by resumption of conventional DAPT with aspirin and clopidogrel for 11 months would be superior to conventional DAPT for 12 months in reducing the prevalence of HOPR and MACE without increasing bleeding.

Inclusion criteria:

Successively recruit all patients who receive stent implantation;
Intended use of conventional DAPT with the combination of aspirin 100mg once daily and clopidogrel 75mg once daily for at least 12 months;
Patient aged over 18 years;
Signed inform consent.

Exclusion criteria:

Allergy or intolerance to study drugs;
History of gastrointestinal or intracranial bleeding;
Need for anticoagulant therapy;
High risk of bleeding (e.g., myelodysplasia, baseline platelet count < 80 × 109/L);
Hemoglobin < 90g/L;
Active malignancy or life expectancy < 1 year;
Patients with other conditions made them unsuitable to be recruited at the discretion of the investigators.

Study procedures:

Following treatment for at least 5 days with the combination of aspirin 100mg once daily and clopidogrel 75mg once daily irrespective of a loading dose we measured platelet aggregation in response to adenosine diphosphate (ADP) (PLADP) using light transmittance aggregometry (LTA). HOPR was defined as PLADP > 40%. Patients with HOPR were continued on aspirin 100mg once daily and were randomly assigned to one of the following 4 groups:

clopidogrel 150mg once daily (CLOP-150);
clopidogrel 75mg once daily plus cilostazol 100mg twice daily (CLOP+CILOST);
ticagrelor 90mg twice daily (TICAG);
clopidogrel 75mg once daily (conventional DAPT, CON). At 1 month, platelet aggregation testing was repeated after which all patients were switched back to conventional DAPT for a further 11 months.

All patients without HOPR were treated with conventional DAPT and followed to 12 months (Non-HOPR).

Sample size calculation:

Based on the published literature, we assumed a 38% rate of persistent HOPR in patients randomized to intensified treatment and 60% in those randomized to CON therapy. With a sample size of 81 per group, we calculated that we would have 80% power to detect this difference with a 2-sided P value of 0.05. After allowing for 20% study drug discontinuation rate at 1 month, we planned a sample size of 405 patients with HOPR.

Platelet Reactivity Assay

ADP-induced platelet aggregation: Light transmittancy aggregation (LTA) in response to 5μM ADP.
Blood sample collection time: baseline (more than 5 days after taking clopidogrel 75mg daily and aspirin 100mg daily), 1month after randomization.

Clinical follow-up:

Time points: 1month, 6month, and 1year after randomization.

The study endpoints:

The primary outcome was the proportion of patients with persistent HOPR at 1 month.

The secondary outcomes included a composite of MACE including cardiovascular death, nonfatal myocardial infarction (MI), ischemic stroke, target vessel revascularization (TVR), stent thrombosis (ST) and cardiac readmission during 12-month follow-up, and any bleeding defined by the Thrombolysis in Myocardial Infarction (TIMI) criteria.

Study Design

Study Type:

Interventional

Actual Enrollment :

1724 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Intensified Antiplatelet Therapy in Post-PCI Patients With High On-treatment Platelet Reactivity: the OPTIMA-2 Trial

Actual Study Start Date :

Oct 5, 2013

Actual Primary Completion Date :

Dec 26, 2016

Actual Study Completion Date :

Nov 28, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CLOP-150 clopidogrel 150mg once daily	Drug: Clopidogrel (ASA 100mg daily + Clopidogrel 150mg daily) x 1 month; (ASA 100mg daily + Clopidogrel 75mg daily) x 11 month. Other Names: Plavix
Experimental: CLOP+CILOST clopidogrel 75mg once daily plus cilostazol 100mg twice daily	Drug: Cilostazol (ASA 100mg daily + Clopidogrel 75mg daily + Cilostazol 150mg Bid) x 1 month; (ASA 100mg daily + Clopidogrel 75mg daily) x 11 month. Other Names: Peida
Experimental: TICAG ticagrelor 90mg twice daily	Drug: Ticagrelor (ASA 100mg daily + Ticagrelor 90mg Bid) x 1 month; (ASA 100mg daily + Clopidogrel 75mg daily) x 11 month. Other Names: Brilinta
Active Comparator: CON(conventional DAPT) clopidogrel 75mg once daily	Drug: Clopidogrel (ASA 100mg daily + Clopidogrel 75mg daily) x 12 month. Other Names: Plavix
Active Comparator: Non-HOPR clopidogrel 75mg once daily	Drug: Clopidogrel (ASA 100mg daily + Clopidogrel 75mg daily) x 12 month. Other Names: Plavix

Outcome Measures

Primary Outcome Measures

the proportion of patients with persistent HOPR at 1 month [1-month after randomization]
platelet aggregation in response to 5μM adenosine diphosphate (PLADP) measured by light transmittancy aggregometer (LTA) ; HOPR was defined as PLADP > 40%.

Secondary Outcome Measures

MACE [1-year after randomization]
a composite of MACE including cardiovascular death, nonfatal myocardial infarction (MI), ischemic stroke, target vessel revascularization (TVR), stent thrombosis (ST) and cardiac readmission during 12-month follow-up,revascularization, and stent thrombosis (ARC definition)

Other Outcome Measures

Bleeding [1-year after randomization]
any bleeding defined by the Thrombolysis in Myocardial Infarction (TIMI) criteria

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion criteria:

Successively recruit all patients who receive stent implantation;
Intended use of standard DAPT with the combination of aspirin 100mg once daily and clopidogrel 75mg once daily for at least 12 months;
Patient aged >18 years and ≦80 years old;
Signed inform consent.

Exclusion criteria:

Allergy or intolerance to study drugs;
History of gastrointestinal or intracranial bleeding;
Need for anticoagulant therapy;
High risk of bleeding (e.g., myelodysplasia, baseline platelet count < 80 × 109/L);
Hemoglobin < 90g/L;
Active malignancy or life expectancy < 1 year;
Patients with other conditions made them unsuitable to be recruited at the discretion of the investigators.