Pharmacodynamic Effect of Prasugrel vs. Ticagrelor in Diabetes

NCT ID: NCT01852214

Last Updated: 2016-10-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 50 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-02-28
• Study Completion Date: 2015-08-31

Brief Summary

Patients with diabetes mellitus (DM) have an increased risk of adverse atherothrombotic events. This may be in part attributed to the fact that these patients have reduced response to oral antiplatelet medications, in particular the P2Y12 receptor inhibitor clopidogrel, used for secondary prevention of ischemic events. Prasugrel and ticagrelor are recently approved P2Y12 receptor inhibitors which, compared with clopidogrel, have more potent antiplatelet effects. Head-to-head comparisons between the two drugs are lacking.

Detailed Description

Patients with diabetes mellitus (DM) have an increased risk of adverse atherothrombotic events. This may be in part attributed to the fact that these patients have reduced response to oral antiplatelet medications, in particular the P2Y12 receptor inhibitor clopidogrel, used for secondary prevention of ischemic events. Upregulation of platelet P2Y12 receptor mediated signaling has been shown in DM patients and may contribute to these pharmacodynamic observations, suggesting the need for more potent P2Y12 inhibiting strategies in these patients. Prasugrel and ticagrelor are recently approved P2Y12 receptor inhibitors which, compared with clopidogrel, have more potent antiplatelet effects. Therefore, prasugrel and ticagrelor represent attractive treatment options for patients with DM. This is also supported by the DM sub-group analysis of the pivotal TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction) and PLATO (Platelet Inhibition and Patient Outcomes) trials, which have led to approval of prasugrel and ticagrelor, respectively. Although results of these sub-group analysis suggest that prasugrel is associated with an enhanced benefit in DM patients, while ticagrelor effects in DM patients are consistent with the overall study population, only head-to-head comparisons between the two drugs can elucidate if these exert differential effects on platelets from DM patients. However, the pharmacodynamic studies comparing prasugrel with ticagrelor in DM patients are lacking. The ever growing DM population at high risk of recurrent atherothrombotic events underscores the need to define antiplatelet treatment strategies leading to more optimal platelet inhibition in these patients.

Conditions

Diabetes Mellitus; Coronary Artery Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Prasugrel first, then ticagrelor

Patients randomized to prasugrel will receive prasugrel loading dose followed by maintenance dose. Randomized treatment will be maintained for 1-week (7±2 days). After completion of the 1-week treatment period, patients will discontinued the study medications for 2-4 weeks (wash-out period) and then will cross over to the alternate treatment (ticagrelor), which will be administered for 1-week.

Group Type: ACTIVE_COMPARATOR

Prasugrel

Intervention Type: DRUG

Patients receiving prasugrel will be treated with 60mg loading dose and 10mg maintenance dose

Ticagrelor

Intervention Type: DRUG

Patients receiving ticagrelor will be treated with a 180mg loading dose and 90mg bid maintenance dose

Ticagrelor first, then prasugrel

Patients randomized to ticagrelor will receive prasugrel loading dose followed by maintenance dose. Randomized treatment will be maintained for 1-week (7±2 days). After completion of the 1-week treatment period, patients will discontinued the study medications for 2-4 weeks (wash-out period) and then will cross over to the alternate treatment (prasugrel), which will be administered for 1-week.

Group Type: ACTIVE_COMPARATOR

Prasugrel

Intervention Type: DRUG

Patients receiving prasugrel will be treated with 60mg loading dose and 10mg maintenance dose

Ticagrelor

Intervention Type: DRUG

Patients receiving ticagrelor will be treated with a 180mg loading dose and 90mg bid maintenance dose

Interventions

Prasugrel

Patients receiving prasugrel will be treated with 60mg loading dose and 10mg maintenance dose

Intervention Type: DRUG

Ticagrelor

Patients receiving ticagrelor will be treated with a 180mg loading dose and 90mg bid maintenance dose

Intervention Type: DRUG

Other Intervention Names

Effient; Brillinta

Eligibility Criteria

Inclusion Criteria

• Patients with known (angiographically documented) CAD.
• On maintenance treatment with aspirin (81 mg per day) for at least 1-month as per standard of care.
• Type 2 DM on treatment with oral hypoglycemic agents and/or insulin.
• Age between 18 and 74 years old.

Exclusion Criteria

• History of stroke, transient ischemic attack or intracranial bleeding.
• On treatment with a P2Y12 receptor antagonist (ticlopidine, clopidogrel, prasugrel, ticagrelor).
• Known allergies to aspirin, ticlopidine, clopidogrel, prasugrel, ticagrelor.
• Weight <60kg.
• On treatment with oral anticoagulant (Vitamin K antagonists, dabigatran).
• Blood dyscrasia or bleeding diathesis.
• Platelet count <80x106/mL.
• Hemoglobin <10 g/dL.
• Active bleeding or hemodynamic instability.
• Creatinine Clearance <30 mL/minute.
• Baseline ALT >2.5 times the upper limit of normal.
• Hb A1c ≥ 10 mg/dL within 3 months.
• Patients with sick sinus syndrome (SSS) or high degree AV block without pacemaker protection.
• Drugs interfering CYP3A4 metabolism (to avoid interaction with Ticagrelor): Ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, and telithromizycin.
• Pregnant females*.

• Women of childbearing age must use reliable birth control (i.e. oral contraceptives) while participating in the study.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 74 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Florida

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Dominick Angiolillo, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Florida

Locations

University of Florida

Jacksonville, Florida, United States

Countries

United States

References

Franchi F, Rollini F, Aggarwal N, Hu J, Kureti M, Durairaj A, Duarte VE, Cho JR, Been L, Zenni MM, Bass TA, Angiolillo DJ. Pharmacodynamic Comparison of Prasugrel Versus Ticagrelor in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease: The OPTIMUS (Optimizing Antiplatelet Therapy in Diabetes Mellitus)-4 Study. Circulation. 2016 Sep 13;134(11):780-92. doi: 10.1161/CIRCULATIONAHA.116.023402. Epub 2016 Aug 24.

Reference Type: DERIVED

PMID: 27559041 (View on PubMed)

Other Identifiers

UFJ 2011-184

Identifier Type: -

Identifier Source: org_study_id