CORRESPONDENCE: LETTER TO THE EDITOR
Switching Thienopyridines: Hypothetical Versus Real Risks
Victor L. Serebruany*
* HeartDrug Research Laboratories, Johns Hopkins University, 7600 Osler Drive, Suite 307, Towson, Maryland 21204 (Email: heartdrug{at}aol.com).
I enjoyed reading the quality paper by Campo et al. (1) that tried to determine whether platelet response after thienopyridines is drug or class specific in a broad spectrum of post-stent patients. The team should be acknowledged for the effort and for realistic rates for low response after clopidogrel (21%), and ticlopidine (19%). The major take-home message conveyed to the readership is that clopidogrel-treated patients may be switched to ticlopidine if "resistance" is determined by the platelet tests. However, the practical implications of this idea are not obvious, may be dangerous, may not be supported by clinical or epidemiologic evidence, and deserve at least some clarification and/or adjustment.
In fact, low response to clopidogrel as a major risk factor for the worsened vascular outcomes has been suspected but never proven to be a real clinical phenomena, especially considering that no load 75 mg clopidogrel saved 119 lives, and provided an absolute mortality benefit after myocardial infarction in COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial) (2). Also, none of the small observation studies monitor compliance by measuring clopidogrel metabolites in plasma. Therefore, "clopidogrel resistance" is a laboratory finding, rather than a clinically relevant hazard unless further randomized evidence became available (3).
On the other hand, substituting clopidogrel with ticlopidine definitely increases the bone marrow toxicity risks. Indeed, neutropenia and thrombocytopenia were 2-fold higher in the ticlopidine arm than in patients treated with clopidogrel in CLASSICS (Clopidogrel Aspirin Stent International Cooperative Study) (4). Doubled cytotoxicity rates after ticlopidine were confirmed in a post-stent study (5) and a recent meta-analysis of 11,668 patients (6). Therefore, the suggestion that in case of low platelet response after clopidogrel patients should be switched to ticlopidine is not valid. Unless there is proof that response after clopidogrel is indeed linked to the clinical outcomes, monitoring compliance and potential tailoring of dual antiplatelet regimens with aspirin and clopidogrel will be a safer alternative than switching thienopyridines.
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1. Campo G, Valgimigli M, Gemmati D, et al. Poor responsiveness to clopidogrel: drug-specific or class-effect mechanism?Evidence from a clopidogrel-to-ticlopidine crossover study. J Am Coll Cardiol 2007;50:1132-1137.[Abstract/Free Full Text]2. Chen ZM, Jiang LX, Chen YP, et al. COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial) Collaborative Group Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial Lancet 2005;366:1607-1621.[CrossRef][Web of Science][Medline] 3. Serebruany VL. The "clopidogrel resistance" trap Am J Cardiol 2007;100:1044-1046.[CrossRef][Medline] 4. Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH, CLASSICS Investigators Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS) Circulation 2000;102:624-629.[Abstract/Free Full Text] 5. Moussa I, Oetgen M, Roubin G, et al. Effectiveness of clopidogrel and aspirin versus ticlopidine and aspirin in preventing stent thrombosis after coronary stent implantation Circulation 1999;99:2364-2366.[Abstract/Free Full Text] 6. Casella G, Ottani F, Pavesi PC, et al. Safety and efficacy evaluation of clopidogrel compared to ticlopidine after stent implantation: an updated meta-analysis Ital Heart J 2003;4:677-684.[Medline]
Related Article
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Reply
- Marco Valgimigli and Gianluca Campo
J. Am. Coll. Cardiol. 2008 51: 775-776.
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