Daily Clopidogrel Research Articles

Lipid-Lowering and Anti-Thrombotic Therapy in Patients With Peripheral Arterial Disease: European Atherosclerosis Society/European Society of Vascular Medicine Joint Statement

An updated evidence-based consensus of the Joint Task Force from the European Atherosclerosis Society and European Society of Vascular Medicine. The guidelines for patients with peripheral arterial disease (PAD) include a low-density lipoprotein cholesterol (LDL-C) goal of a >50% reduction from baseline and <1.4 mmol/L (<55 mg/dL). Lowering LDL-C reduces the incidence of cardiovascular events and major adverse limb events, including amputations, by 25%. The addition of ezetimibe or a PCSK9 (proprotein convertase subtilisin/kexin type 9 serine protease) inhibitor will further decrease the risk of cardiovascular events (the latter has been associated with a reduction in the risk of major adverse limb events by 40%). Statin-based treatment improved patients’ walking distance. Daily clopidogrel 75 mg or the combination of aspirin 100 mg and rivaroxaban (2 × 2.5 mg) is indicated to prevent cardiovascular events and should be used after lower extremity revascularization (with consideration of the bleeding risk). Adherence with these recommendations for lipid-lowering and antithrombotic therapy will improve the morbidity and mortality of patients with PAD.

Comparison of antiplatelet treatment in patients with clopidogrel nonresponders with or without carriage of CYP2C19 polymorphism.

Several interventions exist for overcoming high platelet reactivity (HPR) on clopidogrel therapy. The goal of this study was to identify strategies that improve inhibition of platelet reactivity in clopidogrel nonresponders with or without loss of function CYP2C19 genotypes, resulting in platelet reactivity similar to that in responders. A total of 376 patients with stenting for coronary artery disease underwent platelet function testing in three centers. Blinded platelet function tests were performed after 75 mg daily clopidogrel treatment for 28 days. In total, 183 nonresponders were genotyped, were randomized to four treatment groups with each treatment lasting approximately 28 days, and underwent repeated measurements of platelet reactivity after treatment. With 75 mg of daily clopidogrel, nonresponders had significantly higher HPR than did responders (multiple electrode aggregometry [MEA, arbitrary platelet aggregation unit]: mean, 71.4; 95% confidence intervals [CI], 68.6 to 74.3; and mean, 27.5; 95% CI, 26.0 to 28.9, respectively; p < 0.001). Ticagrelor or ticlopidine treatment in nonresponders resulted in platelet reactivity similar to that in responders in intermediate metabolizers (mean, 24.0; 95% CI, 19.6 to 28.4; p > 0.05; and mean, 30.0; 95% CI, 24.7 to 37.5; p > 0.05, respectively) and poor metabolizers (mean, 23.2; 95% CI, 18.0 to 28.3; p > 0.05; and mean, 30.3; 95% CI, 24.5 to 6.0; p > 0.05, respectively). However, in extensive metabolizers, only ticagrelor treatment showed platelet reactivity similar to that in responders (mean, 26.1; 95% CI, 24.1 to 28.0; p > 0.05). Among clopidogrel nonresponders with cardiovascular disease on 75 mg daily clopidogrel, ticagrelor resulted in a comparable degree of platelet inhibition in all nonresponders compared with 150 mg daily clopidogrel or triple therapy with clopidogrel and cilostazol, irrespective of phenotype.

Challenges in Developing New Therapies for Vascular Access Dysfunction.

Vascular access dysfunction impedes the provision of effective hemodialysis. Dysfunction of arteriovenous fistulas (AVFs) largely reflects maturational failure, whereas dysfunction of arteriovenous grafts (AVGs) is mainly driven by recurrent stenosis and thrombosis at the venous anastomosis. There

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OBJECTIVES/SPECIFIC AIMS: The objective of this study is to measure the association of CYP2C19 (*1-*8,*17), ABCB1(C3435T; rs1045642), PON1 (p.Q192R; rs662), and B4GALT2 (c.909 C&gt;T and c.366 G&gt;C) gene polymorphisms in the Caribbean Hispanic population with major adverse cardiovascular events (MACE). METHODS/STUDY POPULATION: Patients of Caribbean Hispanic ethnicity from all geographic regions of the Island of Puerto Rico, male and female, aged &gt;21 will be recruited. Cases will consist of patients receiving a daily clopidogrel dose of 75 mg following acute coronary syndrome (ACS) who experience a MACE within the first year of treatment. Control study patients must have received clopidogrel 75 mg daily for a minimum of 1 year without experiencing MACE. Genomic DNA samples will be genotyped to determine the frequency distribution of major CYP2C19, ABCB1, PON1, and B4GALT2 gene polymorphisms. Observed frequencies will be compared with other reported populations. An association study will be performed between genetic variables and MACE and a multivariable logistic regression model (additive) will be constructed. RESULTS/ANTICIPATED RESULTS: We anticipate finding a significant association between major genetic determinants of clopidogrel response and MACE where cases with MACE will carry higher frequency of CYP2C19, ABCB1, PON1, and B4GALT2. DISCUSSION/SIGNIFICANCE OF IMPACT: As the range of multiloci allelic combinations in admixed Caribbean Hispanics is higher than in other populations due to its unique 500-year history of genomic admixture, a wide spectrum of genetic variances is expected to be present in the study population. Determining the prevalence and effect of CYP2C19, ABCB1, PON1, and B4GALT2 polymorphisms holds the potential to personalize anti-platelet treatment for Caribbean Hispanic patients requiring treatment after ACS.

