Mg Of Clopidogrel Research Articles

Influence of platelet reactivity and response to clopidogrel on myocardial damage following percutaneous coronary intervention in patients with non-st-segment elevation acute coronary syndrome

Introduction A wide variability in the response to clopidogrel and magnitude of post-treatment platelet reactivity has been described. However, this has been demonstrated by light transmittance aggregometry, a method too laborious for daily practice. Point-of-care devices may overcome this limitation, but little is known on the predictive value of such measurements. Our objective was to determine the relationship between platelet reactivity and the incidence of myocardial damage following percutaneous coronary intervention (PCI) in patients with Non-ST-segment Elevation Acute Coronary Syndrome (NSTEACS). Materials and Methods This prospective study included 93 patients with NSTEACS and PCI. All patients received a loading dose of 300 mg of clopidogrel and 250 mg of aspirin. Myocardial damage was defined as any elevation above upper limit of normal or previous levels of troponin T, assessed every 6 h for at least 24 h following PCI. Platelet reactivity not related to clopidogrel (BASE reactivity), related to P2Y12 inhibition (P2Y12 reactivity) and inhibition of platelet aggregation (IPA) were assessed immediately pre-PCI with the VerifyNow® device. Results Myocardial damage was detected in 60 patients (64.5%). Higher BASE reactivity was associated with myocardial damage (287.8 ± 62.6 vs. 260 ± 55.9 units, p = 0.043) while a trend was found for P2Y12 reactivity (173.4 ± 70.3 vs. 149.2 ± 58.4 units, p = 0.109). No relationship was detected for IPA. Multivariate logistic regression analysis confirmed that BASE reactivity (p = 0.04) and P2Y12 reactivity (p = 0.03) were independent predictors of myocardial damage. Conclusions Platelet reactivity before PCI appears to be better predictor of myocardial damage than does response to clopidogrel.

Guidelines to Practice Gap in the Use of Glycoprotein IIb/IIIa Inhibitors: From ISAR‐REACT to Overreact?

Adjunctive use of glycoprotein IIb/IIIa inhibitors (GPI) is associated with favorable outcomes following percutaneous coronary intervention (PCI). Guidelines for use of GPI have been published by various national societies including National Institute of Clinical Excellence (NICE), United Kingdom. The latter has not been updated since publication. The impact of contemporary trials such as ISAR-REACT (which showed no benefit of abciximab and 600 mg of clopidogrel compared with 600 mg of clopidogrel alone, in elective patients) on adherence to NICE guidelines is unknown. We audited use of GPI against NICE guidelines following publication in May 2002. Data were collected from 1,685 patients between September and November in years 2002, 2003, 2004, and 2007. In 2002 and 2003, only 10.2% and 11.8%, respectively, of patients were noncompliant to NICE guidelines. Over time, there was an increase in patients not given GPI despite meeting NICE criteria. After publication of ISAR-REACT, the comparative figures for noncompliance in 2004 and 2007 were 40.0% and 44.5%. A similar pattern was seen in patients with diabetes; in 2002 and 2003 noncompliance was 16.7% and 11.1%, respectively, and in 2004 and 2007 noncompliance was 38.0% and 44.7%, respectively. Qualitatively, similar findings were recorded in patients with NSTE-ACS. The overall noncompliance to NICE guidelines increased from 11.0% to 42.1% (P < 0.0001) after the ISAR-REACT study. We found a decline in compliance to NICE guidelines on GPI usage during PCI. This was likely influenced by contemporary trials demonstrating little or no benefit of GPI in patients undergoing elective PCI who are adequately pretreated with clopidogrel. Our findings suggest the need for a mechanism whereby regular updates to guidelines can be disseminated following new trial evidence.

Optimal pretreatment timing for high load dosing (600 mg) of clopidogrel before planned percutaneous coronary intervention for maximal antiplatelet effectiveness

The optimal timing for 600 mg clopidogrel pre-treatment before planned PCI in patients with stable coronary artery disease has never been tested in a randomized trial. The time course of platelet inhibition was investigated in 105 patients pre-treated with clopidogrel ≥ 6 h before the planned procedure. Flow cytometric analysis of the vasodilator stimulated phosphoprotein (VASP) phosphorylation state was done and a Platelet Reactivity Index (PRI) was calculated prior to treatment (baseline) and at 12, 28, 36, 60, 84 and 108 h after the clopidogrel loading dose administration. The maximal inhibition of platelet activation was seen at 28 h post administration (PRI mean 36 ± 23%), and 2/3 of patients had PRI value <50%. At 12 h 47% of patients had PRI value ≥ 50% (mean 45±21%). 600 mg of clopidogrel significantly suppressed platelet activation for 4 days. A correlation was between baseline PRI and its values by 28 h (r(S)=0.48, p<0.001), between 12 h-28 h the correlation was strong (r(S)=0.77, p<0.001). The time curve of clopidogrel efficacy was dependent on baseline platelet reactivity. Among stable CAD patients, pre-treatment with 600 mg of clopidogrel resulted in maximal antiplatelet efficacy 1 day after drug administration.

Clopidogrel attenuates atheroma formation and induces a stable plaque phenotype in apolipoprotein E knockout mice

Aim Clopidogrel is a widely used anti-thrombotic for the prevention of stent thrombosis and cardiovascular events in patients with coronary atherosclerosis. Clopidogrel has been shown to exhibit anti-inflammatory effects that are related to the attenuated activation of platelets. Atherosclerosis is a complex process in which the immune system and the endothelium appear to play a prominent role. Herein, we tested the hypothesis that clopidogrel will influence plaque size and composition in the atherosclerosis prone apolipoprotein E knockout (apoE KO) mouse model. Methods and results Eight week old mice were fed daily with either PBS, 1 mg or 2 mg of clopidogrel for 10 weeks. Plaque size was evaluated in the aortic sinus and cellular and humoral responses were studied as well as splenic and bone marrow endothelial progenitors by FACS. Treatment with either 1 mg and 2 mg of clopidogrel significantly reduced plaque size and augmented its stability by increasing atheromatous fibrous area. Whereas antigen specific oxLDL immune response was not influenced by clopidogrel feeding, the number of atheroprotective regulatory CD4+CD25+ T cells was significantly increased. Moreover, clopidogrel treatment resulted in a prominent rise in splenic but not bone marrow derived Sca-1+/flk-1+ endothelial progenitors. Conclusion Clopidogrel significantly reduces atheroma burden and stabilizes aortic sinus plaques in apoE KO mice. These effects may partially be mediated by upregulation of the regulatory T cell pool and splenic endothelial progenitor cells. These findings may expand the potential applications of clopidogrel in human subjects.

Comparison of Low vs Moderate Dose of Atorvastatin in Clopidogrel Resistance After Coronary Stenting in Korean Patients With Acute Coronary Syndrome

The effect of atorvastatin 10 mg vs 40 mg in clopidogrel resistance and clinical events after coronary stenting was compared in patients with acute coronary syndrome (ACS). Platelet aggregation was measured before clopidogrel administration and 4 h, 24 h, 5 days, and 8 months later in 130 ACS patients. Stented patients were randomly assigned to atorvastatin either 10 mg (n=65) or 40 mg (n=65), and received an oral loading dose of 300 mg of clopidogrel followed by 75 mg/day for 8 months. Measurement of platelet aggregation was done by the turbimetric method. The mean % changes in inhibition of platelet aggregation were 35.5 +/-8.3, 50.9 +/-10.1, 38.3 +/-8.3, 40.0 +/-6.8 in the Atorvastatin 10 mg Group and 31.0 +/-7.6, 43.7 +/-9.8, 45.0 +/-10.3, 43.5 +/-7.8 (4 h, 24 h, 5 days, and 8 months, respectively, after 300 mg of clopidogrel pretreatment) in the Atorvastatin 40 mg Group with no significant differences between the 2 groups. Cardiovascular events showed no significant differences during the follow-up. Atorvastatin 10 mg or 40 mg co-administered with clopidogrel for 8 months did not affect the antiplatelet potency of clopidogrel and showed no significant differences in the clinical events in ACS patients.

Study on clopidogrel in inhibition of platelet aggregation in suspected angina patients, treated with a daily dose of 75 mg of clopidogrel for 7 days

This study was performed to assess the clopidogrel activity in inhibition of platelet aggregation in suspected angina patients on a daily dosag of 75 mg of clopidogrel for at least 7 days.

