Randomised, double-blind trial on the value of tapered discontinuation of clopidogrel maintenance therapy after drug-eluting stent implantation

Summary

There is little evidence on the optimal mode of clopidogrel discontinuation. Epidemiological studies observed clustering of thrombotic events after cessation of chronic clopidogrel therapy. The underlying mechanism has been ascribed to transient platelet hyper-reactivity. Gradual tapering of clopidogrel may have the potential to attenuate this phenomenon. The objective of the present study was to assess whether in patients with drug-eluting stents (DES) gradual discontinuation of clopidogrel maintenance therapy is superior to conventional, abrupt discontinuation. Patients with planned discontinuation of chronic clopidogrel therapy after DES implantation were randomised in a double-blinded fashion to either gradual discontinuation (according to a tapering schema over four weeks) or abrupt discontinuation (after continued clopidogrel therapy for additional four weeks). The primary endpoint was the composite of cardiac death, myocardial infarction, stroke, stent thrombosis, major bleeding or rehospitalisation due to an acute coronary syndrome at 90 days. Enrollment of 3,000 patients was planned. The study was stopped prematurely due to slow recruitment after enrollment of 782 patients. At 90 days, nine of 392 patients (2.3%) with tapered cessation reached the primary endpoint compared to five of 390 patients (1.3%) with abrupt cessation (p=0.284). The composite of death or myocardial infarction occurred in three patients with tapered and three patients with abrupt discontinuation (p=0.764). In conclusion, tapered discontinuation of chronic clopidogrel therapy is not superior to abrupt discontinuation regarding the primary endpoint in this study. However, the results must be interpreted in view of the premature termination of the trial and low event rates.

