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Adjunctive Cilostazol Versus High Maintenance-dose ClopidogrEL in Acute Myocardial Infarction (AMI) Patients According to CYP2C19 Polymorphism (ACCELAMI2C19)

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ClinicalTrials.gov Identifier: NCT00915733
Recruitment Status : Completed
First Posted : June 8, 2009
Last Update Posted : November 10, 2009
Sponsor:
Information provided by:
Gyeongsang National University Hospital

Tracking Information
First Submitted Date  ICMJE June 5, 2009
First Posted Date  ICMJE June 8, 2009
Last Update Posted Date November 10, 2009
Study Start Date  ICMJE May 2009
Actual Primary Completion Date October 2009   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 5, 2009)
Absolute reduction of maximal platelet aggregation (Aggmax) by 5 & 20 μM ADP induced LTA [ Time Frame: 30 days ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT00915733 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 5, 2009)
  • Absolute reduction of late platelet aggregation (Agglate) by 5 & 20 μM ADP induced LTA [ Time Frame: 30 days ]
  • Absolute reduction of P2Y12 reaction unit (PRU) [ Time Frame: 30 days ]
  • The rate of high post-treatment platelet reactivity [ Time Frame: 30 days ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Adjunctive Cilostazol Versus High Maintenance-dose ClopidogrEL in Acute Myocardial Infarction (AMI) Patients According to CYP2C19 Polymorphism
Official Title  ICMJE Comparison of Platelet Inhibitory Effect With Adjunctive Cilostazol Versus High Maintenance-dose ClopidogrEL in Acute Myocardial Infarction Patients According to CYP2C19 Polymorphism
Brief Summary

Percutaneous coronary intervention (PCI) with stent implantation is the preferred reperfusion strategy for treatment of acute myocardial infarction (AMI). Despite advances in both devices and pharmacological support for AMI patients undergoing PCI, the risk of recurrent ischemic events has been higher than that of elective PCI. Among therapeutic options for surmounting clopidogrel hyporesponsiveness, higher loading doses and maintenance doses of clopidogrel achieved significant enhancements in the speed of onset and intensity of inhibition and these approaches have been widely adapted in clinical practice. Interestingly, recent studies found that carriers of the loss-of-function hepatic cytochrome (CYP) 2C19 allele had significantly lower levels of the active metabolite of clopidogrel, diminished platelet inhibition, and a higher rate of major adverse cardiovascular events than did non-carriers, in the setting of PCI and acute coronary syndrome (ACS). These findings raise the need of solutions to overcome enhanced post-clopidogrel platelet reactivity by the influence of the loss-of-function CYP2C19 allele. Increasing the dose of clopidogrel, new potent P2Y12 antagonists (such as prasugrel), or other antiplatelet drugs such as cilostazol may be alternative antiplatelet regimens in patients with the loss-of-function CYP variant. A recent study demonstrated that adjunctive cilostazol to dual antiplatelet therapy (triple antiplatelet therapy) intensified platelet inhibition as compared with a high maintenance-dose (MD) of 150 mg/day. Therefore, triple antiplatelet therapy could also be an alternative antiplatelet therapy to improve platelet inhibition and clinical outcomes in carriers of CYP2C19 mutant allele.

The purpose of this study was to determine the impact of adjunctive cilostazol on platelet inhibition in carriers and non-carriers of the loss-of-function CYP2C19 allele. The investigators compared the enhanced inhibition of platelet aggregation by adjunctive cilostazol 100 mg twice daily versus high-MD clopidogrel 150 mg/day in AMI patients treated with emergent coronary stenting, according to the CYP2C19 polymorphism.

Detailed Description
  • Study timeline: Enrollment period - 6 months (2009. 5.- 2009. 10.) (Follow-up period - 1 month after randomization)

    • Stenting, adjunct drug therapy and markers of myonecrosis 1) PCI

      (1) All interventions are performed according to current standard guidelines. (2) Aspiration thrombectomy is dependent on the operator's discretion. (3) If the patients have multiple lesions, culprit lesion coverage is recommended if possible.

      (4) Any kind of DES is permitted for PCI. If the bare-metal stent is needed, it is permitted.

      (5) Direct stenting or predilation is left to the operator's decision.

      2) Antithrombotic medications

      1. Anticoagulation is begun before PCI and performed with low-molecular-weight heparin (enoxaparin) or unfractionated heparin at physician's discretion.
      2. Only tirofiban is administered if and glycoprotein IIb/IIIa inhibitors (GPI) are needed.

