Effect of Proton Pump Inhibitor on Residual Platelet Reactivity After Clopidogrel in Homogenous Genetic Strata

NCT ID: NCT01512953

Last Updated: 2012-01-20

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 522 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-01-31
• Study Completion Date: 2013-08-31

Brief Summary

This study aims to prospectively assess whether there is an interaction between genetic status in terms of 2C19 activity and residual platelet reactivity after clopidogrel intake in patients who underwent coronary stenting for elective, urgent or emergent intervention.

Detailed Description

In managing patients who undergo percutaneous coronary intervention (PCI), rapid and predictable platelet inhibition for all patients is an important therapeutic goal. Determining the optimal dose of antiplatelet therapy to achieve this goal has been hampered by considerable interpatient variability in response to clopidogrel, which largely reflects gene polymorphism. Most of the evidence is centred around cytochrome 450 2C19.

A substudy of TRITON TIMI 38 has recently shown that among persons treated with clopidogrel, carriers of a reduced-function CYP2C19 allele had significantly lower levels of the active metabolite of clopidogrel, diminished platelet inhibition, and a higher rate of major adverse cardiovascular events, including stent thrombosis, than did noncarriers (N Engl J Med 2009;360:354-62). As a contrary, common functional CYP genetic variants do not affect active drug metabolite levels, inhibition of platelet aggregation, or clinical cardiovascular event rates in persons treated with prasugrel (Circulation. 2009 May 19;119(19):2553-60).

More recently, it has been shown that CYP2C19*17 carrier status is significantly associated with enhanced response to clopidogrel and an increased risk of bleeding. (Circulation. 2010;121:512-518). Whether CYP2C19*17 carrier status enhances response to prasugrel is unknown.

Attention has also been placed on a potential interaction observed between clopidogrel and the widely used proton pump inhibitors (PPIs).

The CYP2C19 isoform is the key enzyme in the metabolism of many of the PPIs, which are also inhibitors of the CYP2C19 isoenzyme in varying degrees. This is important because the antiplatelet effects of clopidogrel rely, to a degree, upon CYP2C19 activity. However, the recent COGENT study and sub-analysis of the TRITON-TIMI 38 have both apparently mitigated this concern. Nevertheless, it is unknown whether PPI can father blunt response to clopidogrel especially in patients carrying the loss of function 2C19 allele.

A recent review paper (Aliment Pharmacol Ther 31, 810-823) included 23 studies covering 93,278 patients. There was substantial heterogeneity in the meta-analyses of major cardiovascular events (19 studies, I2 = 79%) or myocardial infarction (12 studies, I2 = 77%). Analysis of propensity-matched or randomized trial participants showed no associated cardiovascular risk with PPIs, whereas other observational studies generally showed a significant association.

Thus, still today there is an emerging need for more studies, especially prospective randomized studies, to investigate the effect of individual PPI agents on clopidogrel's effectiveness. Such studies should also include a genetic component to stratify response based on the presence of reduced-function alleles of the CYP2C19 enzyme

Conditions

Coronary Stenting

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

no PPI

Patients, stratified according to the genetic stratum, will be randomized not to take any PPI on top of clopidogrel

Group Type: NO_INTERVENTION

No interventions assigned to this group

PPI

Patients stratified to the genetic stratum will be randomized to take PPI on top of clopidogrel

Group Type: EXPERIMENTAL

Lansoprazole

Intervention Type: DRUG

Lansoprazole 30 mg once a day

Interventions

Lansoprazole

Lansoprazole 30 mg once a day

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Patients will undergo screening before or soon after PCI depending on their clinical presentation as follows:

• STEMI patients will receive upstream treatment with 600 mg clopidogrel before PCI and will undergo screening for 2C19 status within 24 hours after treatment. Randomization will occur immediately thereafter.
• Stable and NSTEACS patients will be treated upstream with 600 mg clopidogrel and will undergo screening either before PCI or soon after (within 6 hours) revascularisation. In both scenarios randomization will occur immediately after the genotype status is known without any additional delay.

Exclusion Criteria

1. Patients who can not give informed consent or have a life expectancy of < 1 year

2. Ongoing bleeding or bleeding diathesis or increase bleeding risk or history of bleeding in the last 2 months

3. Age > 90

4. Previous stroke or TIA or any intracranial pathology

5. Major surgery or trauma within the previous six weeks

6. Platelet count < 100.000 per cubic mm or HCT ,33% or Hb < 11 gm/dL

7. Subjects with an allergy or intolerance to prasugrel or to clopidogrel

8. Planned elective cardiac or non-cardiac surgery within 1 month.

9. Current or planned therapy with coumadin anticoagulation.

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

Sponsors

Università degli Studi di Ferrara

OTHER

Sponsor Role: lead

Responsible Party

Marco Valgimigli

MD, PhD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

University Hospital of Ferrara

Ferrara, ER, Italy

Site Status: RECRUITING

Countries

Italy

Central Contacts

Marco Valgimigli, MD, PhD

Role: CONTACT

vlgmrc@unife.it

0532326874 ext. +39

Facility Contacts

Monia Monti, bSc

Role: primary

mntmno@unife.it

0532-236298 ext. +39

Other Identifiers

GEN-2011-1

Identifier Type: -

Identifier Source: org_study_id