Thienopyridine-Associated Drug-Drug Interactions: Pharmacologic Mechanisms and Clinical Relevance

The thienopyridines inhibit platelet activation and aggregation by directly inhibiting the platelet P2Y12 adenosine diphosphate receptor. The available thienopyridines are prodrugs and must be converted into active forms by the cytochrome P450 (CYP) enzyme system. An important portion of the variability in platelet response to clopidogrel is explained by the variability in plasma concentrations of the clopidogrel active metabolite. Several reports have thus progressively raised concerns about potential drug interactions as a result of inhibition or induction of CYP450 enzymes. Pharmacokinetics and pharmacodynamics studies have notably shown that concomitant use of clopidogrel and some proton pump inhibitors reduces the antiplatelet effect of clopidogrel. Several other drugs (metabolized through CYP3A4 such as statins or antifungals) similarly impact the pharmacologic response to clopidogrel. Conversely, agents that induce CYP activity increase clopidogrel responsiveness. However, the data supporting the clinical relevance of such pharmacological drug interactions have been controversial. This review will provide an overview of the mechanisms underlying thienopyridine-associated drug-drug interactions, and highlight the most recent developments in the field and propose guidance for the practitioner.     

Resistance to clopidogrel: a review of the evidence

Current available data show that about 4% to 30% of patients treated with conventional doses of clopidogrel do not display adequate antiplatelet response. Clopidogrel resistance is a widely used term that remains to be clearly defined. So far, it has been used to reflect failure of clopidogrel to achieve its antiaggregatory effect. The interpatient variability in clopidogrel response is multifactorial. It can be due to extrinsic or intrinsic mechanisms. Among extrinsic mechanisms are the possibility of clopidogrel underdosing in patients undergoing stenting or with acute coronary syndrome, and drug-drug interactions involving CYP3A4. Intrinsic mechanisms include genetic polymorphisms of the P2Y(12) receptor and of the CYP3As, accrued release of adenosine diphosphate, or up-regulation of other platelet activation pathways. Presently, there is no definite demonstration of an association between low responsiveness to clopidogrel and thrombotic events. The optimal level of clopidogrel-induced platelet inhibition, which will correlate quantitatively with clopidogrel's ability to prevent atherothrombotic events is still lacking. Furthermore, because there is no single and validated platelet function assay to measure clopidogrel's antiplatelet effect, it is not justified to routinely look for clopidogrel resistance in the clinical setting. This review discusses currently available evidence surrounding the variability in the antiplatelet response to clopidogrel.     

Options to overcome clopidogrel response variability

Oral antiplatelet agents targeting the platelet P2Y12 receptor are an integral component of treating patients with acute coronary syndrome and those undergoing percutaneous coronary intervention. Clopidogrel has been the most commonly used agent in this respect worldwide. However, there are certain shortcomings of clopdiogrel, the most important of which is the wide response variability of platelet inhibition. The response to clopidogrel is affected by various clinical variables, genetic variations involved in its activation, and drug-drug interactions. Therefore, clinicians are faced with challenges in situations where high inhibition of platelets is necessary and in cases where the response to clopidogrel may be suboptimal. There are various ways of overcoming the response variability and this review will focus on the practical methods available. Namely, the data and evidence regarding increasing the dose of clopidogrel, adding cilostazol to standard dual antiplatelet therapy, and switching to more recently developed agents will be covered.     

Treatment of overactive bladder: selective use of anticholinergic agents with low drug-drug interaction potential

Overactive bladder (OAB) is highly prevalent in the older population and decreases quality of life. Current therapy consists primarily of anticholinergic drugs. Because older individuals typically take multiple medications, clinicians must pay special attention to potential drug-drug interactions that may cause adverse events or alter drug efficacy. The most clinically important drug-drug interactions occur during cytochrome P450 (CYP450) isoenzyme metabolism, resulting in altered metabolism of one or more of the coadministered agents. Of the drugs indicated for OAB, tolterodine, darifenacin, solifenacin, and oxybutynin are extensively metabolized by CYP450, but trospium is not. Trospium is eliminated as unchanged drug, suggesting that it has lower potential for drug-drug interactions and may, therefore, represent a safer treatment option for OAB, particularly in the context of polypharmacy, a significant concern in older adults.     

