High Maintenance Dose Clopidogrel Research Articles

High maintenance dose of clopidogrel in patients with high on-treatment platelet reactivity after a percutaneous coronary intervention: a meta-analysis.

High on-treatment platelet reactivity (HTPR) has been linked to cardiovascular (CV) events after a percutaneous coronary intervention. There have been some controversies on whether a high maintenance dose (MD) of clopidogrel is effective for HTPR patients. Thus, we carried out a meta-analysis to assess the efficacy and safety of a high MD of clopidogrel in patients with HTPR. Searches of PubMed (from 1966 to May 2014), EMBASE (from 1974 to May 2014), and the Cochrane Library (2 May 2014) were performed. All randomized-controlled trials assessing the efficacy and safety of a high MD of clopidogrel in patients with HTPR were included. A total of eight randomized-controlled trials including 3865 patients were included for analysis. In patients with HTPR, high-dose clopidogrel significantly reduced the risk of major adverse CV events or major adverse cardiac and cerebrovascular events [risk ratio (RR) 0.59; 95% confidence interval (CI) 0.39-0.88], stent thrombosis (RR 0.43; 95% CI 0.20-0.92), and target vessel revascularization (RR 0.31; 95% CI 0.10-0.93), without increasing major bleeding (RR 0.75; 95% CI 0.43-1.31) compared with standard-dose clopidogrel. A high MD of clopidogrel may be a feasible and readily available treatment to lower the risk of recurrent CV events in patients with HTPR after undergoing percutaneous coronary intervention, especially in HTPR patients with coronary artery disease and chronic kidney disease.

ACP Journal Club. Review: In patients having PCI, high-dose clopidogrel reduces major cardiac events vs standard-dose clopidogrel.

Source Citation Ma W, Liang Y, Zhu J, Wang Y, Wang X. Meta-analysis appraising high maintenance dose clopidogrel in patients who underwent percutaneous coronary intervention with and without high on-clopidogrel platelet reactivity. Am J Cardiol. 2014;115:592-601. 25613665

Meta-Analysis Appraising High Maintenance Dose Clopidogrel in Patients Who Underwent Percutaneous Coronary Intervention With and Without High On-Clopidogrel Platelet Reactivity

The CURRENT-OASIS 7 (Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events-Seventh Organization to Assess Strategies in Ischemic Symptoms) trial showed that a 7-day 150-mg maintenance dose (MD) clopidogrel could reduce cardiovascular events in subgroup patients who underwent percutaneous coronary intervention (PCI) compared with the 75 mg/day regimen, although whether prolonging the high MD clopidogrel (≥150 mg) treatment period to at least 4 weeks can reduce major adverse cardiac events in the patients who underwent PCI with and without high on-clopidogrel platelet reactivity (HPR) is still controversial. We searched Pubmed, Embase, and Cochrane Library from inception until September 2014 for randomized controlled trials that compared high versus standard MD clopidogrel in patients who underwent PCI. Seventeen trials involving 4,822 patients who underwent PCI included 2,879 patients who were allocated to the "HPR patients" subgroup and 1,943 to the "native patients" subgroup without paying attention to the clopidogrel reactivity before randomization. Compared with the standard therapy, the high MD clopidogrel was associated with a significant reduction in the risk of major adverse cardiac events (odds ratio [OR] 0.52, 95% confidence interval [CI] 0.39 to 0.71, p <0.0001) in patients who underwent PCI. The HPR patients subgroup was also benefited from such high MD treatment (OR 0.54, 95% CI 0.38 to 0.77, p = 0.0007). The observed benefits were mainly attributed to treatment-associated reduction in stent thrombosis (OR 0.43, 95% CI 0.23 to 0.78, p = 0.006) and target vessel revascularization (OR 0.38, 95% CI 0.20 to 0.74, p = 0.004). There was no difference in the rate of major/minor bleeding event between the high and standard MD group (OR 0.80, 95% CI 0.56 to 1.13, p = 0.21). In conclusion, the efficacy and safety of at least 4 weeks' high MD clopidogrel is greater than that of standard therapy for patients who underwent PCI with and without HPR.

