Platelet Inhibitory Effect of Clopidogrel in Patients Treated With Omeprazole, Pantoprazole, or Famotidine

Current guidelines recommend the addition of proton pump inhibitors (PPI) to patients taking double anti-platelet therapy (Aspirin and Clopidogrel) to prevent upper GI bleeding1. Many post percutaneous coronary intervention (PCI) patients are treated with dual anti-platelet medications as well as PPI to prevent upper GI bleeding.

Recently, it was shown that PPI interact with the P450 system in the liver and reduce the platelet inhibitory effect of Clopidogrel2,3. Clopidogrel is activated by CYP2C19, which also metabolizes PPI4. Furthermore, a recent article showed increased mortality in patients taking PPI and clopidogrel compared with patients taking clopidogrel without PPI protection5. The degree of reduction in the platelet inhibitory properties of clopidogrel might vary among the different PPI4.

The use of PPI for GI protection in patients treated with dual anti-platelet therapy is not based on randomized trials, but rather on expert opinion. Since H2 blockers are also effective in preventing acid secretion and are not known to interact with the P450 system that affects clopidogrel, the investigators hypothesized that these group of drugs will not interfere with the positive antiplatelet effects of clopidogrel and therefore will offer a good alternative treatment option.

Study Overview

• Status: Completed
• Conditions: Coronary Heart Disease; GI Bleeding
• Intervention / Treatment: Drug: omeprazole, 20mg twice daily; Drug: famotidine 40mg twice daily; Drug: pantoprazole 40mg once daily

Detailed Description

In this study we will compare 3 different anti-acids regimens and their effect on platelet function

• Study Type: Interventional
• Enrollment (Actual): 63
• Phase: Phase 4

Contacts and Locations

Study Locations

• Israel
  • Tel Aviv, Israel
    • Tel Aviv Medical Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Subject is at least 18 years old.
2. Subject is willing to comply with pre-specified follow-up evaluation and can be contacted by telephone.
3. Use of Clopidogrel (>=75mg) and Aspirin(>=75mg) for at least 1 month.

Exclusion Criteria:

