Impact of adjunctive cilostazol therapy on platelet function profiles in patients with and without diabetes mellitus on aspirin and clopidogrel therapy

Dominick J. Angiolillo; Piera Capranzano; Jose Luis Ferreiro; Masafumi Ueno; Davide Capodanno; Kodlipet Dharmashankar; Andrew Darlington; Sabrina Sumner; Bhaloo Desai; Ronald K. Charlton; Lyndon C. Box; Martin M. Zenni; Luis A. Guzman; Theodore A. Bass

doi:10.1160/TH11-01-0041

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2011; 106(02): 253-262
DOI: 10.1160/TH11-01-0041

Theme Issue Article

Schattauer GmbH

Impact of adjunctive cilostazol therapy on platelet function profiles in patients with and without diabetes mellitus on aspirin and clopidogrel therapy

Authors

Dominick J. Angiolillo

¹Division of Cardiology, University of Florida College of Medicine Jacksonville, Jacksonville, Florida, USA
Piera Capranzano

¹Division of Cardiology, University of Florida College of Medicine Jacksonville, Jacksonville, Florida, USA
Jose Luis Ferreiro

¹Division of Cardiology, University of Florida College of Medicine Jacksonville, Jacksonville, Florida, USA
Masafumi Ueno

¹Division of Cardiology, University of Florida College of Medicine Jacksonville, Jacksonville, Florida, USA
Davide Capodanno

¹Division of Cardiology, University of Florida College of Medicine Jacksonville, Jacksonville, Florida, USA
Kodlipet Dharmashankar

¹Division of Cardiology, University of Florida College of Medicine Jacksonville, Jacksonville, Florida, USA
Andrew Darlington

¹Division of Cardiology, University of Florida College of Medicine Jacksonville, Jacksonville, Florida, USA
Sabrina Sumner

¹Division of Cardiology, University of Florida College of Medicine Jacksonville, Jacksonville, Florida, USA
Bhaloo Desai

¹Division of Cardiology, University of Florida College of Medicine Jacksonville, Jacksonville, Florida, USA
Ronald K. Charlton

²Jacksonville Transplant Center, Shands Jacksonville, Jacksonville, Florida, USA
Lyndon C. Box

¹Division of Cardiology, University of Florida College of Medicine Jacksonville, Jacksonville, Florida, USA
Martin M. Zenni

¹Division of Cardiology, University of Florida College of Medicine Jacksonville, Jacksonville, Florida, USA
Luis A. Guzman

¹Division of Cardiology, University of Florida College of Medicine Jacksonville, Jacksonville, Florida, USA
Theodore A. Bass

¹Division of Cardiology, University of Florida College of Medicine Jacksonville, Jacksonville, Florida, USA

Abstract

Summary

Cilostazol is a platelet inhibitor which when added to aspirin and clopidogrel has shown to reduce the risk of recurrent ischaemic events without an increase in bleeding. These clinical benefits have shown to be more pronounced in patients with diabetes mellitus (DM). However, it remains unknown whether cilostazol exerts different pharmacodynamic effects in patients with and without DM. This was a randomised, double-blind, placebo-controlled, cross-over pharmacodynamic study comparing platelet function in patients with and without DM on aspirin and clopidogrel therapy. Patients (n=111) were randomly assigned to either cilostazol 100 mg or placebo twice daily for 14 days and afterwards crossed-over treatment for another 14 days. Platelet function was performed at baseline, 14 days post-randomisation, and 14 days post-cross-over. Functional testing to assess P2Y₁₂ signalling included flow cytometric analysis of phosphorylation status of vasodilatorstimulated phosphoprotein measured by P2Y₁₂ reactivity index (PRI), light transmittance aggregometry and VerifyNow. Thrombin generation processes were also studied using thrombelastography. Significantly lower PRI values were observed following treatment with cilostazol compared with placebo both in DM and non-DM groups (p < 0.0001). The absolute between-treatment differences of PRI between groups was a 35.1% lower in patients with DM (p=0.039). Similar results were obtained using all other functional measures assessing P2Y₁₂ signalling. Thrombin generation was not affected by cilostazol. Cilostazol reduces platelet reactivity both in patients with and without DM, although these pharmacodynamic effects are enhanced in patients with DM. Despite the marked platelet inhibition, cilostazol does not alter thrombin-mediated haemostatic processes, which may explain its ischaemic benefit without the increased risk of bleeding.

