Prior chronic clopidogrel therapy is associated with increased adverse events and early stent thrombosis

Summary

Despite the growing use of clopidogrel, limited data exist regarding the prognostic significance of chronic clopidogrel therapy in patients sustaining acute coronary syndrome (ACS). Our aim was to determine whether patients sustaining ACS while on chronic clopidogrel therapy have a worse prognosis than clopidogrel-naïve patients. A total of 5,386 consecutive ACS patients were prospectively characterised and followed-up for 30 days. Of them, 680 (13 %) were treated with clopidogrel prior to the index ACS. Major adverse cardiovascular events (MACE) were defined as death, recurrent ACS, stroke and/or stent thrombosis. Compared with clopidogrel-naïve, chronic clopidogrel-treated patients were older (66 ± 12 vs 63 ± 13, respectively; p< 0.01), suffered more from diabetes mellitus, hypertension, dyslipidaemia, prior cardiovascular history, including prior myocardial infarction, revascularisation, coronary artery bypass graft and stroke (p< 0.01 for all), and were less likely to present with ST-elevation myocardial infarction (21 % vs 45 %; respectively; p < 0.001). Prior clopidogrel therapy was associated with a two-fold increase in in-hospital (1.6 °% vs 0.6, respectively; p =0.006) as well as 30-day stent thrombosis (2.2 % vs 1.0 %, respectively; p=0.007). MACE at 30 days was also higher among chronic clopidogrel-treated compared with clopidogrel-naïve patients [12.3 % vs 9.4 %, respectively; p< 0.01]. In multivariate log regression analysis chronic clopidogrel treatment was an independent predictor of stent thrombosis [OR=2.6 (95 %CI 1.2–5.6), p=0.001]. Patients sustaining ACS while on chronic clopidogrel treatment are at higher risk for in-hospital and 30-day adverse outcomes, including stent thrombosis.

Keywords

Chronic clopidogrel therapy - ACS - stent thrombosis

• References

• 1 Alexander JH, Harrington RA, Tuttle RH. et al. Prior aspirin use predicts worse outcomes in patients with non-ST-elevation acute coronary syndromes. PURSUIT Investigators: Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy. Am J Cardiol 1999; 83: 1147-1151.
• 2 Chen WH, Lee PY, Ng W. et al. Aspirin resistance is associated with a high incidence of myonecrosis after non-urgent percutaneous coronary intervention despite clopidogrel pre-treatment. J Am Coll Cardiol 2004; 43: 1122-1126.
• 3 Antman EM, Cohen M, Bernink PJ. et al. The TIMI risk score for unstable angi-na/non-ST elevation MI: A method for prognostication and therapeutic decision making. J Am Med Assoc 2000; 284: 835-842.
• 4 Krasopoulos G, Brister SJ, Beattie WS. et al. Aspirin �resistance” and risk of cardiovascular morbidity: systematic review and meta-analysis. Br Med J 2008; 336: 195-198.
• 5 King 3rd SB, Smith Jr SC, Hirshfeld Jr JW et al.. 2007 Focused Update of the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: 2007 Writing Group to Review New Evidence and Update the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention, Writing on Behalf of the 2005 Writing Committee. Circulation 2008; 117: 261-295.
• 6 Tantry US, Gurbel PA. Antiplatelet drug resistance and variability in response: the role of antiplatelet therapy monitoring. Curr Pharm Des 2013; 19: 3795-3815.
• 7 Mega JL, Hochholzer W, Frelinger 3rd AL. et al. Dosing clopidogrel based on CYP2C19 genotype and the effect on platelet reactivity in patients with stable cardiovascular disease. J Am Med Assoc 2011; 306: 2221-2228.
• 8 Cutlip DE, Windecker S, Mehran R. et al. Academic Research Consortium. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007; 115: 2344-2351.
• 9 Garcia-Dorado D, Théroux P, Tornos P. et al. Previous aspirin use may attenuate the severity of the manifestation of acute ischaemic syndromes. Circulation 1995; 92: 1743-1748.
• 10 Borzak Sl, Cannon CP, Kraft PL. et al. Effects of prior aspirin and anti-is-chaemic therapy on outcome of patients with unstable angina. Am J Cardiol 1998; 81: 678-681.
• 11 Schreiber TL, Macina G, Bunnell P. et al. Unstable angina and non-Q-wave infarction despite long-term aspirin: response to thrombolytic therapy with implications on mechanisms. Am Heart J 1990; 120: 248-255.
• 12 Portnay EL, Foody JM, Rathore SS. et al. Prior aspirin use and outcomes in elderly patients hospitalized with acute myocardial infarction. J Am Coll Car-diol 2005; 46: 967-974.
• 13 Spencer FA, Santopinto JJ, Gore JM. et al. Impact of aspirin on presentation and hospital outcomes in patients with acute coronary syndromes (The Global Registry of Acute Coronary Events [GRACE]). Am J Cardiol 2002; 90: 1056-1061.
• 14 Matetzky S, Shenkman B, Guetta V. et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004; 109: 3171-3175.
• 15 Angiolillo DJ, Suryadevara S. Aspirin and clopidogrel: efficacy and resistance in diabetes mellitus. Best Pract Res Clin Endocrinol Metab 2009; 23: 375-388.
• 16 Cuisset T, Frere C, Quilici J. et al. Morange Relationship between aspirin and clopidogrel responses in acute coronary syndrome and clinical predictors of non response. Thromb Res 2009; 123: 597-603.
• 17 Asher E, Fefer P, Shechter M. et al. Increased mean platelet volume is associated with non-responsiveness to clopidogrel. Thromb Haemost 2014; 112: 137-141.
• 18 Beinart SC, Kolm P, Veledar E. et al. Long-term cost effectiveness of early and sustained dual oral antiplatelet therapy with clopidogrel given for up to one year after percutaneous coronary intervention results: from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial. J Am Coll Cardiol 2005; 46: 761-769.
• 19 Yusuf S, Zhao F, Mehta SR. et al. Clopidogrel in unstable angina to prevent recurrent events trial investigators. 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.
• 20 Arbel Y, Birati EY, Finkelstein A. et al. Platelet inhibitory effect of clopidogrel in patients treated with omeprazole, pantoprazole, and famotidine: A prospective, randomized, crossover study. Clin Cardiol 2013; 36: 342-346.
• 21 Lancaster GI, Lancaster CJ, Radley D. et al. Prior aspirin use in unstable angina predisposes to higher risk: the aspirin paradox. Int J Cardiol 2001; 80: 201-207.
• 22 Beigel R, Hod H, Fefer P. et al. Relation of aspirin failure to clinical outcome and to platelet response to aspirin in patients with acute myocardial infarction. Am J Cardiol 2011; 107: 339-342.
• 23 Gurbel PA, Antonino MJ, Bliden KP. et al. Platelet reactivity to adenosine dip-hosphate and long-term ischaemic event occurrence following percutaneous coronary intervention: a potential antiplatelet therapeutic target. Platelets 2008; 19: 595.
• 24 Gurbel PA, Bliden KP, Samara W. et al. Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST Study. J Am Coll Cardiol 2005; 46: 1827.
• 25 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.
• 26 Sibbing D, Braun S, Morath T. et al. Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis. J Am Coll Cardiol 2009; 53: 849.
• 27 Hurst NL, Nooney VB, Chirkov YY. et al. Determinants of subacute response to clopidogrel: relative impact of CYP2C19 genotype and PGE1/adenylate cyclase signalling. Thromb Res 2015; 136: 308-314.