Maintenance Dose Of Clopidogrel Research Articles

ASSA13-11-4 The Clinical Application of VerifyNow-P2Y12 Assay in Evaluation of Platelet Inhibition with Clopidogrel

Objective To evaluate the platelet inhibition with VerifyNow-P2Y12 assay in patients under regular maintenance dose of Clopidogrel, and explore the clinical characteristics of Clopidogrel non-responsive and its predicting factors. Methods A total of 99 patients undergone PCI procedure and were receiving Clopidogrel in regular maintenance dose for at least 1 week were enrolled. Platelet reactivity, including Baseline, P2Y12 Reaction Unit (PRU), and platelet inhibition rate were measured with VeifyNow-P1Y12 assay (Accumetrics Inc., San Diego, CA, USA). The dosage of anti-platelet drugs, combination with any other drugs, clinical characters in baseline of all the enrolled patients was recorded in detail for evaluation. PRU ≤ 240 was used as cut-off to indentify Clopidogrel responsive and Clopidogrel non-responsive patients. In the non-responsive group, patients were further separated into 3 sub-groups (types) according to the baseline and platelet inhibition rate. Type I has high baseline, high inhibition rate, represents false non-responsiveness, Type II has low inhibition rate, represents true non-responsive, and Type III is combination. Results In this study, 48 of 99 patients were found to be Clopidogrel non-responsive (48.5%). The ratio of Type I, Type II and Type III in the non-responsive group were 9(9.1%), 27(27.3%), and 12(12.1%), respectively. Female’s baseline value of platelet value was significantly higher than male’s (p OR = 6.5, 95% CI 2.295 ∼ 18.407, P 24 kg/m2 show significant correlation with Clopidorgrel non-responsive (p OR = 3.207, 95% CI 1.375 ∼ 7.485, P Conclusions With VerifyNow-P2Y12 assay, Clopidogrel non-responsive Type I is caused by high baseline, and female patients is an independent predicting factor; Clopidogrel non-responsive Type II has true low platelet inhibition rate, related to the low effectiveness of Clopidogrel, high body weight may have some effects. Clopidogrel non-responsive Type III can have the characters of both type I and type II. Age, Hypertension, Diabetics, smoking, hyperlipidemia, CRP, and Pantoprazole do not relate to Clopidogrel non-responsive.

Impaired platelet P2Y12 inhibition by thienopyridines in chronic kidney disease: mechanisms, clinical relevance and pharmacological options

Patients with chronic kidney disease (CKD) represent an increasing proportion of the population undergoing percutaneous coronary intervention (PCI) and up to 40% of the patients treated for acute coronary syndrome (ACS). Several studies and registries in the setting of ACS and elective PCI have reported a negative association between CKD and mortality, stent thrombosis, post-procedural ischaemic events and bleeding events. Pharmacological inhibition of the adenosine diphosphate receptor by thienopyridines or ticagrelor and disruption of the cyclooxygenase pathway by aspirin constitute the current standards of care to prevent thrombotic complications following stent-based PCI. In CKD patients, the avoidance of anti-platelet therapy may be driven by the lack of clinical trial data to support its efficacy, by errors or omissions, or by a reluctance to use this therapy in a population characterized by its enhanced bleeding risk. However, there is growing evidence to suggest that a severely decreased glomerular filtration rate per se, independent of the presence of diabetes mellitus, is an important determinant of high residual platelet reactivity under a clopidogrel maintenance dose. Recent reports have emphasized that the impact of impaired platelet inhibition by thienopyridines is of paramount importance in CKD patients, with an enhanced mortality rate in low-responder patients. Pharmacodynamic studies indicate the phosphodiesterase 3 inhibitor, cilostazol, the third generation thienopyridine prasugrel and the reversible P2Y12 antagonist ticagrelor to be potent strategies to overcome this biological resistance. In clinical practice, platelet function testing should be considered in CKD patients undergoing PCI, especially in those who experience thrombotic events despite dual therapy. Newer agents should be contemplated in patients who display higher residual platelet aggregability after standard treatment. Among these, the non-thienopyridine P2Y12 receptor antagonist ticagrelor, which does not require biotransformation, could be the drug of choice in CKD patients with ACS. In this population, ticagrelor has been found to reduce mortality and ischaemic events with an acceptable bleeding risk.

