"Pharmacodynamic Comparison of Omeprazole Versus Pantoprazole on Platelet Reactivity in Patients With Acute Coronary Syndromes on Dual Antiplatelet Therapy With New P2Y12 Inhibitors" -Trial dOPPLER- (dOPPLER)

"Pharmacodynamic Comparison of Omeprazole Versus Pantoprazole on Platelet Reactivity in Patients With Acute Coronary Syndromes on Dual Antiplatelet Therapy With New P2Y12 Inhibitors"

Clopidogrel and Prasugrel are pro-drug necessitating conversion in active metabolites through CYP 450 system (CYP), particularly CYP3A and CYP2C19 isoforms.

These drugs are platelet purinergic receptor antagonists, known as P2Y12. The link between active metabolite of Clopidogrel and Prasugrel to P2Y12 receptor prevents ADP receptor activation and inhibits several events leading to conformational change of platelets, therefore facilitating their activation and aggregation, that is the basis of acute coronary syndromes. Proton pump inhibitors (PPI) are actually considered principal agents reducing gastroenteric bleeding risk associated to antiplatelet therapy. Nevertheless the interaction between PPI and antiplatelet therapy has been object of interest. Several studies demonstrated PPI reduce efficacy of clopidogrel on platelet reactivity. Only few data about Prasugrel are available showing a minor effect of PPI on its antiplatelet activity than clopidogrel. Differing from prasugrel and clopidogrel, ticagrelor is a direct inhibitor of P2Y12, not necessitating biotransformation in the liver; therefore its interaction with PPI remains unclear. Interaction between omeprazole and clopidogrel seems related to high inhibitory activity of PPI on CYP2C19, interfering with the conversion of clopidogrel in its active metabolite.

Study Overview

• Status: Unknown
• Conditions: Coronary Artery Disease
• Intervention / Treatment: Drug: Pantoprazole,; Drug: Omeprazole

Detailed Description

Clopidogrel and Prasugrel are pro-drug necessitating conversion in active metabolites through CYP 450 system (CYP), particularly CYP3A and CYP2C19 isoforms.

These drugs are platelet purinergic receptor antagonists, known as P2Y12. The link between active metabolite of Clopidogrel and Prasugrel to P2Y12 receptor prevents ADP receptor activation and inhibits several events leading to conformational change of platelets, therefore facilitating their activation and aggregation, that is the basis of acute coronary syndromes.

Despite double antiplatelet drugs are the principle therapy for the treatment and the prevention of atherothrombotic events in cardiovascular diseases, they are the most important cause of bleeding peptic ulcer. Proton pump inhibitors (PPI) are actually considered principal agents reducing gastroenteric bleeding risk associated to antiplatelet therapy. Nevertheless the interaction between PPI and antiplatelet therapy has been object of interest. Several studies demonstrated PPI reduce efficacy of clopidogrel on platelet reactivity, probably through the inhibition of its metabolism, increasing the risk of cardiovascular events. Only few data about Prasugrel are available showing a minor effect of PPI on its antiplatelet activity than clopidogrel. Differing from prasugrel and clopidogrel, ticagrelor is a direct inhibitor of P2Y12, not necessitating biotransformation in the liver; therefore its interaction with PPI remains unclear. Nevertheless actual studies considered only clinical outcomes (MACEs), such as a subgroup analysis of the Platelet Inhibition and Patient Outcomes (PLATO) trial, showing a higher rate of MACEs in clopidogrel and Ticagrelor patients undergone PPI therapy, especially omeprazole treatment. Interaction between omeprazole and clopidogrel seems related to high inhibitory activity of PPI on CYP2C19, interfering with the conversion of clopidogrel in its active metabolite. It is yet unclear the higher rate of MACEs in the ticagrelor group, similarly to clopidogrel, despite it hasn't a hepatic metabolism.

• Study Type: Interventional
• Enrollment (Anticipated): 150
• Phase: Phase 4

Contacts and Locations

Study Locations

• Italy
  • Rome, Italy, 00166
    • Sapienza Univeristy of Rome

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. All consecutive patients undergone PTCA in our institution in the period between July 2013 and December 2013 will be eligible to be enrolled.
2. Positive biomarker indicating myocardial necrosis.
3. All patients with prior myocardial infarction (MI) or coronary artery bypass grafting; coronary artery disease will be included.

Exclusion Criteria:

1. Increased risk of bleeding (ex. active bleeding, major surgery <30 days).
2. Allergy or adverse reactions to administered drugs.
3. Other drugs or medications that affect CYP3A4 mediated drug metabolism.
4. Patients with missing follow-up data will be dropped out from the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: pantoprazole; Patients were randomly assigned to omeprazole (20 mg day) or pantoprazole (20 mg day) for 30 days. After 1-week wash-out period to avoid any carryover effect, cross-over was performed, and patients were switched to the other drug which was continued for 30 days.	Drug: Pantoprazole,; os, 20 mg, once per day, for 30 days; Other Names: pantorc; Drug: Omeprazole; os, 20 mg, once per day, for 30 days; Other Names: lansox
Active Comparator: Omeprazole; Patients were randomly assigned to omeprazole (20 mg day) or pantoprazole (20 mg day) for 30 days. After 1-week wash-out period to avoid any carryover effect, cross-over was performed, and patients were switched to the other drug which was continued for 30 days.	Drug: Pantoprazole,; os, 20 mg, once per day, for 30 days; Other Names: pantorc; Drug: Omeprazole; os, 20 mg, once per day, for 30 days; Other Names: lansox

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of platelet reaction units	Absolute changes in platelet reactivity (expressed as P2Y(12) reaction units by the point-of-care VerifyNow assay [Accumetrics, San Diego, California]	After 30 days of treatment with each drug

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of high platelet reactivity	Frequency of high platelet reactivity with the 2 study treatments (as defined by a Platelet Reaction Unit value>240	After 30 days of treatment with each drug

Collaborators and Investigators

• Sponsor: University of Roma La Sapienza

Study record dates

Study Major Dates

• Study Start: February 1, 2014
• Primary Completion (Anticipated): March 1, 2015
• Study Completion (Anticipated): April 1, 2016

Study Registration Dates

• First Submitted: January 2, 2014
• First Submitted That Met QC Criteria: January 3, 2014
• First Posted (Estimate): January 7, 2014

Study Record Updates

• Last Update Posted (Estimate): January 8, 2014
• Last Update Submitted That Met QC Criteria: January 6, 2014
• Last Verified: January 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Coronary Artery Disease; Acute Coronary Syndrome; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Gastrointestinal Agents; Anti-Ulcer Agents; Proton Pump Inhibitors; Omeprazole; Pantoprazole
• Other Study ID Numbers: 010114