Keywords

Clopidogrel - tapering - rebound - drug-eluting stent

^* ClinicalTrial.gov, No. NCT00640679

• References

• 1 Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494-502.
• 2 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.
• 3 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.
• 4 Kastrati A, Mehilli J, Pache J. et al. Analysis of 14 trials comparing sirolimuseluting stents with baremetal stents. N Engl J Med 2007; 356: 1030-1039.
• 5 Pfisterer M, Brunner-La Rocca HP, Buser PT. et al. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting versus baremetal stents. J Am Coll Cardiol 2006; 48: 2584-2591.
• 6 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.
• 7 Schulz S, Schuster T, Mehilli J. et al. Stent thrombosis after drug-eluting stent implantation: incidence, timing, and relation to discontinuation of clopidogrel therapy over a 4-year period. Eur Heart J 2009; 30: 2714-2721.
• 8 Stettler C, Wandel S, Allemann S. et al. Outcomes associated with drug-eluting and baremetal stents: a collaborative network meta-analysis. Lancet 2007; 370: 937-948.
• 9 Antithrombotic Trialists C, Baigent C, Blackwell L. et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373: 1849-1860.
• 10 Byrne RA, Schulz S, Mehilli J. et al. Rationale and design of a randomized, double-blind, placebo-controlled trial of 6 versus 12 months clopidogrel therapy after implantation of a drug-eluting stent: The Intracoronary Stenting and Antithrombotic Regimen: Safety And EFficacy of 6 Months Dual Antiplatelet Therapy After Drug-Eluting Stenting (ISAR-SAFE) study. Am Heart J 2009; 157: 620-624. e2
• 11 Mauri L, Kereiakes DJ, Normand SL. et al. Rationale and design of the dual antiplatelet therapy study, a prospective, multicenter, randomized, double-blind trial to assess the effectiveness and safety of 12 versus 30 months of dual antiplatelet therapy in subjects undergoing percutaneous coronary intervention with either drug-eluting stent or bare metal stent placement for the treatment of coronary artery lesions. Am Heart J 2010; 160: 1035-1041. 41 e1
• 12 Kastrati A, Byrne RA, Schulz S. Will we ever know the optimal duration of dual antiplatelet therapy after drug-eluting stent implantation?. JACC Cardiovasc Interv 2011; 04: 1129-1132.
• 13 Iakovou I, Schmidt T, Bonizzoni E. et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. J Am Med Assoc 2005; 293: 2126-2130.
• 14 Kuchulakanti PK, Chu WW, Torguson R. et al. Correlates and long-term outcomes of angiographically proven stent thrombosis with sirolimus- and paclitaxel-eluting stents. Circulation 2006; 113: 1108-1113.
• 15 Ho PM, Peterson ED, Wang L. et al. Incidence of death and acute myocardial infarction associated with stopping clopidogrel after acute coronary syndrome. J Am Med Assoc 2008; 299: 532-539.
• 16 Ho PM, Tsai TT, Wang TY. et al. Adverse events after stopping clopidogrel in post-acute coronary syndrome patients: Insights from a large integrated healthcare delivery system. Circulation Cardiovasc Quality Outcomes 2010; 03: 303-308.
• 17 Charlot M, Nielsen LH, Lindhardsen J. et al. Clopidogrel discontinuation after myocardial infarction and risk of thrombosis: a nationwide cohort study. Eur Heart J 2012; 33: 2527-2534.
• 18 Serebruany VL, Midei MG, Meilman H. et al. Rebound platelet activation after termination of prasugrel and aspirin therapy due to confirmed non-compliance in patient enrolled in the JUMBO Trial. Int J Clin Pract 2006; 60: 863-866.
• 19 Diehl P, Halscheid C, Olivier C. et al. Discontinuation of long term clopidogrel therapy induces platelet rebound hyperaggregability between 2 and 6 weeks post cessation. Clin Res Cardiol 2011; 100: 765-771.
• 20 Mylotte D, Peace AJ, Tedesco AT. et al. Clopidogrel discontinuation and platelet reactivity following coronary stenting. J Thromb Haemost 2011; 09: 24-32.
• 21 Cundiff DK. Benefit of clopidogrel for acute coronary syndrome and percutaneous coronary interventions in doubt due to rebound adverse events. Am J Cardiol 2008; 102: 248.
• 22 Cutlip DE, Windecker S, Mehran R. et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007; 115: 2344-2351.
• 23 Definitions used in TIMI trials. Available at: www.timi.org last accessed April 10, 2010
• 24 Ferrari E, Benhamou M, Cerboni P. et al. Coronary syndromes following aspirin withdrawal: a special risk for late stent thrombosis. J Am Coll Cardiol 2005; 45: 456-459.
• 25 Theroux P, Waters D, Lam J. et al. Reactivation of unstable angina after the discontinuation of heparin. N Engl J Med 1992; 327: 141-145.
