Effect of adjunctive dipyridamole to DAPT on platelet function profiles in stented patients with high platelet reactivity

Summary

Adjunctive use of phosphodiesterase (PDE) inhibitor can enhance antiplatelet and vasoprotective properties in patients with cardiovascular disease. The aim of this study was to evaluate the impact of PDE5 inhibitor dipyridamole on platelet function in stented patients with high platelet reactivity (HPR) during dual antiplatelet therapy (DAPT) with aspirin and clopidogrel. Patients with HPR after 600-mg clopidogrel loading were randomly assigned to adjunctive dipyridamole 75 mg twice daily to standard DAPT (DIP group; n = 45) or double-dose clopidogrel of 150 mg daily (DOUBLE group; n = 46) for 30 days. Platelet function was assessed at baseline and 30-day follow-up with platelet reactivity index (PRI) by vasodilator-stimulated phosphoprotein-phosphorylation (VASP-P) assay and platelet aggregation (PA) by light transmittance aggregometry (LTA). Primary endpoint was PRI at 30-day follow-up. HPR was defined as PRI > 50%. Baseline platelet function did not differ between the groups. Following 30-day therapy, platelet function was significantly reduced in the DIP and DOUBLE groups (all p-values ≤ 0.004 and ≤ 0.068, respectively). PRI values were not significantly different between the two groups (mean difference: 3.1%; 95% confidence interval: –2.8% to 9.0%: p = 0.295). PA values and prevalence of HPR were similar between the groups. However, a significant number of patients still exhibited HPR in the DIP (75.6%) and DOUBLE (67.4%) groups. In conclusion, among stented HPR patients, adding dipyridamole to DAPT does not reduce platelet reactivity and prevalence of HPR compared with double-dose clopidogrel therapy, and therefore both strategies are inadequate to overcome HPR.

