doi: 10.1161/CIRCULATIONAHA.108.857722
(Circulation. 2009;119:2854-2857.)
© 2009 American Heart Association, Inc.
Clinician Update |
Can We Override Clopidogrel Resistance?
From the Institut de Cardiologie, INSERM 937, Université Paris 6 (A.P., J.-P.C., J.S., O.B., F.B., G.M.), and Service de Pharmacologie, Unité de Pharmacogénétique, INSERM 956 (J.-S.H., C.F.-B.), Hôpital Pitié-Salpêtrière (AP-HP), Paris, France.
Correspondence to Gilles Montalescot, MD, PhD, Bureau 236, Institut de Cardiologie, Hôpital Pitié-Salpêtrière, 47 Boulevard de l'Hôpital, 75013, Paris, France. E-mail gilles.montalescot{at}psl.aphp.fr
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Clopidogrel, a thienopyridine antiplatelet agent, has been used alone or in association with aspirin to prevent vascular complications in atherothrombotic patients. It is also, in combination with aspirin, the key treatment to prevent stent thrombosis in patients who have undergone percutaneous coronary intervention. It is estimated that >40 million patients worldwide receive clopidogrel. Recent investigations into genetic mechanisms that influence clopidogrel efficacy suggest that a common variant present in
30% of whites has the potential to identify patients with a deficient clopidogrel metabolic activation who are consequently at risk of recurrent cardiovascular events, including stent thrombosis.1–3 Stent thrombosis is the most serious complication of coronary stent implantation, often leading to empiric modifications of antiplatelet treatments, although stent thrombosis pathogenesis is complex and the weight of the various factors involved is not known.4 We report 7 recent cases of stent thrombosis with demonstrated platelet resistance to clopidogrel, and we describe a novel clinical approach using pharmacodynamic and genetic information to override clopidogrel resistance. |
Clinical Cases |
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Patient Selection and Characteristics
The clinical characteristics of 7 patients who presented with stent thrombosis on clopidogrel treatment (75 mg maintenance dose [MD]) are presented in the Table. Stent thrombosis was angiographically proven in all patients and occurred on days 1, 3, 5, 6 (2 patients), 11, and 70, with a median time from stent implantation to stent occlusion of 6 days (interquartile range, 4 to 8.5 days). Clinical presentation was ST-elevation myocardial infarction in all cases, and 4 of 7 patients had a history of myocardial infarction. Stent thrombosis occurred in 6 patients with a bare metal stent and 1 patient with a drug-eluting stent. Primary percutaneous coronary intervention revascularization of stent thrombosis was performed with a new bare metal stent in 6 patients; in the remaining patient, a drug-eluting stent was implanted.
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Laboratory Procedures
Platelet aggregation studies were performed in all patients in the same laboratory as previously described.5 Aspirin and clopidogrel pharmacodynamic responses were evaluated with light transmission aggregometry (arachidonic acid 1.25 µmol/L and ADP 20 µmol/L; results expressed in percent residual platelet aggregation [RPA]) and with the VerifyNow assay (results expressed in aspirin reaction units with the aspirin cartridge and P2Y12 reaction units and percent inhibition with the P2Y12 cartridge). Aspirin resistance was defined either by an RPA >20% with arachidonic acid or by an aspirin reaction unit 
550. Clopidogrel resistance was defined by an RPA 50% or a P2Y12 reaction unit 235 (or percent of inhibition 
15%). These cutoff values also were used to guide treatment strategies.
Genotyping was performed in all patients, with only the 2C19 alleles tested. Genomic DNA was extracted from peripheral blood leukocytes by use of standard procedures (Puregene DNA isolation kit, Merck Eurolab, Hamburg, Germany). CYP2C19*2 (681G>A; rs4244285) was genotyped with a commercially available validated drug metabolism genotyping assay (TaqMan Validated SNP assays C_25986767_70, Applied Biosystems, Foster City, Calif) with the 7900HT sequence Detection System (Applied Biosystems).
