Higher Doses Of Clopidogrel Research Articles

P212 EFFICACY AND SAFETY OF GENOTYPE–GUIDED AND PLATELET FUNCTION TEST–GUIDED ANTI–P2Y12 THERAPY IN PATIENTS UNDERGOING PCI: A META–ANALYSIS OF RCTS

Abstract Clopidogrel is the most commonly used anti–P2Y12 drug in DAPT. Impaired pharmacological response and antithrombotic efficacy associated with cytochrome–P450 and/or ABCB1 gene mutations is observed in about 1/3 of treated patients. To circumvent this problem, guided therapy has been tested, based on either identification of predisposing gene mutations or results of platelet function tests (PFTs). Patients with with predisposing gene mutations or high platelet reactivity on clopidogrel (HPR) were treated with alternative, potentially more effective regimens: higher clopidogrel doses, prasugrel, ticagrelor, or additional cylostazol. In this meta–analysis, we tested the efficacy and safety of these two different strategies of guided therapy separately. We searched relevant articles published in English until October 1th 2022 on MEDLINE, Embase and Central. Articles included all RCTs comparing standard anti–P2Y12 therapy (ST) versus genotype–guided or PFTs–guided anti–P2Y12 therapy in patients with acute coronary syndromes (ACS) or chronic coronary artery disease (CCAD) undergoing PCI. Two reviewers independently assessed study eligibility and risk of bias, and extracted data. Hazard ratios with 95% CI were calculated based on fixed effects models. Efficacy outcomes comprised major adverse cardiovascular events (MACE) as defined in each study. Main safety outcome included major bleedings (MB) according to BARC. Different sub–analyses were also performed based on type of anti–P2Y12 drug in ST, type of alternative drug, type of PFT, patients’ ethnicity, prevalence of ACS. We retrieved 6 RCTs testing genotype–guided anti–P2Y12 therapy on 10443 patients and 14 RCTs testing PFTs–guided anti–P2Y12 therapy on 11596 patients. MACE were lower in genotype–guided therapy than in ST, RR 0.68 (95% CI, 0.49–0.94) while MB did not significantly differ between the two groups, RR 0.88 (95% CI, 0.63–1.23). MACE and MB did not significantly differ between PFTs–guided anti–P2Y12 therapy and ST: RR 0.83 (95% CI, 0.58–1.18) and 1.24 (95% CI, 1.00–1.53), respectively. Sub–analyses revealed that MACE were lower in PFTs–guided anti–P2Y12 therapy compared to ST in patients of Asian descent. In conclusion, gentotype–guided anti–P2Y12 therapy reduced the incidence of MACE without increasing MB, compared with ST, in patients with ACS or CCAD undergoing PCI; in contrast, PFTs–guided anti–P2Y12 therapy did not affect the incidence of MACE or MB in these patients.

Effectiveness and safety of high dose clopidogrel plus aspirin in ischemic stroke patients with the single CYP2C19 loss-of-function allele: a randomized trial

BackgroundDual antiplatelet aggregation therapy leads to better outcomes in patients with carotid artery stenosis, intracranial artery stenosis, minor strokes, or transient ischaemic attacks. However, carriers of the CYP2C19 loss-of-function allele may not experience the desired effects. We attempted to increase the clopidogrel dose to determine whether it would improve the outcomes of stroke patients who carry a single loss-of-function allele.MethodsWe recruited 131 patients with minor ischaemic stroke, within less than 7 days of stroke onset and a CYP2C19 loss-of-function allele, who had moderate-to-severe cerebral artery stenosis. Patients were divided into the high dose group (clopidogrel 150 mg per day + aspirin 100 mg per day over 21 days.) and a normal dose group (clopidogrel 75 mg per day + aspirin 100 mg per day over 21 days). The reported outcomes included any vascular or major bleeding events as the primary and safety endpoints, respectively.ResultsOne and six vascular events occurred in the high dose and normal dose groups during the 3-months follow-up period, respectively. However, no significant difference was found between the two groups when adjusted for history of diabetes (hazard ratio, 5482; 95% confidence interval, 0.660 to 45.543; P = 0.115). No major bleeding events occurred.ConclusionsIn patients with ischaemic stroke who had a single CYP2C19 loss-of-function allele and moderate to severe cerebral stenosis, fewer vascular events occurred within 3 months with high dose of clopidogrel and aspirin than with normal dose of clopidogrel and aspirin. However, the difference between the two groups was not significant.Trial registrationClinical study of clopidogrel in the treatment of patients with symptomatic moderate to severe cerebral artery stenosis with intermediate metabolites of CYP2C19, URL: http://www.chictr.org.cn/. Unique identifier: ChiCTR1800017411, 07/28/2018;

