Platelet function profiles in the elderly: Results of a pharmacodynamic study in patients on clopidogrel therapy and effects of switching to prasugrel 5 mg in patients with high platelet reactivity

Piera Capranzano; Claudia Tamburino; Davide Capodanno; Eligio Miccichè; Lucia D’Urso; Valeria Calvi; Dominick J. Angiolillo; Corrado Tamburino

doi:10.1160/TH11-05-0346

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2011; 106(06): 1149-1157
DOI: 10.1160/TH11-05-0346

Wound Healing and Inflammation/Infection

Schattauer GmbH

Platelet function profiles in the elderly: Results of a pharmacodynamic study in patients on clopidogrel therapy and effects of switching to prasugrel 5 mg in patients with high platelet reactivity

Piera Capranzano

¹Cardiovascular Department, Ferrarotto Hospital, University of Catania, Italy

²ETNA Foundation, Catania, Italy

,

Claudia Tamburino

¹Cardiovascular Department, Ferrarotto Hospital, University of Catania, Italy

²ETNA Foundation, Catania, Italy

,

Davide Capodanno

¹Cardiovascular Department, Ferrarotto Hospital, University of Catania, Italy

²ETNA Foundation, Catania, Italy

,

Eligio Miccichè

¹Cardiovascular Department, Ferrarotto Hospital, University of Catania, Italy

,

Lucia D’Urso

¹Cardiovascular Department, Ferrarotto Hospital, University of Catania, Italy

,

Valeria Calvi

¹Cardiovascular Department, Ferrarotto Hospital, University of Catania, Italy

,

Dominick J. Angiolillo

²ETNA Foundation, Catania, Italy

³Division of Cardiology, University of Florida College of Medicine-Jacksonville, Jacksonville, Florida, USA

,

Corrado Tamburino

¹Cardiovascular Department, Ferrarotto Hospital, University of Catania, Italy

²ETNA Foundation, Catania, Italy

› Author Affiliations

Abstract

Summary

Studies specifically designed to assess clopidogrel response in the elderly as well as treatment alternatives to improve platelet inhibition in this highrisk population are lacking. This study aimed to define phar-macodynamic (PD) profiles, including high platelet reactivity (HPR) rates, among elderly patients on maintenance clopidogrel therapy and to assess the PD effects of prasugrel 5 mg/day in elderly with HPR. This was a prospective observational PD study enrolling consecutive ≥75-year-old patients on maintenance clopidogrel therapy (75 mg/day) who were tested for clopidogrel response by the VerifyNow P2Y12 assay and light transmittance aggregometry (LTA). HPR rates were estimated using multiple definitions. HPR patients identified by the VerifyNow P2Y12 assay [P2Y12 reaction unit (PRU) ≥230] were switched to prasugrel 5 mg/day, and platelet function testing was performed after 15 days of treatment. PD testing was completed in 100 patients. The HPR prevalence varied between 25% and 32%, depending on the definition used. A PRU ≥230 was observed in 25 patients; of these, 20 switched to prasugrel 5 mg/day. This resulted in significant reduction in PRU mean values (279.8 ± 45.1 vs. 171.7 ± 65.2, p=0.0002) with an absolute between-treatment difference of 108.1 (95% confidence intervals 75.2–140.9). Accordingly, switching to prasugrel 5 mg/day overcame HPR in most (80%) patients. Consistently, all LTA measures were significantly lower after prasugrel compared with clopidogrel. In conclusion, a considerable proportion of elderly patients exhibit HPR while on standard clopidogrel therapy. Switching to 5 mg/day prasugrel in elderly patients with HPR is associated with enhanced platelet inhibition and overcomes HPR in the majority of these patients.

