"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-

Overview[ - collapse ][ - ]

Purpose 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.
ConditionCoronary Artery Disease
InterventionDrug: Pantoprazole,
Drug: Omeprazole
PhasePhase 4
SponsorUniversity of Roma La Sapienza
Responsible PartyUniversity of Roma La Sapienza
ClinicalTrials.gov IdentifierNCT02028234
First ReceivedJanuary 2, 2014
Last UpdatedJanuary 6, 2014
Last verifiedJanuary 2014

Tracking Information[ + expand ][ + ]

First Received DateJanuary 2, 2014
Last Updated DateJanuary 6, 2014
Start DateFebruary 2014
Estimated Primary Completion DateApril 2016
Current Primary Outcome MeasuresAssessment of platelet reaction units [Time Frame: After 30 days of treatment with each drug] [Designated as safety issue: No]Absolute changes in platelet reactivity (expressed as P2Y(12) reaction units by the point-of-care VerifyNow assay [Accumetrics, San Diego, California]
Current Secondary Outcome MeasuresFrequency of high platelet reactivity [Time Frame: After 30 days of treatment with each drug] [Designated as safety issue: No]Frequency of high platelet reactivity with the 2 study treatments (as defined by a Platelet Reaction Unit value>240

Descriptive Information[ + expand ][ + ]

Brief Title"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-
Official Title"Pharmacodynamic Comparison of Omeprazole Versus Pantoprazole on Platelet Reactivity in Patients With Acute Coronary Syndromes on Dual Antiplatelet Therapy With New P2Y12 Inhibitors"
Brief Summary
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.
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 TypeInterventional
Study PhasePhase 4
Study DesignAllocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
ConditionCoronary Artery Disease
InterventionDrug: Pantoprazole,
os, 20 mg, once per day, for 30 days
Other Names:
pantorcDrug: Omeprazole
os, 20 mg, once per day, for 30 days
Other Names:
lansox
Study Arm (s)
  • 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.
  • 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.

Recruitment Information[ + expand ][ + ]

Recruitment StatusNot yet recruiting
Estimated Enrollment150
Estimated Completion DateApril 2016
Estimated Primary Completion DateMarch 2015
Eligibility Criteria
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.
GenderBoth
Ages18 Years
Accepts Healthy VolunteersNo
ContactsContact: MD MARINA POLACCO
+393333347960
dott.mpolacco@gmail.com
Location CountriesItaly

Administrative Information[ + expand ][ + ]

NCT Number NCT02028234
Other Study ID Numbers010114
Has Data Monitoring CommitteeNo
Information Provided ByUniversity of Roma La Sapienza
Study SponsorUniversity of Roma La Sapienza
CollaboratorsNot Provided
Investigators Not Provided
Verification DateJanuary 2014

Locations[ + expand ][ + ]

Sapienza Univeristy of Rome
Rome, Italy, 00166
Contact: MD Marina Polacco | +393333347960 | dott.mpolacco@gmail.com
Principal Investigator: MD Marina Polacco
Not yet recruiting