Abstract 13849: Enhancing Anti-thrombotic Efficacy but Reducing Hemorrhage: Comparison and Combination Use of a Novel Integrin Outside-in Signaling Inhibitor With Current Anti-platelet Drugs

Introduction and Hypothesis: Current anti-platelets drugs cause excessive bleeding. We have developed a novel anti-platelet drug, M3mP6, which selectively inhibits integrin outside-in signaling but not ligand binding to integrin αIIbβ3. Here we test the hypothesis that M3mP6 may synergistically enhance anti-thrombotic effects of current anti-platelet drugs but reduce risk of hemorrhage. Methods and Results: One time bolus injection of M3mP6 (10 uMol/kg,15 min) has superior anti-thrombotic effect compared to high doses of clopidogrel (4 mg/kg, oral, 2 hours), and very high doses of aspirin (36 mg/kg, i.p., 1 hour), using a FeCl 3 -induced occlusive carotid artery thrombosis model in mice. However, unlike the high doses of clopidogrel and aspirin, M3mP6 did not affect bleeding using a tail bleeding time model. We found that M3mP6 was comparable with the loading doses of ticagrelor (3 mg/kg) and cangrelor (30 μg/kg) in anti-thrombotic efficacy. However, ticagrelor or cangrelor cause dramatically increased hemorrhage, which is in contrast to M3mP6’s lack of bleeding side effect. To mimic hemorrhage during intravascular/surgical procedures, we designed a carotid artery puncture model of surgical hemorrhage. Cangrelor caused dramatically excessive bleeding even treated with a hemostatic pad. In contrast, M3mP6-treated mice are not different from control. Importantly, M3mP6 exerts synergistic anti-thrombotic effects when used together with current anti-platelets drugs, without further increases in bleeding. Furthermore, when M3mP6 was used in combination with a reduced dose of cangrelor, the anti-thrombotic effect was significantly more potent than high dose cangrelor, but hemorrhage was greatly reduced. Conclusions: M3mP6 is potentially a superior new anti-platelet drug, ideal for patients with bleeding risk, and also for greatly enhancing anti-thrombotic effects of current anti-platelet drugs while reducing hemorrhage.

Diabetes mellitus, CYP2C19 genotype, and response to escalating doses of clopidogrel. Insights from the ELEVATE-TIMI 56 Trial.