GW24-e1373 Effect and security with triple antiplatelet therapy in patients undergoing drug-eluting stents for the treatment of complex coronary lesions

ObjectivesTo evaluate the efficacy and safety of triple antiplatelet therapy (cilostazol combined with clopidogrel and aspirin) in patients undergoing multiple drug-eluting stents (DES) implantation of complex coronary lesions.MethodsTotally 128 senile...

Adjunctive Cilostazol versus High Maintenance Dose of Clopidogrel in Patients with Hyporesponsiveness to Chronic Clopidogrel Therapy

PurposeWhether addition of cilostazol is superior to increasing dose of clopidogrel in patients with hyporesponsiveness to chronic clopidogrel therapy is unknown.Materials and MethodsWe studied 73 patients with hyporesponsiveness to clopidogrel on standard dual antiplatelet therapy for more than 2 weeks. Clopidogrel hyporesponsiveness was defined as percent inhibition of P2Y12 reaction units (PRU) <30% on VerifyNow P2Y12 assay. Patients were randomly assigned to increased dose of clopidogrel (aspirin 100 mg+clopidogrel 150 mg daily: group A, n=38) or to receiving additional cilostazol (aspirin 100 mg+clopidogrel 75 mg+cilostazol 100 mg bid daily: group B, n=35).ResultsBaseline percent inhibition of PRU and PRU was similar between 2 groups (13.0±10.2% versus 11.8±9.7%, p=0.61, and 286.3±54.7 versus 295.7±53.7, p=0.44, respectively). At follow-up, percent inhibition of PRU was higher and PRU was lower significantly in group B than in group A (38.5±17.9% versus 28.3±16.6%, p=0.02, and 207.3±68.2 versus 241.3±76.7, p=0.050, respectively). Among those still showing hyporesponsiveness to clopidogrel at follow-up (21 patients in group A, 10 patients in group B), 12 patients completed further crossover study. Compared to the baseline, magnitude of change in percent inhibition of PRU and PRU showed an improved tendency after the crossover (from 2.7±8.7% to 15.8±18.4%, p=0.08, and from -18.6±58.0 to -61.9±84.3, p=0.08).ConclusionAdjunctive cilostazol improved clopidogrel responsiveness better than the higher maintenance dose of clopidogrel in hyporesponsive patients with chronic clopidogrel therapy.

EFFECT OF DIFFERENT MAINTENANCE DOSE OF CLOPIDOGREL ON PLATELET FUNCTION IN PATIENTS WITH ACUTE CORONARY SYMPTOM

ObjectivesTo assess the efficacy and safety of the high clopidogrel maintenance dose in acute coronary syndromes (ACS) patients undergoing selective percutaneous coronary intervention (PCI).Methods150 ACS patients were randomly divided into...

Interaction analysis between genetic polymorphisms and pharmacodynamic effect in patients treated with adjunctive cilostazol to dual antiplatelet therapy: results of the ACCEL‐TRIPLE (Accelerated Platelet Inhibition by Triple Antiplatelet Therapy According to Gene Polymorphism) study

