Clopidogrel Research Articles

Chiral stability of an extemporaneously prepared clopidogrel bisulfate oral suspension.

The purpose of this study was to evaluate the chiral stability of clopidogrel bisulfate in an extemporaneously compounded oral suspension for a period of 60 days. A 5 mg/mL oral suspension of clopidogrel bisulfate was prepared from commercially available Plavix tablets. The clopidogrel suspension was then evenly divided between two light-resistant prescription bottles and stored either under refrigeration (4°C) or at room temperature (25°C). Samples were drawn from the stored suspensions immediately after preparation and on days 7, 14, 28, and 60. Samples were subsequently analyzed at each time point by high-performance liquid chromatography using a reversed-phase column, with chemical stability defined as the retention of at least 90% of the initial intact clopidogrel concentration measured. To determine the chiral stability of the suspension, samples were also analyzed by high-performance liquid chromatography using a chiral column to investigate possible enantiomeric inversion. Chiral stability was defined as the retention of at least 90% of the initial concentration of the suspension as the S-enantiomer, the active moiety of Plavix. Regardless of storage conditions, the oral suspension of clopidogrel retained at least 98% of the active S-enantiomer for 60 days after preparation. Compared with the clopidogrel suspension stored in the refrigerator, more chiral inversion was noted in the clopidogrel suspension stored at room temperature. Our investigation of chiral stability indicates that a 5 mg/mL clopidogrel oral suspension stored under refrigeration and at room temperature maintains chiral stability as the active S-enantiomer.

Stent thrombosis after switch from nongeneric to generic clopidogrel

The U.S. Food and Drug Administration recently approved generic versions of clopidogrel bisulfate which should lower the cost and improve compliance in patients requiring dual antiplatelet therapy post stent placement. However, there is marked inter-individual variability in the metabolism and intestinal absorption of clopidogrel. The different binders and fillers used in the generic versions can possibly affect absorption and reduce the bioavailability of the drug. We report a case of very late stent thrombosis in a patient eight days after the switch to generic clopidogrel bisulfate from branded clopidogrel (Plavix). The patient had received a sirolimus drug eluting stent almost three years prior to presentation and was on chronic dual antiplatelet therapy. Subsequent to the event, she was found to be a poor metabolizer of clopidogrel. Although in most cases the use of generic clopidogrel is efficacious and safe, certain individuals, such as poor metabolizers, might be susceptible to increased clinical events when switching. We suggest any suspected cases should be reported to Medwatch so the clinical relevance could be determined.

HPLC in determination of effective contents and related substances in clopidogrel hydrogen sulfate produced by 3 manufacturers

Objective To establish a high performance liquid chromatography( HPLC) method for quantitative determination of S-clopidogrel and its related substance R-clopidogrel in clopidogrel tablets,and to compare their contents between clopidogrel tablets produced by three different manufacturers. Methods An ULTRON ES-OVM column( 4. 6 mm × 150 mm,5μm) was used in this study. The mobile phase consisted of a mixture of acetonitrile and 0. 01 mol/L potassium dihydrogen phosphate solution( 20∶ 80). The flow-rate was 1 mL /min,with the column temperature being 17℃ and the UV detection wave lenth being 220 nm. Results S-clopidogrel and its related substance R-clopidogrel were in good linear relationship within 50-117 mg /L and 1. 52-30.04 mg /L,respectively( both r = 0. 999 8). The precision of our method was satisfactory and the average recoveries were 99. 7% and98. 8%,respectively. The test solution remained stable for 12 h. S-clopidogrel and R-clopidogrel in clopidogrel tablets produced by three manufacturers were in line with the quality requirements of pharmacopoeia. Conclusion Our method is accurate and has good specificity. It can be used for the quality control of clopidogrel tablets.