Thrombin as a common downstream target blocking both platelet and monocyte activation

Thromb Haemost 2009; 101: 220–221 Platelets play a pivotal role in the pathogenesis of thrombotic complications after percutaneous coronary interventions (PCI) (1). The use of optimal antiplatelet therapy is critical in reducing adverse events in this setting. Despite the efficacy of dual antiplatelet therapy in patients undergoing PCI, thrombo-ischaemic events and, in particular, stent thrombosis are frequent complications (2). High post-treatment platelet reactivity is associated with cardiovascular outcome after PCI (3) and coronary stent implantation (4). Different agents are currently in use for adjunctive anticoagulant treatment on top of adequate antiplatelet regimen during PCI. Traditionally, unfractionated heparin (UFH) has been the standard anticoagulant administered during coronary intervention. Enhanced platelet activation in vivo and ex vivo has been shown after UFH treatment (5, 6). Moreover, heparin does not suppress the transient increase in thromboxane biosynthesis associated with coronary angioplasty (7). Low-molecular-weight heparin (LMWH), in contrast, does not affect platelet activation in vivo and ex vivo after PCI (5, 8). Recently bivalirudin, a short-acting direct thrombin inhibitor, has been shown to be effective and safe in patients undergoing PCI (9), with reduced bleeding as compared with heparin. Reduced inhibition of adenosine diphosphate (ADP)-induced platelet aggregation at the time of PCI is associated with an increased risk for adverse thrombotic complications (10). Bivalirudin, given during PCI in patients pretreated with 600 mg of clopidogrel, is unlike UFH associated with further inhibition of platelet aggregation (11). A similar effect by bivalirudin was previously described on platelet P-selectin (12). Moreover, bivalirudin alone or coupled with clopidogrel may significantly down© 2009 Schattauer GmbH, Stuttgart

Aspirin and Extended-Release Dipyridamole vs. Clopidogrel for Recurrent Stroke

Conclusion: Rates of recurrent stroke are similar in patients with stroke treated with aspirin and extended release dipyridamole vs those treated with clopidogrel. Summary: Surviving patients with ischemic stroke are at risk for recurrent stroke. Multiple trials have proven the efficacy of antiplatelet agents in prevention of recurrent stroke after non-cardioembolic stroke. Which particular antiplatelet therapy may work best in the prevention of recurrent stroke is unknown. This trial studied the relative efficacy and safety of aspirin plus extended-release dipyridamole (ERDP) for prevention of recurrent stroke compared with patients treated with clopidogrel. This is a double-blind, two-by-two factorial trial. Patients were randomly assigned to receive 75 mg of aspirin plus 200 mg of ERDP twice daily, or to receive 75 mg of clopidogrel daily. The primary outcome was first recurrence of stroke. The secondary end point was a composite of myocardial infarction, stroke, or death from cardiovascular cause. The trial was designed as a noninferiority trial with sequential statistic testing of noninferiority, followed by superiority testing. A total of 20,332 patients were followed up worldwide, with a mean follow-up of 2.5 years. In patients receiving aspirin and ERDP, recurrent stroke occurred in 916 (9%). In patients receiving clopidogrel, recurrent stroke occurred in 898 (8.8%), with a hazard ratio (HR) of 1.01 (95% confidence interval [CI], 0.92-1.11). The secondary composite outcome occurred in 13.1% of patients in each group (HR for aspirin/ERDP, 0.99; 95% CI, 0.92-1.07). Patients treated with aspirin/ERDP had 4.1% (n = 419) major hemorrhagic events compared with 3.6% (n = 365) in patients treated with clopidogrel (HR, 1.15; 95% CI, 1.00-1.32) and had more intracranial hemorrhage (HR, 1.42; 95% CI, 1.11-1.83). The net risk of a major hemorrhagic event or recurrent stroke was similar in the two groups, 11.7% in the aspirin/ERDP group vs 11.4% in the clopidogrel group (HR, 1.03; 95% CI, 1.95-1.11). Comments: The study indicates no significant difference between the use of aspirin/ERDP vs clopidogrel in preventing recurrent stroke. This was a huge study with high patient numbers and international representation from 35 countries or regions. The results of the study, therefore, should be generalizable worldwide. Although the study failed to identify a superior treatment to prevent recurrent stroke, we now know the expected risk of recurrent stroke in patients treated according to the study protocol. The study has also provided us safety and efficacy data for physicians concerning individual treatment decisions for their patients with ischemic stroke.