Compared with standard dual antiplatelet therapy, adjunctive cilostazol to dual antiplatelet therapy ('triple antiplatelet therapy') has a potential to reduce ischemic event occurrence after percutaneous coronary intervention. The pharmacokinetic and pharmacodynamic effects of clopidogrel have been significantly influenced by the enzyme activity of the ABCB1 C3435T and the CYP2C19 system. • For the pharmacokinetics of cilostazol, genetic polymorphisms of the CYP3A5 and CYP2C19 have been associated with the substantial interindividual variability in healthy volunteers. Loss-of-function polymorphism of the CYP2C19 gene, but not the ABCB1 C3435T and CYP3A5*3 genes, affects the antiplatelet effect of triple antiplatelet therapy. Most of extensive and intermediate East Asian metabolizers (0 or 1 CYP2C19 loss-of-function allele) show adequate platelet inhibition when treated with triple antiplatelet therapy after percutaneous coronary intervention. However, carriage of 2 CYP2C19 loss-of-function alleles is still associated with the risk of high platelet reactivity (defined by by 5 µM ADP-induced maximal platelet aggregation >46%), which clinical impact needs to be validated in future clinical trials. AIMS Although adjunctive cilostazol to dual antiplatelet therapy can reduce the risks of clinical events after percutaneous coronary intervention (PCI), whether genetic polymorphism can influence the pharmacodynamics of this regimen has not been evaluated. One hundred and twenty-seven patients treated with PCI and taking triple antiplatelet therapy (≥1 month) were enrolled. Platelet reactivity was assessed by conventional aggregometry and the VerifyNow P2Y12 assay. High on-treatment platelet reactivity (HPR) was defined as 5 µm ADP-induced maximal platelet reactivity (Agg(max) ) >46%. CYP3A5*3, CYP2C19*2/*3 and ABCB1 3435C > T were genotyped. CYP3A5*3 and ABCB1 3435C > T variants did not affect the antiplatelet effect of triple antiplatelet therapy. For non-carriers, one and two carriers of the CYP2C19 loss-of-function (LOF) allele, Agg(max) consecutively increased after the addition of 5 µm[mean (95% confidence intervals): 24.6% (20.8 to 28.5%) vs. 28.7% (25.4 to 32.0%) vs. 32.3% (25.8 to 38.7%), P = 0.062, respectively] and 20 µm ADP [34.2% (29.3 to 39.0%) vs. 41.7% (37.8 to 45.6%) vs. 44.9% (37.9 to 51.9%), P = 0.007, respectively]. Likewise, late platelet reactivity and P2Y12 reaction units proportionally changed according to the number of CYP2C19 LOF alleles. HPRs were observed in 9.2% of subjects: 6.3%, 7.4% and 20.0% with 0, 1 and 2 carriers of CYP2C19 LOF allele(s) (P = 0.099). In multivariate analysis, carriage of two CYP2C19 LOF alleles was a significant predictor for the prevalence of HPR (odds ratio 5.78, 95% CI 1.21, 27.78, P = 0.028). Among PCI-treated patients, the effect of triple antiplatelet therapy is influenced by the CYP2C19 LOF allele. Its clinical benefit needs to be validated according to the CYP2C19 metabolic phenotype in future clinical trials. [Adjunctive Cilostazol Versus High Maintenance dose ClopidogrEL in Acute Myocardial Infarction Patients According to CYP2C19 Polymorphism (ACCEL-AMI-2C19), NCT00915733 and Adjunctive Cilostazol Versus High Maintenance-dose Clopidogrel According to Cytochrome 2C19 Polymorphism (ACCEL-2C19), NCT01012193].

039 Benefit of tailored therapy with high clopidogrel maintenance dose according to CYP2C19 genotypes in clopidogrel non responders undergoing coronary stenting for acute coronary syndrome

039 Benefit of tailored therapy with high clopidogrel maintenance dose according to CYP2C19 genotypes in clopidogrel non responders undergoing coronary stenting for acute coronary syndrome

Platelet reactivity in patients with chronic kidney disease receiving adjunctive cilostazol compared with a high-maintenance dose of clopidogrel: Results of the Effect of Platelet Inhibition According to Clopidogrel Dose in Patients with Chronic Kidney Disease (PIANO-2 CKD) randomized study

Chronic kidney disease (CKD) is a factor of low response to clopidogrel. We sought to assess the functional impact of cilostazol in CKD patients with undergoing hemodialysis. Seventy-four patients with CKD undergoing hemodialysis and percutaneous coronary intervention were enrolled. Patients were randomly assigned to receive clopidogrel (75 mg/d [group 1, n = 24]), high-maintenance dose of clopidogrel (150 mg/d [group 2, n = 25]), or clopidogrel (75 mg/d) with cilostazol (200 mg/d [group 3, n = 25]) for 14 days. Another 50 patients with normal renal function undergoing percutaneous coronary intervention were treated with 75 mg of clopidogrel and served as the control group. Platelet function was evaluated before and after antiplatelet therapy with light transmittance aggregometry and with VerifyNow P2Y12 assay (Accumetrics, San Diego, CA). Platelet activation markers (soluble CD40 ligand and soluble P-selectin) were also assessed. The baseline platelet function measurements were similar in the 3 groups of patients; however, the CKD groups had significantly higher platelet aggregation activity compared with the control groups. The rate of high on-treatment platelet reactivity was significantly lower in group 3 than in groups 1 and 2 (10% vs 43% vs 32%, respectively; P < .05). After 14 days of antiplatelet therapy, the changes in plasma soluble CD40 ligand and soluble P-selectin levels were significantly higher in group 3 compared with groups 1 and 2 (P < .01); however, there were no significant differences in platelet function and activation markers between groups 1 and 2. Adjunctive cilostazol improves platelet inhibition compared with 75 or 150 mg of clopidogrel in CKD patients undergoing hemodialysis.