Design, development and evaluation of clopidogrel bisulfate floating tablets

Objective:The objective of the present work was to formulate and to characterize a floating drug delivery system for clopidogrel bisulphate to improve bioavailability and to minimize the side effects of the drug such as gastric bleeding and drug resistance development.Materials and Methods:Clopidogrel floating tablets were prepared by direct compression technique by the use of three polymers xanthan gum, hydroxypropyl methylcellulose (HPMC) K15M and HPMC K4M in different concentrations (20%, 25% and 30% w/w). Sodium bicarbonate (15% w/w) and microcrystalline cellulose (30% w/w) were used as gas generating agent and diluent respectively. Studies were carried out on floating behavior and influence of type of polymer on drug release rate. All the formulations were subjected to various quality control and in-vitro dissolution studies in 0.1 N hydrochloric acid (1.2 pH) and corresponding dissolution data were fitted to popular release kinetic equations in order to evaluate release mechanisms and kinetics.Results and Discussion:All the clopidogrel floating formulations followed first order kinetics, Higuchi drug release kinetics with diffusion as the dominant mechanism of drug release. As per Korsmeyer-Peppas equation, the release exponent “n” ranged 0.452-0.654 indicating that drug release from all the formulations was by non-Fickian diffusion mechanism. The drug release rate of clopidogrel was found to be affected by the type and concentration of the polymer used in the formulation (P < 0.05). As the concentration of the polymer was increased, the drug release was found to be retarded.Conclusion:Based on the results, clopidogrel floating tablets prepared by employing xanthan gum at concentration 25% w/w (formulation F2) was the best formulation with desired in-vitro floating time and drug dissolution.

The relationship between CYP2C19 gene polymorphism and the risk score and prognosis after percutaneous coronary intervention

Objective To investigate the relation between CYP2C19 polymorphisms and risk score and prognosis after percutaneous coronary intervention (PCI).Methods From March in 2012 to July in 2012 we randomly selected 40 patients who received PCI treatment and took their blood for the test of CYP2C 19 before admission.The CYP2C 19 genotypes were divided into three groups:extensive metabolisms,medium metabolisms and poor metabolisms.Results The PRI VASP ≥ 50％ of the patients in 6 cases,the PRI VASP ＜ 50％ of the patients in 34 cases,between the two groups of PRI VASP ratio of (55.97 ± 2.98) than (44.01-± 4.16),the difference had statistical significance (P ＜ 0.05).Through multiple regression analysis,this paper analyzes the factors which lead to the PCI postoperative adverse end point events concluded:aging,CYP2C19 poor metabolism,T2DM,LVEF,Renal insufficiency,the five factors for the high risk factors.Conclusion For patients with poor metabolism we can increase the dose of clopidogrel and combining Aspirin to prevent heart attacks. Key words: CYP2C19; Risk score; Percutaneous coronary intervention

Personalized antiplatelet therapy in acute coronary syndromes: a dead-end street or a future scenario?

synthesize an enzyme that works less efficiently and are at a greater risk of developing high platelet reactivity [10]. This genetic determinant is associated with clopidogrel metabolism. Therefore, platelet hyper-reactivity caused by this genetic variant is overcome by the newer antiplatelets, such as prasugrel and ticagrelor. However, acquired determinants are also associated with high platelet reactivity on clopi dogrel [11], and these conditions may also affect the response also to the new antiplatelet drugs. Diabetes, advanced age, reduced ejection fraction, and the entity of platelet turnover and inflammation are conditions associated with a higher platelet reactivity and higher risk of developing an insufficient platelet inhibi tion on therapy [12]. These conditions may be persistent (i.e., diabetes and advanced age) or transient (i.e., platelet turnover and inflamma tion). Indeed, regarding the ‘acute phase’ of ACS, it was found that a proportion of patients with high platelet reactivity on clopidogrel in the acute phase has an adequate platelet inhibition at 6 months from the acute event [12]. This suggests, at least in part, that the reduction of inflammation activation after ACS is associated with a reduced platelet reactivity and, possibly, with a decreased percentage of patients with an inadequate platelet inhibition on the same drug. We have observed that patients with an inadequate platelet inhibition on clopidogrel (measured by light transmission aggregometry, VerifyNow ® [Accumetrics, CA, USA], Multiplate ® [Roche, Mannheim, Germany] or VASP

Abstract 18749: Avoidance of a Reload During the Therapeutic Shift From Clopidogrel to Ticagrelor in Patients With Acs Has No Influence on Residual Platelet Reactivity