A comparison of reduced-dose prasugrel and standard-dose clopidogrel in elderly patients with acute coronary syndromes undergoing early percutaneous revascularization: Design and rationale of the randomized Elderly-ACS 2 study

Elderly patients display higher on clopidogrel platelet reactivity as compared with younger patients. Treatment with prasugrel 5mg has been shown to provide more predictable and homogenous antiplatelet effect, as compared with clopidogrel, suggesting the possibility of reducing ischemic events after an acute coronary syndrome (ACS) without increasing bleeding. The Elderly-ACS 2 study is a multicenter, randomized, parallel-group, open-label trial designed to demonstrate the superiority of a strategy of dual antiplatelet treatment using a reduced 5-mg daily dose of prasugrel over a standard strategy with a daily clopidogrel dose of 75mg in patients older than 74years with ACS (either ST- or non-ST-elevation myocardial infarction) undergoing early percutaneous revascularization. The primary end point is the composite of all-cause mortality, myocardial reinfarction, disabling stroke, and rehospitalization for cardiovascular causes or bleeding within 1 year. Taking advantage of the planned size of 2,000 patients, the secondary objective is to assess the prognostic impact of selected prerandomization variables (age, sex, diabetic status, serum creatinine level, electrocardiogram changes, abnormal troponin levels, basal and residual SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery [SYNTAX] score). The Elderly-ACS 2 study is a multicenter, randomized trial comparing a strategy of dual antiplatelet therapy with a reduced dose of prasugrel with a standard dose of clopidogrel in elderly patients with ACS undergoing percutaneous revascularization (the Elderly ACS 2 trial: NCT01777503).

Effectiveness of clopidogrel dose escalation to normalize active metabolite exposure and antiplatelet effects in CYP2C19 poor metabolizers

Carriers of two copies of the loss-of-function CYP2C19*2 variant convert less clopidogrel into its active metabolite, resulting in diminished antiplatelet responses and higher cardiovascular event rates. To evaluate whether increasing the daily clopidogrel dose in poor metabolizers (PM) overcomes the effect of the CYP2C19 * 2 variant, we enrolled 18 healthy participants in a genotype-stratified, multi-dose, three-period, fixed-sequence crossover study. Six participants with the *1/*1 extensive (EM), *1/*2 intermediate (IM), and *2/*2 poor metabolizer genotypes each received 75 mg, 150 mg, and 300 mg each for 8 days. In each period, maximal platelet aggregation 4 hours post-dose (MPA4) and active metabolite area under the curve (AUC) differed among genotype groups (P < .05 for all). At day 8, PMs needed 300 mg daily and IMs needed 150 mg daily to attain a similar MPA4 as EMs on the 75 mg dose (32.6%, 33.2%, 31.3%, respectively). Similarly, PMs needed 300 mg daily to achieve active metabolite concentrations that were similar to EMs on 75 mg (AUC 37.7 and 33.5 ng h/mL, respectively). These results suggest that quadrupling the usual clopidogrel dose might be necessary to overcome the effect of poor CYP2C19 metabolism.

CES1A −816C as a Genetic Marker to Predict Greater Platelet Clopidogrel Response in Patients with Percutaneous Coronary Intervention

This study was designed to determine whether CES1A -816A/C polymorphism could be associated with altered clopidogrel response. Recruited patients were pretreated with 300 mg clopidogrel loading dose before undergoing percutaneous coronary intervention for stenting and genotyped with CYP2C19 *2, *3, or *17, and CES1A -816A/C, respectively. Adenosine diphosphate-induced maximum platelet aggregation (MPA) was determined on day 3 after initiation of daily clopidogrel maintenance doses. The clinical primary end point was the 1-year incidence of definite stent thrombosis (ST). Multivariable linear regression revealed that the CES1A -816A/C polymorphism was independently associated with MPA measures with an absolute β value of 6.76. Of 617 patients, a subcohort of 249 patients not carrying CYP2C19 *2, *3, or *17 were categorized into 3 groups based on the -816A/C genotype. The median MPA value was lower in 125 carriers of the -816C variant than in 124 noncarriers (21.5% vs. 31.7%, P = 0.001). The 1-year definite ST occurred in 7 patients in that subcohort, and only 1 ST case was one of carriers of the -816 A/A that was associated with higher MPA values. The CES1A -816C would be used to predict greater platelet response to clopidogrel than the CES1A -816A in percutaneous coronary intervention-treated patients not carrying CYP2C19 variants.