Effect of CYP2C19*2 and *17 Genetic Variants on Platelet Response to Clopidogrel and Prasugrel Maintenance Dose and Relation to Bleeding Complications

The present study was performed to compare the influence of cytochrome P459 2C19 (CYP2C19) *2 and *17 genetic variants on the platelet response to clopidogrel and prasugrel maintenance therapy and to assess the relation between platelet reactivity and bleeding complications. A total of 730 patients were included (517 patients treated with clopidogrel 150 mg/day and 213 discharged with prasugrel 10 mg). Platelet reactivity was assessed at 1 month with the platelet reactivity index vasodilator-stimulated phosphoprotein (PRI VASP). High on-treatment platelet reactivity was defined as PRI VASP >50% and low on-treatment platelet reactivity (LTPR) as PRI VASP <20%. The patients were classified according to their genotypes as poor metabolizers (*2/non *17), intermediate metabolizers (*2/*17 or non *2/non *17) and ultrametabolizers (non *2/*17). At 1 month, the prasugrel response was significantly better than the clopidogrel response in all groups of patients, with a lower incidence of high on-treatment platelet reactivity but a greater incidence of LTPR, regardless of the genetic variants. The genetic distribution had a significant effect on the mean PRI VASP values, the incidence of high on-treatment platelet reactivity, and LTPR with both clopidogrel and prasugrel (p <0.05 for all). LTPR identified a group of patients at a greater risk of bleeding (odds ratio 4.8, 95% confidence interval 2.7 to 8.3; p <0.0001). In conclusion, the present study showed that both clopidogrel and prasugrel have genetic modulation by CYP2C19 *2 and *17 alleles and that prasugrel provides greater platelet inhibition, regardless of the genotypes. In addition, LTPR was associated with a greater risk of bleeding.

Influence of Platelet Reactivity on Clinical Outcome of Patients with Stable Coronary Artery Disease

Single antiplatelet therapy with aspirin is actually recommended for cardiovascular prevention in patients with stable coronary disease, whereas dual antiplatelet therapy (aspirin and clopidogrel) represents the established treatment in patients with acute coronary syndromes or stable angina undergoing percutaneous coronary intervention. However, recurrent ischemic events occur in patients on treatment with clopidogrel; this may be due to low responsiveness to this agent, a phenomenon influenced by environmental, clinical, and genetic factors. Different strategies have been tested to overcome this phenomenon, such as increase in clopidogrel loading and maintenance doses and use of newer P2Y12 inhibitors (prasugrel and ticagrelor), which are by now indicated for patients with acute coronary syndromes; the latter agents have been associated with stronger antiplatelet effect than clopidogrel even in patients with stable coronary disease, but further studies are needed to test their net clinical benefit in this setting (reduction of ischemic events without increase in bleeding).

Efficacy and safety of low-dose clopidogrel in Japanese patients after drug-eluting stent implantation: a randomized pilot trial

In Japan, a lower maintenance dose of ticlopidine is used than in the United States and Europe. Therefore a lower maintenance dose of clopidogrel may also be considered appropriate in Japanese patients. The present randomized pilot study evaluated the efficacy and safety of 50 mg clopidogrel in Japanese patients who underwent drug-eluting stent (DES) implantation. A total of 200 patients with 277 lesions who underwent intravascular ultrasound-guided DES implantation were enrolled. The subjects were allocated to the 50- or 75-mg clopidogrel group. All patients received 100 mg aspirin daily before the procedure, and this continued indefinitely. The duration of clinical follow-up was 21.8 ± 5.7 months in the 75-mg group and 21.9 ± 6.1 months in the 50-mg group (P = 0.96). During follow-up, no cardiac death, myocardial infarction, or stent thrombosis was observed in either group. Side effects of clopidogrel were observed in 4 patients (4.0 %) in the 75-mg group and in 4 patients (4.0 %) in the 50-mg group. Following this randomized pilot study, it may be justified to perform a large-scale randomized study comparing 50- and 75-mg dosing of clopidogrel in Japanese patients undergoing coronary stent implantation.

Antiplatelet drug resistance in patients with coronary heart disease

Coronary angioplasty is an important component of coronary heart disease (CHD) management. There is a substantial evidence of the need for dual antiaggregant therapy (clopidogrel and aspirin) in this clinical group, both before and after the intervention. The development of thrombotic complications during antiaggregant therapy suggests the antiplatelet drug resistance. The prevalence of this condition varies from 5% to 45% for aspirin, and from 20% to 45% for clopidogrel, depending on the assessment method and the specific clinical group. For dual antiplatelet therapy, the resistance prevalence is 6-8%. Presently, the gold standard method of the platelet functional activity assessment is optical aggregometry. To assess the resistance to aspirin, arachidonic acid is used as an aggregation inductor, with the calculation of absolute aggregation levels. To assess the resistance to clopidogrel, ADP is used as an aggregation inductor, and the relative aggregation parameters are calculated. The development of aspirin resistance is influenced by biological, clinical, and genetic factors. The clopidogrel resistance is associated with certain medications, hyperglycemia, atherosclerosis, and CYP2C19*2 gene polymorphism. Identification of the patients resistant to antiplatelet drugs enables the clinicians to adjust the antiplatelet treatment reasonably early and to reduce the risk of cardiovascular events. The possible methods of overcoming antiplatelet drug resistance are to double the loading and maintenance doses of clopidogrel and to use new agents.

