Long-term Clopidogrel Therapy Research Articles

The Effects of Clopidogrel Duration on Carotid Artery In-Stent Restenosis

ObjectiveThere is limited data supporting a specific duration for dual antiplatelet therapy in carotid artery stenting (CAS), and most clinical evidence is derived from studies involving coronary interventions. As a result, the appropriate duration of dual antiplatelet therapy after CAS has yet to be determined. We aimed to elucidate whether the duration of dual antiplatelet therapy played a role in the rate of carotid in-stent restenosis. MethodsA retrospective analysis of all patients who underwent CAS at our institution over a 20-year period (1996-2016) was performed (n=279). Patients who did not complete their follow-up duplex studies or were not discharged on clopidogrel were excluded from the study. Patients were separated into short-term (<6 weeks, n=159) and long-term (>6 weeks, n=112) clopidogrel users based on duration of therapy. We defined clinically significant in-stent restenosis as >50% restenosis (PSV = 224 cm/s) in symptomatic patients and >80% restenosis (PSV = 325 cm/s) in asymptomatic patients status-post prior CAS based on published velocity criteria. Rates of in-stent restenosis at 1-year, 2-year, and 5-year intervals were analyzed between the two groups using chi-squared analysis. ResultsDemographic information was largely similar between the two groups; however, short-term clopidogrel users were more likely to have a history of atrial fibrillation (9.43% vs. 1.68%, p=0.008) and were less likely to have a history of CABG (16.35% vs. 29.41%, p=0.009), diabetes (33.34% vs. 49.58%, p=0.006) and CAD (50.31% vs. 63.03%, p=0.035). All patients were on long-term aspirin therapy. There was no significant difference between overall rates of in-stent restenosis between the short-term and long-term clopidogrel users (5.03% vs. 9.24%, p=0.168) within 5 years of the index procedure. Similar results were observed when these groups were evaluated at 1-year (5.61 % vs. 3%, p=0.321), 2-year (2.02% vs. 6.59%, p=0.072), and 5-year (2.24% vs. 3.57%, p=0.635) follow-up. ConclusionNo statistically significant difference was observed in the rate of in-stent restenosis after CAS between short-term and long-term clopidogrel therapy. Patients in whom there is no other indication for longer duration clopidogrel therapy may be considered for shorter duration course of dual antiplatelet therapy following CAS.

Cytochrome P450 2C19*2 Genetic Polymorphism in Patients with Acute Coronary Syndrome

Objectives: The study aimed to investigate the association between CP2C19*2 loss of function polymorphism and acute coronary syndrome (ACS) patients receiving Clopidogrel. It compared genotype frequencies of heterozygous GA, homozygous GG, and homozygous AA between ACS patients and healthy controls. The study assessed the statistical significance of the association in the Pakistani cohort. It contributed to understanding the role of genetic polymorphisms in response to Clopidogrel therapy in ACS patients and provided insights into the need for pharmacogenomics testing for patients with CAD, particularly in the Asian population, who are poor metabolizers and require long-term Clopidogrel therapy.&#x0D; Methodology: COHORT Study.&#x0D; Results: The study found no statistically significant association between the CYP2C19*2 loss of function polymorphism and acute coronary syndrome (ACS) in the Pakistani cohort. The frequency of the CP2C19*2 heterozygous GA genotype was 38.3% in ACS patients and 29.5% in control subjects, while the homozygous GG genotype was 58.7% in patients and 59.0% in controls. The homozygous AA genotype was 3.4% in patients and 11.4% in controls.&#x0D; The genotype frequency analysis showed that the wild type GG genotype was lower in patients (58.7%) compared to controls (59.0%), while the mutant AA genotype was also lower in patients (3.4%) compared to controls (11.4%). The heterozygous GA genotype was higher in patients (38.3%) compared to controls (29.5%).&#x0D; The population studied was in Hardy Weinberg equilibrium, with a frequency of mutant allele A at 0.26 and wild type allele G at 0.73.&#x0D; Conclusion: The study concludes that the CYP2C19*2 loss of function polymorphism is not associated with acute coronary syndrome (ACS) in the Pakistani cohort. The distribution of the CP2C19*2 genetic polymorphism was not statistically significant between ACS patients and healthy controls.&#x0D; The genotype frequency analysis showed no significant differences in the distribution of the heterozygous GA, homozygous GG, and homozygous AA genotypes between the patient and control groups.&#x0D; The population studied was in Hardy Weinberg equilibrium, with a frequency of mutant allele A at 0.26 and wild type allele G at 0.73.

Treatment Outcomes of Clopidogrel in Patients With ACS and Diabetes Undergoing PCI-Analysis of Beijing Municipal Medical Insurance Database.

Background and AimsSeveral clinical trials have proved the efficacy of clopidogrel treatment for patients with percutaneous coronary intervention. There are few large-scale studies to identify the mortality associated with different durations of treatment of clopidogrel in patients with diabetes and ACS undergoing PCI in the Chinese population. The objective of this analysis was to determine the efficacy of long-term clopidogrel therapy (≥12 months) versus short-term use (<12 months) in Chinese patients with diabetes after PCI.Methods and ResultsWe used the Beijing Municipal Medical Insurance Database provided by the Beijing Municipal Medical Insurance Bureau. The Beijing Municipal Medical Insurance Database contained medical data of about 16 million people, including about 990,000 patients with diabetes and a history of taking antidiabetic medicines. Patients were divided into two groups, one group of 9,116 patients receiving consecutive clopidogrel for one year or more, and another group of 3290 patients receiving consecutive clopidogrel for less than one year. The primary outcomes of this analysis were the risk of all-cause death, myocardial infarction, and revascularization. In patients with diabetes after PCI, long-term clopidogrel treatment was associated with a reduced risk of all-cause death (HR, 0.57[95%CI, 0.49-0.67], P<0.0001), myocardial infarction (HR, 0.79[95%CI, 0.68-0.93], P=0.0035) and an increased risk of angina (HR, 1.18[95%CI, 1.10-1.27], P<0.0001]) and revascularization (HR, 1.07[95%CI, 1.01-1.13], P=0.02]). There was no significant difference in the prevalence of all-cause re-hospitalization, diabetes-related re-hospitalization, and cerebrovascular re-hospitalization.ConclusionThe present study concluded that long-term dual antiplatelet therapy including clopidogrel and aspirin could decrease the risks of all-cause death, myocardial infarction. But it could increase the risks of angina and revascularization. Further studies should interpret the cause of this question.

