Ticagrelor With and Without Aspirin in Patients With Diabetes Mellitus

Study Overview
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Brief Summary
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Recent studies have shown that withdrawing aspirin and maintaining P2Y12 inhibitor monotherapy for up to 12 months post-PCI, after a brief period of DAPT, reduces bleeding without increasing ischemic harm. Such effects have shown to of particular benefit in patients with diabetes mellitus (DM). However, if an aspirin-free approach can be considered after this time frame is a matter of debate. The aim of this study is to assess the PD effects of ticagrelor 60 mg with and without aspirin therapy in CAD patients and to compare this with a standard DAPT regimen of aspirin plus clopidogrel.

Detailed Description
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Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor is the standard of care for the prevention of thrombotic complications in patients with coronary artery disease (CAD) undergoing percutaneous coronary interventions (PCI). However, such ischemic benefit occurs at the expense of enhanced bleeding, the risk of which increases in a graded fashion with prolonged exposure to DAPT. Recent studies have shown that withdrawing aspirin and maintaining P2Y12 inhibitor monotherapy for up to 12 months post-PCI, after a brief period of DAPT, reduces bleeding without increasing ischemic harm. Such effects have shown to of particular benefit in patients with diabetes mellitus (DM). However, if an aspirin-free approach can be considered after this time frame is a matter of debate. In fact, current guidelines recommend maintaining P2Y12 inhibiting therapy for high risk patients but which all imply background use of aspirin. P2Y12 inhibitors for long-term (beyond 12 months) secondary prevention mainly include clopidogrel and ticagrelor. In particular, the dosing regimen for clopidogrel remains the standard 75 mg qd, whereas ticagrelor dosing is recommended to be reduced from 90 mg bid to 60 mg bid. However, of these regimens the pharmacodynamics (PD) effects of ticagrelor 60 mg in the absence of aspirin has not yet been tested. Because DM patients are likely to continue with long-term P2Y12 inhibitor therapy, defining the optimal antithrombotic approach for these patients is of critical importance. In light of the above made observations, patients with DM represent an ideal population to define the antiplatelet effects of a ticagrelor 60 mg monotherapy regimen. The aim of this study is to assess the PD effects of ticagrelor 60 mg with and without aspirin therapy in CAD patients and to compare this with a standard DAPT regimen of aspirin plus clopidogrel.

Official Title
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Pharmacodynamic Effects of Different Ticagrelor Maintenance Dosing Regimens With and Without Aspirin in Patients With Diabetes Mellitus: The OPTIMUS (Optimizing Antiplatelet Therapy in Diabetes Mellitus)-7 Study

Conditions
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Diabetes Mellitus, Type 2, Coronary Artery Disease

Intervention / Treatment
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* Drug: Ticagrelor monotherapy
* Drug: Ticagrelor plus aspirin
* Drug: Clopidogrel with aspirin


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: For inclusion in the study patients should fulfill the following criteria: Provision of informed consent prior to any study specific procedures Men or women ≥18 years of age Diagnosed with type 2 DM defined by ongoing glucose lowering therapy (oral medications and/or insulin) treatment for at least 1 month Known CAD with a history of previous PCI on standard of care antiplatelet therapy* *Patients can be treated with any background antiplatelet treatment regimen as part of their standard of care, including aspirin and/or any P2Y12 inhibitor (clopidogrel, ticagrelor, prasugrel). Exclusion criteria: PCI < 6 months prior Recent (< 6 months) type I myocardial infarction Anticipated concomitant oral or intravenous therapy with strong cytochrome P450 3A4 (CYP3A4) inhibitors or CYP3A4 substrates with narrow therapeutic indices that cannot be stopped for the course of the study: Strong inhibitors: ketoconazole, itraconazole, voriconazole, telithromycin, clarithromycin (but not erythromycin or azithromycin), nefazadone, ritonavir, saquinavir, nelfinavir, indinavir, atanazavir CYP3A4 substrates with narrow therapeutic index: quinidine, simvastatin at doses >40 mg daily or lovastatin at doses >40 mg daily Need for chronic oral anticoagulant therapy or chronic low-molecular-weight heparin (at venous thrombosis treatment not prophylaxis doses) Patients with known bleeding diathesis or coagulation disorder History of previous intracerebral bleed at any time, gastrointestinal (GI) bleed within the past 6 months prior to randomization, or major surgery within 30 days prior to randomization Active pathological bleeding Hypersensitivity to aspirin, ticagrelor or clopidogrel Increased risk of bradycardic events (eg, known sick sinus syndrome, second or third degree AV block or previous documented syncope suspected to be due to bradycardia) unless treated with a pacemaker Known severe liver disease Renal failure requiring dialysis Known platelet count <80x106/mL Known hemoglobin <9 g/dL Pregnant or breastfeeding women. *Women of childbearing age must use reliable birth control (i.e. oral contraceptives) while participating in the study.

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: Parallel Assignment
Interventional Model Description: Prospective randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ticagrelor<br>ticagrelor 60 mg bid monotherapy | Drug: Ticagrelor monotherapy<br>* Eligible patients will enter a 7-10 day run-in phase with aspirin 81 mg/ qd plus ticagrelor 90 mg bid after which they will discontinue aspirin and maintain ticagrelor 90 mg bid monotherapy for 10±3 days. After this period, patients will be randomized using a randomly generated computer sequence in a 1:1:1 fashion to either: a) ticagrelor 60 mg bid monotherapy; b) aspirin 81 mg qd plus ticagrelor 60 mg bid; c) aspirin 81 mg qd plus clopidogrel 75 mg qd. Randomized treatment will be maintained for 10±3 days.<br>* Other names: Brilinta;|
| Active Comparator: Aspirin plus Clopidogrel<br>aspirin 81 mg qd plus clopidogrel 75 mg qd | Drug: Clopidogrel with aspirin<br>* Eligible patients will enter a 7-10 day run-in phase with aspirin 81 mg/ qd plus ticagrelor 90 mg bid after which they will discontinue aspirin and maintain ticagrelor 90 mg bid monotherapy for 10±3 days. After this period, patients will be randomized using a randomly generated computer sequence in a 1:1:1 fashion to either: a) ticagrelor 60 mg bid monotherapy; b) aspirin 81 mg qd plus ticagrelor 60 mg bid; c) aspirin 81 mg qd plus clopidogrel 75 mg qd. Randomized treatment will be maintained for 10±3 days.<br>* Other names: Plavix;|
| Active Comparator: Aspirin plus Ticagrelor<br>aspirin 81 mg qd plus ticagrelor 60 mg bid | Drug: Ticagrelor plus aspirin<br>* Eligible patients will enter a 7-10 day run-in phase with aspirin 81 mg/ qd plus ticagrelor 90 mg bid after which they will discontinue aspirin and maintain ticagrelor 90 mg bid monotherapy for 10±3 days. After this period, patients will be randomized using a randomly generated computer sequence in a 1:1:1 fashion to either: a) ticagrelor 60 mg bid monotherapy; b) aspirin 81 mg qd plus ticagrelor 60 mg bid; c) aspirin 81 mg qd plus clopidogrel 75 mg qd. Randomized treatment will be maintained for 10±3 days.<br>* Other names: Brilinta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| P2Y12 reaction units (PRU) | The primary end-point of the study is the comparison of the PRU determined by VerifyNow PRU between between aspirin plus ticagrelor 60 mg and ticagrelor 60 mg monotherapy (trough effect pre-dosing) | 10 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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diabetes mellitus, ticagrelor, clopidogrel, percutaneous coronary intervention