Usefulness of High Clopidogrel Maintenance Dose According to CYP2C19 Genotypes in Clopidogrel Low Responders Undergoing Coronary Stenting for Non ST Elevation Acute Coronary Syndrome

The cytochrome P450 (CYP) 2C19*2 loss-of-function allele has been associated with impaired clopidogrel response and worse prognosis in clopidogrel-treated patients. The benefit of tailored therapy according to platelet function test results remains unclear, and the potential effect of genotypes on this benefit has not been addressed in unstable patients. The present study was designed to evaluate the benefit of tailored therapy with a higher maintenance dose according to CYP2C19 genotypes in patients identified as nonresponders who underwent percutaneous coronary intervention for non-ST-segment elevation acute coronary syndromes. Three hundred forty-six consecutive patients were enrolled and received a loading dose of 600 mg, including 86 *2 carriers (13 homozygotes and 73 heterozygotes) and 260 *2 noncarriers. Clopidogrel response, assessed with platelet reactivity index vasoactive-stimulated phosphoprotein, was significantly affected by genotype, with lower clopidogrel response in CYP2C19*2 allele carriers (p = 0.01). Accordingly, the rate of clopidogrel nonresponse was higher in CYP2C19*2 allele carriers (53% vs 41%, p = 0.04). All clopidogrel nonresponders (n = 151), including 105 *2 noncarriers and 46 *2 carriers, received high 150-mg clopidogrel maintenance doses at discharge to overcome initial low response. After 1 month, high maintenance doses overcame clopidogrel low response in only 44% of the whole population and significantly less frequently in *2 carriers than in noncarriers (28% vs 50%, p = 0.01). In conclusion, higher clopidogrel maintenance doses were able to overcome clopidogrel low response in fewer than half of clopidogrel low responders who underwent percutaneous coronary intervention for non-ST-segment elevation acute coronary syndromes. The benefit of this tailored therapy was significantly reduced in CYP2C19*2 carriers. Therefore, these patients might require alternative strategies with new P2Y₁₂ blockers.

Standard- vs High-Dose Clopidogrel After Percutaneous Coronary Intervention

To the Editor: The results of the Gauging Responsiveness with a VerifyNow assay–Impact on Thrombosis and Safety (GRAVITAS) and Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events–Seventh Organization to Assess Strategies in Ischemic Syndromes (CURRENTOASIS 7) trials suggested that high-dose clopidogrel after percutaneous coronary intervention (PCI) can exhibit different clinical efficacy according to the study design. CURRENT-OASIS 7 found a reduction in cardiovascular death, myocardial infarction (MI), or stroke at 1 month with double-dose clopidogrel (adjusted hazard ratio [HR], 0.86) while GRAVITAS, after 6 months, did not (HR, 1.01). First, ischemic event occurrences may be dependent on the extent of peri-PCI platelet activation. A 600-mg loading dose before coronary angiography in CURRENT-OASIS 7 significantly reduced the primary outcome but not when given 12 to 24 hours after PCI in GRAVITAS. Second, the benefit of intensified platelet inhibition may be different depending on the risk profile, which differed between the trials. The 1-month cardiovascular death and MI rate with the standard dose was approximately 0.7% in GRAVITAS (estimated from Figure 2) vs about 4.5% in CURRENT-OASIS 7. Differences in safety may also be related to the differences in study design. More patients in the standard-dose clopidogrel group in CURRENT-OASIS 7 received heparin or glycoprotein IIb/IIIa inhibitor compared with those in GRAVITAS, and they had a higher rate of major bleeding (1.9% in 1 month in CURRENT-OASIS 7 vs 1.2%-2.3% in 6 months in GRAVITAS). Patients with high ontreatment reactivity were more likely to be women and slightly older in GRAVITAS, and double-dose clopidogrel showed greater benefits in these patients in CURRENT-OASIS 7. However, these characteristics also significantly increased bleeding risk in a meta-analysis. CYP2C19 polymorphism carriage was a main predictor of high on-treatment reactivity with high–maintenance dose clopidogrel in the Accelerated Platelet Inhibition by a Double Dose of Clopidogrel According to Gene Polymorphism (ACCEL-DOUBLE) study. Differences in the genetic composition of the population in GRAVITAS could be related to the modest pharmacodynamic effect. However, despite similarly high prevalences of CYP2C19 poor metabolizers in East and South Asians (10%-20%), these groups had different clinical benefits associated with double-dose clopidogrel (19% decrease in East Asians and 40% increase in South Asians in ischemic events at 1 month in the highvs standard-dose groups). Ischemic event occurrence is a complex process in which platelets, procoagulant and fibrinolytic systems, genes, race, and environment all play a role. Rather than a single measurement of platelet function, future treatment strategies should consider all these factors in an individual patient.

Standard- vs High-Dose Clopidogrel After Percutaneous Coronary Intervention

To the Editor: The results of the Gauging Responsiveness with a VerifyNow assay–Impact on Thrombosis and Safety (GRAVITAS) and Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events–Seventh Organization to Assess Strategies in Ischemic Syndromes (CURRENTOASIS 7) trials suggested that high-dose clopidogrel after percutaneous coronary intervention (PCI) can exhibit different clinical efficacy according to the study design. CURRENT-OASIS 7 found a reduction in cardiovascular death, myocardial infarction (MI), or stroke at 1 month with double-dose clopidogrel (adjusted hazard ratio [HR], 0.86) while GRAVITAS, after 6 months, did not (HR, 1.01). First, ischemic event occurrences may be dependent on the extent of peri-PCI platelet activation. A 600-mg loading dose before coronary angiography in CURRENT-OASIS 7 significantly reduced the primary outcome but not when given 12 to 24 hours after PCI in GRAVITAS. Second, the benefit of intensified platelet inhibition may be different depending on the risk profile, which differed between the trials. The 1-month cardiovascular death and MI rate with the standard dose was approximately 0.7% in GRAVITAS (estimated from Figure 2) vs about 4.5% in CURRENT-OASIS 7. Differences in safety may also be related to the differences in study design. More patients in the standard-dose clopidogrel group in CURRENT-OASIS 7 received heparin or glycoprotein IIb/IIIa inhibitor compared with those in GRAVITAS, and they had a higher rate of major bleeding (1.9% in 1 month in CURRENT-OASIS 7 vs 1.2%-2.3% in 6 months in GRAVITAS). Patients with high ontreatment reactivity were more likely to be women and slightly older in GRAVITAS, and double-dose clopidogrel showed greater benefits in these patients in CURRENT-OASIS 7. However, these characteristics also significantly increased bleeding risk in a meta-analysis. CYP2C19 polymorphism carriage was a main predictor of high on-treatment reactivity with high–maintenance dose clopidogrel in the Accelerated Platelet Inhibition by a Double Dose of Clopidogrel According to Gene Polymorphism (ACCEL-DOUBLE) study. Differences in the genetic composition of the population in GRAVITAS could be related to the modest pharmacodynamic effect. However, despite similarly high prevalences of CYP2C19 poor metabolizers in East and South Asians (10%-20%), these groups had different clinical benefits associated with double-dose clopidogrel (19% decrease in East Asians and 40% increase in South Asians in ischemic events at 1 month in the highvs standard-dose groups). Ischemic event occurrence is a complex process in which platelets, procoagulant and fibrinolytic systems, genes, race, and environment all play a role. Rather than a single measurement of platelet function, future treatment strategies should consider all these factors in an individual patient.