Both diabetes mellitus (DM) and carriage of the CYP2C19*2 allele are associated with a reduced response to clopidogrel. The relative contributions of these factors and whether higher clopidogrel doses can overcome both factors remain unknown. The objective of this study was to test the ability of clopidogrel doses up to 300 mg daily to decrease platelet reactivity in patients with DM and/or CYP2C19*2. ELEVATE-TIMI 56 randomised 333 patients with coronary artery disease to different maintenance doses of clopidogrel in four treatment periods, each lasting approximately 14 days. On-treatment platelet reactivity was compared between patients stratified by DM, CYP2C19*2 status and clopidogrel dose. Both DM and CYP2C19*2 were independently associated with elevated on-treatment platelet reactivity with clopidogrel 75 mg daily (p<0.0001 for each). With 75 mg, mean on-treatment PRU was progressively higher (p trend <0.001) when evaluating patients: with neither DM nor CYP2C19*2 (150.7; 95 % CI 140.5-162.6), with only DM (187.2; 95 % CI, 171.3-206.9), with only CYP2C19*2 (227.9; 95 % CI, 205.1-250.8), and with both DM and CYP2C19*2 (239.9; 95 % CI, 209.7-270.1). Notably, with 75 mg, patients with only CYP2C19*2 had higher on-treatment platelet reactivity than those with only DM (p=0.0068). To achieve on-treatment platelet reactivity similar to that seen with clopidogrel 75 mg in patients with neither DM nor CYP2C19*2, the following doses were required: 150 mg with only DM, 225 mg with only CYP2C19*2, and 300 mg with both DM and CYP2C19*2. Patients with both DM and CYP2C19*2 required a four-fold increase in clopidogrel maintenance dose as compared to patients without these factors to achieve a similar antiplatelet response.

Effect of CYP2C19 Polymorphisms on the Platelet Response to Clopidogrel and Influence on the Effect of High Versus Standard Dose Clopidogrel in Carotid Artery Stenting

Genetic background has been identified to be a major predictor of post-clopidogrel platelet inhibition in patients undergoing coronary stenting. However, there is a lack of data on clopidogrel response regarding genotype in patients undergoing carotid artery stenting (CAS). The influence of the most common allelic variants of CYP2C19 phenotypes and genotypes on response to baseline clopidogrel and on the pharmacodynamic effect of dose adjustment (high or standard dose of clopidogrel) in patients with high on-treatment reactivity after CAS was investigated. Platelet reactivity was assessed before and 30 days after carotid stenting using the VerifyNow P2Y12 assay to obtain P2Y12 reactivity unit (PRU) values. A total of 209 patients (79.4% male, 44.1% currents smokers) were treated by CAS. Smokers improved responsiveness to clopidogrel (p = .034). With respect to CYP2C19 enzymatic function, 61 subjects (29.1%) were ultra-rapid metabolizers, 95 patients (45.5%) were extensive metabolizers, 51 (24.4%) were intermediate metabolizers, and two (0.96%) were poor metabolizers. Baseline PRU was significantly higher among intermediate-poor metabolizers compared with ultra-rapid (p = .001) or extensive metabolizers (p = .005). At 30 days follow up, in non-responding patients with the intermediate-poor metabolizer phenotype, the PRU value and inhibition percentage were significantly reduced with standard dose (p = .008; p = .0029) and high dose of clopidogrel (p = .00 0; p = .000). However, high dose clopidogrel did not achieve a more intense pharmacodynamic effect at 30 days (p = .994) compared with standard dose. In patients undergoing carotid stenting, those with the CYP2C19*2 allele had increased basal PRU values and in fact clopidogrel non-responders increased significantly among intermediate-poor metabolizers. Although high dose and standard dose clopidogrel therapy was effective in lowering the 30 day PRU values in patients with high on-treatment reactivity who are intermediate-poor metabolizers, the use of high dose clopidogrel did not result in statistically significantly greater reductions in reactivity compared with the standard dose.

Focused 2012 Update of the Canadian Cardiovascular Society Guidelines for the Use of Antiplatelet Therapy

The initial 2010 Canadian Cardiovascular Society (CCS) Guidelines for the Use of Antiplatelet Therapy in the Outpatient Setting were published in May 2011. As part of a planned re-evaluation within 2 years, we conducted an extensive literature search encompassing all topics included in the 2010 CCS Guidelines, and concluded that there were sufficient new data to merit revisiting the guidance on antiplatelet therapy for secondary prevention in the first year after acute coronary syndrome (ACS), percutaneous coronary intervention, or coronary artery bypass grafting, and the interaction between clopidogrel and proton pump inhibitors. In addition, new clinical trials information about the efficacy and safety of combining novel oral anticoagulants with antiplatelet therapy in ACS justified the addition of a new section of recommendations to the Guidelines. In this focused update, we provide recommendations for the use of clopidogrel, ticagrelor, and prasugrel in non-ST elevation ACS, avoidance of prasugrel in patients with previous stroke/transient ischemic attack, higher doses of clopidogrel (j) /day) for the first 6 days after ACS, and the preferential use of prasugrel or ticagrelor after percutaneous coronary intervention in ACS. For non-ACS stented patients, we recommend acetylsalicylic acid/clopidogrel for 1 year, with at least 1 month of therapy for bare-metal stent patients and 3 months for drug-eluting stent patients unable to tolerate year-long double therapy. We also consider therapy for patients with a history of stent thrombosis, the indications for longer-term treatment, discontinuation timing preoperatively, indications for changing agents, the management of antiplatelet therapy before and after bypass surgery, and use/selection of proton pump inhibitors along with antiplatelet agents.

THE INFLUENCE OF HIGH FIRST DOSE AND STANDARD DOSE OF CLOPIDOGREL ON THE LEVELS OF SCD40L AND HS-CRP IN THE SERUM OF THE PATIENTS WITH ACS AFTER INTERVENTIONAL PROCEDURES

ObjectivesDiscuss the influence of High loading dose and standard dose of clopidogrel on serum sCD40L, hs-CRP levels in acute coronary syndrome patients after intervention operation and postoperative cardiovascular events for...

Platelet Function Testing and Genotyping Improve Outcome in Patients Treated With Antithrombotic Agents

The only reason P2Y12 inhibitors are administered in addition to aspirin is to improve the prevention of thrombosis. The clinical efficacy of adding clopidogrel to aspirin as a secondary prevention strategy in patients with high-risk coronary artery disease is well established.1 There are no effects of clopidogrel on any receptor other than P2Y12 to explain the magnitude of the clinical benefit. All of the established clinical effects are attributed to reduced platelet responsiveness to ADP.2 Therefore, the patient with inadequate P2Y12 inhibition determined by ex vivo testing logically has an increased risk for thrombosis. Persistent ischemic event occurrence and the irrefutable demonstration of clopidogrel antiplatelet response variability are 2 potent arguments against the widely practiced nonselective or one-size-fits-all strategy of administering clopidogrel therapy. Observational studies conducted in thousands of patients have led to an international consensus that high on-treatment platelet reactivity (HPR) to ADP is a major risk factor for post–percutaneous coronary intervention (PCI) ischemic event occurrence.3,4 Moreover, the recent 2011 American and European guidelines have given a Class IIb recommendation for platelet function testing or genotyping if the results of testing may alter management.5–7 Furthermore, the Society of Thoracic Surgeons gave a Class IIb recommendation for platelet function testing to determine the timing of surgery in patients on clopidogrel therapy (Level of Evidence C).8 These recommendations for personalizing antiplatelet therapy are unprecedented and acknowledge that a large body of data has accrued demonstrating the relation of HPR to ischemic risk in the PCI-treated patient. Finally, the evidence of diminished effectiveness of clopidogrel in poor metabolizers (those having 2 loss-of-function [LoF] cytochrome P450 [ CYP ] 2C19 alleles) has been recognized by the Food and Drug Administration (FDA) boxed warning about treatment with clopidogrel.9 Response by Krishna …

034 High doses of clopidogrel to overcome genetic resistance: the randomized cross-over CLOVIS-2 study

034 High doses of clopidogrel to overcome genetic resistance: the randomized cross-over CLOVIS-2 study

High Doses of Clopidogrel to Overcome Genetic Resistance: The Randomized Crossover CLOVIS-2 (Clopidogrel and Response Variability Investigation Study 2)

This study sought to determine whether the pharmacokinetic (PK) and pharmacodynamic (PD) responses to high or standard clopidogrel loading doses (LDs) differ according to CYP2C19*2 allele. CYP2C19 loss-of-function alleles are associated with reduced responsiveness to standard clopidogrel doses. Young post-myocardial infarction patients heterozygous (wild type [wt]/*2, n = 43) or homozygous (*2/*2, n = 8) for the CYP2C19*2 genetic variant were matched with patients not carrying the variant (wt/wt, n = 58). All patients were randomized to a 300- or 900-mg clopidogrel LD. The relative reduction in residual platelet aggregation (RR-RPA, %) and the area under the plasma concentration time curve of active metabolite from baseline to 6 h after loading (AUC(0-6)) were compared according to both LD and CYP2C19*2 carriage. The 300-mg LD led to a gene-dose effect for RR-RPA (-65.7% ± 35.9% in wt/wt vs. -48.0% ± 38.4% in wt/*2 vs. -14.6% ± 32.4% in *2/*2; overall p value = 0.003, p = 0.03 for wt/wt versus wt/*2, p = 0.04 for wt/*2 versus *2/*2) with minor effect in *2/*2 carriers. After the 900-mg LD, the effect of the CYP2C19*2 variant on platelet inhibition was fully compensated in wt/*2 carriers but not in *2/*2 carriers (-83.6% ± 25.8% in wt/wt vs.-77.2% ± 26.9% in wt/*2 vs. -29.5% ± 26.8% in *2/*2; overall p value = 0.0003, p = 0.20 for wt/wt versus wt/*2, p < 0.001 for wt/*2 versus *2/*2). A similar pattern was observed for the active metabolite AUC(0-6) according to carriage of CYP2C19*2 for both LDs. There was a significant correlation between PK and PD responses irrespective of the LD. Carriers of CYP2C19*2 display significantly lower responses to clopidogrel with a gene-dose effect. Clopidogrel resistance can be overcome by increasing the dose in heterozygous carriers but not in homozygous carriers. (Clopidogrel and Response Variability Investigation Study 2 [CLOVIS-2]; NCT00822666).

Balancing safety and efficacy: recent clinical evidence optimizing outcomes in patients with intermediate to high-risk non-ST-segment elevated acute coronary syndrome

Significant developments have taken place over the past 15 years with respect to greater understanding of ischaemic risk in non-ST-segment elevation (NSTE) acute coronary syndrome (ACS) and respective management strategies. This includes recognition of the clinical benefit of an early invasive strategy and of the value of addressing various antiplatelet targets in the approach to pharmacotherapy. The guidelines focused on management of NSTE-ACS advocate the role of dual antiplatelet therapy with a recommendation for triple antiplatelet therapy, including a glycoprotein (GP) IIb/IIIa inhibitor (GPI), in patients who are determined to be at an elevated risk for ischaemic events. This may include those who are elderly, have a history of diabetes and/or renal impairment, and have elevated cardiac biomarkers (e.g. troponin) or ST-segment deviation at diagnosis. While triple antiplatelet therapy has demonstrated significant improvement in clinical outcomes in patients with NSTE-ACS, there is concern over the potential for an increase in haemorrhagic complications. Newer pharmacotherapies such as prasugrel and ticagrelor have demonstrated significantly greater efficacy as compared with clopidogrel in patients with NSTE-ACS deemed as high risk, although the incidence of certain bleeding complications was significantly increased with both of these agents. Additionally, efficacy has not yet been proved when compared with higher doses of clopidogrel, which has been shown to offer significant clinical benefits in patients who underwent percutaneous coronary intervention. Thus, a regimen of triple antiplatelet therapy including a GPI should remain a strong consideration for standard therapy in patients at high risk for ischaemic events, even in the prasugrel and ticagrelor era.

