PPI and Clopidogrel Response

This study has been completed.
Sponsor:
Collaborators:
Bristol-Myers Squibb
Sanofi
Information provided by (Responsible Party):
University of Florida
ClinicalTrials.gov Identifier:
NCT01170533
First received: July 23, 2010
Last updated: March 5, 2012
Last verified: March 2012
  Purpose

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 Intervention Phase
Drug Interaction
Drug: omeprazole and pantoprazole
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Crossover Assignment
Masking: Open Label
Official Title: Effects of PPI Therapy on Clopidogrel-Induced Antiplatelet Effects: A Randomized Study

Resource links provided by NLM:


Further study details as provided by University of Florida:

Primary Outcome Measures:
  • Platelet Function as Assessed by the P2Y12 Reactivity Index [ Time Frame: 1 week ] [ Designated as safety issue: No ]
    P2Y12 reactivity index which will be assessed by flow cytometry determination of vasodilator-stimulated phosphoprotein (VASP).


Enrollment: 20
Study Start Date: March 2009
Study Completion Date: August 2010
Primary Completion Date: August 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

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).

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01170533

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:
Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT01170533     History of Changes
Other Study ID Numbers: UFJ 2009-2
Study First Received: July 23, 2010
Results First Received: October 31, 2011
Last Updated: March 5, 2012
Health Authority: United States: Institutional Review Board

Keywords provided by University of Florida:
proton pump inhibitor
clopidogrel
platelet function

Additional relevant MeSH terms:
Clopidogrel
Omeprazole
Pantoprazole
Anti-Ulcer Agents
Enzyme Inhibitors
Gastrointestinal Agents
Hematologic Agents
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Pharmacologic Actions
Physiological Effects of Drugs
Platelet Aggregation Inhibitors
Proton Pump Inhibitors
Purinergic Agents
Purinergic Antagonists
Purinergic P2 Receptor Antagonists
Purinergic P2Y Receptor Antagonists
Therapeutic Uses

ClinicalTrials.gov processed this record on October 21, 2014