      3) Markers of myonecrosis

      (1) Blood samples are routinely obtained from all patients before and after PCI for assessment of CK-MB at 8, 24, 48 and 72 hours.

      (2) In case of elevated values, measurements are repeated every 12 hours until a peak value reaches or values are normalized.

      • Assays of platelet function

        1) Blood sampling.

        1. Peripheral venous blood samples are drawn from an antecubital vein using a 21-gauge needle.
        2. Blood samples are collected using the double-syringe technique, in which the first 2 to 4 ml of blood is discarded to avoid spontaneous platelet activation.

        2) Light transmittance aggregometry (LTA)

        1. Blood samples are drawn into Vacutainer tubes containing 0.5 mL of sodium citrate 3.2% (Becton-Dickinson, San Jose, CA, USA) and processed within 60 minutes.
        2. Platelet-rich plasma (PRP) was obtained as a supernatant fluid after centrifuging blood at 800 rpm for 10 min. The remaining blood was further centrifuged at 2,500 rpm for 10 min to prepare platelet-poor plasma (PPP). PRP is adjusted to platelet counts of 250,000/μL by adding PPP as needed.
        3. Platelet aggregation is assessed at 37℃ using a PACKS-4 aggregometer (Helena Laboratories Corp., Beaumont, Texas, USA). Light transmission is adjusted to 0% with PRP and to 100% PPP for each measurement.
        4. Platelet aggregation is systematically measured after the addition of ADP at concentrations of 5 and 20 μM. Curves were recorded for 6 minutes.
        5. Aggregation is measured at by laboratory personnel blinded to group assignment.
        6. Absolute reduction of aggregation values (∆ Aggmax or Agglate) is defined as change of aggregation between pre-procedure and 30-day therapy:

          • Agg = pre-procedure Agg - Agg after 30-day therapy
        7. Inhibition of platelet aggregation (IPA) is defined as relative change in aggregation values (Aggmax and Agglate) between pre-procedure and 30-day therapy:

          IPA (%) = [(pre-procedure Agg - Agg after 30-day therapy)/pre-procedure Agg] X 100

        3) Rapid platelet function assay (RPFA: the VerifyNow P2Y12 assay)

        (1) A point-of-care system (VerifyNow; Accumetrics, San Diego, California) is an automated turbidimetric whole blood assay based on the ability of activated platelets using cartridges containing fibrinogen-coated beads and platelet agonists.

        (2) Blood is drawn into a Greiner Bio-One 3.2% citrate vacuette tube. (3) The channel contains fibrinogen-coated polystyrene beads and 20 μM ADP as platelet agonist. This channel also contains 22 nmol/l PGE1 to suppress intracellular free calcium levels and thereby reduce the non-specific contribution of P2Y1 receptors.

        (4) Results are reported in P2Y12 reaction units (PRU). (5) Absolute reduction of PRU is defined as change of PRU between pre-procedure and 30-day therapy:

        • PRU = pre-procedure PRU - PRU after 30-day therapy (6) Percent inhibition (PI) of PRU is defined as relative change between pre-procedure and 30-day therapy: PI (%) = [(pre-procedure PRU - PRU after 30-day therapy)/pre-procedure PRU] X 100

2-8. CYP2C19 genotyping

  1. CYP2C19 genotype is determined by a polymerase chain reaction (PCR). SNaPshot method, using genomic DNA isolated from leukocytes of peripheral venous blood with an extraction kit (QIAampR DNA Blood Mini Kit, Qiagen, Hilden,Germany).
  2. Two CYP2C19 polymorphisms, CYP2C19*2 (rs4244285, c. 681G>A, p.P227P), and CYP2C19*3 (rs4986893, c. 636G>A, p. W212X), are investigated using the ABI SNaPshot reaction and the ABI 3100 automated genetic analyzer (Applied Biosystems, Foster City, CA, USA).

    • Statistics and Data analysis

      1. Sample Size Estimation

        @ based on previous our study(ACCEL-AMI)

        Absolute reduction of 5 μM ADP-induced maximal aggregation by adjunctive cilostazol after 30 days : 24.0%

        Absolute reduction of 5 μM ADP-induced maximal aggregation by adjunctive high dose maintenance clopidogrel 150mg/day after 30 days : 11.0%

        Relative difference of enhanced platelet inhibition between two regimens :

        54.0%

        • Two-sided α-level = 0.05
        • Power = 95%
        • Triple group: high-MD group = 1: 1
        • Standard deviation = 0.4

        At least 15 patients per each group were required.