Background: Ticagrelor (TICA) was more efficient than clopidogrel (CLO) in preventing cardiovascular events after Acute Coronary Syndrome (ACS) in the PLATO trial. However, it was associated with a higher incidence of non-procedure related bleedings. Despite TICA therapy was always started with the administration of a loading dose in the PLATO trial, the loading dose could be unnecessary in patients with ongoing CLO therapy. Aim of the present study was to verify whether the administration of a loading dose is necessary to mantain the level of inhibition of aggregation during the switch from ongoing CLO to TICA therapy. Methods and Results: Fifty patients with ACS and on CLO treatment were randomly assigned to a starting dose of TICA of 90mg (Group 1) or 180mg (Group 2), on top of aspirin treatment. Platelet aggregation was measured using multiple electrode aggregometry (MEA) at 0, 2, 6, 24 and 72h after the switch, and verified through standard LTA aggregometry. No relevant difference in platelet aggregation between the two study arms was observed at baseline (p=0.256). Residual platelet aggregation measured using MEA was significantly reduced in both arms 2h after the first administration of TICA (both p&lt;0.001). Interestingly, no difference in aggregation was found 2 hours after the switch to TICA (176 72 vs 181 60 AUmin, p=0.281). Similar findings were confirmed with LTA. Conclusions: Therapeutic switch from ongoing clopidogrel therapy to ticagrelor without administration of a loading dose is clinically safe and is not associated to a lower degree of inhibition in patients with ACS. Avoiding the loading dose could be associated to a lower bleeding risk while mantaining the same level of aggregation. Larger trials are needed to confirm data from our proof-of-concept study.

Clopidogrel Increases the Risk for Gastrointestinal Bleeding

Clopidogrel is widely used to prevent vascular thrombotic events. However, the risk for upper gastrointestinal bleeding (UGIB) or lower bleeding (LGIB)

Antiplatelet Drugs Prevent Adverse Cardiovascular Events More Effectively in Smokers

Randomized trials have shown that adenosine diphosphate receptor–blocker drugs such as clopidogrel, which inhibit platelets, prevent adverse cardiovascular (CV) events in patients with acute coronary syndromes. To determine whether smoking status is associated with the efficacy of antiplatelet drugs, researchers undertook a meta-analysis of six studies (74,000 patients with established CV disease, of whom …

TCT-156 Impact of Clopidogrel Hyporesponsiveness on Clinical Outcomes in Patients Receiving Drug-eluting Stents for Stable Coronary Disease in the ADAPT-DES Study

Universitaets-Herzzentrum Freiburg-Bad Krozingen, Bad Krozingen, Germany, LeBauer CV Research Foundation, Greensboro, NC, Lehigh Valley Health Network, Allentown, PA, 4 Pinehurst Cardiology, Pinehurst, NC, 5 Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital, Minneapolis, United States, 6 Columbia University / Cardiovascular Research Foundation, New York, NY, 7 Ohio State University, Dublin, OH, 8 Mount Sinai Hospital, New York, NY, 9 Wellmont CVA Heart Institute, Kingsport, TN, Cardiovascular Research Foundation, NY, NY, Lebauer Cardiovascular Research Foundation, Greensboro, NC, Columbia University, New York, United States, 13 Charite Campus Benjamin Franklin, Berlin, Germany, 14 Cardiovascular Research Foundation, New York, NY, 15 UniversitatsHerzzentrum Freiburg Bad Krozingen, Bad Krozingen, Germany

Grapefruit juice and clopidogrel

Bailey and colleagues[1][1] are to be commended for highlighting the potential of many medications to interact with grapefruit.[1][1] However, one medication on their list (Table 1[1][1]) deserves closer scrutiny. At first glance, clopidogrel seems to fit the criteria of a medication that is a

Haemophilia risk with clopidogrel

Haemophilia risk with clopidogrel

Pretreatment with Prasugrel Before PCI Is Problematic

Despite limited data regarding the timing of antiplatelet administration, clopidogrel pretreatment in patients with acute coronary syndromes who are

Erratum to: Comparison of Clinical Efficacy and Safety of Clopidogrel Resinate With Clopidogrel Bisulfate in Patients Undergoing Percutaneous Coronary Intervention

Erratum to: Comparison of Clinical Efficacy and Safety of Clopidogrel Resinate With Clopidogrel Bisulfate in Patients Undergoing Percutaneous Coronary Intervention

Comparison of Antiplatelet Effect and Safety of Clopidogrel Napadisilate with Clopidogrel Bisulfate in Coronary Artery Disease Patients: Multi-center, Randomized, Double-blind, Phase IV, Non-inferiority Clinical Trial

Clopidogrel napadisilate has better clopidogrel stability than clopidogrel bisulfate. There are no data, however, on the antiplatelet efficacy and tolerability of clopidogrel napadisilate in coronary artery disease (CAD) patients. The aim of this study is to demonstrate that the combination therapy of aspirin and clopidogrel napadisilate is not inferior to that of aspirin and clopidogrel bisulfate with respect to its effectiveness in inhibiting platelet aggregation, if it is given for 4 weeks to CAD patients who had been treated with a drug-eluting stent more than 12 months prior and had remained in a stable condition with a single antiplatelet agent, aspirin. This study was a prospective, randomized, double-blind, double-dummy, parallel-group, phase IV clinical trial. A total of 162 patients were prospectively recruited from three centers. The subjects were randomized to either the test group that was treated with 75mg of clopidogrel napadisilate once daily or to the control group that was treated with 75mg of clopidogrel bisulfate once daily. The primary outcome was the percent inhibition of the platelet aggregation change after the medication, as assessed by a VerifyNow™ P2Y12 assay. The secondary outcome was the change in P2Y12 reaction units (PRUs) from the baseline to the end of 4 weeks of treatment. The prevalence of adverse events was assessed at each visit through a direct interview. The mean increase in the percent inhibition after 4weeks of treatment was 19.4% in the clopidogrel napadisilate group and 19.5% in the clopidogrel bisulfate group. The lower bound of the 95% two-sided confidence interval for the difference in the change between the two groups (-5.46) was greater than the pre-defined non-inferiority margin of (-10.5). Therefore, clopidogrel napadisilate was deemed non-inferior to clopidogrel bisulfate with respect to its effectiveness in inhibiting platelet aggregation. The PRU decreased by 73.1±30.7 in the clopidogrel napadisilate group, which decreased by -7.8 more than in the clopidogrel bisulfate group (65.3±62.1); but the difference between the two groups was statistically insignificant (p=0.435). There was no significant difference in the drug-related adverse events between the two groups (12.3 vs. 10.1%; p=0.804). The platelet inhibitory efficacy of clopidogrel napadisilate is not inferior to that of clopidogrel bisulfate. There were also no statistically significant differences between the two treatment groups in the safety analyses. Therefore, clopidogrel napadisilate can be a suitable alternative to clopidogrel bisulfate in stable CAD patients who have undergone a drug-eluting stent placement. Registered at ClinicalTrials.gov as NCT01830491.

Comparison of the antiplatelet effect of clopidogrel hydrogeno sulfate and clopidogrel besylate in patients with stable coronary artery disease

Purpose: It is well known that patients with poor response to antiplatelet therapy are most likely to have more thrombotic events. Clopidogrel hydrogensulfate (CHS) is a thienopyridine acting as an important antiplatelet agent alone or in combination with acetyl salicylic acid to prevent cardiovascular complications. A different clopidogrel salt, clopidogrel besylate (CB), was recently approved as a generic drug for the same purpose while data about its antiplatelet effect are very scarce. Our study compared the antiplatelet effect of CHS and CB in patients with stable coronary artery disease. Methods: Patients with stable coronary artery disease (n=101) (coronary lesions defined angiographically 30-50%) were randomized to either CHS (n=50) or CB (n=51). After randomization, a 600mg loading dose of the drug was given and monitoring of antiplatelet effect was done at least 12 hours later with VerifyNow assay (Accumetrics, USA). Antiplatelet response was measured with P2Y12 Reaction Units (PRU) and % inhibition P2Y12 from baseline (% inhibition P2Y12). Moreover CYP2C19*2, CYP2C19*3 and CYP3A5 polymorphisms were studied in all patients. Results: Clinical characteristics were similar between the 2 study groups. No statistically significant difference was observed for baseline platelet reactivity between CHS and CB patients (251±29 vs 266±38 respectively, p=0.12). We did not find any difference for antiplatelet response between the CHS and the CB group, assessed by PRU (192±61 vs 194±69 respectively, p=0.9) and by % inhibition P2Y12 (24±22% vs 32±21% respectively, p=0.22) (Figure). Number of patients defined as non expressors for CYP2C19 and CYP3A5 polymorphisms was similar and did not have any difference on platelet reactivity between the study groups. Conclusions: Our results indicated that both CB and CHS had an identical antiplatelet effect in patients with stable coronary artery. No difference on platelet reactivity of non expressors concerning CYP2C19 and CYP3A5 polymorphisms was found between the 2 study groups.