Antiplatelet therapy in percutaneous coronary intervention: recent advances in oral antiplatelet agents

Dual antiplatelet therapy with aspirin and clopidogrel, in conjunction with heparin, is the most common antithrombotic strategy in percutaneous coronary intervention (PCI) used to reduce peri-procedural ischaemic complications. However, there remains significant inter-individual variability in post-treatment platelet inhibition with this current established therapy. This review focuses on recent developments in oral antiplatelet agents used in PCI, which promise to overcome, at least in part, current shortfalls. Genetic polymorphisms and medication interactions involving CYP3A4 or CYP2C19, patient compliance and higher platelet reactivity in certain subgroups, such as those with diabetes, are important factors contributing to inter-individual variability in post-treatment platelet inhibition. Higher clopidogrel doses have been associated with improved clinical outcomes, especially in those presenting with acute coronary syndrome. Newer agents, namely prasugrel and ticagrelor, have been shown to have greater potency and superior clinical outcomes. However, this comes with a price of increased bleeding complications. Whereas more potent antiplatelet therapies are associated with improved outcome, balancing the risk of bleeding and peri-procedural ischaemic complications remains a key aspect to consider when choosing among the ever-increasing number of agents available. The role of intravenous glycoprotein IIb/IIIa (GPIIb/IIIa) needs to be re-examined in the current context of such potent oral antiplatelet agents. Further research will hopefully help to determine the preferred antithrombotic strategy in patients undergoing PCI.

Recent developments in clopidogrel pharmacology and their relation to clinical outcomes

Oral antiplatelet therapy with clopidogrel and aspirin is an important and widely prescribed strategy to prevent ischemic events in patients with cardiovascular diseases. However, the occurrence of thrombotic events including stent thrombosis is still high (> 10%). Current practice guidelines are mainly based on large-scale trials focusing on clinical endpoints and ‘one size fits all’ strategies of treating all patients with the same clopidogrel doses. Pharmacodynamic studies have demonstrated that the latter strategy is associated with wide response variability where a substantial percentage of patients show nonresponsivenes. Translational research studies have established the relation between clopidogrel nonresponsivenes or high on-treatment platelet reactivity to adverse clinical events, thereby establishing clopidogrel nonresponsivenes as an important emerging clinical entity. Clopidogrel response variability is primarily a pharmacokinetic phenomenon associated with insufficient active metabolite generation that is secondary to i) limited intestinal absorption affected by an ABCB1 gene polymorphism; ii) functional variability in P450 isoenzyme activity; and iii) a genetic polymorphism of CYP450 isoenzymes. Personalized antiplatelet treatment with higher clopidogrel doses in selected patients or with newer more potent P2Y12 receptor blockers based on individual platelet function measurement can overcome some of the limitations of current clopidogrel treatment.

Clopidogrel pretreatment before primary percutaneous coronary stenting in patients with acute ST-segment elevation myocardial infarction: comparison of high loading dose (600 mg) versus low loading dose (300 mg)

Aggressive platelet inhibition is crucial to reduce myocardial injury and early cardiac events after coronary intervention. As compared with the conventional 300-mg dose, pretreatment with a 600-mg loading dose of clopidogrel significantly reduced periprocedural myocardial infarction (MI) in patients undergoing percutaneous coronary intervention (PCI). We investigated that the advantage of the 600-mg dose in inhibiting platelet aggregation more rapidly than the 300-mg dose may actually have special value for acute ST-segment elevation MI patients. A total of 171 patients with ST-segment elevation MI underwent primary PCI. A 600-mg (n=73) or 300-mg (n=98) loading regimen of clopidogrel was given before the procedure. We did a follow-up of all patients clinically for 30 days after coronary intervention. The primary endpoint was the 30-day occurrence of death, MI, urgent revascularization, or stroke. The primary endpoint occurred in 1.4% (1 of 73) of patients in the high dose versus 11.2% (11 of 98) of those in the conventional loading dose group (P=0.013). Death, recurrent MI, urgent revascularization, and stroke were lower in patients treated with the high dose of clopidogrel compared with conventional dose. Safety endpoints were similar in the two groups. Pretreatment with a 600-mg loading dose of clopidogrel before the procedure is safe and, as compared with the conventional 300-mg dose, significantly reduces recurrent MI and urgent revascularization in patients with primary PCI.

The treatment of clopidogrel resistance: Triple antiplatelet therapy and future directions

Despite the clinical benefit achieved with the adjunct of clopidogrel in percutaneous coronary intervention, a considerable number of patients continue to have cardiovascular events. There are accumulating evidences that recurrence of ischemic complications may be attributed to poor response to clopidogrel. However, current therapeutic alternatives for treatment of clopidogrel resistance remain limited. More aggressive intervention with higher doses of clopidogrel and the use of newer antiplatelet agents may help overcome resistance to antiplatelet agents.

Akute Intervention beim ST-Streckenhebungsinfarkt

Rapid revascularization of every presenting patient is the goal of modern therapy of ST-elevation myocardial infarction (STEMI). With respect to the current situation at least one half of all these patients will be treated medically using thrombolysis, prehospital or in hospital. Invasive diagnosis and revascularization (percutaneous intervention [PCI], coronary artery to bypass graft [CABG]) should be done promptly. Primary PCI performed in a timely manner by experienced interventional cardiologists in specialized centers is the best option in the management of patients with STEMI. Transfer PCI is an effective method of treatment for patients initially admitted to a hospital without PCI facilities and should be completed within 90 minutes of transfer time. Rescue-PCI following unsuccessful thrombolysis (< 50 % ST-resolution 90 minutes post thrombolysis) improves prognosis by restoring coronary flow. If planned immediate PCI after thrombolytic therapy is not indicated, PCI immediately after high dosage of glycoprotein IIb/IIIa-Inhibitors in combination with a high dose of clopidogrel may give good results.

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

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

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

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

Unmet needs in antiplatelet therapy

Despite antiplatelet therapy, patients with acute coronary syndromes (ACS) and those undergoing coronary intervention continue to experience atherothrombotic events, indicating a need for improvement in both overall patient management and antiplatelet treatments. Limitations of clopidogrel, which is widely used in dual therapy with aspirin, include slow onset of effect, low inhibition of platelet aggregation (IPA) in many patients, interindividual variability in response, and irreversible P2Y12 binding that prevents rapid offset of effect. Higher doses of clopidogrel may overcome some of these issues, and new oral agents such as the thienopyridine prasugrel and the reversible P2Y12 antagonist AZD6140 have faster onset of action and produce greater IPA. However, antiplatelet treatment must strike a balance between reduced atherothrombotic risk and bleeding risk, and it has yet to be determined whether greater platelet inhibition will produce better clinical outcome in terms of ischaemic events with an acceptable bleeding profile. Bleeding is an inherent risk of antiplatelet therapy and an independent predictor of poor prognosis in ACS patients, a factor that should be taken into account in assessing risks and benefits of antiplatelet treatment. New reversible P2Y12 antagonists offer the potential to discontinue antiplatelet therapy closer to invasive procedures compared with the thienopyridines, thus potentially reducing both procedure-related bleeding rates and duration of exposure to atherothrombotic risk prior to procedures. Ongoing large-scale Phase 3 trials will provide important information on whether the strategies of achieving higher levels of P2Y12 inhibition and using reversible inhibitors can improve antiplatelet therapy.

High dose Clopidogrel decreases mice liver mitochondrial respiration function in vitro

The effects of clopidogrel on mitochondrial respiratory function have not been previously investigated. We show in vitro that isolated mice liver mitochondria treated with very high doses of clopidogrel 10 µg/ml significantly reduces pre-treatment mitochondrial respiratory state 3 ( P < 0.05) and state 4 respiration ( P < 0.01), while oxygen consumption in State 3 is prolonged. This suggests a compromise to mitochondrial oxidative phosphorylation following the addition of high dose clopidogrel. Because clopidogrel at human therapeutic doses 40 ng/ml did not affect isolated mitochondrial respiration, it is thus unlikely, in the absence of cellular bioaccumulation, that clinical doses of clopidogrel would affect mitochondrial bioenergetics in vivo.