Pharmacodynamic effect of cilostazol plus standard clopidogrel versus double-dose clopidogrel in patients with type 2 diabetes undergoing percutaneous coronary intervention

Young-Hoon Jeong, Udaya S Tantry, Yongwhi Park, Tae Jung Kwon, Jeong Rang Park, Seok-Jae Hwang, Kevin P Bliden, Eun-Ha Koh, Choong Hwan Kwak, Jin-Yong Hwang, Sunjoo Kim, Paul A Gurbel, Young-Hoon Jeong, Udaya S Tantry, Yongwhi Park, Tae Jung Kwon, Jeong Rang Park, Seok-Jae Hwang, Kevin P Bliden, Eun-Ha Koh, Choong Hwan Kwak, Jin-Yong Hwang, Sunjoo Kim, Paul A Gurbel

Abstract

Objective: To determine the effect of adding cilostazol (100 mg b.i.d.) to standard-dose clopidogrel (75 mg/d) (TRIPLE) compared with double-dose clopidogrel (150 mg/d) (DOUBLE) and the influence of the cytochrome P450 (CYP2C19*2/*3, CYP3A5*3)and ATP-binding cassette subfamily B1(ABCB1 C3435T) genetic polymorphisms in type 2 diabetes (T2DM) patients.

Research design and methods: T2DM patients were treated with TRIPLE (n = 41) or DOUBLE (n = 39) after percutaneous coronary intervention. Conventional aggregometry and VerifyNow were performed at baseline and at 30 days. The primary end point was absolute change in 20-μM ADP-induced maximal platelet aggregation (ΔMPA(20)) between baseline and switching values.

Results: TRIPLE versus DOUBLE showed greater ΔMPA(20) (22.9 ± 11.6 vs.12.7 ± 15.5%; difference, 10.2% [95% CI 4.2-16.3]; P < 0.001). Carriage of one (β coefficient, -5.4%; P = 0.162) and two CYP2C19 loss-of-function allele(s) (-8.3%; P = 0.007) were associated with lower ΔMPA(20) in DOUBLE-treated patients, but not in TRIPLE-treated patients.

Conclusions: Among T2DM patients, adding cilostazol achieves greater platelet inhibition compared with clopidogrel (150 mg/d), which is not influenced by genetic polymorphisms.

Trial registration: ClinicalTrials.gov NCT00915733 NCT01012193.

Figures

Figure 1
Figure 1
Decreases of maximal platelet aggregations (A) and P2Y12 reaction units (B) between baseline and the 30-day follow-up. Decreases of 20 μmol/L ADP-induced maximal platelet aggregation by double-dose clopidogrel (left bars, red) or adding cilostazol (right bars, blue): CYP2C19(C), ABCB1 C3435T(D), and CYP3A5 (E) genotypes. Results are expressed as means with the 95% CIs (error bars).

References

    1. Ferreiro JL, Angiolillo DJ. Diabetes and antiplatelet therapy in acute coronary syndrome. Circulation 2011;123:798–813
    1. Mega JL, Close SL, Wiviott SD, et al. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet 2010;376:1312–1319
    1. Suh JW, Koo BK, Zhang SY, et al. Increased risk of atherothrombotic events associated with cytochrome P450 3A5 polymorphism in patients taking clopidogrel. CMAJ 2006;174:1715–1722
    1. Jeong YH, Tantry US, Bliden KP, Gurbel PA. Cilostazol to overcome high on-treatment platelet reactivity in korean patients treated with clopidogrel and calcium-channel blocker. Circ J 2011;75:2534–2536
    1. Angiolillo DJ, Capranzano P, Ferreiro JL, et al. Impact of adjunctive cilostazol therapy on platelet function profiles in patients with and without diabetes mellitus on aspirin and clopidogrel therapy. Thromb Haemost 2011;106:253–262
    1. Yoo HD, Cho HY, Lee YB. Population pharmacokinetic analysis of cilostazol in healthy subjects with genetic polymorphisms of CYP3A5, CYP2C19 and ABCB1. Br J Clin Pharmacol 2010;69:27–37
    1. American Diabetes Association Diagnosis and classification of diabetes mellitus. Diabetes Care 2012;35(Suppl. 1):S64–S71
    1. Jeong YH, Lee SW, Choi BR, et al. Randomized comparison of adjunctive cilostazol versus high maintenance dose clopidogrel in patients with high post-treatment platelet reactivity: results of the ACCEL-RESISTANCE (Adjunctive Cilostazol Versus High Maintenance Dose Clopidogrel in Patients With Clopidogrel Resistance) randomized study. J Am Coll Cardiol 2009;53:1101–1109
    1. Bonello L, Tantry US, Marcucci R, et al. Working Group on High On-Treatment Platelet Reactivity Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 2010;56:919–933
    1. Ferreiro JL, Ueno M, Desai B, Capranzano P, Capodanno D, Angiolillo DJ. Impact of adjunctive cilostazol therapy versus high maintenance dose of clopidogrel in suboptimal responders with diabetes mellitus. Rev Esp Cardiol 2012;65:105–106
    1. Price MJ. Murray SS, Angiolillo DJ, et al. Influence of genetic polymorphisms on the effect of high- and standard-dose clopidogrel after percutaneous coronary intervention: the GIFT (Genotype Information and Functional Testing) study. J Am Coll Cardiol 2012;59:1928–1937
    1. Mega JL, Hochholzer W, Frelinger AL, 3rd, Kluk MJ, Angiolillo DJ, Kereiakes DJ. Dosing clopidogrel based on CYP2C19 genotype and the effect on platelet reactivity in patients with stable cardiovascular disease. JAMA 2011;306:2221–2228
    1. Takagi H, Umemoto T. Benefit, rather than safety, of cilostazol for long-term mortality in patients undergoing percutaneous coronary intervention: a meta-analysis of randomized trials. Int J Cardiol 2011;153:74–76
    1. El Ghannudi S, Ohlmann P, Jesel L, et al. Impaired inhibition of P2Y(12) by clopidogrel is a major determinant of cardiac death in diabetes mellitus patients treated by percutaneous coronary intervention. Atherosclerosis 2011;217:465–472
    1. Hess K, Grant PJ. Inflammation and thrombosis in diabetes. Thromb Haemost 2011;105(Suppl. 1):S43–S54

Source: PubMed

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