Clopidogrel non-responsiveness and risk of cardiovascular morbidity

Francesco Sofi; Rossella Marcucci; Anna Maria Gori; Betti Giusti; Rosanna Abbate; Gian Franco Gensini

doi:10.1160/TH09-06-0418

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2010; 103(04): 00
DOI: 10.1160/TH09-06-0418

New Technologies, Diagnostic Tools and Drugs

Schattauer GmbH

Clopidogrel non-responsiveness and risk of cardiovascular morbidity

An updated meta-analysis

Authors

Francesco Sofi

¹Department of Medical and Surgical Critical Care, Thrombosis Centre, University of Florence, Azienda Ospedaliero–Universitaria Careggi, Florence, Italy

²Centre for the Study at Molecular and Clinical Level of Chronic, Degenerative and Neoplastic Diseases to Develop Novel Therapies, University of Florence, Italy

³Don Carlo Gnocchi Foundation, IRCCS, Florence, Italy
Rossella Marcucci

¹Department of Medical and Surgical Critical Care, Thrombosis Centre, University of Florence, Azienda Ospedaliero–Universitaria Careggi, Florence, Italy
Anna Maria Gori

¹Department of Medical and Surgical Critical Care, Thrombosis Centre, University of Florence, Azienda Ospedaliero–Universitaria Careggi, Florence, Italy

²Centre for the Study at Molecular and Clinical Level of Chronic, Degenerative and Neoplastic Diseases to Develop Novel Therapies, University of Florence, Italy

³Don Carlo Gnocchi Foundation, IRCCS, Florence, Italy
Betti Giusti

¹Department of Medical and Surgical Critical Care, Thrombosis Centre, University of Florence, Azienda Ospedaliero–Universitaria Careggi, Florence, Italy
Rosanna Abbate

¹Department of Medical and Surgical Critical Care, Thrombosis Centre, University of Florence, Azienda Ospedaliero–Universitaria Careggi, Florence, Italy
Gian Franco Gensini

¹Department of Medical and Surgical Critical Care, Thrombosis Centre, University of Florence, Azienda Ospedaliero–Universitaria Careggi, Florence, Italy

²Centre for the Study at Molecular and Clinical Level of Chronic, Degenerative and Neoplastic Diseases to Develop Novel Therapies, University of Florence, Italy

³Don Carlo Gnocchi Foundation, IRCCS, Florence, Italy

Abstract

Summary

We performed this meta-analysis to update the clinical evidences on the relation between clopidogrel non-responsiveness and clinical outcomes in patients with coronary artery disease (CAD) who underwent percutaneous coronary intervention. An electronic literature search through MEDLINE, EMBASE, Web of Science, and the Cochrane Library and bibliographies of retrieved articles up to January, 2009 was conducted. Studies were included if they had a cohort prospective design, if they analysed clopidogrel responsiveness in CAD patients in relation to death and/or occurrence of adverse coronary events during follow-up, and if they reported an adequate statistical analysis. Fourteen studies, totalling 4,564 CAD patients followed for a time ranging from 14 days to one year, were included. The cumulative analysis reported that residual platelet reactivity despite clopidogrel treatment was significantly associated with an increased risk of death and/or thrombotic recurrences (odds ratio [OR] 5.67, 95% confidence interval [CI] 2.97 to 10.84; p<0.00001). However, four studies contributed to a consistent heterogeneity of the model and evidenced a significant risk of publication bias, so were excluded from the analysis. This exclusion, however, did not influence the overall result, by confirming the increased risk of cardiovascular recurrences for patients with a poor response to clopidogrel treatment (OR 3.58, 95%CI 2.54 to 5.05; p<0.00001). The present updated meta-analysis documents a significant association between residual platelet reactivity under clopidogrel treatment and recurrent cardiovascular events, so suggesting the relevance of ongoing interventional studies aimed at tailoring the antithrombotic therapy in CAD patients.

Keywords

Clopidogrel - antiplatelet therapy - clinical recurrences - meta-analysis

Full Text

References

References
1 CAPRIE Steering Committee.. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: 71-86.
2 Yusuf S, Zhao F, Mehta SR. et al. 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.
3 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.
4 Chen ZM, Jiang LX, Chen YP. et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005; 366: 1607-1621.
5 Sabatine MS, Cannon CP, Gibson CM. et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005; 352: 1179-1189.
6 Ferguson AD, Dokainish H, Lakkis N. Aspirin and clopidogrel response variability. Tex Heart Inst J 2008; 35: 313-320.
7 Sofi F, Marcucci R, Gori AM. et al. Residual platelet reactivity on aspirin therapy and recurrent cardiovascular events. A meta-analysis. Int J Cardiol 2008; 128: 166-171.
8 Snoep JD, Hovens MMC, Eikenboom JCJ. et al. Clopidogrel nonresponsiveness in patients undergoing percutaneous coronary intervention with stenting: a systematic review and meta-analysis. Am Heart J 2007; 154: 221-231.
9 Muller I, Besta F, Schulz C. et al. Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb Haemost 2003; 89: 783-787.
10 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: 3064-3067.
11 Gurbel PA, Bliden KP, Guyer K. et al. Platelet reactivity in patients and recurrent events post-stenting. Results of the PREPARE POST-STENTING Study. J Am Coll Cardiol 2005; 46: 1820-1826.
12 Cuisset T, Frere C, Quilici J. et al. High post-treatment platelet reactivity identified low-responders to dual antiplatelet therapy at increased risk of recurrent cardiovascular events after stenting for acute coronary syndromes. J Thromb Haemost 2006; 04: 542-549.
13 Cuisset T, Frere C, Quilici J. et al. Benefit of a 600-mg loading dose of clopidogrel on platelet reactivity and clinical outcomes in patients with non-ST-segment elevation acute coronary sindrome undergoing coronary stenting. J Am Coll Cardiol 2006; 48: 1339-1345.
14 Geisler T, Langer H, Wydymus M. et al. Low response to clopidogrel is associated with cardiovascular outcome after coronary implantation. Eur Heart J 2006; 27: 2420-2425.
15 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.
16 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.
17 Frere C, Cuisset T, Quilici J. et al. ADP-induced platelet aggregation and platelet reactivity index VASP are good predictive markers for clinical outcomes in nonST elevation acute coronary syndrome. Thromb Haemost 2007; 98: 838-843.
18 Blindt R, Stellbrink K, de Taeye A. et al. The significance of vasodilator-stimulated phosphoprotein for risk stratification of stent thrombosis. Thromb Haemost 2007; 98: 1329-1334.
19 Price MJ, Endemamm 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.
20 Patti G, Nusca A, Mangiacapra F. et al. Point-of-care measurement of clopidogrel responsiveness predicts clinical outcome in patients undergoing percutaneous coronary intervention. J Am Coll Cardiol 2008; 52: 1128-1133.
21 Wang ZJ, Zhou YJ, Liu YY. et al. Impact of clopidogrel resistance on thrombotic events after percutaenous coronary intervention with drug-eluting stent. Thromb Res. 2008 doi:10.1016/j.thromres.2008.10.007
22 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.
23 Buch AN, Singh S, Roy P. et al. Measuring aspirin resistance, clopidogrel responsiveness, and postprocedural markers of myonecrosis in patients undergoing percutaneous coronary intervention. Am J Cardiol 2007; 99: 1518-1522.
24 Gori AM, Marcucci R, Migliorini A. et al. Impact and clinical impact of dual non-responsiveness to aspirin and clopidogrel in patients with drug-eluting stents. J Am Coll Cardiol 2008; 52: 734-739.
25 Giusti B, Gori AM, Marcucci R. et al. Cytochrome P450 2C19 loss-of-function polymorphism, but not CYP3A4 IVS10 + 12G/A and P2Y₁₂ T744C polymorphisms, is associated with response variability to dual antiplatelet treatment in high-risk vascular patients. Pharmacogenet Genomics 2007; 17: 1057-1064.
26 Mega JL, Close SL, Wiviott SD. et al. Cytochrome P450 polymorphisms and response to clopidogrel. N Engl J Med. 2009 epub ahead of print.
27 Simon T, Verstuyft C, Mary-Krause M. et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med. 2009 epub ahead of print.
28 Muller I, Seyfarth M, Rudiger S. et al. Effect of a high loading dose of clopidogrel on platelet function in patients udergoing coronary stent placement. Heart 2001; 85: 92-93.
29 Wolfram RM, Torguson RL, Hassani SE. et al. Clopidogrel loading dose (300 versus 600 mg) strategies for patients with stable angina pectoris subjected to percutaneous coronary intervention. Am J Cardiol 2006; 97: 984-989.