Ignite Creation Date:
2024-05-05 @ 9:32 PM
Last Modification Date:
2024-10-26 @ 10:06 AM
Study NCT ID:
NCT00915733
Status:
COMPLETED
Last Update Posted:
2009-11-10
First Post:
2009-06-05
Brief Title:
Adjunctive Cilostazol Versus High Maintenance-dose ClopidogrEL in Acute Myocardial Infarction AMI Patients According to CYP2C19 Polymorphism
Sponsor:
Gyeongsang National University Hospital
Organization:
Gyeongsang National University Hospital
Study Overview
Official Title:
Comparison of Platelet Inhibitory Effect With Adjunctive Cilostazol Versus High Maintenance-dose ClopidogrEL in Acute Myocardial Infarction Patients According to CYP2C19 Polymorphism
Status:
COMPLETED
Status Verified Date:
2009-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
ACCELAMI2C19
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 mgday 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 mgday in AMI patients treated with emergent coronary stenting according to the CYP2C19 polymorphism
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 mgday 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 operators 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 operators decision
2 Antithrombotic medications
1 Anticoagulation is begun before PCI and performed with low-molecular-weight heparin enoxaparin or unfractionated heparin at physicians discretion
2 Only tirofiban is administered if and glycoprotein IIbIIIa 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 05 mL of sodium citrate 32 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 2500 rpm for 10 min to prepare platelet-poor plasma PPP PRP is adjusted to platelet counts of 250000μL 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 therapypre-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 32 citrate vacuette tube
3 The channel contains fibrinogen-coated polystyrene beads and 20 μM ADP as platelet agonist This channel also contains 22 nmoll 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 therapypre-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 HildenGermany
2 Two CYP2C19 polymorphisms CYP2C192 rs4244285 c 681GA pP227P and CYP2C193 rs4986893 c 636GA 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 studyACCEL-AMI
Absolute reduction of 5 μM ADP-induced maximal aggregation by adjunctive cilostazol after 30 days 240
Absolute reduction of 5 μM ADP-induced maximal aggregation by adjunctive high dose maintenance clopidogrel 150mgday after 30 days 110
Relative difference of enhanced platelet inhibition between two regimens
540 - Two-sided α-level 005 - Power 95 - Triple group high-MD group 1 1 - Standard deviation 04
At least 15 patients per each group were required
based on previous another studyCYP2C19 polymorphism study
The ratio of Korean patients carrying wild type CYP2C19 vs mutant type46
The required patients of wild type group 15 patients The required patients of mutant type group 23 patients
Final required patients 1523276 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 Fishers exact tests if an expected frequency was 5 The characteristics and platelet function measures of the 3 groups were analyzed by Friedmans 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 005 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
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 operators 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 operators decision
2 Antithrombotic medications
1 Anticoagulation is begun before PCI and performed with low-molecular-weight heparin enoxaparin or unfractionated heparin at physicians discretion
2 Only tirofiban is administered if and glycoprotein IIbIIIa 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 05 mL of sodium citrate 32 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 2500 rpm for 10 min to prepare platelet-poor plasma PPP PRP is adjusted to platelet counts of 250000μL 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 therapypre-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 32 citrate vacuette tube
3 The channel contains fibrinogen-coated polystyrene beads and 20 μM ADP as platelet agonist This channel also contains 22 nmoll 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 therapypre-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 HildenGermany
2 Two CYP2C19 polymorphisms CYP2C192 rs4244285 c 681GA pP227P and CYP2C193 rs4986893 c 636GA 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 studyACCEL-AMI
Absolute reduction of 5 μM ADP-induced maximal aggregation by adjunctive cilostazol after 30 days 240
Absolute reduction of 5 μM ADP-induced maximal aggregation by adjunctive high dose maintenance clopidogrel 150mgday after 30 days 110
Relative difference of enhanced platelet inhibition between two regimens
540 - Two-sided α-level 005 - Power 95 - Triple group high-MD group 1 1 - Standard deviation 04
At least 15 patients per each group were required
based on previous another studyCYP2C19 polymorphism study
The ratio of Korean patients carrying wild type CYP2C19 vs mutant type46
The required patients of wild type group 15 patients The required patients of mutant type group 23 patients
Final required patients 1523276 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 Fishers exact tests if an expected frequency was 5 The characteristics and platelet function measures of the 3 groups were analyzed by Friedmans 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 005 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None