Platelet Inhibition by Adjunctive Cilostazol Versus High Maintenance-Dose Clopidogrel in Patients With Acute Myocardial Infarction According to Cytochrome P450 2C19 Genotype

The aim of this study was to assess the degree of platelet inhibition by adjunctive cilostazol in patients with acute myocardial infarction (AMI) according to hepatic cytochrome P450 2C19 (CYP2C19) genotype. Although adjunctive cilostazol intensifies platelet inhibition in AMI patients, it is not established whether this regimen can be free from the effect of CYP2C19 loss-of-function variants (*2/*3). We randomly assigned 126 AMI patients with available CYP2C19 genotyping to receive adjunctive cilostazol (triple group; n = 64) or high maintenance-dose (MD) clopidogrel of 150 mg/day (high-MD group; n = 62). Using conventional aggregometry and VerifyNow (Accumetrics Inc., San Diego, California), platelet reactivity was measured at pre-discharge and 30-day follow-up. Primary endpoint was change in maximal platelet aggregation (ΔAgg(max)) between pre-discharge and 30-day follow-up. High on-treatment platelet reactivity (HPR) was defined as 20 μmol/l adenosine diphosphate-induced maximal platelet aggregation (Agg(max)) >59%. In noncarriers, despite numerically greater inhibition by adjunctive cilostazol, changes in platelet measures and the rate of HPR did not significantly differ between the 2 groups. In carriers, ΔAgg(max) after 5 and 20 μmol/l adenosine diphosphate stimuli was significantly higher in the triple (n = 39) versus high-MD group (n = 38) (21.8 ± 13.9% vs. 9.0 ± 13.3%, p < 0.001, and 24.2 ± 17.2% vs. 7.7 ± 15.5%, p < 0.001, respectively). Likewise, changes in late platelet aggregation and P2Y12 reaction unit were consistently greater in the triple versus high-MD group. Fewer patients in the triple group met the criteria of HPR at 30-day follow-up than in the high-MD group (15.4% vs. 44.7%, p = 0.005). Compared with high-MD clopidogrel, adjunctive cilostazol significantly enhances platelet inhibition and reduces the rate of HPR, especially in AMI patients with CYP2C19 loss-of-function variants. (Adjunctive Cilostazol Versus High Maintenance-Dose Clopidogrel in Acute Myocardial Infarction (AMI) Patients According to CYP2C19 Polymorphism [ACCELAMI2C19]; NCT00915733).

AS-252 A Comparison of Clopidogrel Responsiveness in Patients with Chronic Renal Failure: Results of the Adjunctive Cilostazol Versus High Maintenance Dose Clopidogrel (PIANO) Study

AS-252 A Comparison of Clopidogrel Responsiveness in Patients with Chronic Renal Failure: Results of the Adjunctive Cilostazol Versus High Maintenance Dose Clopidogrel (PIANO) Study

Platelet Inhibition by Adjunctive Cilostazol Versus High Maintenance-Dose Clopidogrel In Patients with Acute Myocardial Infarction According to Cytochrome P450 2C19 Genotype

AbstractAbstract 3322 ObjectivesThe aim of this study was to assess the degree of platelet inhibition by adjunctive cilostazol in patients with acute myocardial infarction (AMI) according to CYP2C19 genotype. BackgroundAlthough adjunctive cilostazol intensifies platelet inhibition in AMI patients, it is not established whether this regimen can overcome the loss-of-function effect of CYP2C19 variants. MethodsWe randomly assigned 126 AMI patients with available CYP2C19 genotyping to receive adjunctive cilostazol (triple group; n = 64) or high maintenance-dose (MD) clopidogrel of 150-mg/day (high-MD group; n = 62). Using conventional aggregometry and VerifyNow, platelet reactivity was measured at pre-discharge and 30-day follow-up. Primary endpoint was change in maximal platelet aggregation (Aggmax). High post-treatment platelet reactivity (HPPR) was defined as 5 μmol/l ADP-induced Aggmax > 50%. ResultsIn non-carriers, the two groups did not differ with respect to changes in platelet measures, and could achieve fewer rates of HPPR at 30-day follow-up (< 5%). In carriers, changes in 5 and 20 μmol/l ADP-induced Aggmax were significantly higher in the triple (n = 39) versus high-MD group (n = 38) (21.8 ± 13.9% vs. 9.0 ± 13.3%, p < 0.001, and 24.2 ± 17.2% vs. 7.7 ± 15.5%, p < 0.001, respectively). Likewise, changes in late platelet aggregation and P2Y12 reaction unit were consistently greater in the triple vs. high-MD group. Fewer patients in the triple group met the criteria of HPPR at 30-day follow-up compared with the high-MD group (2.6% vs. 21.1%, p = 0.014). ConclusionsAmong AMI patients with CYP2C19 variants, adjunctive cilostazol enhances platelet inhibition and reduces the rate of HPPR, as compared with high-MD clopidogrel. (Adjunctive Cilostazol Versus High-MD ClopidogrEL in Patients With Acute Myocardial Infarction According to CYP2C19 genotype [ACCEL-AMI-CYP2C19]; NCT00915733). Disclosures:No relevant conflicts of interest to declare.