Drug insight: Clopidogrel nonresponsiveness

Platelet reactivity to agonists and subsequent activation are important factors that affect the development of atherothrombosis and resultant ischemic events. Pharmacologic intervention with clopidogrel and aspirin during acute coronary syndromes and percutaneous coronary intervention is considered the gold standard for attenuating platelet activation and aggregation. Despite significant benefits reported with dual antiplatelet treatment in major clinical trials, the occurrence of adverse ischemic events, including stent thrombosis, remains a serious clinical problem. Nonresponsiveness, also called resistance, to current clopidogrel regimens might play a part in the occurrence of ischemic events. Various mechanisms have been implicated in nonresponsiveness to clopidogrel, including variability in intestinal absorption and hepatic conversion to the active metabolite, drug-drug interactions and receptor polymorphisms. Increased loading and maintenance doses and the use of new and more-potent P2Y12-receptor blockers might overcome the phenomenon of clopidogrel nonresponsiveness. The aim of this article is to provide a comprehensive and current review of clopidogrel response variability and nonresponsiveness.     

Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects

The capacity of clopidogrel to inhibit ADP-induced platelet aggregation shows wide intersubject variability. To determine whether frequent functional variants of genes coding for candidate cytochrome P450 (CYP) isoenzymes involved in clopidogrel metabolic activation (CYP2C19*2, CYP2B6*5, CYP1A2*1F, and CYP3A5*3 variants) influence the platelet responsiveness to clopidogrel, we conducted a prospective pharmacogenetic study in 28 healthy white male volunteers treated for 7 days with clopidogrel 75 mg/d. We observed that pharmacodynamic response to clopidogrel was significantly associated with the CYP2C19 genotype. Twenty of the subjects were wild-type CYP2C19 (*1/*1) homozygotes, while the other 8 subjects were heterozygous for the loss-of-function polymorphism CYP2C19*2 (*1/*2). Baseline platelet activity was not influenced by the CYP2C19 genotype. In contrast, platelet aggregation in the presence of 10 muM ADP decreased gradually during treatment with clopidogrel 75 mg once daily in *1/*1 subjects, reaching 48.9% +/- 14.9% on day 7 (P < .001 vs baseline), whereas it did not change in *1/*2 subjects (71.8% +/- 14.6% on day 7, P = .22 vs baseline, and P < .003 vs *1/*1 subjects). Similar results were found with VASP phosphorylation. The CYP2C19*2 loss-of-function allele is associated with a marked decrease in platelet responsiveness to clopidogrel in young healthy male volunteers and may therefore be an important genetic contributor to clopidogrel resistance in the clinical setting.     

血小板功能检测与P2Y12受体拮抗剂个体化抗血小板治疗的研究进展

P2Y12受体拮抗剂广泛应用于急性冠脉综合征（ACS）及经皮冠状动脉介入治疗（PCI）后血栓事件的预防。由于抗血小板治疗反应多样性的存在,经典的P2Y12受体拮抗剂氯吡格雷的治疗期间高血小板反应性（HTPR）被证实与患者不良心血管事件的发生密切相关。尽管新药普拉格雷和替格瑞洛的抗栓疗效优于氯吡格雷,但是由于治疗期间低血小板反应性（LTPR）的存在,出血风险明显增加。如何权衡血栓和出血风险,实现个体化抗血小板治疗,已经成为临床的重要挑战。研究证实,血小板反应性（PR）与缺血和出血事件的发生密切有关,基于血小板功能检测（PFT）的治疗窗将有助于个体化抗血小板治疗。本文就PFT与P2Y12受体拮抗剂个体化抗血小板治疗的研究进展作一综述。     

Personalized Antiplatelet Therapy: Review of the Latest Clinical Evidence

P2Y12-ADP receptor antagonist use has been critical in the development of percutaneous coronary intervention, dramatically reducing the rate of early stent thrombosis. However, it recently was observed that a significant proportion of patients do not achieve optimal platelet reactivity inhibition after clopidogrel loading dose. The large interindividual variability in clopidogrel responsiveness is related to several factors, including the genetic polymorphism of hepatic cytochrome P450 2C19 (CYP2C19*2), which recently has been highlighted by a warning from the U.S. Food and Drug Administration. Of importance, patients exhibiting reduced clopidogrel metabolism and/or low clopidogrel responsiveness (ie, high on-treatment platelet reactivity) have an increased rate of thrombotic events after percutaneous coronary intervention. This review summarizes the current knowledge on this important clinical issue. While the future of genetic testing remains undetermined, several trials are underway to demonstrate the potential utility of platelet reactivity testing with P2Y12-ADP receptor antagonists.     

'Fire and forget?' - pharmacological considerations in coronary care

The potential risk of drug-drug interactions is often overlooked during drug therapy selection. Multiple risk factors for drug-drug interactions exist in both the acute and chronic phases of acute coronary syndrome (ACS), including concomitant medications and underlying diseases. Some statins have been used for secondary prevention of coronary heart disease (CHD) in these patients and are not all equivalent in their susceptibility to drug-drug interactions. The lipophilic drugs lovastatin, simvastatin, atorvastatin, cerivastatin and fluvastatin are metabolized via the cytochrome P450 (CYP450) system in the liver and the gut, making them subject to potential interactions with concomitantly administered drugs that are competing for metabolism via this system. Clinically important interactions with simvastatin or lovastatin and drugs that inhibit the 3A4 isoenzyme (part of the CYP450 system) may result in myopathy and rhabdomyolysis, which can be fatal. However, pravastatin is water-soluble, it does not undergo metabolism via CYP450 to any significant extent (<1%), is excreted essentially unchanged and has not been shown to participate in any clinically relevant drug-drug interactions with CYP450 agents. When selecting drug therapy, knowledge of a drug's route of metabolism is important to predict and prevent life-threatening drug-drug interactions.     

The P2Y 12 receptor as a therapeutic target in cardiovascular disease

Coronary thrombosis complicating rupture of atherosclerotic plaque is the predominant cause of acute coronary syndromes and platelets play a crucial role in this thrombus formation. Whilst aspirin has been successful in reducing cardiovascular morbidity and mortality, appreciation of its limited antiplatelet effects has stimulated the search for more effective antiplatelet agents. The thienopyridines, ticlopidine and clopidogrel, act, via metabolites, on the platelet ADP receptor subtype now designated P2Y 12 (formerly P 2T , P2T AC , P2Y ADP or P2Y cyc ) and these agents have proven clinical efficacy. Analogues of the natural P2Y 12 receptor antagonist ATP have been developed that act directly on the receptor and have a rapid onset of action. One such antagonist, AR-C69931MX, is being developed for clinical use. AR-C69931MX is a potent antagonist of ADPinduced platelet activation, aggregation and secretion and also antagonises platelet responses, including procoagulant activity, induced by all other agonists in view of the central role of the P2Y 12 receptor in amplifying platelet responses. Phase II studies of intravenous AR-C69931MX in patients with acute coronary syndromes show that this agent has a rapid onset of action, rapidly achieving steady-state inhibition of platelet aggregation, with a half-life of only a few minutes. AR-C69931MX appears to be safe and well tolerated as adjunctive therapy in these patients, and more effective inhibition of platelet function is achieved than with clopidogrel. Orally active ATP analogues are also being developed that may be more effective than clopidogrel. Limitations of platelet glycoprotein IIb/IIIa antagonists leave scope for development of alternative antiplatelet agents.     

Pharmacodynamic effects of cangrelor and clopidogrel: the platelet function substudy from the cangrelor versus standard therapy to achieve optimal management of platelet inhibition (CHAMPION) trials

Cangrelor is an intravenous antagonist of the P2Y(12) receptor characterized by rapid, potent, predictable, and reversible platelet inhibition. However, cangrelor was not superior to clopidogrel in reducing the incidence of ischemic events in the cangrelor versus standard therapy to achieve optimal management of platelet inhibition (CHAMPION) trials. A prospectively designed platelet function substudy was performed in a selected cohort of patients to provide insight into the pharmacodynamic effects of cangrelor, particularly in regard to whether cangrelor therapy may interfere with the inhibitory effects of clopidogrel. This pre-defined substudy was conducted in a subset of patients from the CHAMPION-PCI trial (n = 230) comparing cangrelor with 600 mg of clopidogrel administered before percutaneous coronary intervention (PCI) and from the CHAMPION-PLATFORM trial (n = 4) comparing cangrelor at the time of PCI and 600 mg clopidogrel given after the PCI. Pharmacodynamic measures included P2Y12 reaction units (PRU) assessed by VerifyNow P2Y12 testing (primary endpoint marker), platelet aggregation by light transmittance aggregometry following 5 and 20 μmol/L adenosine diphosphate stimuli, and markers of platelet activation determined by flow cytometry. The primary endpoint was the percentage of patients who achieved <20 % change in PRU between baseline and >10 h after PCI. The main trial was stopped early limiting enrollment in the platelet substudy. A total of 167 patients had valid pharmacodynamic assessments for the primary endpoint. The percent of individuals achieving <20 % change in PRU between baseline and >10 h after PCI was higher with cangrelor + clopidogrel (32/84, 38.1 %) compared with placebo + clopidogrel (21/83, 25.3 %), but this was not statistically significant (difference:12.79 %, 95 % CI: -1.18 %, 26.77 %;p = 0.076). All pharmacodynamic markers as well as the prevalence of patients with high on-treatment platelet reactivity were significantly lower in patients treated with cangrelor. A rapid platelet inhibitory effect was achieved during cangrelor infusion and a rapid offset of action after treatment discontinuation. This CHAMPION platelet function substudy represents the largest pharmacodynamic experience with cangrelor, demonstrating its potent P2Y(12) receptor inhibitory effects, and rapid onset/offset of action. Although there was no significant pharmacodynamic interaction when transitioning to clopidogrel therapy, further studies are warranted given that enrollment in this study was limited due to premature interruption of the main trial.     

Variable extent of platelet responsiveness to clopidogrel inhibition: "clopidogrel resistance"?

During percutaneous coronary angioplasty, platelet inhibition by clopidogrel and aspirin has drastically decreased the risk of thrombotic occlusion of the stented vessels. However, despite the widespread use of these drugs, the incidence of acute or subacute stent thrombosis remains elevated, concerning 1 to 2% of the treated patients. Considerable differences in the responsiveness to clopidogrel could be observed, suggesting a possible underlying biological resistance. "Clopidogrel resistance" has recently been associated to an increased risk of thrombotic events following coronary angioplasty. Variations in enteric absorption, biotransformation in the liver by the CYP3A4, changes in the ADP receptor P2Y12, abnomalies of intraplatelet signal transduction, extent of platelet activation, class angina, diabetes mellitus may account for the considerable interindividual response variability widely reported. In this view, laboratory tests evaluating "clopidogrel resistance" might be useful tools for the identification and follow-up of patients at higher thrombotic risk. Indeed, in these patients, further platelet inhibition can be achieved by higher doses of clopidogrel.     

Common sequence variations in the P2Y12 and CYP3A5 genes do not explain the variability in the inhibitory effects of clopidogrel therapy

The efficacy of the platelet P2Y12 receptor antagonist clopidogrel, which undergoes cytochrome-mediated metabolism to its active form, shows marked inter-individual variability. We investigated whether polymorphic variations in the P2Y12 gene, which have been linked to platelet aggregation phenotypes, or the cytochrome P450 3A5 gene 6986G > A polymorphism, which largely determines CYP3A5 expression, influence the response to clopidogrel therapy. Fifty-four patients listed for elective percutaneous coronary intervention were studied using ADP-induced optical aggregometry, whole-blood single platelet counting (WBSPC) aggregometry, and flow-cytometric analysis of platelet P-selectin expression and platelet-monocyte conjugate formation. Platelet reactivity was measured at baseline, 4 h post clopidogrel 300 mg, and 10 and 28 days following clopidogrel 75 mg daily. A further 55 patients were studied using ADP-induced WBSPC at baseline and 4 h post clopidogrel 600 mg. Patients were genotyped for P2Y12 haplotype and the CYP3A5 6986G > A single nucleotide polymorphism. Neither genotype was found to significantly influence the inhibition of platelet responses by either clopidogrel regimen. In conclusion, common sequence variations within the P2Y12 and CYP3A5 genes do not contribute any major effect to the inter-patient variability in clopidogrel efficacy.     

Clopidogrel and proton pump inhibitors-where do we stand in 2012?