• 26 Angiolillo DJ, Sabate M, Fernandez-Ortiz A, Macaya C. Acute stent thrombosis after early withdrawal of platelet glycoprotein IIb/IIIa antagonists: potential rebound prothrombotic effect?. Catheter Cardiovasc Interv 2003; 58: 481-484.
• 27 Schomig A, Neumann FJ, Kastrati A. et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med 1996; 334: 1084-1089.
• 28 Park SJ, Kang SJ, Virmani R. et al. In-stent neoatherosclerosis: a final common pathway of late stent failure. J Am Coll Cardiol 2012; 59: 2051-2057.
• 29 Cassese S, Byrne RA, Tada T. et al. Clinical impact of extended dual antiplatelet therapy after percutaneous coronary interventions in the drug-eluting stent era: a meta-analysis of randomized trials. Eur Heart J 2012; 33: 3078-3087.
• 30 Magd A, Elsawy E, Ramzy A. et al. Is there a platelet reboud effect to stopping clopidogrel?. Am J Cardiol 2009; 104: 173D. (Abstract)
• 31 Lordkipanidze M, Diodati J, Schampaert E. et al. Effect of Clopidogrel Discontinuation on Platelet Function. Circulation 2009; 120: S1032. (abstract)
• 32 Magd A, Osman M, Ramzy A. et al. Does gradual tapering of clopidogrel ameliorate the potential for rebound enhanced platelet aggregation post sudden discontinuation?. J Am Coll Cardiol 2010; 56: B2. abstract TCT-8)
• 33 Sambu N, Warner T, Curzen N. Clopidogrel withdrawal: is there a “rebound” phenomenon?. Thromb Haemost 2011; 105: 211-220.
• 34 Lordkipanidze M, Harrison P. Beware of being caught on the rebound. J Thromb Haemost 2011; o9: 21-23.
• 35 Baurand A, Eckly A, Bari N. et al. Desensitisation of the platelet aggregation response to ADP: differential down-regulation of the P2Y1 and P2cyc receptors. Thromb Haemost 2000; 84: 484-491.
• 36 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. Clopidogrel withdrawal is associated with proinflammatory and prothrombotic effects in patients with diabetes and coronary artery disease. Diabetes 2006; 55: 780-784.
• 37 Wykrzykowska JJ, Warnholtz A, de Jaeger P. et al. Effect of clopidogrel discontinuation at 1 year after drug eluting stent placement on soluble CD40L, P-selectin and C-reactive protein levels: DECADES (Discontinuation Effect of Clopidogrel After Drug Eluting Stent): a multicenter, open-label study. J Thromb Thrombolysis 2009; 28: 410-417.
• 38 Wurtz M, Grove EL, Wulff LN. et al. Patients with previous definite stent thrombosis have a reduced antiplatelet effect of aspirin and a larger fraction of immature platelets. JACC Cardiovasc Interv 2010; 03: 828-835.
• 39 Sambu N, Dent H, Englyst N. et al. Effect of clopidogrel withdrawal on platelet reactivity and vascular inflammatory biomarkers 1 year after drug-eluting stent implantation: results of the prospective, single-centre CESSATION study. Heart 2011; 97: 1661-1667.
• 40 Angiolillo DJ, Jakubowski JA, Frelinger AL. et al. Lack of rebound in platelet reactivity following cessation of prasugrel and clopidogrel in type 2 diabetes melllitus patients with coronary artery disease: insights from OPTIMUS-3. Eur Heart J 2010; 31: 389. (abstract)
• 41 Djukanovic N, Todorovic Z, Obradovic S. et al. Abrupt cessation of one-year clopidogrel treatment is not associated with thrombotic events. J Pharmacol Sci 2011; 117: 12-18.
• 42 Yedidya I, Netzer A, Vaduganathan M. et al. Clopidogrel tapering as a strategy to attenuate platelet rebound phenomenon in patients with baremetal stents. J Thromb Thrombolysis 2012; 33: 16-21.
• 43 Frelinger 3rd AL, Barnard MR, Fox ML. et al. The Platelet Activity After Clopidogrel Termination (PACT) study. Circ Cardiovasc Interv 2010; 03: 442-449.
• 44 Sibbing D, Stegherr J, Braun S. et al. A double-blind, randomized study on prevention and existence of a rebound phenomenon of platelets after cessation of clopidogrel treatment. J Am Coll Cardiol 2010; 55: 558-565.
• 45 Trenk D, Stone GW, Gawaz M. et al. A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study. J Am Coll Cardiol 2012; 59: 2159-2164.
• 46 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.
• 47 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.
• 48 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.
• 49 Jakubowski JA, Li YG, Payne CD. et al. Absence of “rebound” platelet hyperreactivity following cessation of prasugrel. Thromb Haemost 2011; 106: 174-176.
• 50 Tada T, Byrne RA, Simunovic I. et al. Risk of stent thrombosis among baremetal stents, first-generation drug-eluting stents, and second-generation drug-eluting stents: results from a registry of 18,334 patients. JACC Cardiovasc Interv 2013; 06: 1267-1274.