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

Myocardial Infarction Clinical Trial

— ACCELAMI2C19  

Official title:

Comparison of Platelet Inhibitory Effect With Adjunctive Cilostazol Versus High Maintenance-dose ClopidogrEL in Acute Myocardial Infarction Patients According to CYP2C19 Polymorphism

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00915733
• Other study ID #: ACCEL-AMI-2C19
• Status: Completed
• Phase: Phase 4
• First received: June 5, 2009
• Last updated: November 9, 2009
• Start date: May 2009
• Est. completion date: November 2009

Study information

• Verified date: November 2009
• Source: Gyeongsang National University Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: South Korea: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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)

Recruitment information / eligibility

• Status: Completed
• Enrollment: 80
• Est. completion date: November 2009
• Est. primary completion date: October 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Infarction
• Myocardial Infarction

Intervention

Drug:
• cilostazol
100 mg twice daily for at least 1 month
• clopidogrel (Plavix)
150 mg once daily (high maintenance dose group arm), 75 mg once daily (triple group arm)

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.

Drug:
• aspirin (Acetylsalicylic acid)
aspirin 100 mg qd

Locations

Country	Name	City	State
Korea, Republic of	Gyeongsang National University Hospital	Jinju

Sponsors (1)

Lead Sponsor	Collaborator
Gyeongsang National University Hospital

Country where clinical trial is conducted

Korea, Republic of, 

References & Publications (10)

Angiolillo DJ, Capranzano P, Goto S, Aslam M, Desai B, Charlton RK, Suzuki Y, Box LC, Shoemaker SB, Zenni MM, Guzman LA, Bass TA. A randomized study assessing the impact of cilostazol on platelet function profiles in patients with diabetes mellitus and co — View Citation

Angiolillo DJ, Shoemaker SB, Desai B, Yuan H, Charlton RK, Bernardo E, Zenni MM, Guzman LA, Bass TA, Costa MA. Randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the Opti — View Citation

Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J, Payot L, Brugier D, Cayla G, Beygui F, Bensimon G, Funck-Brentano C, Montalescot G. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a c — View Citation

Jeong YH, Lee SW, Choi BR, Kim IS, Seo MK, Kwak CH, Hwang JY, Park SW. Randomized comparison of adjunctive cilostazol versus high maintenance dose clopidogrel in patients with high post-treatment platelet reactivity: results of the ACCEL-RESISTANCE (Adjun — View Citation

Kim IS, Choi BR, Jeong YH, Kwak CH, Kim S. The CYP2C19*2 and CYP2C19*3 polymorphisms are associated with high post-treatment platelet reactivity in Asian patients with acute coronary syndrome. J Thromb Haemost. 2009 May;7(5):897-9. doi: 10.1111/j.1538-783 — View Citation

Lee BK, Lee SW, Park SW, Lee SW, Park DW, Kim YH, Lee CW, Hong MK, Kim JJ, Jang S, Chi HS, Park SJ. Effects of triple antiplatelet therapy (aspirin, clopidogrel, and cilostazol) on platelet aggregation and P-selectin expression in patients undergoing coro — View Citation

Lee SW, Park SW, Hong MK, Kim YH, Lee BK, Song JM, Han KH, Lee CW, Kang DH, Song JK, Kim JJ, Park SJ. Triple versus dual antiplatelet therapy after coronary stenting: impact on stent thrombosis. J Am Coll Cardiol. 2005 Nov 15;46(10):1833-7. Epub 2005 Oct — View Citation

Lee SW, Park SW, Kim YH, Yun SC, Park DW, Lee CW, Hong MK, Kim HS, Ko JK, Park JH, Lee JH, Choi SW, Seong IW, Cho YH, Lee NH, Kim JH, Chun KJ, Park SJ. Drug-eluting stenting followed by cilostazol treatment reduces late restenosis in patients with diabete — View Citation

Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009 Jan 22;360(4):354-62. doi: 10.1056/NEJMoa0809171. Epub 2 — View Citation

Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias WL, Braunwald E, Sabatine MS. Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical ou — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Absolute reduction of maximal platelet aggregation (Aggmax) by 5 & 20 µM ADP induced LTA		30 days	No
Secondary	Absolute reduction of late platelet aggregation (Agglate) by 5 & 20 µM ADP induced LTA		30 days	No
Secondary	Absolute reduction of P2Y12 reaction unit (PRU)		30 days	No
Secondary	The rate of high post-treatment platelet reactivity		30 days	No