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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01512953
Recruitment Status : Unknown
Verified January 2012 by Marco Valgimigli, Università degli Studi di Ferrara.
Recruitment status was:  Recruiting
First Posted : January 20, 2012
Last Update Posted : January 20, 2012
Information provided by (Responsible Party):
Marco Valgimigli, Università degli Studi di Ferrara

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.

Condition or disease Intervention/treatment Phase
Coronary Stenting Drug: Lansoprazole Phase 4

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 522 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Randomized Comparison of PPI Versus no PPI on Top of Standard Dose Clopidogrel Therapy in Patients Stratified Based on CYC2C19 Activity Via a Genetic Point of Care System.
Study Start Date : January 2011
Estimated Primary Completion Date : August 2012
Estimated Study Completion Date : August 2013

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
No Intervention: no PPI
Patients, stratified according to the genetic stratum, will be randomized not to take any PPI on top of clopidogrel
Experimental: PPI
Patients stratified to the genetic stratum will be randomized to take PPI on top of clopidogrel
Drug: Lansoprazole
Lansoprazole 30 mg once a day

Primary Outcome Measures :
  1. Maximal platelet aggregation at light transmission aggregometry after 20 μmol/l ADP [ Time Frame: 30 days ]
    IPA expressed as maximal platelet aggregation (MPA) after 20 μmol/l ADP according to genetic stratum defined as follows: [(Poor metabolizers: 2C19*2+ and 2C19*17-); (intermediate metabolizers: wild type patients or its carrying both 2C19*2 and *170; (ultra metabolizers: 2c19*2- and 2C19*17+).

  2. maximal platelet aggregation after 5 μmol/l ADP in PPI versus no PPI treated patients [ Time Frame: 30 days ]
    Patients, stratified by genetic stratum, will be randomized to PPI or no PPI. We assume that that will be an interaction in the IPA after 5 μmol/l ADP at 30 days so that PPI will blunt responsiveness to clopidogrel in poor metabolizer patients only but in intermediate or ultra metabolizers.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria: All comer patients undergoing PCI will be recruited on a consecutive basis.

• 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01512953

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Contact: Marco Valgimigli, MD, PhD 0532326874 ext +39

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University Hospital of Ferrara Recruiting
Ferrara, ER, Italy, 44100
Contact: Monia Monti, bSc    0532-236298 ext +39   
Sponsors and Collaborators
Università degli Studi di Ferrara

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Responsible Party: Marco Valgimigli, MD, PhD, Università degli Studi di Ferrara Identifier: NCT01512953     History of Changes
Other Study ID Numbers: GEN-2011-1
First Posted: January 20, 2012    Key Record Dates
Last Update Posted: January 20, 2012
Last Verified: January 2012
Keywords provided by Marco Valgimigli, Università degli Studi di Ferrara:
Additional relevant MeSH terms:
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Platelet Aggregation Inhibitors
Purinergic P2Y Receptor Antagonists
Purinergic P2 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Anti-Ulcer Agents
Gastrointestinal Agents
Proton Pump Inhibitors
Enzyme Inhibitors