Response to Clopidogrel and Management
Only 1 patient had a poor response to aspirin, and his daily MD was increased from 100 to 200 mg. All 7 patients resistant to a 75-mg MD of clopidogrel were loaded with 900 mg when they were admitted with stent thrombosis and discharged on 150-mg MD. Patients were retested 3 weeks later, and resistance to 150-mg MD of clopidogrel was found again in the 7 patients with both assays (Figure 1). All patients except 1 were found to be carriers of the genetic variant 2C19*2 (5 heterozygous, 1 homozygous), indicating a poor metabolizer profile. To check treatment compliance, a new loading dose of 900 mg clopidogrel also was administered in 4 patients in whom percent of inhibition <5% with the VerifyNow P2Y12 assay and the RPA was >50% (Figure 1). Four hours after the load, 2 patients remained fully resistant, whereas the other 2 patients had a mild increase in platelet inhibition (Figure 1). The daily MD of clopidogrel was increased to 225 mg in all patients except 1 who was >80 years of age with a prior history of stroke.
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Three weeks later, resistance to 225-mg MD was found again in 4 of the 6 patients, leading to an increase in the daily MD of clopidogrel to 300 mg in these patients. Three weeks later, 2 patients were still resistant, and 2 had improved platelet inhibition; however, side effects (stomach discomfort and joint pain) did not allow prolongation of such a high MD in these 2 patients. Compassionate use of prasugrel (authorization of temporary use) was sought from the French drug agency (Agence Française de Sécurité Sanitaire pour les Produits de Santé) in 6 of the 7 patients. The last patient died of a new ST-elevation myocardial infarction resulting from recurrent stent thrombosis before the request was sent to the agency. The authorization was obtained for 4 of the 6 patients, and 2 demands were rejected: 1 because of low body weight and 1 for age >75 years. Prasugrel was initiated at 10-mg MD without loading in the 4 resistant patients. Four weeks later, the 4 patients were reevaluated, and all had an optimal response to all tests performed (Figure 1).
Figure 2 shows light transmission aggregometry curves in 1 patient, a carrier of 1 allele of the CYP2C19*2 variant who was resistant to all MDs ranging from 75 to 300 mg and to acute reloading with 900 mg, demonstrating that out-of-hospital compliance to treatment was not the issue. In this case, increasing the dose of clopidogrel did not override the effect of the CYP2C19*2, whereas a 10-mg MD of prasugrel did.
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It has been suggested that in many patients hyporesponsive to a 75-mg MD of clopidogrel, increasing the MD to 150 mg can overcome the poor initial pharmacodynamic response. However, such a strategy appears to work in only 40% of diabetics, a group of patients exposed to frequent vascular ischemic events.6 Stent thrombosis also has been related to inadequate pharmacodynamic response to clopidogrel, and an important clinical question is whether such resistance to clopidogrel is a modifiable factor.7 We report here a series of patients on clopidogrel treatment accumulating clinical resistance (stent thrombosis), biological resistance (high platelet aggregation), and a genetic profile of resistance (2C19*2 genetic variant in 6 of the 7 patients). Our report shows that a strategy of an incremental increase in the clopidogrel MD in such patients is time consuming and minimally effective. Daily MDs of clopidogrel as high as 225 mg were ineffective in the majority of our patients. Increasing the clopidogrel MD up to 300 mg slightly improved platelet inhibition in a dose-effect manner, but only 2 patients became responders to 300 mg daily, and they had side effects precluding continuation of treatment at this dose regimen. All patients who were switched to prasugrel had an impressive and significant improvement in platelet inhibition with all tests used, and there have been no bleeding or side effect concerns over a 3-month period of exposure. Because patients were their own controls for the different MDs of clopidogrel and for prasugrel, the pharmacodynamic information provided here appears to be reliable and important.
