PPI and Clopidogrel Response

• ClinicalTrials.gov Identifier: NCT01170533
• Recruitment Status: Completed
• First Posted: July 27, 2010
• Results First Posted: March 6, 2012
• Last Update Posted: March 6, 2012
• Sponsor: University of Florida
• Collaborators: Bristol-Myers Squibb; Sanofi
• Information provided by (Responsible Party): University of Florida

Study Description

Brief Summary:

Clopidogrel, in combination with aspirin, is currently the recommended treatment for secondary prevention of ischemic events in high-risk patients and for prevention of coronary artery stent thrombosis. Patients receiving aspirin and clopidogrel are frequently treated with proton pump inhibitors, such as omeprazole or pantoprazole, in order to prevent the risk of gastrointestinal bleeding, accorded to guidelines. An interaction between proton pump inhibitors and clopidogrel has been suggested, which may lead to a decrease of clopidogrel effects. It remains unclear whether this interaction between PPIs and clopidogrel might be a class effect or if this may be affected by timing regimen.

The objectives of this two-phase investigation are:

1. to compare clopidogrel platelet inhibitory effects when taken at the same time versus separated at least 8 hours from omeprazole administration.
2. to compare clopidogrel-induced inhibitory effects when taken at the same time versus staggered at least 8 hours from pantoprazole administration.

Condition or disease	Intervention/treatment	Phase
Drug Interaction	Drug: omeprazole and pantoprazole	Phase 1

Detailed Description:

Clopidogrel, in combination with aspirin, is currently the recommended treatment for secondary prevention of ischemic events in high-risk patients and for prevention of coronary artery stent thrombosis. Patients receiving aspirin and clopidogrel are frequently treated with proton pump inhibitors, such as omeprazole or pantoprazole, in order to prevent the risk of gastrointestinal bleeding, accorded to guidelines. An interaction between proton pump inhibitors and clopidogrel has been suggested, which may lead to a decrease of clopidogrel effects. It remains unclear whether this interaction between PPIs and clopidogrel might be a class effect or if this may be affected by timing regimen. The objectives of this two-phase investigation are: 1. to compare clopidogrel platelet inhibitory effects when taken at the same time versus separated at least 8 hours from omeprazole administration. 2. to compare clopidogrel-induced inhibitory effects when taken at the same time versus staggered at least 8 hours from pantoprazole administration. The clopidogrel dose will be a 600mg loading dose followed by a 75mg daily maintenance dose, starting the next day for 7 days. Omeprazole will be used at a daily dose of 40mg and pantoprazole at 80mg.

The proposed study will have a prospective, randomized, cross-over design. Subjects are randomized in a 1:1 fashion to take PPI concomitantly (CONC regimen) or staggered by 8-12 hours (STAG regimen) for one-week on a background of clopidogrel therapy. In particular, in the CONC regimen both drugs were taken in the morning, while in the STAG regimen clopidogrel was taken in the morning and omeprazole in the evening. After a 2-4 week washout period, subjects crossed-over treatment regimen. After completing these two treatment phases, subjects underwent another washout period of 2-4 weeks and were treated for 1 week with clopidogrel alone, without receiving omeprazole therapy (CLOP regimen). The sequence with the PPI pantoprazole will have the same prospective, randomized, cross-over design as the omeprazole sequence. A CLOP regimen in the absence of pantoprazole will be collected before entering randomization phase with adequate wash-out period.