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.

Clinical Impact of Genetically Determined Platelet Reactivity

Dual antiplatelet therapy with aspirin and clopidogrel dramatically reduced the rate of major adverse cardiac events following percutaneous coronary intervention. Clopidogrel is a prodrug which requires a two-step hepatic biotransformation thanks to the cytochrome P450 (CYP450) enzyme system. Genetic polymorphism of CYP450 system (e.g., CYP2C19*2) responsible for altered clopidogrel metabolism is a major cause of high on-treatment platelet reactivity (HTPR), which translates into thrombotic events in stented patients. Studies demonstrated that HTPR could be overcome in poor metabolizers thanks to increased loading doses or maintenance doses of clopidogrel or with the use of more potent antiplatelet agents such as prasugrel. Other genetic polymorphisms have also been correlated with HTPR: ABCB1, ATP2B2, and TIAM2. Large-scale randomized trials with clinical endpoints remain necessary to determine the optimal antiplatelet therapy in patients carrying genetic polymorphism associated with HTPR and thrombotic events.

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

Drug eluted balloon has the potential to treat in-stent restenosis and small vessels disease

Background In-stent restenosis still a major problem after percutanous coronary intervention. One-quarter of DESs can result in restenosis, paclitaxel-coated coronary balloons showed an advantage in patients with in-stent restenosis in different clinical studies, small vessels disease is a challenge in coronary intervention Methods Single center study in our cath lab between Jan 2010–Oct 2011, a total of 36 patients, with either in-stent restenosis more than 50%, or small vessel disease, under went balloon angioplasty using a Dior Eurocor, Drug Eluted Balloon to treat those lesions. And patients were prepared in the same way of regular PCI, given heparin and clopidogrel loading and maintenance dose accordingly. We are planning to f/u the patients clinically for 6 months to 2 years. Results Total of 36 patients, 10 (28%) patients had in-stent restenosis treated by DEB. 26 (72%) patients had a small vessels disease, diameter Conclusion The vast majority of our patients are diabetic and this technique could resolve the PCI limitations in those patients even after DES implantation.

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...

Prasugrel Versus High Dose Clopidogrel to Overcome Early High on Clopidogrel Platelet Reactivity in Patients with ST Elevation Myocardial Infarction

There is a paucity of data regarding the early effectiveness of the proposed 600 mg clopidogrel loading dose (LD) on platelet reactivity (PR) in ST elevation myocardial infarction (STEMI) patients. If high on-treatment platelet reactivity (HTPR) is present, prasugrel reloading and subsequent maintenance dose (MD), might offer faster and stronger platelet inhibition than high clopidogrel MD. In 93 STEMI patients treated by primary percutaneous coronary intervention we assessed PR using the VerifyNow P2Y12 platelet function test, 2 h following 600 mg LD of clopidogrel. All the 60 (64.5 %) patients exhibiting HTPR (defined as PR ≥ 235 P2Y12 reaction units), were randomized to 1 of 2 therapeutic strategies: reloading with prasugrel 60 mg/10 mg MD or high (150 mg) clopidogrel MD. The primary endpoint of PR at 24 h post randomization was lower in the prasugrel compared to the clopidogrel group (51.3, 25.7-77.0 versus 242.4, 215.8-268.9 P2Y12 reaction units, least square estimates, 95 % confidence intervals, p < 0.001). PR at 2 h and 5 days post randomization was lower in the prasugrel compared to the clopidogrel group (117.2, 70.9-163.4 and 101.6, 70.1-133.2 least square mean difference, 95 % confidence intervals, p < 0.001 for both). At all the time points of PR assessment, HTPR rates were lower in prasugrel than in clopidogrel group. HTPR is commonly observed early post 600 mg clopidogrel LD in STEMI patients. In this case, prasugrel 60 mg LD/10 mg MD provides faster and stronger platelet inhibition than a high clopidogrel MD regimen.

Obesity and intracranial in-stent thrombosis

A morbidly obese, diabetic, hypertensive patient, with severe intracranial left middle cerebral artery (MCA) stenosis, suffered recurrent stereotyped transient ischemic attacks over 2 months, despite taking daily antiplatelet agents, high...