Keywords

Platelets - dipyridamole - clopidogrel - intervention

• References

• 1 Levine GN, Bates ER, Blankenship JC. et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol 2011; 58: e44-122.
• 2 Tantry US, Bonello L, Aradi D. et al. Working Group on On-Treatment Platelet Reactivity. Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischaemia and bleeding. J Am Coll Cardiol 2013; 62: 2261-2273.
• 3 Wallentin L, Becker RC, Budaj A. et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361: 1045-1057.
• 4 Wiviott SD, Braunwald E, McCabe CH. et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001-2015.
• 5 Gurbel PA, Tantry US. Combination antithrombotic therapies. Circulation 2010; 121: 569-583.
• 6 Gajos G, Rostoff P, Undas A, Piwowarska W. Effects of polyunsaturated omega-3 fatty acids on responsiveness to dual antiplatelet therapy in patients undergoing percutaneous coronary intervention: the OMEGA-PCI (OMEGA-3 fatty acids after PCI to modify responsiveness to dual antiplatelet therapy) study. J Am Coll Cardiol 2010; 55: 1671-1678.
• 7 Tricoci P, Huang Z, Held C. et al. TRACER Investigators. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N Engl J Med 2012; 366: 20-33.
• 8 Mega JL, Braunwald E, Wiviott SD. et al. ATLAS ACS 2-TIMI 51 Investigators. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012; 366: 9-19.
• 9 Gresele P, Momi S, Falcinelli E. Anti-platelet therapy: phosphodiesterase inhibitors. Br J Clin Pharmacol 2011; 72: 634-646.
• 10 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.
• 11 Han Y, Li Y, Wang S, Jing Q. 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.
• 12 Chen KY, Rha SW, Li YJ. et al. Triple versus dual antiplatelet therapy in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Circulation 2009; 119: 3207-3214.
• 13 Kim IS, Jeong YH, Park Y. et al. Platelet inhibition by adjunctive cilostazol versus high maintenance-dose clopidogrel in patients with acute myocardial infarction according to cytochrome P450 2C19 genotype. JACC Cardiovasc Interv 2011; 04: 381-391.
• 14 Jang JS, Jin HY, Seo JS. et al. A meta-analysis of randomized controlled trials appraising the efficacy and safety of cilostazol after coronary artery stent implantation. Cardiology 2012; 122: 133-143.
• 15 Ueno M, Ferreiro JL, Tomasello SD. et al. Impact of pentoxifylline on platelet function profiles in patients with type 2 diabetes mellitus and coronary artery disease on dual antiplatelet therapy with aspirin and clopidogrel. JACC Cardiovasc Interv 2011; 04: 905-912.
• 16 Kim HH, Liao JK. Translational therapeutics of dipyridamole. Arterioscler Thromb Vasc Biol 2008; 28: s39-42.
• 17 Hankey GJ, Eikelboom JW. Antithrombotic drugs for patients with ischaemic stroke and transient ischaemic attack to prevent recurrent major vascular events. Lancet Neurol 2010; 09: 273-284.
• 18 Malloy RJ, Kanaan AO, Silva MA. et al. Evaluation of antiplatelet agents for secondary prevention of stroke using mixed treatment comparison meta-analysis. Clin Ther 2013; 35: 1490-1500.e7.
• 19 Verro P, Gorelick PB, Nguyen D. Aspirin plus dipyridamole versus aspirin for prevention of vascular events after stroke or TIA: a meta-analysis. Stroke 2008; 39: 1358-1363.
• 20 Liu Y, Cone J, Le SN. et al. Cilostazol and dipyridamole synergistically inhibit human platelet aggregation. J Cardiovasc Pharmacol 2004; 44: 266-273.
• 21 Kim IS, Jeong YH, Tantry US. et al. Relation between the vasodilator-stimulated phosphoprotein phosphorylation assay and light transmittance aggregometry in East Asian patients after high-dose clopidogrel loading. Am Heart J 2013; 166: 95-103.
• 22 Park Y, Jeong YH, Tantry US. et al. Accelerated platelet inhibition by switching from atorvastatin to a non-CYP3A4-metabolized statin in patients with high platelet reactivity (ACCEL-STATIN) study. Eur Heart J 2012; 33: 2151-2162.
• 23 Jeong YH, Bliden KP, Tantry US, Gurbel PA. High on-treatment platelet reactivity assessed by various platelet function tests: is the consensus-defined cut-off of VASP-P platelet reactivity index too low?. J Thromb Haemost 2012; 10: 487-489.
• 24 Angiolillo DJ, Bernardo E, Zanoni M. et al. Impact of insulin receptor substrate-1 genotypes on platelet reactivity and cardiovascular outcomes in patients with type 2 diabetes mellitus and coronary artery disease. J Am Coll Cardiol 2011; 58: 30-39.
• 25 Francis SH, Blount MA, Corbin JD. Mammalian cyclic nucleotide phosphodiesterases: molecular mechanisms and physiological functions. Physiol Rev 2011; 91: 651-690.
• 26 Rondina MT, Weyrich AS. Targeting phosphodiesterases in anti-platelet therapy. Handb Exp Pharmacol 2012; 210: 225-238.
• 27 Bender AT, Beavo JA. Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev 2006; 58: 488-520.
• 28 Aktas B, Utz A, Hoenig-Liedl P. et al. Dipyridamole enhances NO/cGMP-mediated vasodilator-stimulated phosphoprotein phosphorylation and signalling in human platelets: in vitro and in vivo/ex vivo studies. Stroke 2003; 34: 764-769.
• 29 Eikelboom JW, Hirsh J, Spencer FA, Baglin TP, Weitz JI. Antiplatelet drugs: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (Suppl. 02) e89S-119S.
• 30 De Schryver EL, Algra A, van Gijn J. Dipyridamole for preventing stroke and other vascular events in patients with vascular disease. Cochrane Database Syst Rev 2007; 03: CD001820.
• 31 Picano E. PISA (Persantin In Stable Angina) study group. Dipyridamole in chronic stable angina pectoris; a randomized, double blind, placebo-controlled, parallel group study. Eur Heart J 2001; 22: 1785-1793.
• 32 Massel DR, Little SH. Antiplatelet and anticoagulation for patients with prosthetic heart valves. Cochrane Database Syst Rev 2013; 07: CD003464.
• 33 Magnusson M, Gunnarsson M, Berntorp E. et al. Effects of pentoxifylline and its metabolites on platelet aggregation in whole blood from healthy humans. Eur J Pharmacol 2008; 581: 290-295.
• 34 Smolenski A. Novel roles of cAMP/cGMP-dependent signalling in platelets. J Thromb Haemost 2012; 10: 167-176.
• 35 Jeong YH. Clopidogrel with aspirin in minor stroke or transient ischaemic attack. N Engl J Med 2013; 369: 1376.
• 36 Wang Y, Wang Y, Zhao X. et al. Clopidogrel with aspirin in acute minor stroke or transient ischaemic attack. N Engl J Med 2013; 369: 11-19.
• 37 Bath PM. Triple Antiplatelets for Reducing Dependency After Ischaemic Stroke (TARDIS). Available at: clinicaltrials.gov/show/NCT01661322 Accessed January 5, 2014.
• 38 Alexopoulos D, Galati A, Xanthopoulou I. et al. Ticagrelor versus prasugrel in acute coronary syndrome patients with high on-clopidogrel platelet reactivity following percutaneous coronary intervention: a pharmacodynamic study. J Am Coll Cardiol 2012; 60: 193-199.
• 39 Jeong YH, Kim IS, Park Y. et al. Carriage of cytochrome 2C19 polymorphism is associated with risk of high post-treatment platelet reactivity on high maintenance-dose clopidogrel of 150 mg/day: results of the ACCEL-DOUBLE (Accelerated Platelet Inhibition by a Double Dose of Clopidogrel According to Gene Polymorphism) study. JACC Cardiovasc Interv 2010; 03: 731-741.
• 40 Zhang ZY, Chen M, Chen J. et al. Biotransformation and in vitro assessment of metabolism-associated drug-drug interaction for CRx-102, a novel combination drug candidate. J Pharm Biomed Anal 2009; 50: 200-209.
• 41 Halkes PH, van Gijn J, Kappelle LJ. et al. ESPRIT Study Group. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet 2006; 367: 1665-1673.
• 42 Sacco RL, Diener HC, Yusuf S. et al. PRoFESS Study Group. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med 2008; 359: 1238-1251.
• 43 Nijjer SS, Davies JE, Francis DP. Quantitative comparison of clopidogrel 600 mg, prasugrel and ticagrelor, against clopidogrel 300 mg on major adverse cardiovascular events and bleeding in coronary stenting: synthesis of CURRENT-OASIS-7, TRITON-TIMI-38 and PLATO. Int J Cardiol 2012; 158: 181-185.