Keywords

Diabetes mellitus - coronary artery disease - platelets

Full Text

References

References
1 Goto S. Cilostazol: potential mechanism of action for antithrombotic effects accompanied by a low rate of bleeding. Atheroscler Suppl 2005; 6: 3-11.
2 Douglas JS. Jr. Pharmacologic approaches to restenosis prevention. Am J Cardiol 2007; 100: 10K-6K.
3 Tamhane U, Meier P, Chetcuti S. et al. Efficacy of cilostazol in reducing restenosis in patients undergoing contemporary stent based PCI: a meta-analysis of randomised controlled trials. EuroIntervention. 2009; 5: 384-393.
4 Douglas JS, Jr Holmes DR, Jr Kereiakes DJ. et al. Cilostazol for Restenosis Trial (CREST) Investigators. Coronary stent restenosis in patients treated with cilostazol. Circulation 2005; 112: 2826-2832.
5 Lee SW, Park SW, Kim YH. et al. DECLARE-Long Study Investigators. Comparison of triple versus dual antiplatelet therapy after drug-eluting stent implantation (from the DECLARE-Long trial). Am J Cardiol 2007; 100: 1103-1108.
6 Chen KY, Rha SW, Li YJ. et al. Korea Acute Myocardial Infarction Registry Investigators. Triple versus dual antiplatelet therapy in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Circulation 2009; 119: 3207-3214.
7 Lee SW, Park SW, Kim YH. et al. Drug-eluting stenting followed by cilostazol treatment reduces late restenosis in patients with diabetes mellitus the DECLARE-DIABETES Trial (A Randomized Comparison of Triple Antiplatelet Therapy with Dual Antiplatelet Therapy After Drug-Eluting Stent Implantation in Diabetic Patients). J Am Coll Cardiol 2008; 51: 1181-1187.
8 Ahn Y, Jeong MH, Jeong JW. et al. Randomized comparison of cilostazol vs clopidogrel after drug-eluting stenting in diabetic patients–clilostazol for diabetic patients in drug-eluting stent (CIDES) trial. Circ J 2008; 72: 35-39.
9 Han Y, Li Y, Wang S. et al. Cilostazol in addition to aspirin and clopidogrel improves long-term outcomes after percutaneous coronary intervention in patients with acute coronary syndromes: A randomized, controlled study. Am Heart J 2009; 157: 733-739.
10 Lee SW, Park SW, Hong MK. et al. Triple versus dual antiplatelet therapy after coronary stenting: impact on stent thrombosis. J Am Coll Cardiol 2005; 46: 1833-1837.
11 Lee SW, Park SW, Yun SC. et al. Triple antiplatelet therapy reduces ischemic events after drug-eluting stent implantation: Drug-Eluting stenting followed by Cilostazol treatment REduces Adverse Serious cardiac Events (DECREASE registry). Am Heart J 2010; 159: 284-291.
12 Ferreira IA, Mocking AI, Feijge MA. et al. Platelet inhibition by insulin is absent in type 2 diabetes mellitus. Arterioscler Thromb Vasc Biol 2006; 26: 417-422.
13 Ferroni P, Basili S, Falco A, Davi G. Platelet activation in type 2 diabetes mellitus. J Thromb Haemost 2004; 2: 1282-1291.
14 Angiolillo DJ. Antiplatelet therapy in diabetes: efficacy and limitations of current treatment strategies and future directions. Diabetes Care 2009; 32: 531-540.
15 Angiolillo DJ, Capranzano P, Goto S. et al. A randomized study assessing the impact of cilostazol on platelet function profiles in patients with diabetes mellitus and coronary artery disease on dual antiplatelet therapy: results of the OPTI-MUS-2 study. Eur Heart J 2008; 29: 2202-2211.
16 Angiolillo DJ, Shoemaker SB, Desai B. et al. A randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the OPTIMUS (Optimizing anti-Platelet Therapy In diabetes MellitUS) study. Circulation 2007; 115: 708-716.
17 Angiolillo DJ, Costa MA, Shoemaker SB. et al. Functional effects of high clopidogrel maintenance dosing in patients with inadequate platelet inhibition. Am J Cardiol 2008; 101: 440-445.
18 Fox SC, Behan MW, Heptinstall S. Inhibition of ADP-induced intracellular Ca2+ responses and platelet aggregation by the P2Y₁₂ receptor antagonists AR-C69931MX and clopidogrel is enhanced by prostaglandin E1. Cell Calcium 2004; 35: 39-46.
19 Angiolillo DJ, Capranzano P, Desai B. et al. Impact of P2Y12 inhibitory effects induced by clopidogrel on platelet procoagulant activity in type 2 diabetes mellitus patients. Thromb Res 2009; 124: 318-322.
20 Gurbel PA, Bliden KP, Guyer K. et al. Delayed thrombin-induced platelet-fibrin clot generation by clopidogrel: a new dose-related effect demonstrated by throm-belastography in patients undergoing coronary artery stenting. Thromb Res 2007; 119: 563-570.
21 Rivard GE, Brummel-Ziedins KE, Mann KG. et al. Evaluation of the profile of thrombin generation during the process of whole blood clotting as assessed by thrombelastography. J Thromb Haemost 2005; 3: 2039-2043.
