Clopidogrel Therapy In Patients Research Articles

Effects of cytochrome P450 2C19 and paraoxonase 1 polymorphisms on antiplatelet response to clopidogrel therapy in patients with coronary artery disease.

Clopidogrel is an antiplatelet prodrug that is recommended to reduce the risk of recurrent thrombosis in coronary artery disease (CAD) patients. Paraoxonase 1 (PON1) is suggested to be a rate-limiting enzyme in the conversion of 2-oxo-clopidogrel to active thiol metabolite with inconsistent results. Here, we sought to determine the associations of CYP2C19 and PON1 gene polymorphisms with clopidogrel response and their role in ADP-induced platelet aggregation. Clopidogrel response and platelet aggregation were determined using Multiplate aggregometer in 211 patients with established CAD who received 75 mg clopidogrel and 75–325 mg aspirin daily for at least 14 days. Polymorphisms in CYP2C19 and PON1 were genotyped and tested for association with clopidogrel resistance. Linkage disequilibrium (LD) and their epistatic interaction effects on ADP-induced platelet aggregation were analysed. The prevalence of clopidogrel resistance in this population was approximately 33.2% (n = 70). The frequencies of CYP2C19*2 and *3 were significantly higher in non-responder than those in responders. After adjusting for established risk factors, CYP2C19*2 and *3 alleles independently increased the risk of clopidogrel resistance with adjusted ORs 2.94 (95%CI, 1.65–5.26; p<0.001) and 11.26 (95%CI, 2.47–51.41; p = 0.002, respectively). Patients with *2 or *3 allele and combined with smoking, diabetes and increased platelet count had markedly increased risk of clopidogrel resistance. No association was observed between PON1 Q192R and clopidogrel resistance (adjusted OR = 1.13, 95%CI, 0.70–1.82; p = 0.622). Significantly higher platelet aggregation values were found in CYP2C19*2 and *3 patients when compared with *1/*1 allele carriers (p = 1.98×10−6). For PON1 Q192R genotypes, aggregation values were similar across all genotype groups (p = 0.359). There was no evidence of gene-gene interaction or LD between CYP2C19 and PON1 polymorphisms on ADP-induced platelet aggregation. Our findings indicated that only CYP2C19*2 and *3 alleles had an influence on clopidogrel resistance. The risk of clopidogrel resistance increased further with smoking, diabetes, and increased platelet count.

Evidence of platelet sensitization to ADP following discontinuation of clopidogrel therapy in patients with stable coronary artery disease

Epidemiological studies have linked clopidogrel discontinuation with an increased incidence of ischemic events. This has led to the hypothesis that clopidogrel discontinuation may result in a pharmacological rebound. We evaluated the impact of clopidogrel discontinuation on platelet function. Platelet aggregation was measured by light transmission aggregometry (LTA) in response to adenosine diphosphate (ADP) 0.5, 1, 1.5, 2.5, 5 and 10 µM and by VerifyNow® P2Y12, in 37 clinically stable coronary artery disease (CAD) patients scheduled to discontinue clopidogrel treatment, and 37 clinically stable CAD patients not taking clopidogrel. Platelet function was assessed the day before clopidogrel cessation and 1, 3, 7, 14, 21 and 28 days after. Clopidogrel had been initiated a median of 555 days (ranging from 200 to 2280 days) before the treating cardiologist recommended its discontinuation. All participants were taking aspirin, most commonly 80 mg daily although a minority was prescribed 325 mg daily. Following clopidogrel discontinuation, VerifyNow® P2Y12 did not detect any rebound platelet activity, but ADP-induced LTA showed platelet sensitization to ADP, particularly at low ADP levels. Increased platelet activity was detectable seven days after clopidogrel cessation and remained higher than in controls 28 days after discontinuation. No clinical event occurred in any of the participants during the 28 days following clopidogrel cessation. In conclusion, platelet sensitization to ADP as a consequence of chronic clopidogrel administration may partially explain the recrudescence of ischemic events following clopidogrel discontinuation in otherwise stable coronary artery patients.

Benefit of clopidogrel therapy in patients with myocardial infarction and chronic kidney disease-a Danish nation-wide cohort study.

BackgroundThe aim of the present study was to evaluate clopidogrel treatment after incident myocardial infarction (MI) in patients with and without chronic kidney disease (CKD).Methods and ResultsBy linking nation‐wide registries, information about patients admitted with incident MI was found. Primary endpoints were all‐cause and cardiovascular (CV) mortality, a composite of all‐cause mortality and recurrent MI, and a composite of fatal and nonfatal bleedings. Effect of clopidogrel use versus clopidogrel nonuse was estimated using an adjusted Cox's regression model stratified according to percutaneous coronary intervention (PCI) treatment.A total of 69 082 incident MI patients in the period 2002–2011 were included. Clopidogrel treatment was associated with hazard ratios (HRs) for the combined endpoint of all‐cause mortality and recurrent MI in PCI‐treated patients of 0.90 (95% confidence interval [CI], 0.47 to 1.72) in renal replacement therapy (RRT) patients, 0.59 (95% CI: 0.40 to 0.88) in non‐end‐stage CKD patients and 0.69 (95% CI, 0.61 to 0.77) in patients without kidney disease (P for interaction=0.60). In patients not treated with PCI, HRs were 0.90 (95% CI, 0.68 to 1.21) in RRT patients, 0.86 (95% CI, 0.75 to 0.99) in non‐end‐stage CKD patients, and 0.91 (95% CI, 0.87 to 0.95) in patients without kidney disease (P for interaction=0.74). An increase in bleeding events (not significant) was noted for clopidogrel‐treated patients not undergoing PCI and for non‐end‐stage CKD patients undergoing PCI, whereas clopidogrel was associated with less bleedings in PCI‐treated RRT patients and patients without kidney disease.ConclusionsDuring a 1‐year follow‐up, after MI, clopidogrel was associated with improved outcomes in patients with non‐end‐stage CKD. Even though no effect difference, compared to patients without CKD, was observed, the benefit associated with the use of clopidogrel after MI in patients requiring RRT is less clear.

P-006 Initial Response to Aspirin Therapy Measured with the PFA-100 Assay in Patients Undergoing Endovascular Treatment of Unruptured Cerebral Aneurysms

Background and purposeRecent studies have examined the variability in response to clopidogrel therapy in patients undergoing endovascular treatment of unruptured cerebral aneurysms; however, no study has systematically assessed patient response...

Effects of Clopidogrel Therapy on Oxidative Stress, Inflammation, Vascular Function, and Progenitor Cells in Stable Coronary Artery Disease

Traditional cardiovascular risk factors lead to endothelial injury and activation of leukocytes and platelets that initiate and propagate atherosclerosis. We proposed that clopidogrel therapy in patients with stable coronary artery disease imparts a pleiotropic effect that extends beyond antiplatelet aggregation to other atheroprotective processes. Forty-one subjects were randomized in a double-blind, placebo-controlled, crossover study to receive either clopidogrel 75 mg daily or placebo for 6 weeks and then transitioned immediately to the other treatment for an additional 6 weeks. We assessed (1) endothelial function as flow-mediated dilation of the brachial artery, (2) arterial stiffness and central augmentation index using applanation tonometry, (3) vascular function as fingertip reactive hyperemia index, (4) inflammation by measuring plasma CD40 ligand and serum high-sensitivity c-reactive protein levels, (5) oxidative stress by measuring plasma aminothiols, and (6) circulating progenitor cells, at baseline and at the end of each 6-week treatment period. Clopidogrel therapy resulted in a significant reduction in soluble CD40 ligand (P = 0.03), a prothrombotic and proinflammatory molecule derived mainly from activated platelets. However, clopidogrel therapy had no effect on endothelial function, arterial stiffness, inflammatory and oxidative stress markers, or progenitor cells. Our findings suggest a solitary antiplatelet effect of clopidogrel therapy in patients with stable coronary artery disease, with no effect on other subclinical markers of cardiovascular disease risk.

Clinical Implications and Correlates of Q Waves in Patients With ST‐Elevation Myocardial Infarction Treated With Fibrinolysis: Observations from the CLARITY‐TIMI 28 Trial

The relationships between Q waves that appear during the acute phase of ST-elevation myocardial infarction (STEMI), clinical characteristics, ST-segment resolution (STRes), and clopidogrel therapy in patients treated with fibrinolysis are not well described. We hypothesized that Q waves would be associated with less successful reperfusion and increased cardiovascular events. In the CLARITY-TIMI 28 trial, 3491 STEMI patients treated with fibrinolysis were randomized to clopidogrel or placebo. Electrocardiograms were evaluated for STRes post-fibrinolysis and the presence of pathologic Q waves during the index hospitalization in 3322 patients. Q waves were identified in 2045 patients (61.6%) prior to discharge and were associated with increased odds of congestive heart failure (CHF) (adjusted odds ratio [ORadj ]: 2.10, P = 0.002) or the composite of cardiovascular death/CHF at 30 days (ORadj : 2.08, P ≤ 0.001). Q waves were associated with lower odds of Thrombolysis in Myocardial Infarction [TIMI] flow grade 2 to 3 (ORadj : 0.78, P = 0.028), TIMI myocardial perfusion grade 3 (ORadj : 0.83, P = 0.029), and complete STRes at 90 minutes (ORadj : 0.80, P = 0.030). Patients with both a Q wave and incomplete STRes 90 minutes after fibrinolysis were at higher risk for cardiovascular death or CHF (11.1%) than patients with no Q wave and at least partial STRes (1.9%). Overall, clopidogrel tended to be equally or more effective in patients without Q waves compared to those with Q waves. Among STEMI patients treated with fibrinolysis, evaluating for Q waves prior to discharge is a simple method of assessing for less successful reperfusion and an increased risk of adverse 30-day cardiovascular outcomes. The combination of Q waves and 90-minute STRes allows additional risk refinement.

Impact of Cigarette Smoking on P2Y12 Receptor Binding Activity Before and After Clopidogrel Therapy in Patients with Coronary Artery Disease

Smoking enhances the P2Y12 receptor inhibitory effects of clopidogrel. Nicotine increases P2Y12 receptor expression in platelet lysates from healthy volunteers. However, the impact of cigarette smoking on platelet P2Y12 receptor binding in clopidogrel-treated patients with coronary artery disease (CAD) is unknown. Clopidogrel-naïve patients with stable CAD (n = 20) were enrolled and stratified according to smoking status. P2Y12 receptor binding activity was determined by radioligand receptor binding prior and 24h after a 600-mg loading dose of clopidogrel. Baseline P2Y12 receptor binding was 1.8-fold higher in smokers compared with nonsmokers. After a 600-mg loading dose of clopidogrel, smokers showed a 6.4-fold reduction in P2Y12 receptor binding indicative of marked clopidogrel-mediated blockade, while there were minimal changes among nonsmokers. Among patients with stable CAD, smokers have more P2Y12 receptor binding than nonsmokers and have a higher degree of clopidogrel-mediated platelet inhibition.

Variability in initial response to standard clopidogrel therapy, delayed conversion to clopidogrel hyper-response, and associated thromboembolic and hemorrhagic complications in patients undergoing endovascular treatment of unruptured cerebral aneurysms

Background and purposeVariability in response to clopidogrel therapy is increasingly being recognized as an important factor in thromboembolic and hemorrhagic complications encountered after neurointerventional procedures. This study aims to determine...

A Randomized Controlled Trial of Platelet Activity Before and After Cessation of Clopidogrel Therapy in Patients With Stable Cardiovascular Disease

The aim of this randomized placebo-controlled trial was to determine if withdrawing clopidogrel therapy leads to increased platelet activity compared with pre-treatment values in patients with stable coronary artery or peripheral arterial disease. Reports of increased cardiovascular events after planned cessation of clopidogrel therapy have raised concerns over the possible existence of a rebound in platelet activity. In all, 171 patients receiving established aspirin therapy were randomly assigned to placebo or clopidogrel (75 mg daily) for 28 days. Blood samples were taken at pre-treatment baseline, on treatment just before discontinuation of study drug, and on days 7, 14, and 28 after discontinuation. The primary outcome measure was adenosine diphosphate (ADP)-stimulated platelet fibrinogen binding. Six secondary outcomes were assessed: ADP-stimulated platelet P-selectin, unstimulated platelet fibrinogen binding, and light transmission aggregometry with ADP 5 and 10 μmol/l recorded at maximum and at 6 min. The ADP-stimulated platelet fibrinogen binding, P-selectin expression, and platelet aggregation were lower on treatment with clopidogrel compared with baseline (p< 0.0001), but returned to baseline levels by 7 days after discontinuation. Mixed model analyses excluding the on-treatment timepoint showed no overall differences between the clopidogrel and placebo groups (p > 0.05). Furthermore, there was no evidence of an interaction between platelet inhibition over time and treatment allocation. This trial found no evidence for rebound of platelet activity to above baseline after stopping clopidogrel in patients with stable coronary artery disease or peripheral arterial disease. (Is Cessation of Clopidogrel Therapy Associated With Rebound of Platelet Activity in Stable Vascular Disease Patients?; ISRCTN77887299/77887299).

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CYP2C19 Poor Metabolizer Is Associated With Clinical Outcome of Clopidogrel Therapy in Acute Myocardial Infarction But Not Stable Angina

More intensive platelet suppression is required in patients with acute myocardial infarction (AMI) than in those with stable angina because of differential platelet activation between AMI and stable angina. In this context, CYP2C19 genotype leading to reduced active metabolite formation may profoundly affect the clinical outcome of clopidogrel therapy in patients with AMI compared with those with stable angina. Effects of CYP2C19 genotypes on the clinical outcome of clopidogrel therapy were evaluated in 2188 patients (532 patients with AMI and 1656 patients with stable angina) undergoing percutaneous coronary intervention. The primary clinical outcome was a composite of major adverse cardiac and cerebrovascular events defined as death from any cause, nonfatal myocardial infarction, or stroke during 1 year of clopidogrel therapy. Compared with extensive metabolizer, the CYP2C19 poor metabolizer was significantly associated with higher risk of major adverse cardiac and cerebrovascular events in patients with AMI (hazard ratio, 2.88; 95% confidence interval, 1.27-6.53; P=0.011). However, this finding was not seen in patients with stable angina. A significant interaction between CYP2C19 genotypes and disease subsets of AMI and stable angina was identified with respect to major adverse cardiac and cerebrovascular events (adjusted interaction P=0.045). The patients with AMI showed lower percent inhibition of P2Y12 compared with patients with stable angina in CYP2C19 poor metabolizer or CYP2C19 intermediate metabolizer genotype groups but not in CYP2C19 extensive metabolizer genotype group. CYP2C19 poor metabolizer is associated with poor clinical outcome of clopidogrel therapy in Asian patients with AMI but not in those with stable angina possibly because of differential requirement of platelet suppression in patients with AMI and stable angina. URL: clinicaltrials.gov. Identifier: NCTO1239914.

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Usefulness of the baseline lymphocyte count to predict platelet reactivity during clopidogrel therapy in patients with stable angina pectoris

Usefulness of the baseline lymphocyte count to predict platelet reactivity during clopidogrel therapy in patients with stable angina pectoris

Prolonged clopidogrel use improves clinical outcomes following drug eluting but not bare metal stent implantation

Purpose: Current guidelines recommend clopidogrel for 6-12 months following drug eluting stent (DES) implantation. The role of clopidogrel beyond 12 months is unclear. Methods: We linked hospital administrative, community pharmacy and cardiac revascularization data to determine clopidogrel use and outcomes for all patients receiving a coronary stent in British Columbia 2004 - 2006 with follow-up to 5 years. Cox proportional hazard regression analysis was performed to determine the effect of prolonged clopidogrel use (>12 months) on outcomes. Patients who died ≤12 months from index stent placement were excluded. Results: 15,629 patients were included in the study. Of 3,599 patients who received at least 1 DES and 12030 patients who received only bare metal stents (BMS), 1326 (37%) and 2121 (18%) respectively filled a prescription for clopidogrel >12 months from the index procedure. The mean duration of clopidogrel prescription in patients who received clopidogrel >12 months was 406±35 days in the DES group and 407±37 days in the BMS group, compared with 217±115 days (p<0.0001) and 117±116 days (p<0.0001) respectively for those who did not. Compared with ≤12 months clopidogrel, prolonged clopidogrel use was associated with a reduction in mortality (HR 0.67, 95% CI [0.46–0.98], p=0.038), mortality and readmission for myocardial infarction combined (HR 0.70, 95% CI [0.54–0.92], p=0.01) and an indication of a reduction in readmission for myocardial infarction alone (HR 0.70, 95% CI [0.49–1.00], p=0.051) in patients treated with DES, but not with BMS alone. ![Figure][1] Conclusions: In contrast to BMS, clopidogrel use beyond 12 months following DES implantation was associated with improved clinical outcomes. Our data support a longer duration of clopidogrel therapy for patients treated with DES. [1]: pending:yes

Abstract 285: Impact of Prescription Refill Reminders for Clopidogrel Therapy in Patients Receiving Drug-Eluting Stents

Purpose: Premature discontinuation of antiplatelet therapy in ACS patients receiving a drug-eluting stent (DES) can be associated with increased morbidity and mortality. The purpose of this study was to determine if refill notification reminders for clopidgrel by a pharmacist would improve long term adherence and outcomes for patients receiving a DES. Methods: A prospective, randomized, controlled study was conducted to evaluate adherence to clopidogrel for up to one year in ACS patients receiving a DES. Patients randomized to the Pharmacist Reminder group were contacted by a pharmacist on a monthly basis with a refill reminder for their clopidogrel prescription and the ability to discuss any medication issues. Patients randomized to the No Reminder group did not receive any refill reminder notification from a pharmacist. Both groups were contacted at 6 and 12 months to complete a follow-up survey. Pharmacy refill records were evaluated to determine monthly adherence and actual out-of-pocket expenses for clopidogrel up to one year after enrollment. Adherence was assessed by both the proportion of months covered (PMC) and complete continuous adherence over 1 year. A PMC of &gt;80% was considered adherent. Patients were enrolled from September 2007 to August 2009. Assuming premature discontinuation rates of 5% and 14% for Pharmacist Reminder and No Reminder groups respectively, 120 patients were required to detect significance with an alpha level of 0.05 and a power of 0.80. Results: A total of 114 patients were enrolled in the study with 53% (N=60) patients in the No Reminder group and 47% (N=54) in the Pharmacist Reminder group. The majority of patients were male (75%) with an average age of 62 years. Approximately 18% had a previous stent and had taken clopidogrel previously. Of the total population, 89% were adherent (102/114) with a PMC &gt;80%, 2.6% (3/114) had a PMC 60-79%, and 7.9% (9/114) had a PMC &lt;60%. Similarly, 88% (100/114) had complete continuous adherence to clopidogrel over 1 year. More patients in the Pharmacist Reminder group had continuous adherence to clopidogrel over 1 year (91% vs. 85%, p=NS) and a PMC &gt;80% (93% vs. 87%, p=NS) compared to the No Reminder group. More patients who were not adherent to clopidogrel reported recent hospitalizations through follow-up (33% vs. 10%, p=NS). No significant improvement in long term adherence to clopidogrel was found through pharmacist reminder on a monthly basis, however the enrollment goal was not met and other factors could have influenced adherence. Conclusions: For patients receiving a DES for ACS, 1 in 9 patients was nonadherent to clopidogrel at 1 year. Pharmacist refill reminder can positively impact long term adherence to clopidogrel. Nonadherence to clopidgrel was associated with a higher rate of hospitalization. Further research is necessary to determine which factors impact long term adherence to clopidogrel in patients receiving a DES.

Impact of clinical factors on response to clopidogrel therapy in patients with acute coronary syndrome

Background A heterogeneous platelet reactivity response to clopidogrel exists, and the clinical or biochemical predictors of suboptimal response to clopidogrel remain unclear. Objectives The goal of this study was to identify factors associated with higher platelet aggregation following clopidogrel therapy in subjects with acute coronary syndrome (ACS). Methods This study was conducted on 62 subjects with ACS requiring treatment with clopidogrel (75 mg daily for 7 days or more). The subjects were divided into diabetic and non diabetic groups. Chrono-log Aggergometer Series 490 used to estimate platelet aggregation. Factors associated with lower response to clopidogrel were identified. Results A heterogeneous, normally distributed platelet aggregation (mean 38.58 ± 18.6%) was observed in 62 subjects (age 56.13 ± 7.9 years; 66.1% men). Statistical analysis revealed significant increased platelet aggregation in patients with history of coronary artery disease (CAD) (44.17 ± 16.3 vs 31.33 ± 19.17, p = 0.006), hypertension (44.47 ± 18.79 vs 31.43 ± 15.91, p = 0.005) and body mass index (BMI) ⩾ 5 kg/m 2 (42.54 ± 17.6 vs 27.19 ± 17.04, p = 0.004). Diabetic patients demonstrated a trend to lower response to clopidogrel treatment with platelet aggregation (42.87 ± 18.54) compared to non diabetic patients (34.29 ± 17.93) but this did not reach a statistical significance ( p = 0.069). Positive correlations were found between platelet aggregation % and the level of fasting blood sugar ( P p = 0.023) and BMI ( P = 0.005). Conclusions Hypertension, past history of CAD, BMI ⩾25 kg/m 2 and diabetes mellitus are associated with higher platelet aggregation following clopidogrel treatment in patients with ACS. Positive correlations were found between platelet aggregation and the level of fasting blood sugar, body weight and BMI in those patients.

Platelet Function During Extended Prasugrel and Clopidogrel Therapy for Patients With ACS Treated Without Revascularization

The relationship of platelet function testing measurements with outcomes in patients with acute coronary syndromes (ACS) initially managed medically without revascularization is unknown. To characterize the differences and evaluate clinical outcomes associated with platelet reactivity among patients with ACS treated with clopidogrel or prasugrel. Patients with medically managed unstable angina or non-ST-segment elevation myocardial infarction were enrolled in the TRILOGY ACS trial (2008 to 2011) comparing clopidogrel vs prasugrel. Of 9326 participants, 27.5% were included in a platelet function substudy: 1286 treated with prasugrel and 1278 treated with clopidogrel. Aspirin with either prasugrel (10 or 5 mg/d) or clopidogrel (75 mg/d); those 75 years or older and younger than 75 years but who weighed less than 60 kg received a 5-mg prasugrel maintenance dose. Platelet reactivity, measured in P2Y12 reaction units (PRUs), was performed at baseline, at 2 hours, and at 1, 3, 6, 12, 18, 24, and 30 months after randomization. The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke through 30 months. Among participants younger than 75 years and weighing 60 kg or more, the median PRU values at 30 days were 64 (interquartile range [IQR], 33-128) in the prasugrel group vs 200 (IQR, 141-260) in the clopidogrel group (P < .001), a difference that persisted through all subsequent time points. For participants younger than 75 years and weighing less than 60 kg, the median 30-day PRU values were 139 (IQR, 86-203) for the prasugrel group vs 209 (IQR, 148-283) for the clopidogrel group (P < .001), and for participants 75 years or older, the median PRU values were 164 (IQR, 105-216) for the prasugrel group vs 222 (IQR, 148-268) for the clopidogrel group (P < .001). At 30 months the rate of the primary efficacy end point was 17.2% (160 events) in the prasugrel group vs 18.9% (180 events) in the clopidogrel group (P = .29). There were no significant differences in the continuous distributions of 30-day PRU values for participants with a primary efficacy end point event after 30 days (n = 214) compared with participants without an event (n = 1794; P = .07) and no significant relationship between the occurence of the primary efficacy end point and continuous PRU values (adjusted hazard ratio [HR] for increase of 60 PRUs, 1.03; 95% CI, 0.96-1.11; P = .44). Similar findings were observed with 30-day PRU cut points used to define high on-treatment platelet reactivity-PRU more than 208 (adjusted HR, 1.16; 95% CI, 0.89-1.52, P = .28) and PRU more than 230 (adjusted HR, 1.20; 95% CI, 0.90-1.61; P = .21). Among patients with ACS without ST-segment elevation and initially managed without revascularization, prasugrel was associated with lower platelet reactivity than clopidogrel, irrespective of age, weight, and dose. Among those in the platelet substudy, no significant differences existed between prasugrel vs clopidogrel in the occurence of the primary efficacy end point through 30 months and no significant association existed between platelet reactivity and occurrence of ischemic outcomes. clinicaltrials.gov Identifier: NCT00699998.

PCV18 Evaluation of Response to Loading Doses of Clopidogrel Therapy in Patients Undergoing Percutaneous Coronary Intervention (PCI)

Coronary artery diseases constitute a major health problem in many parts of the world and are an important cause of morbidity and mortality. It is predicted that by the year 2020, CAD will be the main cause of disability worldwide. In Egypt and other deve

Short- Versus Long-Term Duration of Dual-Antiplatelet Therapy After Coronary Stenting

Background— The optimal duration of dual-antiplatelet therapy and the risk-benefit ratio for long-term dual-antiplatelet therapy after coronary stenting remain poorly defined. We evaluated the impact of up to 6 versus 24 months of dual-antiplatelet therapy in a broad all-comers patient population receiving a balanced proportion of Food and Drug Administration–approved drug-eluting or bare-metal stents. Methods and Results— We randomly assigned 2013 patients to receive bare-metal, zotarolimus-eluting, paclitaxel-eluting, or everolimus-eluting stent implantation. At 30 days, patients in each stent group were randomly allocated to receive up to 6 or 24 months of clopidogrel therapy in addition to aspirin. The primary end point was a composite of death of any cause, myocardial infarction, or cerebrovascular accident. The cumulative risk of the primary outcome at 2 years was 10.1% with 24-month dual-antiplatelet therapy compared with 10.0% with 6-month dual-antiplatelet therapy (hazard ratio, 0.98; 95% confidence interval, 0.74–1.29; P =0.91). The individual risks of death, myocardial infarction, cerebrovascular accident, or stent thrombosis did not differ between the study groups; however, there was a consistently greater risk of hemorrhage in the 24-month clopidogrel group according to all prespecified bleeding definitions, including the recently proposed Bleeding Academic Research Consortium classification. Conclusions— A regimen of 24 months of clopidogrel therapy in patients who had received a balanced mixture of drug-eluting or bare-metal stents was not significantly more effective than a 6-month clopidogrel regimen in reducing the composite of death due to any cause, myocardial infarction, or cerebrovascular accident. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00611286.

Platelet proteome and clopidogrel response in patients with stable angina undergoing percutaneous coronary intervention

We analyzed the platelet proteome of circulating platelets during the onset of clopidogrel therapy in patients with stable angina underwent percutaneous coronary intervention in order to investigate the mechanisms that control platelet reactivity and clopidogrel response in this context. Twenty patients were enrolled in this study. Blood samples were collected before coronary angiography (T0), 12 h after 600 mg of clopidogrel (T1) and 24 h after percutaneous coronary intervention (PCI) (T2). Platelet reactivity, Clopidogrel response and proteomic analysis were examined. Clopidogrel loading dose produced a significant inhibition in all markers of platelet activation in both flow cytometry and aggregation tests. Among the proteins found differentially expressed, eighteen were identified by MS/MS analysis and they resulted involved in the cytoskeleton rearrangement (profilin-1, calpain, α-soluble NSF attachment protein, thrombospondin), in the energetic metabolism (ubiquitin-like modifier-activating enzyme 1, protein-L-isoaspartate-(D-aspartate) O-methyltransferase and nucleoside diphosphate kinase B) and in the oxidative stress (heat shock 70 kDa protein 5 and anti-stress induced phosphoprotein 1. The present study provides novel information on platelet proteome changes associated with platelet activation and clopidogrel response. This investigation supports the development of further proteomic studies for the identification of novel platelet biomarkers.