Switching from clopidogrel to prasugrel resolves vascular inflammation in patients receiving long-term aspirin plus clopidogrel therapy after coronary stent implantation

Switching from clopidogrel to prasugrel resolves vascular inflammation in patients receiving long-term aspirin plus clopidogrel therapy after coronary stent implantation

Abstract TMP88: Cyp2c19 Polymorphisms Are Not Associated With the Long-term Clinical Outcomes in Stroke Patients Treated With Clopidogrel

Introduction: Active metabolite of clopidogrel blocks P2Y12 receptor and consequently reduces cardiovascular events (CVEs) in stroke patients. Since CYP2C19 is the major enzyme involved in the generation of active metabolite, several large-scale studies of the patients who mostly underwent percutaneous coronary intervention have indicated that the genotypes of CYP2C19 are associated with recurrent CVEs. However, reliable prospective data regarding this association in stroke patients are sparse. Methods: A multicenter, prospective cohort study of stable stroke patients receiving long-term clopidogrel therapy (for at least 28 days before enrollment) for the secondary prevention of CVEs was conducted at 14 hospitals in Japan. Between September 2010 and March 2012, 511 patients were enrolled and underwent CYP2C19 genotyping to identify loss-of-function polymorphisms (*2 and *3). On-treatment platelet reactivity was assessed by ADP-induced platelet aggregation and vasodilator-stimulated phosphoprotein (VASP) index. We followed all patients for 2 years to evaluate the association of CYP2C19 polymorphisms with the composite outcome including cardiac death, stroke, myocardial infarction and cerebral/carotid vascularization. Results: Median follow-up period was 728 days. Of 511 patients, 243 (48%) and 76 (15%) patients were classified as intermediate (IM:*1/*2 or *1/*3) and poor (PM:*2/*2, *2/*3, or *3/*3) metabolizers, respectively. The prevalence of IM/PM was substantially higher than that of studies on Caucasian populations. On-treatment platelet reactivity (mean±SD) assessed by ADP-induced platelet aggregation (52±18% in extensive metabolizer [EM:*1/*1], 60±16% in IM, and 69±71% in PM) or VASP index (43±15% in EM, 52±16% in IM, and 67±14% in PM) was significantly different among the groups (p&lt;0.0001). However, there was no significant difference in the incidence of the composite outcome among the groups (EM vs IM; hazard ratio [HR] 0.99 [95% CI 0.48—2.04], p=0.97, vs PM; HR 0.80 [0.26—2.51], p=0.70). Conclusions: Despite the significant association of CYP2C19 polymorphisms with on-treatment platelet reactivity, these parameters did not predict the recurrence of CVEs in stroke patients with long-term clopidogrel therapy.

A single-centre, randomised study on platelet reactivity after abrupt or gradual discontinuation of long-term clopidogrel therapy in patients after percutaneous coronary intervention.

Clinical studies have suggested increased risk of thrombotic events after planned cessation of clopidogrel therapy, due to increased platelet reactivity (platelet rebound); however, in many studies platelet function was not assessed before introducing clopidogrel. Patients who are scheduled to stop clopidogrel therapy, do it abruptly, so a gradual drug cessation might provide a beneficial treatment strategy. To determine whether a clopidogrel discontinuation results in platelet rebound hyperaggregability with increased activity compared to pre-treatment values and to assess whether abrupt or tapering clopidogrel cessation may affect platelet reactivity. Patients with stable coronary artery disease (n = 49), on chronic acetylsalicylic acid treatment, who underwent coronary angiography, and were scheduled for elective percutaneous coronary intervention with stent implantation were en-rolled. Patients were randomised to either a tapering clopidogrel discontinuation during a two-week period (tapering group, n = 25) or abrupt drug cessation (abrupt group, n = 24). After 12 months of dual antiplatelet therapy with clopidogrel and acetylsalicylic acid, we performed three follow-up visits with blood sampling. Platelet aggregation was assessed using a mul-tiple electrode aggregometer at inclusion, at cessation day, and seven and 14 days after complete clopidogrel discontinuation. The primary endpoint was the level of adenosine-diphosphate (ADP)-induced platelet aggregation. We also analysed platelet function in the ASPI test and platelet count as secondary endpoints. In 36 patients included in the main analysis, we found significant differences between the two study groups in the levels of ADP-induced platelet aggregation at days seven and 14 after cessation of clopidogrel (p = 0.004 and p = 0.04, respectively). In the abrupt group, platelet aggregation returned to the values similar to baseline at day seven. There were no significant differences between baseline, seven, and 14 days after drug cessation (p = 0.92 and p = 0.37, respectively). However, in the tapering group, ADP values at seven and 14 days after drug cessation were significantly decreased, comparing to baseline (p < 0.0001 and p = 0.009, respectively). For the ASPI test and platelet count we did not find significant differ-ences between the groups. All values returned to levels similar to the baseline. During the follow-up there were no serious cardiovascular events or bleedings. Tapering vs. abrupt discontinuation of clopidogrel treatment results in significantly lower platelet aggregation values after 14 days from complete drug cessation. We found no evidence of a platelet rebound effect.

Men with Lower HDL Cholesterol Levels have Significant Increment of Soluble CD40 Ligand and High-sensitivity CRP Levels Following the Cessation of Long-term Clopidogrel Therapy

The aim of this study was to examine whether the termination of long-term clopidogrel therapy results in a proinflammatory state and whether lipid parameters influence the inflammatory response after stopping the drug. A prospective, multicenter study was conducted among 200 patients with implanted coronary stents who received dual antiplatelet therapy for one year, without ischemic or bleeding events. According to the guidelines, clopidogrel was discontinued after one year. In all patients, the high-sensitivity C-reactive protein (hsCRP), soluble CD40 ligand (sCD40L) and lipid [total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C)] levels were measured twice: on the day of cessation of clopidogrel and 45 days after the termination of clopidogrel treatment. In men (n=151), the sCD40L serum levels were significantly higher 45 days after the discontinuation of clopidogrel (p=0.007), while the hsCRP levels were not significantly different (p=0.407). Furthermore, when analyzed across the HDL-C quartiles, the hsCRP and sCD40L values were found to be associated with the levels of HDL-C after the discontinuation of clopidogrel in men. In addition, the men in the first HDL-C quartile exhibited the most pronounced increase in the sCD40L levels (p=0.001) and had significantly higher hsCRP levels (p=0.001) compared to the subjects in the other quartiles. Other lipid parameters did not show any associations with the sCD40L or hsCRP levels. The discontinuation of clopidogrel is associated with higher increments in the sCD40L level, and a pronounced proinflammatory response is associated with a lower HDL-C concentration.

Discontinuation of Long-Term Clopidogrel Therapy Is Associated With Death and Myocardial Infarction After Saphenous Vein Graft Percutaneous Coronary Intervention

This study sought to examine the pattern of death and myocardial infarction (MI) after clopidogrel cessation in patients undergoing percutaneous coronary intervention (PCI) of the saphenous vein graft (SVG). The timing and incidence of adverse events by different durations of clopidogrel therapy after SVG PCI remain unknown. This is a cohort study of patients undergoing SVG PCI between 2000 and 2009, followed for all-cause mortality or MI after stopping clopidogrel. Incidence rates were calculated across different time periods after clopidogrel cessation. Adjusted incidence rate ratios (IRR) were calculated with multivariable regression (piecewise exponential and Poisson). There were 603 patients who underwent SVG PCI, of which 411 were event-free at the time of clopidogrel cessation. The incidence rate (95% confidence interval: [CI])/1,000 person-days of death or MI after stopping clopidogrel in the time intervals of 0 to 90 days, 91 to 365 days, and 1 to 2 years were 1.26 (95% CI: 0.93 to 1.70), 0.41 (95% CI: 0.30 to 0.56), and 0.41 (95% CI: 0.30 to 0.55), respectively. In multivariable analyses, the overall IRR (95% CI) for death or MI in the 0- to 90-day interval after stopping clopidogrel compared with the 91- to 365-day interval was 2.58 (95% CI: 1.64 to 4.07). Similar results were observed over a broad range of clopidogrel treatment durations (<6 months, 6 months to 1 year, 1 to 2 years, or >2 years). The results were also consistent across subgroups, including sex, stent type, stent diameter, PCI period, and diabetes status. When death alone was evaluated, there remained a significant increase in the event rate in the 0- to 90-day interval compared with the 91- to 365-day interval (IRR: 2.33; 95% CI: 1.32 to 4.11). A clustering of events was observed in the initial 0 to 90 days after clopidogrel cessation in all treatment durations of clopidogrel investigated after SVG PCI. These results might have important implications in high-risk cohorts undergoing PCI. Additional studies are needed to elucidate the mechanisms underlying the early clustering of events after clopidogrel cessation.

TCT-729 Discontinuation of Long-Term Clopidogrel Therapy is Associated with Death and Myocardial Infarction after Saphenous Vein Graft Percutaneous Coronary Intervention

TCT-729 Discontinuation of Long-Term Clopidogrel Therapy is Associated with Death and Myocardial Infarction after Saphenous Vein Graft Percutaneous Coronary Intervention

Impact of Anemia on Platelet Response to Clopidogrel in Patients Undergoing Percutaneous Coronary Stenting

High residual platelet reactivity (HRPR) on clopidogrel is a predictor of recurrent ischemic events in patients undergoing percutaneous coronary interventions (PCI). Significant intraindividual variability in platelet aggregation on repeat testing has been reported. To understand factors contributing to the variability in platelet aggregation testing, we examined clinical and laboratory elements linked to HRPR in 255 consecutive patients tested ≥12 hours after PCI using light transmission aggregometry (LTA) in response to adenosine diphosphate 5 μmol/L and VerifyNow P2Y12 assay (VNP2Y12; Accumetrics). HRPR was defined as >46% residual aggregation for LTA and >236 P2Y12 response units (PRUs) for VNP2Y12. On multivariate analysis the only variable independently associated with HRPR with both LTA and VNP2Y12 was laboratory-defined anemia. Prevalences of HRPR by LTA were 34.3% in anemic patients, 15.6% in patients with normal hemoglobin levels, and 59.8% versus 25.9% by VNP2Y12 (p <0.005 for the 2 comparisons). In a subgroup of 50 patients, testing was done before and after the clopidogrel loading dose. At baseline there were no differences in platelet aggregation with either assay; however, absolute decrease in reactivity after the clopidogrel load was significantly less in anemic patients compared to patients with normal hemoglobin (change in residual aggregation by LTA 15.8 ± 5.8% vs 28.8 ± 3.2%, p <0.05; change in PRU by VNP2Y12 56.5 ± 35.5 vs 145.0 ± 14.2 PRUs, p <0.05, respectively). In conclusion, anemia is an important contributor to apparent HRPR on clopidogrel and may explain some of the intraindividual variability of platelet aggregation testing.

Safety and Efficacy of Clopidogrel Reloading in Patients on Chronic Clopidogrel Therapy Who Present With an Acute Coronary Syndrome and Undergo Percutaneous Coronary Intervention

The clinical safety and efficacy of clopidogrel reloading in patients receiving long-term clopidogrel therapy who present with acute coronary syndromes and undergo percutaneous coronary intervention have not yet been evaluated. The study cohort comprised 1,368 consecutive patients receiving long-term clopidogrel therapy (75 mg/day) who had presented with acute coronary syndromes and underwent coronary artery stent implantation. In total, 926 patients were given a 600-mg clopidogrel loading dose (reload cohort) before cardiac catheterization, while 442 patients were not reloaded (no-reload cohort). Patients who had presented with cardiogenic shock or stable angina were excluded. The 2 cohorts were well matched for the conventional risk factors for coronary artery disease. The analyzed clinical end points of death (1.1% vs 0.9%, p = 0.77), death or Q-wave myocardial infarction (0.9% vs 0.9%, p = 1.0), target lesion revascularization (0.2% vs 0.8%, p = 0.45), target vessel revascularization (1.1% vs 1.1%, p = 1.0), and major adverse cardiac events (2.0% vs 1.8%, p = 0.8) were similar between the no-reload and reload groups at 30 days. The in-hospital rates of major bleeding and gastrointestinal bleeding were also similar between the 2 cohorts. There were no cases of definite stent thrombosis. In conclusion, patients receiving long-term clopidogrel therapy who present with acute coronary syndromes do not gain any clinical benefit from additional reloading with clopidogrel.

Safety of clopidogrel and proton pump inhibitors in patients undergoing drug-eluting stent implantation

A pharmacodynamic interaction between clopidogrel and proton pump inhibitors (PPIs) has been suggested, leading to reduced clopidogrel-induced platelet inhibitory effects. However, data from clinical studies are conflicting. The aim of this study was to evaluate the safety of long-term clopidogrel and PPI therapy. A total of 1328 consecutive patients (age 63±11 years; 81% male) undergoing drug-eluting stent implantation and 1-year follow-up were included. All patients were treated with a standard aspirin and clopidogrel treatment regimen for 12 months. The concomitant PPI therapy for the same duration was at the discretion of the clinical cardiologist. PPI therapy included lansoprazole (30 mg/day), pantoprazole (20 mg/day), or omeprazole (20 mg/day). At 1-year follow-up, major adverse cardiac events (MACE), defined as death, myocardial infarction (MI), acute coronary syndrome leading to hospitalization and nonfatal stroke, were recorded. All cause death, any stent thrombosis (ST), and bleeding (Thrombolysis in MI major and minor) were also assessed. Lansoprazole, pantoprazole, and omeprazole were administered to 855, 178, and 125 patients, whereas 170 were not prescribed any PPI therapy. Among patients treated with PPIs, those on pantoprazole had more often prior MI, multivessel coronary artery disease, and chronic kidney disease, whereas earlier peptic ulcer was more frequent among patients treated with omeprazole. The incidence of 1-year MACE was not statistically different between patients in the PPI and no-PPI groups (7.5 vs. 5.0%; P=0.26). Similarly, 1-year rates of all cause death, ST, and Thrombolysis in MI major and minor bleedings did not significantly differ. After statistical adjustment for potential confounders, the concomitant use of clopidogrel and PPIs was not associated with the risk of 1-year MACE [odds ratio (OR) 1.54, P=0.38], death (OR: 0.97, P=0.961), and ST (OR: 1.01, P=0.998). No differences across the three PPI types were found. The association of clopidogrel and PPIs after drug-eluting stent implantation, prescribed on clinical judgement, seems safe.

Discontinuation of long term clopidogrel therapy induces platelet rebound hyperaggregability between 2 and 6 weeks post cessation

Stent thrombosis occurs frequently within the first weeks after cessation of longterm clopidogrel therapy. We investigated if rebound platelet hyperreactivity occurs to provide a mechanism for this clinical observation. ADP- and TRAP-induced platelet aggregation was measured by impedance aggregometry in 28 patients with coronary stent implantation (observational group, OG) before and 1, 2, 6 and 17weeks after clopidogrel cessation. Data were compared intraindividually as well as to 67 controls (control group, CG). On-clopidogrel platelet activity was significantly reduced (ADP-stimulation, OG vs. CG, 30±3U vs. 67±3U, p<0.001) and reached control levels 1week after clopidogrel cessation (ADP-stimulation, OG vs. CG, 70±4U vs. 67±3U, p=n.s.). Most patients (57%) showed a significant platelet hyperaggregation after 2weeks (ADP, OG vs. CG, 83±6U vs. 67±3U, p=0.02) to 6weeks (ADP, OG vs. CG, 85±5U vs. 67±3U, p=0.01) post-cessation. This temporary hyperaggregability was also observed in intra-individual time courses (ADP, 2 vs. 17weeks, 83±6U vs. 73±4U, p=0.007; 6 vs. 17weeks, 85±5U vs. 73±4U, p=0.0002). After 17weeks post-cessation, ADP-induced platelet aggregation returned towards physiological levels. The total capacity of platelet aggregability as reflected by stimulation with thrombin receptor activating peptide (TRAP) was not different between time points confirming a clopidogrel-specific rebound effect. Abrupt clopidogrel cessation after 1year of clopidogrel treatment results in ADP specific platelet hyperreactivity between 2 and 6weeks post withdrawal. This mechanism may contribute to explain increased rates of stent thrombosis at this time as it was observed in clinical studies.

Intra-individual variability in clopidogrel responsiveness in coronary artery disease patients under long term therapy

Clopidogrel responsiveness (CR) following a loading dose (LD) predicts thrombotic events after percutaneous coronary interventions (PCI). Some of the mechanisms involved in large inter-individual variability in CR may be varied. We therefore postulated that there may be an intra-individual variability in CR. Two hundred and one patients receiving long-term therapy with aspirin and clopidogrel after drug-eluting stents PCI were prospectively included in this monocentre study along with any patient re-admitted within 12 months post-PCI. Platelet reactivity (PR) inhibition was assessed by the vasodilator phosphoprotein (VASP) index following a 600 mg loading dose of clopidogrel on each admission to determine CR (VASP 1 during the first admission and VASP 2 during re-admission). DeltaVASP = VASP 2 –VASP 1 was used to study intra-individual variability in CR. We observed that the response to a 600 mg LD of clopidogrel was poorly correlated within an individual (kappa = 0.33; p < 0.001 (n = 201)). Although most patients had increased platelet inhibition at the time of readmission, 35.3% of patients exhibited a decreased platelet inhibition despite chronic clopidogrel therapy and a 600 mg reload. Quartiles analysis of DeltaVASP demonstrated that insulin-treated diabetes was associated with decreased CR over time (p = 0.03). In addition to the large inter-individual variability in clopidogrel responsiveness, there is large intra-individual variability. Decreased clopidogrel responsiveness despite long-term clopidogrel therapy could be a trigger for recurrent thrombotic events.

Combination Antithrombotic Therapies

HomeCirculationVol. 121, No. 4Combination Antithrombotic Therapies Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBCombination Antithrombotic Therapies Paul A. Gurbel and Udaya S. Tantry Paul A. GurbelPaul A. Gurbel From the Sinai Center for Thrombosis Research, Baltimore, Md. Search for more papers by this author and Udaya S. TantryUdaya S. Tantry From the Sinai Center for Thrombosis Research, Baltimore, Md. Search for more papers by this author Originally published2 Feb 2010https://doi.org/10.1161/CIRCULATIONAHA.109.853085Circulation. 2010;121:569–583Atherothrombosis is the major pathophysiological process responsible for the occurrence of severe ischemic events in patients with cardiovascular diseases. In the United States, atherothrombosis strongly influenced mortality in 2004: One in 2.8 deaths was due to CVD, 1 in 5 deaths to coronary heart disease, and 1 in 17 deaths to stroke.1 Because cardiovascular disease is a progressive and systemic disease, long-term antithrombotic therapies that effectively target the entire arterial vasculature and modulate the key components responsible for thrombus generation are essential to improve patient outcomes. Because platelet activation is determined by multiple receptor-mediated signaling pathways, clinical studies have evaluated the efficacy of multidrug administration in the prevention of atherothrombotic complications.2,3 The major concern with these therapies is the critical balance between anti-ischemic effect and bleeding risk. This review summarizes our understanding of the role of combination antiplatelet therapies in the treatment and prevention of atherothrombosis.Pathophysiology of AtherothrombosisPlatelet activation and aggregation play a pivotal role in the generation of occlusive thrombus at the site of coronary arterial plaque rupture. In addition, platelets influence various endothelial and inflammatory responses during the initiation and progression of atherosclerosis. Under normal conditions, anucleate circulating platelets are in a quiescent state. Healthy vascular endothelium prevents adhesion and activation of platelets by producing antithrombotic factors such as CD39 (ectoADPase), prostaglandin I2, nitric oxide, heparin, matrix metalloproteinase-9, protein S, and thrombomodulin.3,4 Endothelial activation and denudation and frank atherosclerotic plaque rupture expose the subendothelial matrix and release prothrombotic factors during acute coronary syndromes (ACS) and percutaneous interventions. These processes result in localized platelet adhesion and platelet activation. After adhesion to the exposed subendothelial matrix, platelets are activated by shear and the soluble agonists thromboxane A2 (TxA2), ADP, and thrombin. TxA2 is produced from arachidonic acid, which originates from membrane phospholipids and binds to Tx receptors; ADP is secreted from dense granules and binds to P2Y12 and P2Y1 receptors. These 2 secondary agonists, through an autocrine and paracrine fashion, produce sustained activation of glycoprotein IIb/IIIa receptors, leading to stable platelet-rich thrombus generation. The ADP-P2Y12 interaction contributes most to ADP-induced aggregation measured by conventional aggregometry.5 Platelet activation also results in the membrane exposure of phosphatidyl serine, providing binding sites for coagulation factors. The coagulation process results in the generation of thrombin and subsequent platelet-fibrin clot formation.3 Endogenous phosphodiesterase (PDE) activity that affects intraplatelet cAMP levels also modulates platelet function (the Figure). Finally, isoprostanes derived from membrane arachidonic acid through peroxidation have been shown to induce platelet aggregation by activating the receptor for TxA2.6 Inhibition of PDE and cyclooxygenase (COX) may play a more important role in the treatment of peripheral and cerebrovascular disease, whereas antiplatelet therapy with clopidogrel and aspirin is the cornerstone of ACS and poststent treatment.7 Finally, the relative contribution of each pathway (ADP-platelet, TxA2-platelet, thrombin-platelet, coagulation, and PDE activity) to the development of thrombus formation in the individual patient is unknown. Therefore, despite immense research, determination of the optimal antiplatelet and antithrombotic therapy remains an elusive goal. The side effects observed during contemporary antithrombotic therapy may be related in part to the uniform dosing regimens used that ignore the inherent variability in the antiplatelet and antithrombotic response. Download figureDownload PowerPointFigure. Mechanism of action of oral antiplatelet drugs. Ticlopidine, clopidogrel, and prasugrel irreversibly block the P2Y12 receptor, whereas ticagrelor and elinogrel irreversibly block the P2Y12 receptor. Aspirin irreversibly inhibits the COX-1 enzyme and thereby attenuates TxA2 production and TxA2-medicated platelet response. SCH530348 and E5555 block the PAR-1 receptor, thereby inhibiting thrombin-mediated platelet response. PDE inhibitors such as cilostazol and dipyridamole stimulate synthesis of prostaglandin I2 (PGI2) and nitric oxide (NO) in endothelial cells and inhibit the active transport of adenosine into cells, particularly red blood cells. By stimulating adenylyl/guanylyl cyclase (AC/GC) activity in platelets, PGI2, NO, and adenosine all increase intracellular cAMP levels and thus attenuate platelet aggregation. AA indicates arachidonic acid; PI3K, phosphatidylinositol 3 kinase; ATP/GTP, adenosine triphosphate/guanosine triphosphate; VASP-P, vasodilator-stimulated phosphoprotein phosphorylation; GP, glycoprotein; PKA, phosphokinase A; and A2a receptor, adenosine 2a receptor.AspirinAspirin is the primary component of combination antiplatelet therapy. The antiplatelet effect of aspirin is attributed primarily to the irreversible inhibition of platelet COX-1 by acetylation of serine residue 529, resulting in a downstream reduction in the synthesis of TxA2 and consequent TxA2-induced platelet activation/aggregation. However, recent studies indicate that the antiplatelet effect of aspirin may also involve inhibition of pathways distinct from COX-1 (non–COX-1 pathways). In addition, aspirin is known to reduce thrombin generation, to enhance fibrin clot permeability and clot lysis, and to promote nitric oxide production in platelets. Aspirin also has antiinflammatory properties that may enhance its antithrombotic effect.8Recent pharmacodynamic studies have demonstrated that low-dose aspirin has variable effects in inhibiting platelet non–COX-1 pathways. The term “aspirin nonresponsiveness or resistant” has been used to describe selected patients, especially high-risk patients and diabetics, exhibiting high platelet function as measured by assays that are nonspecific in their assessment of COX-1 activity.9,10 Ischemic event recurrence is also higher in patients found to be aspirin resistant by COX-1–nonspecific assays.11,12 The dose dependence of aspirin in the inhibition of non–COX-1 pathways suggests that selected patients require a dose >81 mg to achieve an optimal antiplatelet effect. However, this observation conflicts with the results of meta-analyses demonstrating no conclusive clinical benefits of high-dose aspirin therapy.12,13Aspirin Dose and BleedingIn a recent meta-analysis of randomized controlled trials of low-dose aspirin (75 to 325 mg/d), aspirin treatment was associated with a 0.13% absolute increase in any major bleeding and a 0.12% increase in major gastrointestinal bleeding compared with placebo in cardiovascular disease patients. There was an increased relative risk (RR) of major bleeding (RR, 1.71; 95% confidence interval [CI], 1.41 to 2.08), major gastrointestinal bleeding (RR, 2.07; 95% CI, 1.61 to 2.66), and intracranial bleeding (RR, 1.65; 95% CI, 1.06 to 5.99). No difference in bleeding was observed in patients treated with 75 to 162.5 mg/d versus >162.5 to 325 mg/d.14ThienopyridinesBecause ADP plays a critical role in the amplification of platelet aggregation and the genesis of a stable occlusive thrombus, the inhibition of ADP-induced platelet activation was an early focus of alternative antiplatelet treatment. Moreover, drug intolerance, gastrointestinal bleeding, and treatment failure associated with aspirin therapy also stimulated the development of new antiplatelet agents. Thienopyridines are prodrugs that require metabolic activation by the cytochrome P450 pathway. The active metabolite forms a disulfide bond with the P2Y12 receptor, rendering the receptor unable to bind ADP and thus attenuating the subsequent response of the platelet to ADP.Aspirin Monotherapy Versus Thienopyridine MonotherapyTiclopidine was the first thienopyridine to be widely used clinically. In the Ticlopidine Aspirin Stroke Study (TASS), ticlopidine treatment (500 mg daily) was superior to aspirin (1300 mg QD) in reducing nonfatal stroke or death at 3 years (17% versus 19%; RR reduction [RRR], 12%; P=0.048) in patients with previous stroke.15 In the Ticlopidine Versus Aspirin After Myocardial Infarction (STAMI) trial, 1470 patients with acute myocardial infarction (MI) treated with thrombolysis received either aspirin (160 mg QD) or ticlopidine (500 mg QD) therapy. In that trial, there was no difference between the 2 treatment arms in primary combined end point of death, recurrent MI, stroke, or angina.16 In the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial, aspirin (325 mg QD) was compared with clopidogrel therapy (75 mg/d) in patients at risk for ischemic events, and an RRR of 8.7% was observed in clopidogrel-treated patients in the composite end point of MI, ischemic stroke, or vascular death17 (the Table). Most of the benefit was observed in patients with peripheral arterial disease. Although the overall safety profile was similar between the 2 groups, the aspirin-treated group had a greater rate of gastrointestinal bleeding (2.66% versus 1.99; RR, 1.34; 95% CI, 1.11 to 1.61; P<0.05).17 Subgroup analysis revealed that clopidogrel reduced the risk of acute MI (≈19%) more significantly than aspirin in both low- and high-risk patients.18 On the basis of the favorable results of the CAPRIE trial, the US Food and Drug Administration (FDA) approved the use of a 75-mg daily dose of clopidogrel for patients with a history of recent heart attack, recent stroke, or established peripheral arterial disease. Table. Important Clinical Trials Evaluating Clinical Efficacy of Clopidogrel and Aspirin TherapyTrialPatients (n)ProtocolEnd PointsOutcomeSafety OutcomeCLP indicates clopidogrel; ASA, aspirin; IS, ischemic stroke; GI, gastrointestinal; LD, loading dose; CV, cardiovascular; CAD, coronary artery disease; CVD, CV disease; PAD, peripheral vascular disease; US, unstable angina; and DM, diabetes mellitus.CAPRIE17Symptomatic atherosclerotic disease (19 185)75 mg CLP vs 325 mg ASA for median of 1.9 yFirst occurrence of IS, MI, or vascular deathRRR=8.7%; 95% CI=0.3–16.5; P=0.043No significant difference in rate of a bleeding disorder (9.28% vs 9.27%); ASA recipients had a greater rate of GI bleeding (2.66% vs 1.9%; P<0.05)CURE27ACS (12 562)300 mg LD+75 mg/d CLP-vs placebo+75–325 mg ASA for 3 to 12 moCV death, nonfatal MI, or strokeRR=0.8; 95% CI=0.72–0.90; P<0.001Significant increase in major bleeding (RR=1.38; 95% CI=1.13–1.67; P=0.0001) and minor bleeding (RR=2.12; 95% CI=1.75–2.56; P<0.001)PCI-CURE28PCI (2658)CLP vs placebo+ASACV death, nonfatal MI, or stroke4.5% vs 6.5%; RRR=30%; P=0.003CREDO29Symptomatic CAD patients (n=2116) undergoing PCI with and without stenting300 mg CLP vs placebo; 75 mg/d CLP+325/d ASA for 28 d; 75 mg CLP or placebo+81–325 mg ASA for 12 mo28-d CV death, MI, and urgent vessel revascularization; 1-y CV death, MI, and stroke; safety end point: modified TIMI major, minor, or insignificant28-d outcome (RRR=18.5%; 95% CI=−4.2–41.8; P=0.23); patients with CLP LD >6 h before PCI (RRR=38.6%; 95% CI=−1.6–62.9; P=0.051); 1-year outcome (RRR=26.9%; 95% CI=3.9–44; P=0.02)A trend toward increased major bleeding with CLP (8.8% vs 6.7%; P=0.07)CLARITY-TIMI 2830Patients within 12 h of STEMI receiving lytic therapy (3491)300 mg LD+75 mg MD CLP or placebo+ASA+ fibrinolyitc+heparinOccluded infarct artery, death, or recurrent MI (before angiography)RRR=36%; 95% CI=0.53–0.76; P<0.001TIMI-defined major bleeding and intracranial hemorrhage and TIMI minor bleedings were not statistically differentPCI-CLARITY31Patients treated with PCI (1863)Same as above30-d CV death, recurrent MI, or recurrent ischemia leading to urgent revascularizationRR=0.80; 96% CI=0.65-0.97; P=0.03.COMMIT32STEMI patients within 24 h of symptom onset (45 852)72 mg/d CLP+162 mg/d ASA+metoprolol vs 162 mg/d ASA+metoprolol for 4 wkDeath, infarction, or strokeOR=0.91; 95% CI=0.87–0.99; P=0.03No significant difference in composite of all transfused, fatal, or cerebral bleedings (0.58% vs 0.555%; P=0.59), but CLP increased minor bleeding (3.6% vs 3.1%; P=0.005)CHARISMA34Documented CAD, CVD, or PAD or ≥3 atherothrombotic risk factors (15 603)75–162 mg ASA+75 mg CLP vs 75–162 mg/d ASA+placebo–media for 28 moPrimary end point of first occurrence of MI, IS, or vascular death; secondary end point of hospitalization for UA, TIA, or revascularization procedurePrimary end point: RR=0.93; 95% CI=0.83–1.05; P=0.22; secondary end point: RR=0.92; 95% CI=0.85–0.995; P=0.004Increase in severe bleeding according GUSTO definition (RR=1.25; 95% CI=0.97–1.61; P=0.09) and rate moderate bleeding (RR=1.62; 95% CI=1.27–2.08; P<0.001)Posthoc analysis of CHARISMA35Patients with documented prior MI, IS, or symptomatic PAD75–162 mg ASA+75 mg CLP vs 75–162 mg/d ASA+placeboSame as aboveRRR=17%; 95% CI=4–28; P=0.01Nonsignificant increase in severe bleeding (RR=1.11; 95% CI=0.81–1.57; P=0.509)MATCH37Recent history of IS and TIA and previous MI, angina, DM, or symptomatic PAD (7599)75 mg/d CLP vs 75 mg/d CLP+75 mg/d ASA for 18 moIS, MI, vascular death, or rehospitalization for acute ischemic eventRRR=6.5%; 95% CI=−4.6–16.3; P=0.244More common major (2% vs 1%) and life-threatening (3% vs 1%) bleedings with CLP+ASAThienopyridine Plus Aspirin: StentingGiven the important contributions of P2Y12 and COX-1 to the amplification of platelet aggregation mediated by ADP and TxA2, respectively, it was hypothesized that simultaneous inhibition of both pathways would provide a superior antithrombotic effect compared with single pathway inhibition. Nonhuman primate investigations using exteriorized arteriovenous shunts treated with metallic endovascular stents demonstrated the enhanced antithrombotic effect of clopidogrel with the addition of aspirin.19 Subsequent investigations in human volunteers treated with aspirin and clopidogrel similarly demonstrated the synergistic effect of dual antiplatelet therapy compared with aspirin monotherapy in a perfusion chamber assay measuring ex vivo thrombus formation.20 However, the results of large-scale clinical trials of dual antiplatelet therapy confirmed what was expected from the laboratory observations and changed the treatment paradigm for many cardiovascular disease states. In these trials, thienopyridines added to aspirin therapy demonstrated the potent effect in the inhibition of ischemic events across the spectrum of cardiovascular disease settings.2In the Stent Anticoagulation Restenosis Study (STARS), a significant decrease in the combined end point of death, MI, acute MI, angiographically evident thrombosis, and revascularization of the target vessel within 30 days was observed in patients undergoing stenting randomized to aspirin plus ticlopidine therapy (0.55%) compared with aspirin therapy alone (3.6%) and aspirin plus warfarin therapy (2.7%; P<0.001 for the comparison of all groups).21 This important trial led the way for dual antiplatelet therapy to become the standard of care in patients undergoing coronary arterial stenting. Other studies of ticlopidine plus aspirin versus aspirin plus anticoagulation demonstrated concordant effects.22–24 All of these studies influenced a change in the antithrombotic treatment paradigm, and dual antiplatelet therapy became the standard of care for the poststent patient. However, unfavorable side effects (neutropenia, bone marrow aplasia, and thrombotic thrombocytopenic purpura) were associated with ticlopidine treatment, which led to the development of the second-generation thienopyridine, clopidogrel.25In the Clopidogrel Aspirin Stent Interventional Cooperative Study (CLASSICS), the safety of clopidogrel was compared with that of ticlopidine after successful coronary stenting. Treatment with clopidogrel 75 mg QD with or without a loading dose was associated with fewer major bleeding complications, less neutropenia, less thrombocytopenia, and early discontinuation of study drug because of noncardiac adverse events (4.6% versus 9.1%; P=0.005).26 Similar recurrent ischemic event rates were observed between groups. The results of CLASSICS influenced the nearly uniform use of clopidogrel as the thienopyridine of choice that continues today.Clopidogrel Plus Aspirin and Versus Aspirin MonotherapyAcute Coronary SyndromesThe major clinical trials evaluating the efficacy and safety of dual antiplatelet with clopidogrel and aspirin versus aspirin monotherapy in ACS are summarized in the Table. The first large-scale trial was the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study. Dual antiplatelet therapy of clopidogrel (300-mg loading dose followed by 75 mg/d) and aspirin (75 to 325 mg/d) in patients with unstable angina and non–ST-elevation acute MI (NSTEMI) was associated with a superior reduction in 9-month cardiovascular mortality, nonfatal MI, and stroke across a broad range of risk groups.27 In a subset analysis of the CURE study (PCI-CURE), there was a reduction in the risk of MI before percutaneous coronary intervention (PCI) and cardiovascular death or MI 4 weeks after PCI in patients receiving clopidogrel and aspirin pretreatment for up to 10 days and continuing on long-term treatment.28 The results of the CURE trial strongly influenced cardiologists to adopt the strategy of a 300-mg clopidogrel loading dose during PCI in all patients as the standard of care. This strategy was approved by the FDA for the treatment of patients with ACS. In the Clopidogrel for the Reduction of Events During Observation (CREDO) trial, there was a significantly reduced risk of adverse ischemic events with long-term clopidogrel therapy. However, substantial benefits of a prestent clopidogrel loading dose (300 mg) were seen only when administered >6 hours before PCI.29The Clopidogrel as Adjunctive Reperfusion Therapy–Thrombolysis in Myocardial Infarction (CLARITY-TIMI) 28 study investigated the efficacy of a 300-mg clopidogrel load/75 mg QD administered to patients within 12 hours of onset of an STEMI treated with fibrinolytic therapy. Clopidogrel therapy was associated with a 20% reduction (P=0.03) in the composite end point of cardiovascular death, reinfarction, or recurrent ischemia requiring urgent revascularization at 30 days.30 The PCI-CLARITY study examined 57% of the patients from CLARITY-TIMI 28 who underwent PCI and showed that clopidogrel pretreatment was also associated with a 46% reduction in the odds of cardiovascular death, recurrent MI, or stroke within 30 days with no significant increase in the incidence of bleeding complications. This benefit was observed regardless of glycoprotein IIb/IIIa inhibitor treatment or a loading dose of open-label clopidogrel at the time of PCI.30 It is also interesting that patients who were pretreated with a daily dose of 75 mg clopidogrel and received an additional loading dose of 300 mg at the time of PCI had the maximum protection against death, reinfarction, or stroke.31,32In the Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT) trial of acute STEMI patients, adjunctive clopidogrel therapy was associated with a modest but significant RRR in the primary end point of death, reinfarction, or stroke at hospital discharge and was not associated with an increased risk of major bleeding. The benefit of clopidogrel therapy was observed within the first 24 hours.33Primary and Secondary PreventionIn the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial, the efficacy and safety of long-term treatment with clopidogrel (75 mg QD) in addition to aspirin (75 to 162 mg QD) were compared with aspirin monotherapy (75 to 162 mg QD) in patients at high risk for cardiovascular events. Overall, there was a nonsignificant decrease in the primary end point of first occurrence of MI, stroke, or cardiovascular death, and a significant decrease in the secondary end point of hospitalization for unstable angina, transient ischemic attack (TIA), or a revascularization procedure (RR, 0.92; 95% CI, 0.85 to 0.995; P=0.04) in patients treated with dual antiplatelet therapy compared with aspirin monotherapy. At the same time, dual antiplatelet therapy was associated with a marginal increase in the primary safety end point of severe bleeding and a significant increase in the rate of moderate bleeding compared with aspirin monotherapy according to the Global Utilization of Streptokinase and tPa for Occluded Arteries (GUSTO) definition. In the predefined subgroup of patients with clinically evident atherothrombosis (symptomatic group), there was a statistically significant decrease in the primary end point observed with dual antiplatelet therapy compared with aspirin monotherapy but not in a subgroup of patients with multiple risk factors (asymptomatic group). In that analysis, moderate bleeding was increased nonsignificantly in asymptomatic patients but significantly in symptomatic patients (P<0.001).34 In another subgroup analysis of patients with documented prior MI, ischemic stroke, or symptomatic peripheral arterial disease (CAPRIE-like cohort), there was a significant reduction in the primary end point of cardiovascular death, MI, or stroke (hazard ratio [HR], 0.83; 95% CI, 0.72 to 0.96; P=0.01) associated with long-term clopidogrel plus aspirin treatment. Although there was no significant difference in the rate of severe bleeding, moderate bleeding was significantly increased with clopidogrel plus aspirin treatment (HR, 1.60; 95% CI, 1.16 to 2.20; P=0.0004).35Finally, a meta-analysis of 5 randomized trials (CURE, CREDO, CLARITY, COMMIT, and CHARISMA) in 79 624 patients demonstrated that the incidence of all-cause mortality was 6.3% in the aspirin plus clopidogrel group versus 6.7% in the aspirin group (odds ratio [OR], 0.94; 95% CI, 0.89 to 0.99; P=0.026). The incidence of MI was 2.7% and 3.3% (OR, 0.82; 95% CI, 0.75 to 0.89; P<0.0001) and of stroke was 1.2% and 1.4% (OR, 0.82; 95% CI, 0.73 to 0.93; P=0.002) in the clopidogrel plus aspirin versus aspirin group, respectively. Similarly, the incidence of major bleeding was 1.6% and 1.3% (OR, 1.26; 95% CI, 1.11 to 1.41; P<0.0001) and of fatal bleeding was 0.28% and 0.27% (OR, 1.04; 95% CI, 0.76 to 1.43; P=0.79) in the aspirin plus clopidogrel versus aspirin group alone, respectively.36Clopidogrel Plus Aspirin Versus Clopidogrel Monotherapy: TIA and StrokeIn the Management of Atherothrombosis With Clopidogrel in High-Risk Patients (MATCH) trial, there was no additional value of adding aspirin to clopidogrel in patients with a recent history of TIA or ischemic stroke who had >1 additional cardiovascular risk factor (ie, history of MI, angina, peripheral arterial disease, or diabetes mellitus; RRR, 6.4%; 95% CI, 4.6 to 16.3; P=0.24). However, significantly higher life-threatening bleeding (3% versus 1%; P<0.0001), specifically intracranial hemorrhage, was observed with clopidogrel therapy.37Thus, a clear net benefit of dual antiplatelet therapy was observed in a wide range of patients with ACS and in patients undergoing coronary stenting as a secondary prevention strategy. However, current data do not support its use in the primary prevention or treatment of cerebrovascular disease.Limitations of Clopidogrel Plus AspirinEarly pharmacodynamic studies evaluating the antiplatelet response during clopidogrel and aspirin therapy, especially in patients undergoing stenting treated with a 300-mg loading dose and a 75-mg maintenance dose of clopidogrel, revealed various limitations: a delayed antiplatelet response and overall modest degree of platelet inhibition (≈30% to 50%), normally distributed response variability, nonresponsiveness in a substantial percentage of patients, and irreversible platelet inhibition and interindividual variability in the recovery of platelet function that may affect the outcomes of patients needing urgent surgery with exposure to an unpredictable risk of bleeding and ischemia. The prevalence of clopidogrel resistance varies from ≈8% to 30% and is dependent on dose and time of measurement in relation to dosing.38 In addition, various methods, including point-of-care methods reflecting P2Y12 reactivity, have been used to measure clopidogrel responsiveness. Although a good correlation has been demonstrated among these methods, measurement of vasodilator-stimulated phosphoprotein phosphorylation assay by flow cytometry has been considered by some investigators to be the most specific method to indicate P2Y12 reactivity.38,39 More recently described limitations include potentially important drug-drug interactions, interactions with cigarette smoking, and the influence of CYP450 genotype. Numerous reports associate the occurrence of post-PCI ischemic events, including stent thrombosis, with clopidogrel nonresponsiveness indicated by high on-treatment platelet reactivity.40Clopidogrel is metabolized in a 2-step process. The thienopyridine ring of clopidogrel is oxidized to 2-oxo-clopidogrel, which is subsequently hydrolyzed to a highly labile active metabolite, R-130964.41 It has been reported that CYP2C19, CYP1A2, and CYP2B6 participate the first step, whereas CYP2C19, CYP2C9, CYP2B6, and CYP3A participate in the second step.42In the Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect (ISAR-CHOICE) study, the effects of higher loading doses were investigated. An increase in the clopidogrel loading dose from 300 to 600 mg increased platelet inhibition. However, 900 mg did not result in further suppression of ADP-induced platelet aggregation and was associated with a reduced increase in plasma concentration of the active metabolite. These data suggest that intestinal absorption limited the amount of the 900-mg load accessible to the liver for conversion to the active metabolite.43 Similarly, only a moderate and nonsignificant increase in antiplatelet effects was observed after a 900-mg clopidogrel loading dose compared with 600 mg in the Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis (ALBION) study.44Multiple lines of evidence strongly suggest that insufficient active metabolite generation is the primary explanation for clopidogrel response variability and nonresponsiveness.45 Variable levels of active metabolite generation after clopidogrel administration have been attributed to variability in intestinal absorption influenced by polymorphism of an ABCB1 gene that encodes p-glycoprotein. Moreover, the ABCB1 gene variant has been identified with decreased clopidogrel active metabolite generation and a 70% relative increased risk of 1-year cardiovascular events.46,47 Functional variability in P450 isoenzyme activity has also been associated with variable levels of active metabolite generation. In earlier studies, coadministration of lipophilic statins (which compete with clopidogrel for CYP3A4) such as atorvastatin or simvastatin has been shown to attenuate the antiplatelet effect of clopidogrel in pharmacodynamic studies.48 However, this interaction has not been proven to affect clinical outcomes significantly in patients treated with dual antiplatelet therapy. However, a trend toward a better clinical outcome in patients coadministered clopidogrel and non–CYP3A4-metabolized statins compared with CYP3A4-metabolized statins has been demonstrated in some retrospective analyses.49Similar to statins, various proton pump inhibitors (PPIs), frequently used with clopidogrel and aspirin, are also metabolized by CYP450 isoenzymes. In a randomized controlled study involving patients undergoing stenting, coadministration of omeprazole with aspirin and clopidogrel significantly reduced the antiplatelet effect of clopidogrel as measured by the vasodilator-stimulated phosphoprotein phosphorylation assay.50 Coadministration of clopidogrel with PPIs, especially CYP2C19-metabolized PPIs such as omeprazole, lansoprazole, and rabeprazol, has been shown to be associated with reduced clinical efficacy in some but not all retrospective analyses.51,52 At this time, there is no conclusive evidence that PPIs influence clopidogrel metabolism and attenuate the clinical benefits of clopidogrel treatment. However, it has been recommended by some that PPIs be used in patients administered clopidogrel only when there are solid clinical indications.Cigarette smoking has been reported to induce CYP1A2 activity, thereby potentially affecting clopidogrel metabolism. In the CREDO trial, a larger reduction in clinical events occurred in patients receiving clopidogrel who were smokers compared with nonsmokers receiving clopidogrel treatment.53 A recent retrospective analysis of patients undergoing elective stenting treated with clopidogrel and aspirin reported that current smokers had greater platelet inhibition

Reasonable Duration of Clopidogrel Use After Drug-Eluting Stent Implantation in Korean Patients

Current guidelines recommend that clopidogrel be given to patients for 12 months after drug-eluting stent (DES) implantation. However, the evidence is insufficient to support the benefit of long-term clopidogrel therapy, especially in Asian patients. The aim of this study was to evaluate whether different durations of clopidogrel use might influence long-term outcomes after DES implantation. A total of 844 patients from 4 medical centers in Korea who had undergone successful DES implantation from November 2004 to April 2006 were enrolled. Patients who were event free at 6-month follow-up were divided into 2 groups by clopidogrel use (575 users, 163 nonusers) and followed. The end point was a composite of death, myocardial infarction, and stent thrombosis. During 1,056.4 patient-years of follow-up (median 2.02), there were 7 deaths, 3 myocardial infarctions, and 2 episodes of stent thrombosis. No significant differences in the primary end point were observed between clopidogrel users and nonusers (cumulative incidence 2.9% vs 2.8%, p = 0.578; adjusted hazard ratio 0.67, 95% confidence interval 0.16 to 2.77). In analysis with time-dependent covariates, the incidence rates of the primary end point during observation periods with and without clopidogrel were similar, although the effect estimates were broad (9.9 with and 10.6 without clopidogrel per 1,000 patient-years; adjusted hazard ratio 0.52, 95% confidence interval 0.09 to 3.17). Interestingly, the effect estimates from propensity score analyses, although they also had wide confidence intervals, were closer to the null than those from conventional Cox analyses. In conclusion, this cohort of Korean patients failed to show an absolute benefit of long-term clopidogrel therapy after DES implantation. The benefit of clopidogrel use beyond 6 months after DES implantation remains uncertain, and hence the decision to use long-term dual-antiplatelet therapy should be based on the risk factors of each patient.

Effect of Long-Term Clopidogrel Treatment on Platelet Function and Inflammation in Patients Undergoing Coronary Arterial Stenting

A clopidogrel loading dose administered during stenting attenuates inflammation marker release. However, less is known of the anti-inflammatory effect of clopidogrel maintenance therapy. Platelet reactivity to adenosine diphosphate and inflammation markers were measured in 110 consecutive patients (69 clopidogrel-naive patients and 41 patients receiving long-term clopidogrel therapy for >6 months) before nonemergent stenting by turbidimetric aggregometry and flow cytometry and multianalyte profiling, respectively. All patients were treated with aspirin. Prestenting adenosine diphosphate-induced platelet aggregation, P-selectin, and activated glycoprotein IIb/IIIa expression were lower in patients receiving long-term clopidogrel therapy compared with the clopidogrel-naive group (p <0.001), accompanied by lower levels of selected inflammation markers (p < or = 0.05). Additionally, there were strong correlations between platelet aggregation and flow cytometric measurements (p < or = 0.04) and between specific inflammation markers (p < or = 0.02). In conclusion, in addition to markedly lowering platelet reactivity to adenosine diphosphate, long-term clopidogrel therapy is associated with an anti-inflammatory effect.

The efficacy and safety of short- and long-term dual antiplatelet therapy in patients with mild or moderate chronic kidney disease: Results from the Clopidogrel for the Reduction of Events During Observation (CREDO) Trial

Mild and moderate chronic kidney disease (CKD) is associated with decreased survival and increased adverse events after a percutaneous coronary intervention (PCI). Therapy with clopidogrel decreases adverse events in large patient populations. Therefore, we sought to determine the efficacy and safety of long-term clopidogrel therapy in patients with CKD. Two thousand two patients from the CREDO trial in whom an elective PCI of a single or multiple vessels was planned were analyzed. Patients were randomly assigned to a 300-mg loading dose of clopidogrel before PCI followed by clopidogrel 75 mg/d for a year versus a placebo loading dose at the time of the PCI procedure and clopidogrel 75 mg/d for 28 days and placebo for the remainder of a year. Patients were categorized by their estimated creatinine clearance (>90 [normal, n = 999], 60-89 [mild CKD, n = 672], <60 mL/min [moderate CKD, n = 331]). Diminished renal function was associated with worse outcomes. Patients with normal renal function who received 1 year of clopidogrel had a marked reduction in death, myocardial infarction, or stroke compared with those who received placebo (10.4% vs 4.4%, P < .001), whereas patients with mild and moderate CKD did not have a significant difference in outcomes with clopidogrel therapy versus placebo (mild: 12.8% vs 10.3%, P = .30; moderate: 13.1% vs 17.8%, P = .24). Clopidogrel use was associated with an increased relative risk of major or minor bleeding, but this increased risk was not different based on renal function (relative risk 1.2, 1.3, 1.1). Clopidogrel in mild or moderate CKD patients may not have the same beneficial effect as it does in patients with normal renal function, but was not associated with a greater relative risk of bleeding based on renal function. Further studies are needed to define the role of clopidogrel therapy in patients with CKD.

Consistent Platelet Inhibition During Long-Term Maintenance Clopidogrel Therapy Among Three Hundred Fifty-Nine Compliant Outpatients with Documented Vascular Disease

Conclusion: Long-term therapy with clopidogrel provides more consistent platelet inhibition than that observed following initiation of therapy after acute vascular events. Summary: There have been conflicting reports on the effects of clopidogrel therapy on platelet inhibition after an acute vascular event. Some reports have documented a high incidence of clopidogrel nonresponsiveness, but these reports have been complicated by varying definitions and different platelet aggregation tests. This study sought to assess the effect of clopidogrel on platelet characteristics in outpatients who received maintenance dosages of clopidogrel (75 mg/d) for >30 days. This was a secondary analysis of presumably compliant patients treated with clopidogrel and aspirin. The patient cohort consisted of 237 who had undergone coronary artery stenting and 122 who had sustained an ischemic stroke. The mean duration of treatment was 5.8 months (range, 1-21 months). All patients exhibited inhibition of adenosine diphosphate-induced platelet activation (mean, 52.9%; range, 36%-70%) compared with preclopidogrel measurements. A diminished expression of platelet-endothelial cell adhesion molecule 1 (r = 0.75), glycoprotein 2B-3A (r = 0.62), and protease-activated receptor 1 (r = 0.71) were all correlated with inhibition of platelet aggregation. No patients were found to have platelet hyporesponsiveness or profound inhibition of platelet activity. Comment: The wide response variability to clopidogrel in the acute setting does not hold up with more long-term administration of the drug. The article suggests that problems related to clopidogrel resistance may be exaggerated by previous emphasis on short-term rather than long-term maintenance data.

Long-term clopidogrel therapy improves outcomes after drug-eluting stent placement

Long-term clopidogrel therapy improves outcomes after drug-eluting stent placement