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

The clinical impact of platelet aggregation assessed by point-of-care assays is unknown. We sought to evaluate whether high residual platelet reactivity (RPR) to ADP during clopidogrel therapy, measured by a point-of-care assay, predicts adverse clinical events in acute coronary syndrome patients undergoing percutaneous coronary intervention. We used the VerifyNow P2Y12 assay (Accumetrics Inc, San Diego, Calif) to determine RPR to ADP in 683 patients with acute coronary syndrome undergoing dual-antiplatelet therapy who underwent percutaneous coronary intervention with bare-metal or drug-eluting stent implantation. All patients received a single 600-mg clopidogrel loading dose followed by 75 mg of clopidogrel daily and 100 to 325 mg of aspirin daily. The end points of the study at follow-up of 12 months were cardiovascular death, nonfatal myocardial infarction (MI), and target-vessel revascularization. At a 12-month follow-up, we found 51 ischemic events (24 cardiovascular deaths [3.5%], 27 nonfatal MIs [3.9%]) and 40 target-vessel revascularizations (5.8%). By receiver operating characteristic curve (ROC) analysis, the optimal cutoff value in predicting 12-month cardiovascular death and nonfatal MI was P2Y12 reaction unit values > or =240. RPR, defined in the presence of P2Y12 reaction unit values above this cutoff, was found to be a significant and independent predictor of cardiovascular death and nonfatal MI in a model that adjusted for cardiovascular risk factors, renal failure, reduced left ventricular ejection fraction, multivessel disease, total stent length, bifurcation lesions, number of lesions treated, type of stent, and use of glycoprotein IIb/IIIa inhibitors (cardiovascular death: hazard ratio 2.55, 95% CI 1.08 to 6.07, P=0.034; nonfatal MI: hazard ratio 3.36, 95% CI 1.49 to 7.58, P=0.004). No significant association was found between high RPR and the risk of target-vessel revascularization. RPR to ADP with clopidogrel therapy, measured by the point-of-care assay VerifyNow P2Y12, is able to detect acute coronary syndrome patients at risk of 12-month cardiovascular death and nonfatal MI. The optimal cutoff value was identified as being 240 P2Y12 reaction units.

Randomized trial comparing 600- with 300-mg loading dose of clopidogrel in patients with non–ST elevation acute coronary syndrome undergoing percutaneous coronary intervention: Results of the Platelet Responsiveness to Aspirin and Clopidogrel and Troponin Increment after Coronary intervention in Acute coronary Lesions (PRACTICAL) Trial

There is uncertainty about the benefit of a higher loading dose (LD) of clopidogrel in patients with non-ST elevation acute coronary syndrome (NSTEACS) undergoing early percutaneous coronary intervention (PCI). We compared the effects of a 600- versus a 300-mg LD of clopidogrel on inhibition of platelet aggregation, myonecrosis, and clinical outcomes in patients with NSTEACS undergoing an early invasive management strategy. Patients with NSTEACS (n = 256, mean age 63 years, 81.6% elevated troponin) without thienopyridine for at least 7 days were randomized to receive 600- or 300-mg LD of clopidogrel. Percutaneous coronary intervention was performed in 140 patients, with glycoprotein IIb/IIIa inhibitor use in 68.6%. Adenosine diphosphate (ADP)-induced platelet aggregation was measured by optical platelet aggregometry immediately before coronary angiography. Post-PCI myonecrosis was defined as a next-day troponin I greater than 5 times the upper limit of reference range and greater than baseline levels. Clopidogrel 600-mg LD compared with 300-mg LD was associated with significantly reduced ADP-induced platelet aggregation (49.7% vs 55.7% with ADP 20 micromol/L) but did not reduce post-PCI myonecrosis or adverse clinical outcomes to 6 months. There was no association between preprocedural platelet aggregation and outcome. These data confirm a modest incremental antiplatelet effect of a 600-mg clopidogrel LD compared with 300-mg LD but provide no support for a clinical benefit in patients with NSTEACS managed with an early invasive strategy including a high rate (69%) of glycoprotein IIb/IIIa inhibitor use during PCI.