        @ based on previous another study(CYP2C19 polymorphism study)

        The ratio of Korean patients carrying wild type CYP2C19 vs mutant type=4:6

        The required patients of wild type group : 15 patients The required patients of mutant type group : 23 patients

        Final required patients (15+23)*2=76 patients

      2. Analysis Continuous variables are presented as means ± SD and compared using Student unpaired t or Mann-Whitney U tests. Categorical variables are presented as numbers or percentages and were compared using chi-square or Fisher's exact tests (if an expected frequency was < 5). The characteristics and platelet function measures of the 3 groups were analyzed by Friedman's repeated ANOVA on ranks. After demonstration of significant differences among variables by ANOVA, post hoc comparisons between therapy pairs were made with the Student-Newman-Keuls procedure for multiple comparisons. A p value < 0.05 was considered to indicate a significant difference. Statistical analysis was performed using commercially available software (SPSS version 13; SPSS Inc., Chicago, Illinois, USA).
      3. Data modulation DSMB (Data Safety Monitoring Board) CEC (Clinical Event Committee)
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Myocardial Infarction
Intervention  ICMJE
  • Drug: cilostazol
    100 mg twice daily for at least 1 month
    Other Name: Otsuka brand of cilostazol
  • Drug: clopidogrel (Plavix)
    150 mg once daily (high maintenance dose group arm), 75 mg once daily (triple group arm)
    Other Name: Plavix
  • Genetic: CYP2C19
    CYP2C19 polymorphism study: Two CYP2C19 polymorphisms, CYP2C19*2 (rs4244285, c. 681G>A, p.P227P), and CYP2C19*3 (rs4986893, c. 636G>A, p. W212X), are investigated using the ABI SNaPshot reaction and the ABI 3100 automated genetic analyzer.
    Other Name: Cytochrome 2C19
  • Drug: aspirin (Acetylsalicylic acid)
    aspirin 100 mg qd
    Other Name: Acetylsalicylic acid
Study Arms  ICMJE
  • Active Comparator: triple group

    Additive cilostazol to dual antiplatelet therapy (triple antiplatelet therapy) in patients with acute myocardial infarction (AMI).

    Received cilostazol 100 mg twice daily in addition to aspirin 100 mg and clopidogrel 75 mg once daily.

    Interventions:
    • Drug: cilostazol
    • Drug: clopidogrel (Plavix)
    • Genetic: CYP2C19
    • Drug: aspirin (Acetylsalicylic acid)
  • Active Comparator: high maintenance dose group

    High maintenance dose dual antiplatelet therapy in patients with acute myocardial infarction (AMI).

    Received clopidogrel 150 mg/day with aspirin 100 mg once daily.

    Interventions:
    • Drug: clopidogrel (Plavix)
    • Genetic: CYP2C19
    • Drug: aspirin (Acetylsalicylic acid)
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 5, 2009)
80
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE November 2009
Actual Primary Completion Date October 2009   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. The patient must be at least 18 years of age.
  2. clinical symptoms compatible with acute myocardial ischemia within 12 h before admission with a subsequently documented increase in cardiac markers.
  3. Measured pre-discharge platelet reactivity in case of normalized CK-MB value after coronary stenting.

Exclusion Criteria:

  1. A history of active bleeding and bleeding diatheses.
  2. Oral anticoagulation therapy with coumadin.
  3. Contraindication to antiplatelet therapy.
  4. LV ejection fraction < 30% or NYHA 3/4.
  5. Leukocyte count < 3,000/mm3 and/or platelet count < 100,000/mm3.
  6. AST or ALT ≥ 3 times upper normal.
  7. Serum creatinine level ≥ 2.5 mg/dl.
  8. Stroke within 3 months.
  9. Non-cardiac disease with a life expectancy < 1 year.
  10. Inability to follow the protocol.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Korea, Republic of
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00915733
Other Study ID Numbers  ICMJE ACCEL-AMI-2C19
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party In-Suk Kim, Assistant Professor, Gyeongsang National University Hospital
Study Sponsor  ICMJE Gyeongsang National University Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: In-Suk Kim, MD.PhD. Gyeongsang National University Hospital
PRS Account Gyeongsang National University Hospital
Verification Date November 2009

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP