Elsevier

American Heart Journal

Volume 154, Issue 2, August 2007, Pages 221-231
American Heart Journal

Curriculum in Cardiology
Clopidogrel nonresponsiveness in patients undergoing percutaneous coronary intervention with stenting: A systematic review and meta-analysis

https://doi.org/10.1016/j.ahj.2007.04.014Get rights and content

Background

Despite clopidogrel therapy, patients undergoing percutaneous coronary intervention (PCI) with stenting are at risk of recurrent coronary events. This could be partly explained by a reduced efficacy of clopidogrel to inhibit platelet aggregation, an ex vivo defined phenomenon called clopidogrel nonresponsiveness or resistance. However, both prevalence and associated cardiovascular risks remain unclear. We systematically reviewed evidence on prevalence and clinical consequences of laboratory clopidogrel nonresponsiveness in patients undergoing PCI.

Methods

Using predefined strategies, we searched electronic databases. To be included, articles should report on PCI patients treated with clopidogrel, contain a clear description of the method used to establish the effects of clopidogrel, and report the prevalence of clopidogrel nonresponsiveness or incidence of cardiovascular events. We analyzed prevalences with a linear mixed model that accounts for study covariates and we pooled odds ratios of clinical consequences with a random-effects model.

Results

We identified 25 eligible studies that included a total of 3688 patients. Mean prevalence of clopidogrel nonresponsiveness was 21% (95% CI, 17%-25%) and was inversely correlated with time between clopidogrel loading and determination of nonresponsiveness and used loading dose. The pooled odds ratio of cardiovascular outcome was 8.0 (95% CI, 3.4-19.0).

Conclusions

Laboratory clopidogrel nonresponsiveness can be found in approximately 1 in 5 patients undergoing PCI. Patients ex vivo labeled nonresponsive are likely to be also “clinically nonresponsive,” as they exhibit increased risks of worsened cardiovascular outcomes. Our results indicate that use of a 600-mg clopidogrel loading dose will reduce these risks, which needs to be confirmed in large prospective studies.

Section snippets

Methods

We searched MEDLINE (from January 1966 until October 2006), EMBASE (from January 1974 until October 2006), the Cochrane Central Register of Controlled trials (CENTRAL) (from 1800 until October 2006), and Web of Science (from 1945 until October 2006), using predefined search terms (Appendix A). We used no language restrictions. Furthermore, we searched reference lists of relevant studies and reading reviews, editorials, and letters on this topic. Authors of identified appropriate studies were

Results

By subsequent screening and assessment of titles, abstracts, and full-text articles, we included 25 studies that incorporated a total of 3688 patients (Figure 1). Nineteen full-text articles13, 14, 15, 16, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36 and 3 meeting abstracts37, 38, 39 (2574 patients) addressed the prevalence of laboratory clopidogrel nonresponsiveness in patients undergoing PCI, whereas clinical consequences were studied in 10 full-text articles14, 25, 31, 32, 33,

Discussion

Among studies in patients on clopidogrel to prevent cardiovascular events after PCI, our meta-analysis showed an overall prevalence of 21% of laboratory-defined clopidogrel nonresponsiveness. A wide range of prevalences was found, which is largely explained by differences in time between clopidogrel loading and determination of nonresponsiveness and loading dose of clopidogrel used. Our findings indicate that patients ex vivo labeled clopidogrel resistant have an increased risk of stent

References (53)

  • T. Cuisset 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 syndrome undergoing coronary stenting

    J Am Coll Cardiol

    (2006)
  • E.I. Lev et al.

    Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention: the role of dual drug resistance

    J Am Coll Cardiol

    (2006)
  • P.A. Gurbel et al.

    Clopidogrel Effect on Platelet REactivity in Patients With Stent Thrombosis: results of the CREST study

    J Am Coll Cardiol

    (2005)
  • P.A. Gurbel et al.

    Platelet reactivity in patients and recurrent events post-stenting: results of the PREPARE POST-STENTING study

    J Am Coll Cardiol

    (2005)
  • W. Hochholzer 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)
  • G. Montalescot et al.

    A randomized comparison of high clopidogrel loading doses in patients with non–ST-segment elevation acute coronary syndromes: the ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) trial

    J Am Coll Cardiol

    (2006)
  • T.A. Nguyen et al.

    Resistance to clopidogrel: a review of the evidence

    J Am Coll Cardiol

    (2005)
  • P.W. Serruys et al.

    A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease

    N Engl J Med

    (1994)
  • D.L. Fischman et al.

    A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease

    N Engl J Med

    (1994)
  • D.E. Cutlip et al.

    Stent thrombosis in the modern era : a pooled analysis of multicenter coronary stent clinical trials

    Circulation

    (2001)
  • G.N. Levine et al.

    Management of patients undergoing percutaneous coronary revascularization

    Ann Intern Med

    (2003)
  • P. Savi et al.

    Clopidogrel and ticlopidine: P2Y12 adenosine diphosphate-receptor antagonists for the prevention of atherothrombosis

    Semin Thromb Hemost

    (2005)
  • D. Woulfe et al.

    ADP and platelets: the end of the beginning

    J Clin Invest

    (2001)
  • S.R. Steinhubl et al.

    Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial

    JAMA

    (2002)
  • M.S. Sabatine et al.

    Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study

    JAMA

    (2005)
  • S.D. Wiviott et al.

    Clopidogrel resistance: a new chapter in a fast-moving story

    Circulation

    (2004)
  • Cited by (384)

    • Antiplatelet Therapy for Secondary Prevention of Stroke

      2021, Stroke: Pathophysiology, Diagnosis, and Management
    View all citing articles on Scopus
    View full text