On-clopidogrel platelet reactivity as predictor for long-term clinical outcome in patients after planned discontinuation of clopidogrel

Summary

It is unknown whether the known association of high on-treatment platelet reactivity (HTPR) with worse clinical outcome in patients on clopidogrel following coronary stent implantation persists after planned discontinuation of clopidogrel. This study investigated the association of HTPR with major ischaemic events after planned discontinuation of clopidogrel. Consecutive patients undergoing elective coronary stent implantation after loading with clopidogrel 600 mg were followed for up to seven years (n=765). Platelet reactivity was tested on day 1 after coronary intervention. Clopidogrel was continued for six months after implantation of drug-eluting stents and for one month if only bare-metal stents were used. The combined primary endpoint was death of any cause or non-fatal myocardial infarction (MACE). HTPR was found in 217 of 765 patients (28%). During a median follow-up of 5.7 years, the primary endpoint occurred in 145 subjects after planned discontinuation of clopidogrel. Patients with HTPR showed a higher incidence of MACE after discontinuation of clopidogrel. There was a significant interaction of HTPR and time following discontinuation of clopidogrel beyond one year (p for interaction 0.08). Landmark analyses confirmed that the association of HTPR and MACE was only significant within the first year (HR: 2.93, 95%-CI 1.13–7.60, p=0.03), but not beyond the first year following discontinuation of clopidogrel (HR: 1.19, 95%-CI 0.82–1.72, p=0.37). In conclusion, patients with HTPR persist to be at high risk for death or myocardial infarction even following planned discontinuation of clopidogrel. However, this association was only significant for the first year following discontinuation of clopidogrel.

Keywords

Antiplatelet therapy - platelet function - discontinuation - outcome

• References

• 1 Levine GN, Bates ER, Bittl JA. et al. Focused Update Writing Group, 2016 ACC/ AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease. J Am Coll Cardiol 2016; 68: 1082-1115.
• 2 Windecker S, Kolh P, Alfonso F. et al. 2014 ESC/EACTS Guidelines on myocardial revascularisation: The Task Force on Myocardial Revascularisation of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014; 35: 2541-2619.
• 3 Hochholzer W, Trenk D, Frundi D. et al. Time dependence of platelet inhibition after a 600-mg loading dose of clopidogrel in a large, unselected cohort of candidates for percutaneous coronary intervention. Circulation 2005; 111: 2560-2564.
• 4 Tantry US, Bonello L, Aradi D. et al. 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.
• 5 Aradi D, Kirtane A, Bonello L. et al. Bleeding and stent thrombosis on P2Y12-inhibitors: collaborative analysis on the role of platelet reactivity for risk stratification after percutaneous coronary intervention. Eur Heart J 2015; 36: 1762-1771.
• 6 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.
• 7 Mehta SR, Yusuf S, Peters RJ. et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358: 527-533.
• 8 Steinhubl SR, Berger PB, Mann 3rd JT. et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. J Am Med Assoc 2002; 288: 2411-2420.
• 9 Airoldi F, Colombo A, Morici N. et al. Incidence and predictors of drug-eluting stent thrombosis during and after discontinuation of thienopyridine treatment. Circulation 2007; 116: 745-754.
• 10 Brar SS, Kim J, Brar SK. et al. Long-term outcomes by clopidogrel duration and stent type in a diabetic population with de novo coronary artery lesions. J Am Coll Cardiol 2008; 51: 2220-2227.
• 11 von Beckerath N, Kastrati A, Wieczorek A. et al. A double-blind, randomized study on platelet aggregation in patients treated with a daily dose of 150 or 75 mg of clopidogrel for 30 days. Eur Heart J 2007; 28: 1814-1819.
• 12 Mehran R, Baber U, Steg PG. et al. Cessation of dual antiplatelet treatment and cardiac events after percutaneous coronary intervention (PARIS): 2 year results from a prospective observational study. Lancet 2013; 382: 1714-1722.
• 13 Bonaca MP, Bhatt DL, Cohen M. et al. Long-Term Use of Ticagrelor in Patients with Prior Myocardial Infarction. New Engl J Med 2015; 372: 1791-1800.
• 14 Mauri L, Kereiakes DJ, Yeh RW. et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. New Engl J Med 2014; 371: 2155-2166.
• 15 Yeh RW, Secemsky EA, Kereiakes DJ. et al. Development and Validation of a Prediction Rule for Benefit and Harm of Dual Antiplatelet Therapy Beyond 1 Year After Percutaneous Coronary Intervention. J Am Med Assoc 2016; 315: 1735-1749.
• 16 Thygesen K, Alpert JS, Jaffe AS. et al. Third universal definition of myocardial infarction. Eur Heart J 2012; 33: 2551-2567.
• 17 Hochholzer W, Valina CM, Bomicke T. et al. Intrinsic platelet reactivity before start with clopidogrel as predictor for on-clopidogrel platelet function and long-term clinical outcome. Thromb Haemost 2015; 114: 109-114.
• 18 Trenk D, Hochholzer W, Fromm MF. et al. Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol 2008; 51: 1925-1934.
• 19 Feres F, Costa RA, Abizaid A. et al. Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial. J Am Med Assoc 2013; 310: 2510-2522.
• 20 Kim BK, Hong MK, Shin DH. et al. A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation). J Am Coll Cardiol 2012; 60: 1340-1348.
• 21 Palmerini T, Benedetto U, Bacchi-Reggiani L. et al. Mortality in patients treated with extended duration dual antiplatelet therapy after drug-eluting stent implantation: a pairwise and Bayesian network meta-analysis of randomised trials. Lancet 2015; 385: 2371-2382.
• 22 Roffi M, Patrono C, Collet JP. et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2016; 37: 267-315.
• 23 Finn AV, Joner M, Nakazawa G. et al. Pathological correlates of late drug-eluting stent thrombosis: strut coverage as a marker of endothelialisation. Circulation 2007; 115: 2435-2441.
• 24 Joner M, Finn AV, Farb A. et al. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. J Am Coll Cardiol 2006; 48: 193-202.
• 25 Gatto P, Dumonteil N, Boudou N. et al. Incomplete stent apposition and very late stent thrombosis after everolimus eluting stent implantation and dual antiplatelet therapy interruption. A case of OCT guided therapy. Int J Cardiol 2015; 180: 52-54.
• 26 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.
• 27 Droppa M, Tschernow D, Muller KA. et al. Evaluation of clinical risk factors to predict high on-treatment platelet reactivity and outcome in patients with stable coronary artery disease (PREDICT-STABLE). PLoS One 2015; 10: e0121620.