Drugs Prove Equal Against Recurring Strokes

Drugs Prove Equal Against Recurring Strokes

Glycoprotein IIb/IIIa Inhibitors Improve Outcome After Coronary Stenting in Clopidogrel Nonresponders: A Prospective, Randomized Study

The aim of this study was to assess, in clopidogrel nonresponders undergoing elective percutaneous coronary intervention (PCI), the benefit of adjusted antiplatelet therapy with glycoprotein (GP) IIb/IIIa antagonist administration during PCI for 1-month clinical outcome. Numerous biological studies have reported interindividual variability in platelet response to clopidogrel with clinical relevance, and high post-treatment platelet reactivity (adenosine diphosphate-induced aggregation >70%) has been proposed to define nonresponse to clopidogrel. These nonresponders might benefit from tailored antiplatelet therapy. One hundred forty-nine clopidogrel nonresponders referred for elective PCI were prospectively included and randomized to "conventional group" (n = 75) or "active group" with GP IIb/IIIa antagonist (n = 74). All patients received 250-mg aspirin and 600-mg clopidogrel before PCI and platelet testing. The rate of cardiovascular events at 1 month was significantly lower in the "active group" than in the "conventional group": 19% (n = 14) versus 40% (n = 30), p = 0.006, odds ratio: 2.8; 95% confidence interval: 1.4 to 6.0. No patient in either group had post-procedural Thrombolysis In Myocardial Infarction major bleeding or required transfusions. The present study suggested benefit of tailored antiplatelet therapy during elective PCI with GP IIb/IIIa antagonist for clopidogrel nonresponders without increased bleeding risk.

Patients With Poor Responsiveness to Thienopyridine Treatment or With Diabetes Have Lower Levels of Circulating Active Metabolite, but Their Platelets Respond Normally to Active Metabolite Added Ex Vivo

We evaluated the prevalence and mechanism of poor responsiveness to clopidogrel and prasugrel in coronary artery disease patients with and without diabetes. Low platelet inhibition by clopidogrel is associated with ischemic clinical events. A higher 600-mg loading dose (LD) has been advocated to increase responsiveness to clopidogrel. In this study, 110 aspirin-treated patients were randomized to double-blind treatment with clopidogrel 600 mg LD/75 mg maintenance dose (MD) for 28 days or prasugrel 60 mg LD/10 mg MD for 28 days. Pharmacodynamic (PD) response was evaluated by light transmission aggregometry and vasodilator-stimulated phosphoprotein phosphorylation. The PD poor responsiveness was defined with 4 definitions previously associated with worse clinical outcomes. Active metabolites (AM) of clopidogrel and prasugrel were measured. Clopidogrel AM was added ex vivo. The proportion of patients with poor responsiveness was greater in the clopidogrel group for all definitions at all time points from 1 h to 29 days. Poor responders had significantly lower plasma AM levels compared with responders. Patients with diabetes were over-represented in the poor-responder groups and had significantly lower levels of AM. Platelets of both poor responders and diabetic patients responded fully to AM added ex vivo. Prasugrel treatment results in significantly fewer PD poor responders compared with clopidogrel after a 600-mg clopidogrel LD and during MD. The mechanism of incomplete platelet inhibition in clopidogrel poor-responder groups and in diabetic patients is lower plasma levels of its AM and not differences in platelet P2Y(12) receptor function.

Impact of high loading and maintenance dose of clopidogrel within the first 15 days after percutaneous coronary intervention on patient outcome

An increase in clopidogrel dose results in an improved inhibition of platelet aggregation. However, whether an increase in clopidogrel dose may improve patient outcome is still debated. The aim of this study was to analyze the impact on patient outcome of an increase in clopidogrel loading and maintenance doses within the first 15 days after percutaneous coronary intervention (PCI). Between 2003 and 2007, we included 2,954 consecutive patients who underwent PCI and stent implantation. We compared 2 historical groups. In the "low-dose" group (2003-2005, n = 1,984), patients were pretreated with a 300-mg clopidogrel loading dose followed by 75 mg/d after PCI. In the "high-dose" group (2006-2007, n = 970), patients were pretreated with a 600-mg clopidogrel loading dose followed by 150 mg/d within the first 15 days and 75 mg/d thereafter. The composite primary end point (death, myocardial infarction, stent thrombosis) and bleeding were systematically indexed during the 2-month follow-up period. Clinical and most of angiographic characteristics were similar between the 2 groups. By multivariate analysis, high dose of clopidogrel was associated with a decrease in the composite primary end point (hazard ratio 0.694, 95% CI 0.485-0.993, P = .046). The other predictors were age, left ventricular ejection fraction, diabetes, renal failure, and acute coronary syndrome. Major bleeding was similar in the low- and high-dose groups (2.8% vs 3.4%, respectively, P = .379). After propensity score matching, the high-dose group was still associated with a significant clinical benefit. Our results show that a 600-mg loading dose followed by a 150-mg maintenance dose of clopidogrel within the first 15 days after PCI is independently associated with a decrease in the composite death-myocardial infarction-stent thrombosis at 2 months without increase in hemorrhagic complications.