Clopidogrel Generic Formulations in the Era of New Antiplatelets: A Systematic Review

Clopidogrel is a thienopyridine that selectively and irreversibly inhibits the ADP purinergic receptor P2Y12 and the subsequent ADP-mediated platelet activation. Clopidogrel has been approved for clinical use as clopidogrel hydrogen sulfate (bisulfate) salt. The clinical usefulness of clopidogrel bisulfate salt has been proved in a wide variety of large scale clinical trials, thus clopidogrel bisulfate has been extensively used in a large spectrum of patients been under thrombotic risk. Recently, several generic clopidogrel formulations have been approved for clinical use. Consequently, clopidogrel is currently a cost-effective antiplatelet agent. Only small studies have compared the pharmacokinetic and pharmacodynamic properties of various clopidogrel generic salt formulations with the innovator bisulfate salt. In addition few data are available concerning the clinical efficacy and safety of these generic clopidogrel formulations in order to guide clinicians in deciding when generic substitution is appropriate. The aim of this review is to summarize the physicochemical properties as well as the pharmacokinetic and pharmacodynamic characteristics of the generic clopidogrel salts. We also critically present existing data on the clinical efficacy and safety of the generic clopidogrel formulations compared with the innovator clopidogrel bisulfate salt in patients with cardiovascular disease.

Triple anti-platelet therapy protecting acute coronary syndrome patients from complication within 30 days after PCI

Objective To investigate the efficacy and safety of triple anti-platelet therapy (low-dose tirofiban plus aspirin and clopidogrel) comparing to dual anti-platelet therapy (aspirin and clopidogrel) in preventing stent thrombosis (ST) and major adverse cardiac events (MACE) within 30 days after implantation of drug-eluting stent (DES) in ACS patients.Methods A total of 2904 ACS patients treated with DES from March 2004 to November 2010 were enrolled for retrospective study.Of them,1145 patients were treated with dual anti-platelet therapy (DAT) and 1759 patients with triple anti-platelet therapy (TAT).The incidences of ST,MACE (cardiac death,urgent target vessel revasculanization and myocardial infarction) and side effects occurred within 30 days after PCI were compared between two groups by Fisher' s exact test.Results (1)Although there were significant differences in age,the degree of coronary stenosis,the number of smokers,diabetes,hyperlipidemia and coronary diffuse lesion between two groups,but these differences did not impact on the end point events showed by Cox analysis.The rest of the general condition of patients between two groups was no difference.(2) The incidence of ST as primary end point was lower in TAT group than that in DAT group (0.11％ vs.1.05％,P =0.0036),reducing the relative risk by 89.52％.In addition,the incidence of MACT as secondary end point was also lower in TAT group than that in DAT group (0.17％ vs.1.48％,P =0.0005),reducing the relative risk by 88.51％.Among the total,the incidences of cardiac death and urgent target vessel re-vascularization in TAT group were lower than those in DAT group with significant differences.However,there was no difference in the incidence of myocardial infarction between two groups.(3) Both two groups had no severe hemorrhage complication,the incidence of mild hemorrhage was similar in two groups (0.45％ vs.0.35％,P =0.6720).Nesides,the incidence of acute thrombocytopenia between two groups was also similar (0.45％ vs.0.09％,P =0.083).Conclusions The patients with ACS in the TAT group have significant lower incidence of ST and MACE than those in the DAT group within 30 days after PCI.While the risk of bleeding and the incidence of acute thrombocytopenia do not increase. Key words: Stent thrombosis; Major adverse cardiac events; Triple anti-platelet therapy; Dual anti-platelet therapy