E0633 The effect on Left Ventricular Function and Safety of High Maintenance Dose of Clopidogrel in Patients with Acute Anterior Myocardial Infarction Undergoing Selective PCI

ObjectiveTo assess the beneficial efficacy and safety of the high maintenance dose of clopidogrel in acute anterior myocardial infarction (AMI) patients undergoing selective percutaneous coronary intervention (PCI).MethodsFifty two patients were...

E0455 Effect on left ventricular function and safety of high maintenance dose of clopidogrel in patients with acute anterior myocardial infarction undergoing selective PCI

ObjectiveTo assess the beneficial efficacy and safety of the high maintenance dose of clopidogrel in acute anterior myocardial infarction (AMI) patients undergoing selective percutaneous coronary intervention (PCI).Methods25 patients were enrolled...

Carriage of Cytochrome 2C19 Polymorphism Is Associated With Risk of High Post-Treatment Platelet Reactivity on High Maintenance-Dose Clopidogrel of 150 mg/day: Results of the ACCEL-DOUBLE (Accelerated Platelet Inhibition by a Double Dose of Clopidogrel According to Gene Polymorphism) Study

This study sought to determine the impact of gene polymorphisms on platelet reactivity (PR) after clopidogrel 150 mg/day in patients treated with percutaneous coronary intervention (PCI). Although high maintenance-dose (MD) clopidogrel reduces PR, it is unknown whether gene polymorphisms are related with the risk of high post-treatment PR (HPPR) after high-MD clopidogrel. We included mostly patients receiving high-MD clopidogrel after PCI from previously registered Gyeongsang National University Hospital data. A total of 126 PCI-treated patients receiving high-MD clopidogrel were enrolled. Platelet reactivity was assessed with conventional aggregometry and VerifyNow (Accumetrics Inc., San Diego, California) after receiving clopidogrel 150 mg/day for at least 1 month. CYP3A5, CYP2C19, and ABCB1 genotyping was performed. We defined HPPR as 5 micromol/l adenosine diphosphate (ADP)-induced maximal PR (PR(max)) >50%. CYP3A5 and ABCB1 polymorphisms did not influence PR. Carriers of CYP2C19 variant (*2 or *3) (n = 80) had significantly higher 5 and 20 micromol/l ADP-induced PR(max) than did noncarriers (n = 46) (40.7 +/- 16.8% vs. 30.3 +/- 12.6%, p < 0.001; 54.2 +/- 16.2% vs. 40.5 +/- 15.8%, p < 0.001, respectively). Late PR and VerifyNow results indicated consistently greater measures in carriers versus noncarriers of CYP2C19 variant. All platelet measures proportionally increased according to the number of CYP2C19 variant alleles. Twenty-seven (21.4%) patients met the criteria for HPPR. Prevalence of HPPR was 8.7%, 21.7%, and 50.0% in carriers of 0, 1, and 2 CYP2C19 variant alleles, respectively (p < 0.001). By multivariate analysis, carriage of CYP2C19 variant was a significant predictor of HPPR (odds ratio: 5.525, 95% confidence interval: 1.333 to 23.256, p = 0.018). Among PCI-treated patients receiving high-MD clopidogrel, carriage of CYP2C19 variant relates to increased PR and predicts risk of HPPR. (Adjunctive Cilostazol Versus High Maintenance-dose ClopidogrEL in Acute Myocardial Infarction [AMI] Patients According to CYP2C19 Polymorphism [ACCELAMI2C19]; NCT00915733; and Comparison of Platelet Inhibition With Adjunctive Cilostazol Versus High Maintenance-Dose Clopidogrel According to Hepatic Cytochrome 2C19 Allele (CYP2C19) Polymorphism [ACCEL2C19]; NCT00891670).