Persistent platelet reactivity in patients with unprotected left main disease treated by percutaneous coronary intervention

Purpose: Angioplasty is emerging as an alternative technique for patients with unprotected left main disease (ULMD). Persistent platelet reactivity (PPR) under aspirin or thienopyridines is associated with acute events after angioplasty. We aimed to determine the rate and potential clinical impact of PPR in patients treated by angioplasty for ULMD. Methods: We prospectively included 125 patients referred for angioplasty for ULMD in a single-centre registry. For the first 64 patients (ALMA-1), angioplasty was performed under aspirin and clopidogrel treatment without previous platelet reactivity assessment. For the last 61 patients (ALMA-2), platelet reactivity was assessed (light transmission aggregometry triggered by arachidonic acid and ADP and VASP index) systematically before angioplasty: patients found to have aspirin-related PPR were administered aspirin twice daily and those with clopidogrel-related PPR had their daily clopidogrel dose doubled or replaced by prasugrel. Results: Overall, patients mean age was 69±13y.o., 37% were diabetic, 37% had NSTEMI and 62% had multivessel disease. The left main lesion was ostial in 23%, medial in 8% and distal or both in 69%. Mean SYNTAX score was 22.8±9.2. More than 30% of the patients have an additive EuroSCORE≥6. Procedural characteristics were similar in both groups. Follow-up was successful at 1 year in all patients. In ALMA-2, concerning aspirin pathway, mean maximal aggregation intensity (MAI) was 15.4±17.0%. The proportion of patients with aspirin-related PPR (MAI≥20%) was 28% and aspirin was switched twice a day in those patients. Concerning thienopyridines pathway, mean MAI triggered by ADP 20μmol was 53.6±18.5%, mean VASP index was 46±19% and considering both MAI>65% and VASP>50%, 26% of patients (n=16) had PPR under thienopyridines. Following these results, 31% of patients (n=19) were switched to prasugrel and 26% (n=16) were treated by high-dose clopidogrel. Finally, 8% of patients (n=5) had PPR under both, aspirin and thienopyridine treatment. Dual antiplatelet therapy at 1 year was continued in 86% of patients in ALMA-1 and 92% in ALMA-2 (p=NS). The rate of 1-year major cardiovascular events was significantly decreased in ALMA-2 vs. ALMA-1 (8.2% vs. 20.8%; p=0.04) as a composite endpoint of cardiovascular death and stent thrombosis (0.0% vs. 8.3%; p=0.02). Conclusion: In our real life study, PPR for dual antiplatelet therapy is frequent in patients undergoing angioplasty for ULMD and appears to be strongly associated with subsequent major events.

O-018 Variability in Response to a 75mg Daily Clopidogrel Dose in a Cohort of 90 Patients Undergoing Endovascular Treatment of Unruptured Cerebral Aneurysms

Background and PurposeRecent studies have suggested that variability in response to clopidogrel therapy may explain some of the thromboembolic and hemorrhagic complications encountered after endovascular treatment of cerebral aneurysms with...