Abstract 4017: Reduced Anti-Platelet Response to Clopidogrel in Diabetic Patients Undergoing Percutaneous Coronary Intervention

Despite dual antiplatelet therapy with aspirin and clopidogrel, patients with diabetes mellitus (DM) suffer from frequent recurrent ischemic events. Previous studies have shown that DM patients have a higher prevalence of aspirin resistance than non-DM patients. The aim of this analysis was to determine if DM patients have a decreased antiplatelet response to either maintenance or high loading clopidogrel administration when compared to non-DM patients. One hundred and thirty eight patients that underwent percutaneous coronary intervention (PCI) in the Clear Platelets-2 Study were included in this analysis. Patients were grouped according to clopidogrel dose use and presence of DM. Subjects were either on maintenance therapy with 75mg of clopidogrel (C75 group; n=72) or received a loading dose of 600mg of clopidogrel immediately after PCI (C600 group; n=66). All patients received 325-mg aspirin. Platelet function was measured by Light Transmission Aggregometry using ADP (5 and 20μM), TRAP (15 μM), and collagen (2μg/ml). Overall, DM patients in the C75 group had higher platelet aggregation using 5 and 20μM ADP and 2μg/ml collagen. DM patients had lower relative platelet inhibition at 24hrs with 5 μM ADP and 2μg/ml collagen in the C600 group when compared to non-DM patients (Table ). DM patients undergoing PCI exhibit higher platelet aggregation when receiving standard clopidogrel maintenance dose and lower relative platelet inhibition with high clopidogrel loading dose. Higher doses of clopidogrel or more potent P2Y12 receptor antagonists may be needed in DM patients to obtain comparable platelet inhibition to non-DM patients.

Abstract 4450: Does the Evidence Support Guideline Recommendations for Clopidogrel Pretreatment?

Although few concrete data exist about the optimal timing and dose of clopidogrel pretreatment, the ACC/AHA &amp; ESC guidelines endorse pretreatment with 300 – 600 mg of clopidogrel at least 2– 6 hours before PCI as Class IA (ACS) and Class IC (elective PCI) recommendation. To evaluate the current evidence base in support for clopidogrel pretreat-ment. Five trials examining the impact of clopidogrel pretreatment in stable and unstable CAD were evaluated: PCI-CURE, PCI-CLARITY, CREDO, PRAGUE-8, ARMYDA-5. Because of substantial clinical heterogeneity in trial design and population, concomitant therapies (glycoprotein 2b/3a inhibitors, thrombolysis, etc), loading dose, pretreatment duration and analysis plan between PCI-CURE, PCI-CLARITY and the rest, a formal meta-analysis was confined only to CREDO, PRAGUE-8, ARMYDA-5. The key data are summarized in the Table . Clopidogrel pretreatment was associated with significant reduction in ischemic outcomes without a significant increase in major bleeding in two out of the 5 trials (PCI-CURE and PCI-CLARITY). Both these trials utilized nonrandomized subgroup comparisons with pretreatment duration longer than that typically encountered in clinical practice (&lt;48h). A meta-analysis of the 3 trials demonstrated a nonsignificant 23% odds reduction in efficacy (P=0.1) and a nonsignificant 29% odds increase in major bleeding (P=0.24). No significant heterogeneity was observed for pooled efficacy (P=0.79) or bleeding (P=0.77) outcomes. Pretreatment hypothesis is currently not validated in rigorous prospective assessments, thereby calling into question the Class I recommendation (benefit &gt;&gt;&gt;risk) endorsed by the guidelines. Clearly, further clinical data regarding dose, time course of pretreatment and associated benefit are warranted to provide unequivocal support. Until then, it is prudent to rule out surgical CAD before pretreatment to avoid bleeding risk. Trials Assessing Clopidogrel Pretreatment

Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention

Several studies have demonstrated that the mutant *2 allele of the CYP2C19 681G>A loss-of-function polymorphism is associated with diminished metabolization of clopidogrel into its active thiol metabolite and an attenuated platelet response to clopidogrel treatment. It is not known whether patients carrying the mutant CYP2C19*2 allele have a higher risk of stent thrombosis (ST) compared with homozygous CYP2C19*1 wild-type allele carriers following percutaneous coronary intervention (PCI). The aim of this study was to assess the impact of the CYP2C19 681G>A loss-of-function polymorphism on ST following PCI performed after pre-treatment with clopidogrel. The study population included 2485 consecutive patients undergoing coronary stent placement after pre-treatment with 600 mg of clopidogrel. Genotypes were determined with a TaqMan assay. The primary endpoint of the study was the incidence of definite ST within 30 days following PCI. Of the patients studied, 1805 (73%) were CYP2C19 wild-type homozygotes (*1/*1) and 680 (27%) carried at least one *2 allele (*1/*2 or *2/*2). The cumulative 30-day incidence of ST was significantly higher in CYP2C19*2 allele carriers (*1/*2 or *2/*2) vs. CYP2C19 wild-type homozygotes (*1/*1) [10 patients (1.5%) in CYP2C19*2 allele carriers vs. 7 (0.4%) in CYP2C19 wild-type homozygotes (*1/*1), HR 3.81, 95% CI 1.45-10.02, P = 0.007; P = 0.006 after adjustment for confounding variables]. The risk of ST was highest (2.1%) in patients with the CYP2C19 *2/*2 genotype (P = 0.002). CYP2C19*2 carrier status is significantly associated with an increased risk of ST following coronary stent placement.

Pre-procedural C-reactive protein levels and clinical outcomes after percutaneous coronary interventions with and without abciximab: pooled analysis of four ISAR trials

Objective: To assess the prognostic value of the baseline C-reactive protein (CRP) level in patients undergoing percutaneous coronary intervention (PCI) after pre-treatment with 600 mg of clopidogrel and whether there...

Aspirin and Extended-Release Dipyridamole versus Clopidogrel for Recurrent Stroke

Recurrent stroke is a frequent, disabling event after ischemic stroke. This study compared the efficacy and safety of two antiplatelet regimens--aspirin plus extended-release dipyridamole (ASA-ERDP) versus clopidogrel. In this double-blind, 2-by-2 factorial trial, we randomly assigned patients to receive 25 mg of aspirin plus 200 mg of extended-release dipyridamole twice daily or to receive 75 mg of clopidogrel daily. The primary outcome was first recurrence of stroke. The secondary outcome was a composite of stroke, myocardial infarction, or death from vascular causes. Sequential statistical testing of noninferiority (margin of 1.075), followed by superiority testing, was planned. A total of 20,332 patients were followed for a mean of 2.5 years. Recurrent stroke occurred in 916 patients (9.0%) receiving ASA-ERDP and in 898 patients (8.8%) receiving clopidogrel (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11). The secondary outcome occurred in 1333 patients (13.1%) in each group (hazard ratio for ASA-ERDP, 0.99; 95% CI, 0.92 to 1.07). There were more major hemorrhagic events among ASA-ERDP recipients (419 [4.1%]) than among clopidogrel recipients (365 [3.6%]) (hazard ratio, 1.15; 95% CI, 1.00 to 1.32), including intracranial hemorrhage (hazard ratio, 1.42; 95% CI, 1.11 to 1.83). The net risk of recurrent stroke or major hemorrhagic event was similar in the two groups (1194 ASA-ERDP recipients [11.7%], vs. 1156 clopidogrel recipients [11.4%]; hazard ratio, 1.03; 95% CI, 0.95 to 1.11). The trial did not meet the predefined criteria for noninferiority but showed similar rates of recurrent stroke with ASA-ERDP and with clopidogrel. There is no evidence that either of the two treatments was superior to the other in the prevention of recurrent stroke. (ClinicalTrials.gov number, NCT00153062.)

Catastrophic Thrombus Formation During Optical Coherence Tomography

A 71-year-old patient underwent follow-up coronary angiography to assess the patency of a left anterior descending (LAD) artery stent. Seven months previously, she had received percutaneous coronary intervention at the LAD because of anterior wall ST-elevation myocardial infarction. At that time, 2 drug-eluting stents (Cypher 3.0×28 mm and Cypher 2.75×28 mm) were inserted at the proximal and distal LAD. After percutaneous coronary intervention, she had taken 100 mg of aspirin, 75 mg of clopidogrel, and 200 mg of cilostazol daily. Coronary angiography at 7 months follow-up was performed as …