22 Suh JW, Lee SP, Park KW. et al. Multicenter Randomized Trial Evaluating the Efficacy of Cilostazol on Ischemic Vascular Complications After Drug-Eluting Stent Implantation for Coronary Heart Disease Results of the CILON-T (Influence of CILostazol-based triple antiplatelet therapy ON ischemic complication after drug-eluting stenT implantation) Trial. J Am Coll Cardiol 2011; 57: 280-289.
23 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol 2007; 49: 1505-1516.
24 Ferreiro JL, Angiolillo DJ. Clopidogrel response variability: Current status and future directions. Thromb Haemost 2009; 102: 7-14.
25 Wiviott SD, Braunwald E, McCabe CH. et al. TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001-2015.
26 Wallentin L, Becker RC, Budaj A. et al. PLATO Investigators, Freij A, Thorsén M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361: 1045-1057.
27 Mehta SR, Tanguay JF, Eikelboom JW. et al. CURRENT-OASIS 7 trial investigators. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet 2010; 9 376: 1233-1243.
28 Eikelboom JW, Mehta SR, Anand SS. et al. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 2006; 114: 774-782.
29 Ndrepepa G, Berger PB, Mehilli J. et al. Periprocedural bleeding and 1-year outcome after percutaneous coronary interventions: appropriateness of including bleeding as a component of a quadruple end point. J Am Coll Cardiol 2008; 51: 690-697.
30 Pocock SJ, Mehran R, Clayton TC. et al. Prognostic modeling of individual patient risk and mortality impact of ischemic and hemorrhagic complications: assessment from the Acute Catheterization and Urgent Intervention Triage Strategy trial. Circulation 2010; 121: 43-51.
31 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.
32 Jeong YH, Park Y, Kim IS. et al. Enhanced platelet inhibition by adjunctive cilostazol to dual antiplatelet therapy after drug-eluting stent implantation for complex lesions. Thromb Haemost 2010; 104: 1286-1289.
33 Ueno M, Ferreiro JL, Tomasello SD. et al. Functional profile of the platelet P2Y12 receptor signalling pathway in patients with type 2 diabetes mellitus and coronary artery disease. Thromb Haemost 2011; 105: 730-732.
34 Sim DS, Merrill-Skoloff G, Furie BC. et al. Initial accumulation of platelets during arterial thrombus formation in vivo is inhibited by elevation of basal cAMP levels. Blood 2004; 103: 2127-2134.
35 Nomura S, Inami N, Iwasaka T. et al. Platelet activation markers, microparticles and soluble adhesion molecules are elevated in patients with arteriosclerosis obliterans: therapeutic effects by cilostazol and potentiation by dipyridamole. Platelets 2004; 15: 167-172.
36 Hayashi H, Sudo T. Effects of the cAMP-elevating agents cilostamide, cilostazol and forskolin on the phosphorylation of Akt and GSK-3beta in platelets. Thromb Haemost 2009; 102: 327-335.
37 Kim JS, Lee KS, Kim YI. et al. A randomized crossover comparative study of aspirin, cilostazol and clopidogrel in normal controls: analysis with quantitative bleeding time and platelet aggregation test. J Clin Neurosci 2004; 11: 600-602.
38 Wilhite DB, Comerota AJ, Schmieder FA. et al. Managing PAD with multiple platelet inhibitors: the effect of combination therapy on bleeding time. J Vasc Surg 2003; 38: 710-713.
39 Monroe DM, Hoffman M, Roberts HR. Platelets and thrombin generation. Arterioscler Thromb Vasc Biol 2002; 22: 1381-1389.
40 Leon C, Ravanat C, Freund M. et al. Differential involvement of the P2Y1 and P2Y₁₂ receptors in platelet procoagulant activity. Arterioscler Thromb Vasc Biol 2003; 23: 1941-1947.
41 van der Meijden PE, Feijge MA, Giesen PL. et al. Platelet P2Y₁₂ receptors enhance signalling towards procoagulant activity and thrombin generation. A study with healthy subjects and patients at thrombotic risk. Thromb Haemost 2005; 93: 1128-1136.
42 Gachet C, Léon C, Hechler B. The platelet P2 receptors in arterial thrombosis. Blood Cells Mol Dis 2006; 36: 223-227.
43 Angiolillo DJ, Capodanno D, Goto S. Platelet thrombin receptor antagonism and atherothrombosis. Eur Heart J 2010; 31: 17-28.
44 Shinohara Y, Katayama Y, Uchiyama S. et al. CSPS 2 group. Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial. Lancet Neurol 2010; 9: 959-968.
45 Kumbhani DJ, Bhatt DL. Secondary prevention of stroke: can we do better than aspirin?. Lancet Neurol 2010; 9: 942-943.
46 Katakami N, Kim YS, Kawamori R. et al. The phosphodiesterase inhibitor cilostazol induces regression of carotid atherosclerosis in subjects with type 2 diabetes mellitus: principal results of the Diabetic Atherosclerosis Prevention by Cilostazol (DAPC) study: a randomized trial. Circulation 2010; 121: 2584-2591.