A Novel Strategy For Personalized Long-Term Dual Antiplatelet Therapy (RAPID EXTEND PILOT STUDY)

Study Overview
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Brief Summary
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In patients with heart attacks, the current standard of care is to restore blood flow through percutaneous coronary intervention (PCI). This is done using stents (metal meshes) that opens up blockages. Following PCI, standard preventative drug treatment includes the use of dual antiplatelet therapy (DAPT) using both aspirin and a platelet P2Y12 receptor inhibitor (Ticagrelor 90 mg twice a day or Clopidogrel 75 mg once a day) for one year to prevent clotting that can result in additional heart attacks, sudden clotting of stents or death. New studies have shown that there is a benefit to continuing DAPT beyond this one year mark. Longer-term DAPT has been shown to reduce ischemic events (heart attack, stroke) but increase the risk of bleeding. Present guidelines state that the decision to continue DAPT beyond the one year mark should be made on an individualized basis. The present study is a pilot study that seeks to compare Long-Term use of Ticagrelor (LTT) versus a Personalized Approach (PA). We will be recruiting patients who have been stable (free of ischemic or bleeding outcomes) on DAPT for 1 year after initial presentation with a heart attack. The PA group will use a modified DAPT score based on patient demographics to decide whether treatment is warranted. Patient will also undergo bedside genetic testing to identify potential at-risk genes. Those identified as carriers will be treated with ticagrelor while non-carriers will be treated with clopidogrel. The present study will determine whether a personalized approach will decrease bleeding versus an approach of universal ticagrelor use. The hypothesis is that patients receiving a personalized strategy will have a decreased risk of bleeding.

Official Title
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Reassessment of Long-Term Dual Anti-Platelet Therapy Using InDividualized Strategies - Using a Novel Combined Demographic and Pharmacogenomic Strategy: The RAPID EXTEND Pilot Study

Conditions
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Stable Coronary Syndrome, Percutaneous Coronary Intervention, Antiplatelet Therapy, Ticagrelor

Intervention / Treatment
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* Drug: Ticagrelor 60mg
* Drug: Clopidogrel 75mg
* Drug: Aspirin 81 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: non-ST-elevation myocardial infarction (NSTEMI) or ST-elevation myocardial infarction (STEMI) at presentation for index PCI who have successfully completed >1-year follow-up of RAPID MANAGE or TAILOR-PCI trials without having incurred an ischemic or bleeding outcome while on DAPT Patients with DAPT interruption after 1 year will be eligible, if within 3 years of index MI Patients must also have 1 of the following atherothrombotic risk enrichment criteria: age ≥ 65 years diabetes 2nd prior MI (> 1 year ago) multi-vessel coronary disease Creatinine Clearance < 60mL/min Exclusion Criteria: Patients will be excluded from the study if they: refuse consent are > 3 years post MI are deemed to require a P2Y12 inhibitor require oral anticoagulation have a history of stroke, transient ischemic attack (TIA) or intracranial bleed have had a recent GI bleed or major surgery have a life expectancy of < 1 year have a platelet count < 100,000/μl have a bleeding diathesis have hematocrit < 30% or > 52% are on dialysis or have severe liver disease are at risk for bradycardia

Ages Eligible for Study
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Minimum Age: 50 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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Personalized Treatment Algorithm<br>A DAPT score using various patient demographics will be calculated: If score under 2, patients will receive only aspirin 81 mg once daily If DAPT score is ≥ 2 A point-of-care bedside genetic test using a buccal swab will be conducted in order to determine medication regimen Those with a positive genetic test (presence of CYP2C19*2 or CYP2C19*3), will receive 60mg Ticagrelor twice daily Those with a negative genetic test (absence of CYP2C19*2/*3) will receive 75mg clopidogrel once daily | Drug: Ticagrelor 60mg<br>* twice daily<br>Drug: Clopidogrel 75mg<br>* once daily<br>Drug: Aspirin 81 mg<br>* once daily<br>|
| Active Comparator: Long-Term Ticagrelor<br>Patients will be given 60mg Ticagrelor twice daily with no aspirin | Drug: Ticagrelor 60mg<br>* twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients with Decreased Bleeding Risk | The primary endpoint is the proportion of patients with low on-treatment platelet reactivity (LPR) in the PA group compared to the LTT group at 1 month. P2Y12 reactivity units (PRU) as a continuous variable will be measured using a VerifyNow P2Y12 assay a PRU value of < 85 is associated with increased bleeding risk | 1 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Platelet Reactivity Index (PRI) as a continuous variable | Platelet function as measured by Vasodilator-stimulated phosphoprotein (VASP) a PRI of < 16% is associated with increased bleeding risk | 1 month | 
| ADP-induced Aggregation (AU) as a continuous variable | Platelet function as measured by Multiplate analyzer an AU of < 19 is associated with increased bleeding risk | 1 month | 
| Bleeding according to Bleeding Academic Research Consortium (BARC) criteria | the incidence and severity of bleeding as defined by BARC classification system | 1 month, 6 months, 1 year, 1.5 years, 2 years, 2.5 years, 3 years | 
| Bleeding according to Thrombolysis in Myocardial Infarction (TIMI) score | the incidence and severity of bleeding as defined by TIMI classification systems | 1 month, 6 months, 1 year, 1.5 years, 2 years, 2.5 years, 3 years | 
| Bleeding according to Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) criteria | the incidence and severity of bleeding as defined by GUSTO classification systems | 1 month, 6 months, 1 year, 1.5 years, 2 years, 2.5 years, 3 years | 
| Ischemic Endpoints (To be collected but blinded to investigators, as this data will be carried from the pilot study into a future definitive clinical trial). | all-cause mortality incidence | 1 month, 6 months, 1 year, 1.5 years, 2 years, 2.5 years, 3 years | 
| Ischemic Endpoints (To be collected but blinded to investigators, as this data will be carried from the pilot study into a future definitive clinical trial). | recurrent myocardial infarction (MI) incidence | 1 month, 6 months, 1 year, 1.5 years, 2 years, 2.5 years, 3 years | 
| Ischemic Endpoints (To be collected but blinded to investigators, as this data will be carried from the pilot study into a future definitive clinical trial). | stroke incidence | 1 month, 6 months, 1 year, 1.5 years, 2 years, 2.5 years, 3 years | 
| Ischemic Endpoints (To be collected but blinded to investigators, as this data will be carried from the pilot study into a future definitive clinical trial). | stent thrombosis incidence | 1 month, 6 months, 1 year, 1.5 years, 2 years, 2.5 years, 3 years |