1. Known allergy to PPI of H2 blockers
2. Known thrombocytopenia or thrombocytopathia
3. Subject is currently enrolled in another investigational study of a new drug, biologic or device at the time of study screening. NOTE: Subjects who are participating in the long term follow-up phase of a previously investigational and now FDA-approved product are not excluded by this criterion.
4. Subject with symptomatic heart failure of LVEF ≤ 25%
5. Acute myocardial infarction within the past 30 days.
6. No acute inflammatory event during the past month (e.g. infection, autoimmune or acute coronary event)
7. Concurrent medical condition with a life expectancy of less than 12 months.
8. Known severe renal failure (serum creatinine level >2.5 mg/dl).
9. History of bleeding diathesis or coagulopathy or inability or unwillingness to receive blood transfusions.
10. Evidence of active gastrointestinal bleeding or a history of such bleeding that is not known to have been treated and proven to have resolved.
11. History of hepatitis (viral, ischemic or chemically-induced); clinical jaundice, history of cirrhosis.
12. Patient treated with anticoagulant medication (Coumadin, LMWH)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 4 weeks of omeprazole, 20mg twice daily; Each patient will undergo 3 phases of drug therapy: A- 4 weeks of PPI treatment (omeprazole, 20mg twice daily)) B- 4 weeks of H2 blocker treatment (famotidine 40mg twice daily) C- 4 weeks of PPI treatment (pantoprazole 40mg once daily). At the end of each phase- each patient will undergo the following evaluation: Platelet reactivity	Drug: omeprazole, 20mg twice daily; Each patient will undergo 3 phases of drug therapy: A- 4 weeks of PPI treatment (omeprazole, 20mg twice daily)) B- 4 weeks of H2 blocker treatment (famotidine 40mg twice daily) C- 4 weeks of PPI treatment (pantoprazole 40mg once daily). At the end of each phase- each patient will undergo the following evaluation: Platelet reactivity; Other Names: PPI Platelet Inhibitory; Drug: famotidine 40mg twice daily; Each patient will undergo 3 phases of drug therapy: A- 4 weeks of PPI treatment (omeprazole, 20mg twice daily)) B- 4 weeks of H2 blocker treatment (famotidine 40mg twice daily) C- 4 weeks of PPI treatment (pantoprazole 40mg once daily). At the end of each phase- each patient will undergo the following evaluation: Platelet reactivity; Other Names: PPI Platelet Inhibitory; Drug: pantoprazole 40mg once daily; Each patient will undergo 3 phases of drug therapy: A- 4 weeks of PPI treatment (omeprazole, 20mg twice daily)) B- 4 weeks of H2 blocker treatment (famotidine 40mg twice daily) C- 4 weeks of PPI treatment (pantoprazole 40mg once daily). At the end of each phase- each patient will undergo the following evaluation: Platelet reactivity; Other Names: PPI Platelet Inhibitory
Experimental: 4 weeks of famotidine 40mg twice daily; Each patient will undergo 3 phases of drug therapy: A- 4 weeks of PPI treatment (omeprazole, 20mg twice daily)) B- 4 weeks of H2 blocker treatment (famotidine 40mg twice daily) C- 4 weeks of PPI treatment (pantoprazole 40mg once daily). At the end of each phase- each patient will undergo the following evaluation: Platelet reactivity	Drug: omeprazole, 20mg twice daily; Each patient will undergo 3 phases of drug therapy: A- 4 weeks of PPI treatment (omeprazole, 20mg twice daily)) B- 4 weeks of H2 blocker treatment (famotidine 40mg twice daily) C- 4 weeks of PPI treatment (pantoprazole 40mg once daily). At the end of each phase- each patient will undergo the following evaluation: Platelet reactivity; Other Names: PPI Platelet Inhibitory; Drug: famotidine 40mg twice daily; Each patient will undergo 3 phases of drug therapy: A- 4 weeks of PPI treatment (omeprazole, 20mg twice daily)) B- 4 weeks of H2 blocker treatment (famotidine 40mg twice daily) C- 4 weeks of PPI treatment (pantoprazole 40mg once daily). At the end of each phase- each patient will undergo the following evaluation: Platelet reactivity; Other Names: PPI Platelet Inhibitory; Drug: pantoprazole 40mg once daily; Each patient will undergo 3 phases of drug therapy: A- 4 weeks of PPI treatment (omeprazole, 20mg twice daily)) B- 4 weeks of H2 blocker treatment (famotidine 40mg twice daily) C- 4 weeks of PPI treatment (pantoprazole 40mg once daily). At the end of each phase- each patient will undergo the following evaluation: Platelet reactivity; Other Names: PPI Platelet Inhibitory
Experimental: 4 weeks of pantoprazole 40mg once daily; Each patient will undergo 3 phases of drug therapy: A- 4 weeks of PPI treatment (omeprazole, 20mg twice daily)) B- 4 weeks of H2 blocker treatment (famotidine 40mg twice daily) C- 4 weeks of PPI treatment (pantoprazole 40mg once daily). At the end of each phase- each patient will undergo the following evaluation: Platelet reactivity	Drug: omeprazole, 20mg twice daily; Each patient will undergo 3 phases of drug therapy: A- 4 weeks of PPI treatment (omeprazole, 20mg twice daily)) B- 4 weeks of H2 blocker treatment (famotidine 40mg twice daily) C- 4 weeks of PPI treatment (pantoprazole 40mg once daily). At the end of each phase- each patient will undergo the following evaluation: Platelet reactivity; Other Names: PPI Platelet Inhibitory; Drug: famotidine 40mg twice daily; Each patient will undergo 3 phases of drug therapy: A- 4 weeks of PPI treatment (omeprazole, 20mg twice daily)) B- 4 weeks of H2 blocker treatment (famotidine 40mg twice daily) C- 4 weeks of PPI treatment (pantoprazole 40mg once daily). At the end of each phase- each patient will undergo the following evaluation: Platelet reactivity; Other Names: PPI Platelet Inhibitory; Drug: pantoprazole 40mg once daily; Each patient will undergo 3 phases of drug therapy: A- 4 weeks of PPI treatment (omeprazole, 20mg twice daily)) B- 4 weeks of H2 blocker treatment (famotidine 40mg twice daily) C- 4 weeks of PPI treatment (pantoprazole 40mg once daily). At the end of each phase- each patient will undergo the following evaluation: Platelet reactivity; Other Names: PPI Platelet Inhibitory

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Platelet function as assessed by a CPA system	6 weeks

Collaborators and Investigators

• Sponsor: Tel-Aviv Sourasky Medical Center
• Collaborators: Tel Aviv Medical Center
• Investigators: Study Chair: Shmuel Banai, MD, Tel Aviv Medical Center, Israel

Publications and helpful links

General Publications

• Arbel Y, Birati EY, Finkelstein A, Halkin A, Kletzel H, Abramowitz Y, Berliner S, Deutsch V, Herz I, Keren G, Banai S. Platelet inhibitory effect of clopidogrel in patients treated with omeprazole, pantoprazole, and famotidine: a prospective, randomized, crossover study. Clin Cardiol. 2013 Jun;36(6):342-6. doi: 10.1002/clc.22117. Epub 2013 Apr 29.

Study record dates

Study Major Dates

• Study Start: August 1, 2009
• Primary Completion (Actual): June 1, 2011
• Study Completion (Actual): August 1, 2011

Study Registration Dates

• First Submitted: April 19, 2009
• First Submitted That Met QC Criteria: July 30, 2009
• First Posted (Estimate): July 31, 2009

Study Record Updates

• Last Update Posted (Estimate): July 7, 2016
• Last Update Submitted That Met QC Criteria: July 6, 2016
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Keywords: prevention; clopidogrel; aspirin; angiography; GI bleeding
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Gastrointestinal Diseases; Heart Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Hemorrhage; Gastrointestinal Hemorrhage; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Gastrointestinal Agents; Anti-Ulcer Agents; Proton Pump Inhibitors; Histamine Antagonists; Histamine Agents; Histamine H2 Antagonists; Famotidine; Omeprazole; Pantoprazole
• Other Study ID Numbers: TASMC-09-SB-0196-09-TLV-CTIL

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No