Clopidogrel in association with aspirine is considered state of the art of medical treatment for acute coronary syndrome by reducing the risk of new ischemic events. Concomitant treatment with proton pump inhibitors in order to prevent gastrointestinal side effects is recommended by clinical guidelines. Clopidogrel needs metabolic activation predominantly by the hepatic cytochrome P450 isoenzyme Cytochrome 2C19 (CYP2C19) and proton pump inhibitors (PPIs) are extensively metabolized by the CYP2C19 isoenzyme as well. Several pharmacodynamic studies investigating a potential clopidogrel-PPI interaction found a significant decrease of the clopidogrel platelet antiaggregation effect for omeprazole, but not for pantoprazole. Initial clinical cohort studies in 2009 reported an increased risk for adverse cardiovascular events, when under clopidogrel and PPI treatment at the same time. These observations led the United States Food and Drug Administration and the European Medecines Agency to discourage the combination of clopidogrel and PPI (especially omeprazole) in the same year. In contrast, more recent retrospective cohort studies including propensity score matching and the only existing randomized trial have not shown any difference concerning adverse cardiovascular events when concomitantly on clopidogrel and PPI or only on clopidogrel. Three meta-analyses report an inverse correlation between clopidogrel-PPI interaction and study quality, with high and moderate quality studies not reporting any association, rising concern about unmeasured confounders biasing the low quality studies. Thus, no definite evidence exists for an effect on mortality. Because PPI induced risk reduction clearly overweighs the possible adverse cardiovascular risk in patients with high risk of gastrointestinal bleeding, combination of clopidogrel with the less CYP2C19 inhibiting pantoprazole should be recommended.     

Oral antiplatelet therapy for atherothrombotic disease: current evidence and new directions

Despite the proven efficacy of dual antiplatelet therapy with aspirin and one of the first-generation P2Y(12) antagonists (clopidogrel, prasugrel) in patients with atherothrombotic disease, residual ischemic risk remains substantial, and bleeding rates are increased. Incomplete protection against ischemic events can be attributed to the fact that these therapies each target a single platelet activation pathway, allowing continued platelet activation via other pathways, including the protease-activated receptor-1 (PAR-1) pathway stimulated by thrombin. Increased bleeding with dual antiplatelet therapy can be attributed to blockade of the thromboxane A(2) (by aspirin) and adenosine diphosphate (by P2Y(12) antagonist) platelet activation pathways that are essential to hemostasis. The second-generation P2Y(12) inhibitor ticagrelor plus aspirin demonstrated superior ischemic outcomes, including reduction in total mortality, versus clopidogrel plus aspirin, but event rates remain high, and major bleeding not related to coronary artery bypass grafting is increased. The novel P2Y(12) antagonist elinogrel, available in intravenous and oral formulations, may have a more favorable benefit-to-risk profile than existing agents in this class because of reversible and competitive binding to the P2Y(12) receptor. Inhibition of PAR-1 is an attractive, novel approach in antiplatelet therapy because it may provide incremental ischemic protection without increasing bleeding. The PAR-1 antagonist vorapaxar (SCH 530348) has been associated with favorable efficacy and safety in phase 2 trials. Two phase 3 trials are evaluating the efficacy and safety of vorapaxar in patients presenting with non-ST-segment elevation acute coronary syndromes and in patients with documented atherothrombotic disease.     

Prasugrel loading dose in diabetic patients with acute STEMI – Always sufficiently effective? Observation in two cases and review of current knowledge

The activation and subsequent platelet aggregation play a key role in the formation of arterial thrombosis and therefore is the key therapeutic target in the treatment of acute coronary syndromes. Dual antiplatelet therapy containing aspirin and P2Y12 ADP receptor antagonist forms currently the basis in acute ST – elevation myocardial infarction (STEMI) pharmacological treatment. Nevertheless, there is a wide variability in pharmacodynamic response to administration of clopidogrel, the most frequently used P2Y12 ADP receptor antagonist. High platelet reactivity after clopidogrel administration is associated with increased risk of stent thrombosis and points to the suitability of laboratory monitoring of antiplatelet therapy efficacy in clinical practice. Laboratory monitoring of antiplatelet therapy by ex vivo platelet function tests may help to identify individuals with poor antiplatlet response. Recently, there is a growing number of data reporting a failure in antiplatelet response following clopidogrel administration, which is specifically associated with insulin resistance and diabetes mellitus. Prasugrel, a new, potent P2Y12 ADP receptor antagonist, provides faster and more consistent inhibition of platelet function compared with clopidogrel. Prasugrel therapy was repeatedly described as an effective method to overcome clopidogrel resistance and prasugrel resistance has not yet been reliably described. We report two cases of patients with diabetes mellitus type 2 at the stage of organ complications, in whom a prasugrel loading dose of 60 mg did not reach adequate antiplatelet response in 60 min after prasugrel administration. The antiplatelet response was measured by light transmission aggregometry and by VASP protein phosphorylation assessment.     