Genetics Altered Blood Results in Cardiovascular Study

Orlando – Genotyping can provide more targeted use of the commonly prescribed drug clopidogrel among patients with cardiovascular disease, according to data from the ELEVATE-TIMI 56 trial. “We’re at the point that clopidogrel may not be a one-size-fits-all drug for our patients,” Dr. Jessica Mega said at the annual scientific sessions of the American Heart Association. She reported on the prospective trial involving 333 patients with stable cardiovascular disease who were genotyped for alleles of CYP2C19, which is primarily responsible for producing the active metabolite from clopidogrel (Plavix). Research has shown that patients who carry nonfunctional alleles of CYP2C19 such as *2 have less active metabolite, increased risk of residual platelet activity, and a greater risk of cardiac events. Based on the genotyping results, 86 carriers (80 heterozygotes and 6 homozygotes) of the CYP2C19*2 allele were randomized to daily clopidogrel doses of 75 mg, 150 mg, 225 mg, or 300 mg for four 14-day treatment periods, while 247 noncarriers of CYP2C19*2 were assigned to daily 75 mg or 150 mg doses for two 14-day periods each. Platelet testing at the end of each treatment period revealed that both CYP2C19*2 heterozygotes and homozygotes had significantly higher platelet reactivity than did noncarriers, said Dr. Mega, a cardiologist at Brigham and Women’s Hospital, Boston. Among CYP2C19*2 heterozygotes, tripling the daily maintenance dose of clopidogrel to 225 mg was needed to reduce platelet reactivity to the levels achieved with a standard 75-mg dose in noncarriers, she said. Among CYP2C19*2 homozygotes, who made up 2% of the study population, even 300 mg, or four times the standard dose, of clopidogrel did not result in optimal degrees of platelet inhibition. “It’s good news for patients that we’re able to optimize their [platelet] inhibition with clopidogrel,” she said. “I think we need to get creative in how we use clopidogrel, and this study is one step in the right direction.” Invited discussant Lawrence Lesko, PhD, director of the center for pharmacometrics and systems pharmacology at the University of Florida in Lake Nona, noted that clopidogrel carries a “black box” warning that poor metabolizers are at heightened risk for cardiovascular events, and that ELEVATE-TIMI 56 fills in some of the gaps in the labeling of what to do with these patients as well as intermediate metabolizers. “The results of this study point us in the direction of higher doses for the *1 and *2 genotypes to normalize them to the active metabolites of 75 mg,” he said. “The most important open question in my mind after the study is, What do we do next to integrate genotyping more routinely into clinical practice for patients about to go on clopidogrel or already on clopidogrel?” Dr. Mega responded that point of care tests are already available that can be run by individuals in a laboratory and deliver genotype results in 1 hour. “So, I don’t think technology is going to be the rate-limiting step,” she said. ELEVATE-TIMI 56 included patients taking 75 mg clopidogrel for a myocardial infarction and/or undergoing percutaneous coronary intervention at least 4 weeks and not more than 6 months prior to study entry. Compliance during the study was 97.3% at the 75-mg dose, 98.1% at the 150-mg dose, 98.6% at the 225-mg dose, and 98.3% at the 300-mg dose. There were no deaths, cerebral events, or Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding events, Dr. Mega said. The study was also published online in JAMA. Bristol-Myers Squibb and SanofiAventis sponsored the trial. Accumetrics and Nanosphere provided research supplies. Dr. Mega and Dr. Lesko reported having no relevant financial conflict of interest. CfA

Gesundheitsökonomische Modellierung zum Einsatz von Medikamente freisetzenden Stents im Vergleich zu Bypassoperationen bei koronarer Herzkrankheit

The therapy of coronary heart disease (CHD) leads to an enormous economic burden on health-care systems. Coronary artery bypass grafting (CABG) and percutaneous revascularizations with implantation of drug-eluting stents (DES) are important treatment methods in CHD. The presented evaluation addresses cost efficacy of the use of DES versus CABG in CHD patients. A health-economic model considering linear resource use was performed from a restricted societal perspective for time periods of 1 and 3 years. Because of the short time horizon discounting was not applied. The clinical assumptions for event rates at 1 and 3 years were derived from the ARTS-I study for CABG, and from the ARTS-II study for DES (sirolimus-eluting stents). Cost assumptions for the resources used were based on the German Diagnosis Related Groups 2007 (G-DRG-2007). The base case value was assumed to be 2,800 Euros, the average DES price 1,200 Euros, and the average DES use per patient 3.7. The average per-patient daily clopidogrel costs were assumed to be 2.57 Euros, and the duration of the clopidogrel therapy 12 months. Within the scope of sensitivity analyses, different model parameters were varied and the evaluation was tested for its robustness. The average costs for percutaneous coronary intervention (PCI) without DES were found to be 4,420 Euros, for CABG 12,840 Euros, and for DES intervention 8,860 Euros (Table 4). 1-year clopidogrel intake resulted in 938 Euros, the treatment of patients with myocardial infarction during follow-up in 3,989 Euros. The 1-year per-patient total costs after CABG were calculated to be 13,373 Euros and after DES 10,443 Euros, leading to a difference of 2,930 Euros in favor of DES implantation (Table 6). The 3-year per-patient total costs after CABG were estimated to be 13,630 Euros and after DES 10,905 Euros, showing a Rehabilitationsmasscost difference of 2,725 Euros in favor of DES implantation (Table 6). Changes in cost-weights of G-DRG-2007 for CABG and PCI, DES price and DES use per patient as well as in the duration of the clopidogrel therapy influenced the cost differences considerably; however, they did not reach a break-even point (Figures 2 and 3). Changes in the clinical follow-up assumptions showed a lower effect on the difference in total costs (Figures 2 and 3). The presented data, indicating a possible economic middle-term advantage of DES versus CABG, should be proven with clinical assumptions derived from randomized clinical trials.