Comparison of Clinical Efficacy and Safety of Clopidogrel Resinate With Clopidogrel Bisulfate in Patients Undergoing Percutaneous Coronary Intervention

A new polymeric salt form of clopidogrel, clopidogrel resinate (CR), is a resinate complex of the (+)-clopidogrel optical isomer wherein the (+)-clopidogrel isomer binds to a water-soluble cation exchange resin via sulfonic acid groups. CR was approved for marketing by the Korean Food and Drug Administration based on a Phase I bioequivalence study. However, no data are available regarding its impact on adverse clinical outcomes in patients undergoing percutaneous coronary intervention (PCI). Clopidogrel bisulfate (CB) was used exclusively from January 2004 through April 2010, after which CR was exclusively administered from May 2010 through September 2011, in 8 centers. We categorized the overall population (N = 10,487) into two groups according to the prescribed clopidogrel type: CB (n = 9,127) or CR (n = 1,360). To minimize the covariate imbalance and confounding in comparing CB and CR, we used a multivariable Cox proportional hazard regression model and the propensity score (PS) method to identify a 1:1 matched cohort (n = 2,470). We compared cumulative adverse outcomes during a 1-year follow-up after PCI in the overall population and in the PS-matched cohort. In the overall population, there is no difference in the 1-year cumulative event rates between the two groups (CB : CR) : composite of any death, nonfatal myocardial infarction or stroke (6.0 % vs. 6.0 %, adjusted HR, 0.82; 95 % CI, 0.61-1.11, p = 0.57), stent thrombosis (0.4 % vs. 0.2 %; adjusted HR, 0.40; 95 % CI, 0.09-1.72, p = 0.31), and bleeding (0.9 % vs. 0.6 %; adjusted HR, 0.67; 95 % CI, 0.28-1.58, p = 0.22). In the PS-matched cohort, the overall findings were consistent. In this large real-world PCI population, CR was as effective and as safe as CB in preventing adverse clinical outcomes.

Oral clopidogrel improves cutaneous microvascular function through EDHF-dependent mechanisms in middle-aged humans

Platelet P₂Y₁₂-ADP and COX-1 receptor inhibition with oral clopidogrel (CLO) and low-dose aspirin (ASA), respectively, attenuates reflex-mediated cutaneous vasodilation, but little is known about how these medications affect local vasodilatory signaling. Reactive hyperemia (RH) results in vasodilation that is mediated by sensory nerves and endothelium-derived hyperpolarization factors (EDHF) through large-conductance calcium-activated potassium channels, whereas slow local heating (LH) elicits vasodilation largely through the production of nitric oxide (NO). We hypothesized that CLO and ASA would attenuate locally mediated cutaneous vasodilation assessed by RH and LH (0.5°C/min). In a randomized, cross-over, double-blind placebo-controlled study, nine healthy men and women (56 ± 1 yr) took CLO (75 mg), ASA (81 mg), and placebo for 7 days. Skin blood flow was measured (laser-Doppler flowmetry, LDF) and cutaneous vascular conductance (CVC) was calculated (LDF/mean arterial pressure) and normalized to maximal CVC (%CVCmax: 43°C and 28 mM sodium nitroprusside). RH response parameters, including area under the curve (AUC), total hyperemic response (THR), and the decay constant tau (λ) were calculated. NO-dependent vasodilation during LH was assessed by calculating the difference in %CVCmax between a control site and an NO synthase-inhibited site (10 mM l-NAME: intradermal microdialysis). CLO augmented the AUC and THR (AUCclo = 3,783 ± 342; THRclo = 2,306 ± 266% CVCmax/s) of the RH response compared with ASA (AUCASA = 3,101 ± 325; THRASA = 1,695 ± 197% CVCmax/s) and placebo (AUCPlacebo = 3,000 ± 283; THRPlacebo = 1,675 ± 170% CVCmax/s; all P < 0.0001 vs. CLO). There was no difference in the LH response or calculated NO-dependent vasodilation among treatments (all P > 0.05). Oral CLO treatment augments vasodilation during RH but not LH, suggesting that CLO may improve cutaneous microvascular function.