The platelet P2Y₁₂ receptor for adenosine diphosphate: congenital and drug-induced defects

P2Y??, the G(i)-coupled platelet receptor for adenosine diphosphate (ADP), plays a central role in platelet function. Patients with congenital P2Y?? defects display a mild to moderate bleeding diathesis, characterized by mucocutaneous bleedings and excessive post-surgical and post-traumatic blood loss. Defects of P2Y?? should be suspected when ADP, even at high concentrations (≥ 10 μM), is unable to induce full, irreversible platelet aggregation. Tests that evaluate the degree of inhibition of adenylyl cyclase by ADP should be used to confirm the diagnosis. Drugs that inhibit P2Y?? are potent antithrombotic drugs, attesting the central role played by P2Y?? in platelet thrombus formation. Clopidogrel, the most widely used drug that inhibits P2Y??, is effective both in monotherapy and in combination with acetylsalicylic acid. The most important drawback of clopidogrel is its inability to inhibit adequately P2Y??-dependent platelet function in approximately one-third of patients who are therefore not protected from major cardiovascular events. New drugs, such as prasugrel and ticagrelor, which effectively inhibit P2Y?? in the majority of patients, proved to be more efficacious than clopdidogrel in preventing major cardiovascular events. Although they increase the incidence of major bleedings, the net clinical benefit is in favor of the new P2Y?? inhibitors.     

Comparison of platelet P2Y(12) ADP receptor-mediated pathway inhibition in triple versus dual antiplatelet therapy as assessed by VASP-phosphorylation in Japanese patients undergoing coronary stenting

Despite wide interindividual variability in response to clopidogrel, platelet P2Y(12) ADP receptor inhibition in Japanese patients has not been fully studied using specific methodology. This study compared platelet P2Y(12) ADP receptor inhibition during treatment with clopidogrel versus clopidogrel plus cilostazol in patients undergoing coronary stenting. Forty-two patients in whom platelet function was measured within 2 months after coronary stenting were enrolled. All patients were treated with aspirin 100 or 200 mg/day, and were divided into a dual therapy group (aspirin plus clopidogrel 75 mg/day; n = 34) and a triple therapy group (aspirin plus clopidogrel 75 mg/day plus cilostazol 200 mg/day; n = 8). Vasodilator-stimulated phosphoprotein (VASP) phosphorylation analysis and 5 and 20 μmol/L-induced maximal platelet aggregation were assessed. No differences were found in baseline characteristics except for a higher incidence of diabetes mellitus (DM) in the triple therapy group. Although there were no differences in platelet aggregation between the 2 groups, VASP index was significantly lower in the triple therapy group than in the dual therapy group (23.1 ± 15.3% versus 51.2 ± 19.9%; P = 0.001). The rate of low responsiveness to clopidogrel, defined by VASP index > 50%, was lower in the triple therapy group than in the dual therapy group (12.5% versus 55.9%; P = 0.047). Similarly, in DM patients the triple therapy group had a lower VASP index compared with the dual therapy group (23.1 ± 15.3% versus 47.0 ± 23.5%; P = 0.015).Clopidogrel plus cilostazol is more effective in inhibiting the platelet P2Y(12) ADP receptor pathway than clopidogrel alone. This may be useful for reducing clopidogrel resistance in Japanese patients.     

Clopidogrel – klinischer Einsatz und mögliche Therapieprobleme

Platelet activation is a major component in the pathogenesis of coronary thrombosis and myocardial infarction. Therefore, antiplatelet therapy has become the cornerstone in the therapy of ischemic heart disease. Thienopyridines, especially clopidogrel, have a highly significant effect on treated patients with regard to reduction of stent thrombosis and functional inhibition of adenosine diphosphate-(ADP-)induced platelet activation. Clopidogrel, a specific inhibitor of the P2Y(12) ADP receptor, is a prodrug which releases the active compound after metabolization. Actual ACC/AHA/SCAI guidelines recommend the use of 75 mg clopidogrel once daily after stent implantation. Nevertheless, there is a high incidence of impaired clopidogrel responsiveness in patients potentially leading to subacute stent thrombosis and other adverse cardiovascular events following coronary interventions (incidence of about 1% within the first 4 weeks). Therefore, individual risk testing and adjusted antiplatelet therapy might be recommendable under certain circumstances, e.g., high-risk interventions such as last patent vessel, dominant vessel, or planned drug-eluting stent implantation. Furthermore, identification of a nonresponder requires increased clinical attention. Newly developed antiplatelet substances might overcome the nonresponse problem and allow sufficient platelet inhibition in all patients. Further prospective studies are needed to determine the risk reduction by an individually adjusted antiplatelet therapy.