Keywords

Clopidogrel non-responsiveness - elderly patients - prasugrel

Full Text

References

References
1 Kushner FG, Smith Jr SC, King III SB. et al. 2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (Updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (Updating the 2005 Guideline and 2007 Focused Update). J Am Coll Cardiol 2009; 54: 2205-2241.
2 Anderson JL, Adams CD, Antman EM. et al. 2011 ACCF/AHA Focused Update Incorporated Into the ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011; 123: e426-579.
3 Wijns W, Kolh P, Danchin N. et al. Guidelines on myocardial revascularization. The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2010; 31: 2501-2555.
4 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.
5 Ferreiro JL, Angiolillo DJ. Clopidogrel response variability: Current status and future directions. Thromb Haemost 2009; 102: 7-14.
6 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.
7 Angiolillo DJ, Ueno M. Optimizing platelet inhibition in clopidogrel poor metabolizers therapeutic options and practical considerations. JACC Cardiovasc Interv 2011; 4: 411-414.
8 Geisler T, Grass D, Bigalke B. et al. The Residual Platelet Aggregation after Deployment of Intracoronary Stent (PREDICT) score. J Thromb Haemost 2008; 6: 54-61.
9 Hochholzer W, Trenk D, Fromm MF. et al. Impact of cytochrome P450 2C19 loss-of-function polymorphism and of major demographic characteristics on residual platelet function after loading and maintenance treatment with clopidogrel in patients undergoing elective coronary stent placement. J Am Coll Cardiol 2010; 55: 2427-2434.
10 Breet NJ, van Donkersgoed HE, van Werkum JW. et al. Is platelet inhibition due to thienopyridines increades in elderly patients, in patients with previous stroke and patients with low body weight as a possible explanation of an increased bleeding risk?. Neth Heart J 2011; 19: 279-284.
11 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.
12 Wrishko RE, Ernest CS, Small DS. et al. Population pharmacokinetic analyses to evaluate the influence of intrinsic and extrinsic factors on exposure of prasugrel active metabolite in TRITON-TIMI 38. J Clin Pharmacol 2009; 49: 984-998.
13 European Medicines Agency. Efient: European Public Assessment Report. Available at. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/000984/WC500021975.pdf Accessed March 13, 2009
14 Gurbel PA, Bliden KP, Hiatt BL. et al. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003; 107: 2908-2913.
15 Price MJ, Berger PB, Teirstein PS. et al. GRAVITAS Investigators. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. J Am Med Assoc 2011; 305: 1097-1105.
16 Campo G, Parrinello G, Ferraresi P. et al. Prospective evaluation of on-clopidogrel platelet reactivity over time in patients treated with percutaneous coronary intervention relationship with gene polymorphisms and clinical outcome. J Am Coll Cardiol 2011; 57: 2474-2483.
17 Collet JP, Cayla G, Cuisset T. et al. Randomized comparison of platelet function monitoring to adjust antiplatelet therapy versus standard of care: rationale and design of the assessment with a double randomization of (1) a fixed dose versus a monitoring-guided dose of aspirin and clopidogrel after DES implantation, and (2) treatment interruption versus continuation , 1 year after stenting (ARCTIC) study. Am Heart J 2011; 161: 5-12. e5
18 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 OPTIMUS-2 study. Eur Heart J 2008; 29: 2202-2211.
19 Angiolillo DJ, Badimon JJ, Saucedo JF. et al. A pharmacodynamic comparison of prasugrel vs. high-dose clopidogrel in patients with type 2 diabetes mellitus and coronary artery disease: results of the Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 Trial. Eur Heart J 2011; 32: 838-46.
20 Angiolillo DJ, Shoemaker SB, Desai B. et al. Randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) study. Circulation 2007; 115: 708-716.
21 Angiolillo DJ, Bernardo E, Palazuelos J. et al. Functional impact of high clopidogrel maintenance dosing in patients undergoing elective percutaneous coronary intervention. Results of a randomized study. Thromb Haemost 2008; 99: 161-168.
22 Lancaster GA, Dodd S, Williamson PR. Design and analysis of pilot studies: recommendations for good practice. J Eval Clin Pract 2004; 10: 307-312.
23 Price MJ, Endemann S, Gollapudi RR. et al. Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation. Eur Heart J 2008; 29: 992-1000.
24 Marcucci R, Gori AM, Paniccia R. et al. Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point-of-care assay: a 12-month follow-up. Circulation 2009; 119: 237-242.
25 Hochholzer W, Trenk D, Bestehorn HP. et al. Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement. J Am Coll Cardiol 2006; 48: 1742-1750.
26 Buonamici P, Marcucci R, Migliorini A. et al. Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis. J Am Coll Cardiol 2007; 49: 2312-2317.
27 Gremmel T, Steiner S, Seidinger D. et al. Adenosine diphosphate-inducible platelet reactivity shows a pronounced age dependency in the initial phase of antiplatelet therapy with clopidogrel. J Thromb Haemost 2010; 8: 37-42.
28 Capodanno D, Angiolillo DJ. Antithrombotic therapy in the elderly. J Am Coll Cardiol 2010; 56: 1683-1692.
29 Guagliumi G, Stone GW, Cox DA. et al. Outcome in elderly patients undergoing primary coronary intervention for acute myocardial infarction: results from the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial. Circulation 2004; 110: 1598-1604.
30 Hasdai D, Holmes Jr DR, Criger DA. et al. Age and outcome after acute coronary syndromes without persistent ST-segment elevation. Am Heart J 2000; 139: 858-866.
31 Hannan EL, Racz MJ, Arani DT. et al. Short- and long-term mortality for patients undergoing primary angioplasty for acute myocardial infarction. J Am Coll Cardiol 2000; 36: 1194-1201.
32 Zahn R, Hamm CW, Schneider S. et al. German Cypher Stent Registry. Predictors of death or myocardial infarction during follow-up after coronary stenting with the sirolimus-eluting stent. Results from the prospective multicenter German Cypher Stent Registry. Am Heart J 2006; 152: 1146-1152.
33 Doyle BJ, Rihal CS, Gastineau DA. et al. Bleeding, blood transfusion, and increased mortality after percutaneous coronary intervention: implications for contemporary practice. J Am Coll Cardiol 2009; 53: 2019-2027.
34 Ferreiro JL, Sibbing D, Angiolillo DJ. Platelet function testing and risk of bleeding complications. Thromb Haemost 2010; 103: 1128-1135.
35 Bates ER, Lau WC, Angiolillo DJ. Clopidogrel-drug interactions. J Am Coll Cardiol 2011; 57: 1251-1263.
36 Capranzano P, Ferreiro JL, Angiolillo DJ. Prasugrel in acute coronary syndrome patients undergoing percutaneous coronary intervention. Expert Rev Cardiovasc Ther 2009; 7: 361-369.
37 Patti G, Pasceri V, Vizzi V. et al. Usefulness of platelet response to clopidogrel by point-of-care testing to predict bleeding outcomes in patients undergoing percutaneous coronary intervention (from the Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty-Bleeding Study). Am J Cardiol 2011; 107: 995-1000.
38 Sibbing D, Schulz S, Braun S. et al. Antiplatelet effects of clopidogrel and bleeding in patients undergoing coronary stent placement. J Thromb Haemost 2010; 8: 250-256.
39 Food and Drug Administration. Cardiovascular and Renal Drug Advisory Committee briefing document: Questions, prasugrel for ACS. February 3, 2009. Available at. http://www.fda.gov/ohrms/dockets/ac/09/briefing/2009-4412b1-01-FDA.pdf Accessed May 18, 2009