A large part (80%) of the prodrug clopidogrel is transformed by esterases into inactive metabolites. The conversion of clopidogrel to its active metabolite is a 2-step process involving several cytochrome P450 (CYP) enzymes, and the activity of these CYP enzymes varies considerably between individuals. The loss of function associated with the CYP2C19*2 polymorphism is associated with inactivation of the enzyme and impaired metabolism of clopidogrel, leading to poor response to the drug.8 Prasugrel, the new thienopyridine, is not inactivated by esterases and depends less on CYP2C19 oxidation than clopidogrel. Recent studies have provided compelling new data that underscore the major importance of the CYP2C19*2 polymorphism on clinical outcome of clopidogrel-treated patients, with a rate of stent thrombosis that was greater by a factor 3 to 6 than the rate in noncarriers of the CYP2C19*2 genetic variant.1–3 The rate of carriers is 30% in the general white population compared with 85% in our small series, with 5 patients heterozygous (*1/*2) and 1 homozygous (*2/*2). So far, no study has shown the benefit of systematic genotyping to identify CYP2C19*2 carriers and contribute to risk stratification and choice in treatment options for coronary patients. However, our report, focusing on a highly selected group of patients who survived an episode of stent thrombosis and exhibited a poor functional response to clopidogrel, suggests that systematic genotyping combined with platelet functional testing may help physicians choose the optimal antiplatelet strategy. While we wait for randomized studies demonstrating the clinical benefit of tailored antiplatelet therapy on the basis of functional and/or genetic tests, our practical report is the first attempt of such guided strategy in a group of very-high-risk patients exposed to potentially fatal recurrence caused by ineffectiveness of standard therapy. Nowadays, this pharmacogenetic and pharmacodynamic information can be easily obtained and could be useful in many situations involving high-risk vascular patients who can no longer afford clopidogrel failure.
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Acknowledgments |
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We are grateful to E. Villard, G. Anzaha, D. Brugier, and S. Galier for their expert technical assistance.
Sources of Funding
This study was sponsored by the Fédération Française de Cardiologie and INSERM.
Disclosures
Dr Montalescot has received research grants (to the institution) from Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly, Guerbet Medical, Medtronic, Boston Scientific, Cordis, Stago, Centocor, Fondation de France, INSERM, Fédération Française de Cardiologie, and Société Française de Cardiologie; consulting fees from Sanofi-Aventis, Eli Lilly, Bristol-Myers Squibb, The Medicines Co, and Schering Plough; and lectures fees from Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly, Merck Sharpe & Dohme, Cordis, GlaxoSmithKline, and Schering Plough. Dr Collet has received research grants from Bristol-Myers Squibb, Sanofi -Aventis, Eli Lilly, Guerbet Medical, Medtronic, Boston Scientific Co, Cordis, Stago, Centocor, Fondation de France, INSERM, Federation Francaise de Cardiologie, and Societe Francaise de Cardiologie; consulting fees from Sanofi-Aventis, Eli Lilly, and Bristol-Myers Squibb; and lecture fees from Bristol-Myers Squibb, Sanofi-Aventis, and Eli Lilly. Dr Hulot has received research grants from Fondation de France, INSERM, and consulting fees from Sanofi-Aventis and Eli Lilly. The other authors report no conflicts.
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References |
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2. Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009; 360: 354–362.
3. Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J, Payot L, Brugier D, Cayla G, Beygui F, Bensimon G, Funck-Brentano G, Montalescot G. Cytochrome P450 2c19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet. 2009; 373: 309–317.[CrossRef][Medline] [Order article via Infotrieve]
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5. Collet JP, Silvain J, Landivier A, Tanguy Ml, Cayla G, Bellemain A, Vignolles N, Gallier S, Beygui F, Pena A, Montalescot G. Dose effect of clopidogrel reloading in patients already on 75-mg maintenance dose: the Reload With Clopidogrel Before Coronary Angioplasty in Subjects Treated Long Term With Dual Antiplatelet Therapy (RELOAD) study. Circulation. 2008; 118: 1225–1233.
6. Angiolillo DJ, Shoemaker SB, Desai B, Yuan H, Charlton RK, Bernardo E, Zenni MM, Guzman LA, Bass TA, Costa MA. Randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (Optimus) Study. Circulation. 2007; 115: 708–716.
7. Marcucci R, Gori AM, Paniccia R, Giusti B, Valente S, Giglioli C, Buonamici P, Antoniucci D, Abbate R, Gensini GF. 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.
8. Hulot JS, Bura A, Villard E, Azizi M, Remones V, Goyenvalle C, Aiach M, Lechat P, Gaussem P. Cytochrome P450 2c19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood. 2006; 108: 2244–2247.
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  G. Montalescot, J.-S. Hulot, and J.-P. Collet Stent thrombosis: who's guilty? Eur. Heart J., November 2, 2009; 30(22): 2685 - 2688. [Full Text] [PDF]
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