Blood sampling for platelet function assessments were performed at all three phases of the study at the following time points: a) baseline, b) 24 hours after LD (before intake of study medication), and c) 7 days (24 hours after the last MD).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Official Title: Effects of PPI Therapy on Clopidogrel-Induced Antiplatelet Effects: A Randomized Study
• Study Start Date: March 2009
• Actual Primary Completion Date: August 2010
• Actual Study Completion Date: August 2010

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Omeprazole; prospective, open-label, two-sequence, three-period, randomized crossover study	Drug: omeprazole and pantoprazole; The clopidogrel dose will be a 600mg loading dose followed by a 75mg daily maintenance dose, starting the next day for 7 days. Omeprazole will be used at a daily dose of 40mg and pantoprazole at 80mg.
Active Comparator: Pantoprazole; prospective, open-label, two-sequence, three-period, randomized crossover study	Drug: omeprazole and pantoprazole; The clopidogrel dose will be a 600mg loading dose followed by a 75mg daily maintenance dose, starting the next day for 7 days. Omeprazole will be used at a daily dose of 40mg and pantoprazole at 80mg.

Outcome Measures

Primary Outcome Measures :

1. Platelet Function as Assessed by the P2Y12 Reactivity Index [ Time Frame: 1 week ]
   P2Y12 reactivity index which will be assessed by flow cytometry determination of vasodilator-stimulated phosphoprotein (VASP).

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Healthy volunteers aged between 18 and 75 years

Exclusion Criteria:

1. Known allergies to clopidogrel or omeprazole.
2. Blood dyscrasia or bleeding diathesis.
3. Recent antiplatelet treatment (< 30 days) with a glycoprotein IIb/IIIa antagonist, thienopyridine (ticlopidine, clopidogrel), cilostazol or dipyridamole.
4. Treatment with other medications that may interfere with the CYP system (ketoconazole, itraconazole, diltiazem, erythromycin, clarithromycin, fluvoxamine, fluoxetine, nefazodone, or sertraline).
5. Platelet count <100x106/microL.
6. Diabetes mellitus
7. History of coronary artery disease, gastrointestinal bleed, gastroesophageal reflux disease (GERD), cerebrovascular event or any active malignancy.
8. Active bleeding or hemodynamic instability.
9. Serum creatinine >2mg/dL.
10. Baseline ALT >2.5 times the upper limit of normal.
11. Pregnant females.
12. Patients taking omeprazole or any H2 antagonist or proton pump inhibitors

Contacts and Locations

Locations

United States, Florida

University of Florida

Jacksonville, Florida, United States, 32209

Sponsors and Collaborators

University of Florida

Bristol-Myers Squibb

Sanofi

Investigators

• Principal Investigator: Dominick J Angiolillo, MD, PhD; University of Florida

More Information

Publications of Results:

Ferreiro JL, Ueno M, Capodanno D, Desai B, Dharmashankar K, Darlington A, Charlton RK, Bass TA, Angiolillo DJ. Pharmacodynamic effects of concomitant versus staggered clopidogrel and omeprazole intake: results of a prospective randomized crossover study. Circ Cardiovasc Interv. 2010 Oct;3(5):436-41. doi: 10.1161/CIRCINTERVENTIONS.110.957829. Epub 2010 Sep 21.

Ferreiro JL, Ueno M, Tomasello SD, Capodanno D, Desai B, Dharmashankar K, Seecheran N, Kodali MK, Darlington A, Pham JP, Tello-Montoliu A, Charlton RK, Bass TA, Angiolillo DJ. Pharmacodynamic evaluation of pantoprazole therapy on clopidogrel effects: results of a prospective, randomized, crossover study. Circ Cardiovasc Interv. 2011 Jun;4(3):273-9. doi: 10.1161/CIRCINTERVENTIONS.110.960997. Epub 2011 Apr 26.

• Responsible Party: University of Florida
• ClinicalTrials.gov Identifier: NCT01170533
• Other Study ID Numbers: UFJ 2009-2
• First Posted: July 27, 2010
• Results First Posted: March 6, 2012
• Last Update Posted: March 6, 2012
• Last Verified: March 2012

Keywords provided by University of Florida:

proton pump inhibitor; clopidogrel; platelet function

Additional relevant MeSH terms:

Omeprazole; Pantoprazole; Anti-Ulcer Agents; Gastrointestinal Agents; Proton Pump Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action