Clopidogrel Proton-Pump Inhibitors Study

NCT ID: NCT01016717

Last Updated: 2016-10-21

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE4
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-12-31
• Study Completion Date: 2012-12-31

Brief Summary

To find out the impact of two different proton-pump inhibitors (PPIs) (Omeprazole and Pantoprazole) on platelet function in patients with stable coronary artery disease (CAD) on clopidogrel therapy.

Detailed Description

On June 19, 2009 The European Medicines Agency (EMEA) has issued a public statement on a possible interaction between clopidogrel (Plavix, Sanofi-Aventis/Bristol-Myers Squibb)and proton-pump inhibitors (PPIs) and has recommended that the product information for all clopidogrel-containing medicines be amended to discourage concomitant use of PPIs unless absolutely necessary. The UK medicines regulator, the Medicines and Healthcare Products Regulatory Agency (MHRA), has also issued advice to GPs that concomitant use of a PPI with clopidogrel is not recommended unless considered essential, urging a review of the prescribing of PPIs at the next appointment for patients taking clopidogrel. This follows an "early communication" issued by the US FDA earlier this year, stating that PPIs might interfere with the effectiveness of clopidogrel and that clinicians should reevaluate starting or continuing treatment with a PPI in patients taking clopidogrel.

There is a concern that the studies on which these warnings are based have many limitations and that it is far from certain whether there really is an interaction between clopidogrel and PPIs.

Another point of uncertainty is whether there may be a difference between individual PPIs, with some pharmacodynamic studies suggesting an interaction with omeprazole but not with pantoprazole. The clinical evidence, however, is conflicting. There has been one clinical trial from Canada suggesting an interaction with omeprazole but not with pantoprazole. From a mechanistic view it is known that omeprazole is metabolized by the CYP219 enzyme, which converts clopidogrel into its active metabolite. And while pantoprazole can also be metabolized by this enzyme, it also uses other routes.

Thus, the primary goal of the current study is to find out the impact of two different PPIs (Omeprazole, Losec, and Pantoprazole) on platelet function in patients with stable coronary artery disease (CAD) on clopidogrel therapy.

Forty patients with stable CAD will be randomized to receive either omeprazole tables (Losec, 40 mg/day, Abic Inc., Israel) or pantoprazole tables (Controloc 40, 40 mg/day, Nycomed, Perrigo Inc., Israel) for 1 month (Phase 1), followed by a 4-week washout period, and the alternative treatment for 1 month (Phase 2).Platelet function tests will be assessed 4 times: before and after each study phase. Following an overnight fast, ECG and blood tests for measurements of platelet function, lipids, blood cell count, electrolytes, fasting glucose, and high-sensitivity C-reactive protein (hs-CRP), will be performed. The blood samples, except those for platelet function, will be centrifuged immediately for 15 minutes at 3000/min. The sera will be stored at -20° C, and will be tested at the end of the study. Blood samples for platelet function will be assessed immediately after the blood is drawn. All blood samples will be evaluated in the same laboratory and by the same operator who will be blinded to the patients' clinical status and PPIs allocation.

All patients will be instructed to continue taking their regular medications throughout the study period. In addition, patients will be instructed not to add any medications (including over the counter medications) and to record any change in concomitant medications throughout the study period.

Conditions

Coronary Artery Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Omeprazole

Patients will be taking omeprazole tablets 40 mg QD for 30 days

Group Type: ACTIVE_COMPARATOR

Omeprazole

Intervention Type: DRUG

All patients will be taking omeprazole (Losec, Abic Inc., Israel) tablets 40 mg QD for 30 days

Pantoprazole

Patients will be taking Pantoprazole tablets 40 mg QD for 30 days

Group Type: ACTIVE_COMPARATOR

Pantoprazole

Intervention Type: DRUG

Pantoprazole tablets (Controloc 40, 40 mg/day, Nycomed, Perrigo Inc., Israel). All patients will take pantoprazole tablets 40 mg QD for 30 days

Interventions

Omeprazole

All patients will be taking omeprazole (Losec, Abic Inc., Israel) tablets 40 mg QD for 30 days

Intervention Type: DRUG

Pantoprazole

Pantoprazole tablets (Controloc 40, 40 mg/day, Nycomed, Perrigo Inc., Israel). All patients will take pantoprazole tablets 40 mg QD for 30 days

Intervention Type: DRUG

Other Intervention Names

Losec; Controloc

Eligibility Criteria

Inclusion Criteria

1. Male or female ≥ 18 years; signed informed consent

2. Outpatient CAD patients on aspirin tablets 100-325 mg daily and clopidogrel tablets 75 mg daily.

3. Left ventricular (LV) systolic dysfunction ≥ 40% measured within the past 6 months.

4. No changes in cardiac medications during 2 weeks prior to enrollment.

Exclusion Criteria

1. Presence of transplanted tissue or organ or LVAD

2. AICD or CRT or CRTD patients.

3. Acute MI, CABG, PCI within past 3 months.

4. Congestive heart failure (CHF) ≥ NYHA 2.

5. Ejection fraction < 40% measured within the past 6 months.

6. Malignancy.

7. Active myocarditis, or cardiomyopathy.

8. HIV infection or immunodeficiency state.

9. Chronic viral infection.

10. Acute systemic infection requiring antibiotics.

11. Chronic diarrhea or malabsorption.

12. Statin therapy initiation ≤ 3 months.

13. Diabetes mellitus type 1.

14. Diabetes mellitus type 2 with HbA1C > 7%

15. Low-density lipoprotein cholesterol (LDL-C) > 100 mg/dL.

16. Not on statin therapy.

17. Liver function tests (LFT) ≥ x 3 upper limit of normal (ULN) or creatinine kinase (CPK) ≥ x 10 ULN.

18. Hypo/hyper thyroidism.

19. Liver dysfunction.

20. Renal failure with serum creatinine ≥ 2 mg/dL.

21. Alcohol or drug abuse.

22. Refuse to sign informed consent.

23. On the following therapy: Amiodarone, coumadin, any antibiotics.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Sheba Medical Center

OTHER_GOV

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Michael Shechter, MD, MA

Role: PRINCIPAL_INVESTIGATOR

Leviev Heart Center, Sheba Medical Center, Tel Hashomer

Locations

Leviev Heart Center, Sheba Medical Center

Tel Litwinsky, , Israel

Countries

Israel

Other Identifiers

SHEBA-09-7345-MS-CTIL

Identifier Type: -

Identifier Source: org_study_id