Antiplatelet Therapy After Percutaneous Coronary Intervention

Current guidelines recommend dual antiplatelet therapy (DAPT) that includes aspirin and the platelet P2Y12 ADP receptor antagonist clopidogrel after percutaneous coronary intervention (PCI). These recommendations are based on data that DAPT with the P2Y12 inhibitors clopidogrel reduces major adverse cardiac events after PCI in stable angina and acute coronary syndrome (ACS) patients when compared with aspirin, or aspirin in combination with warfarin.1 Despite treatment with DAPT, patients with ACS undergoing PCI are at elevated risk for recurrent ischemic events compared with stable angina patients in part because of increased platelet thrombotic activity in ACS. In addition, there is considerable interindividual variability in the degree of platelet inhibition achieved by clopidogrel, and high residual platelet activity in the setting of clopidogrel therapy (hyporesponsiveness) is associated with adverse cardiovascular (CV) events after PCI. Clopidogrel hyporesponsiveness is related to a variety of clinical and genetic factors that alter pharmacokinetics, and diabetes, congestive heart failure (CHF), and obesity are associated with reduced efficacy. Clopidogrel is a prodrug that requires conversion by the hepatic cytochrome P450 system (CYP) to an active metabolite, and it can take up to 6 hours for clopidogrel to have maximal effect after the loading dose. Genetic polymorphisms that reduce CYP activity result in decreased hepatic metabolism of clopidogrel. Among persons treated with clopidogrel, carriers of specific reduced function CYP2C19 alleles have impaired clopidogrel conversion, significantly lower levels of active metabolite, diminished platelet inhibition, and higher rates of adverse CV events and stent thrombosis after PCI.2 The prevalence of CYP2C19 polymorphisms ranges from 30% to 60% depending on ethnicity.2,3 Medications that inhibit CYP activity also reduce clopidogrel conversion, and some proton pump inhibitors (PPI) that reduce CYP function (eg, omeprazole) diminish clopidogrel metabolite levels and efficacy measured by platelet function testing. The interaction between clopidogrel and …

Genotyping, Clopidogrel Metabolism, and the Search for the Therapeutic Window of Thienopyridines

It is somewhat remarkable to note that not until recently, nearly 12 years and tens of millions of treated patients after its initial approval, has the metabolism of clopidogrel, an inactive prodrug, begun to be more fully understood. Although this lack of knowledge may not be unique among common cardiovascular drugs, there are 4 characteristics of clopidogrel therapy that make this gap in understanding disconcerting: The potential for life-threatening complications (bleeding or thrombosis) at both ends of its therapeutic spectrum; the fact that 1 dose is supposed to fit all; the lack of a measureable, proven end point (such as blood pressure for antihypertensive drugs) that allows for titration to a target response; and the nearly mandatory need by many patients for clopidogrel, with no acceptable alternative until recently. Article see p 512 Historically, understanding the metabolism of a drug has been critical in identifying those patients most likely to benefit from and, more important, potentially be harmed by that drug. This is especially true for drugs with relatively narrow therapeutic windows, such as phenytoin, warfarin, and others. Although it seems safe to assume, on the basis of our extensive clinical experience, that the therapeutic window of clopidogrel is unlikely to be narrow, this certainly does not represent the depth of knowledge we would hope for after so much clinical experience and research. What we do know is that P2Y12 inhibition with thienopyridines is beneficial in preventing arterial thrombotic events, presumably requiring the achievement of some minimal level of receptor inhibition that may or may not vary on the basis of the patient and clinical scenario. We also know that it is associated with a significant increase in serious bleeding events, with higher levels of inhibition associated with greater bleeding. In the present and future practice environment, with a growing …