Impact of proton pump inhibitor omeprazole on the antiplatelet effect of clopidogrel in individuals with various CYP2C19*2 genotypes

To investigate the impact of omeprazole on platelet response to clopidogrel and the effect of polymorphisms of CYP2C19 on the antiplatelet effect of clopidogrel. Platelet aggregation (PA) was assessed before 300 mg aspirin plus 300 mg loading dose of clopidogrel and after 300 mg aspirin plus 75 mg maintenance dose of clopidogrel 7 days later in 414 patients with acute coronary syndrome who have undergone percutaneous coronary intervention (PCI). Thereafter, gastric mucosal protective drugs were given (omeprazolem 20 mg, n=224 or cimetidine 800 mg, n=190). Fourteen days later, PA was measured again. Genotypes of CYP2C19*2 were analyzed with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). After taken aspirin and clopidogrel, PA has decreased significantly in both groups. Compared with cimetidine, omeprazole had no significant impact on PA on 7 and 21 days post PCI. Compared with homozygotes or heterozygotes for the wild-type CYP2C19*2, patients with CYP2C19*2 AA genotype had significantly higher PA on 7 and 21 days post PCI (P<0.05). No attenuating effect on platelet response to clopidogrel has been observed for Omeprazole. The variant of CYP2C19*2 AA genotype is significantly associated with attenuated response to clopidogrel.

Clopidogrel resistance in North Indian patients of coronary artery disease and lack of its association with platelet ADP receptors P2Y1 and P2Y12 gene polymorphisms

Aspirin and Clopidogrel are used in prophylaxis of patients undergoing percutaneous coronary intervention and long-term prevention of cardiovascular and cerebrovascular events. Clopidogrel resistance has been attributed to P2Y1 and P2Y12 adenosine diphosphate (ADP) receptor polymorphisms. This study enrolled 100 patients of coronary artery disease (CAD) who were on the maintenance dose of clopidogrel (75 mg OD) with or without aspirin. In addition, 10 received loading dose (300 mg) prior to percutaneous coronary intervention. Relevant clinical and drug history were elicited. ADP-induced platelet aggregation study and PCR-RFLP for P2Y1 (1622A > G) and P2Y12 (i-T744C) polymorphisms were performed. Two groups of controls were used for defining cut-off for platelet aggregation response. Follow-up data, wherever available was recorded. The most common pattern of aggregation response was disaggregation, either complete (46.4%) or partial (53.6%). A frequency of 13% clopidogrel non-responders and 19% semi-responders was found. All the cases were H1/H1 haplotype for P2Y12 gene polymorphism and 28 (29.2%) patients carried P2Y1 1622A > G (21(21.9%) AG and 7(7.3%) GG) gene polymorphism, the frequency being greater in clopidogrel responders compared to semi/non-responders but difference was not statistically significant. There was no statistically significant difference between responders and semi/non-responders in terms of the history of risk factor for CAD, concurrent atorvastatin use or past history of an acute vascular event. On follow up, the two patients who developed myocardial infarction/acute coronary syndromes (MI/ACS) were clopidogrel semi- and non-responder, respectively. Variability in clopidogrel response with 13% non-responders and 19% semi-responders was seen in this study with adverse outcome (MI/ACS) on follow up seen in two patients. Hence, poor response to clopidogrel may be related to increased likelihood of adverse long-term coronary event that may benefit from additional or alternative anti-platelet therapy. Clopidogrel resistance was not associated with ADP receptor P2Y1 and P2Y12 gene polymorphisms. Hence, it is postulated that clopidogrel resistance in CAD patients is multifactorial and not caused by single-gene polymorphisms.

Efficacy and safety of intensified antiplatelet therapy on the basis of platelet reactivity testing in patients after percutaneous coronary intervention: Systematic review and meta-analysis

BackgroundADP-specific platelet function assays were shown to predict thrombotic events, and might be helpful to select candidates for more potent antiplatelet therapy. We aimed to determine the efficacy and safety of giving intensified antiplatelet therapy on the basis of platelet reactivity testing for patients undergoing percutaneous coronary intervention (PCI). MethodsElectronic databases were searched to find prospective, randomized trials that reported the clinical impact of using an intensified antiplatelet protocol (repeated loading or elevated maintenance doses of clopidogrel, prasugrel or glycoprotein IIb/IIIa inhibitor) on the basis of ADP-specific platelet reactivity testing (VerifyNow, Multiplate, VASP or light transmission aggregometry) compared to standard-dose clopidogrel. Evaluated efficacy measures included cardiovascular death, non-fatal myocardial infarction and definite/probable stent thrombosis (ST), while major bleeding events were recorded as safety endpoint. ResultsBetween 2008 and 2011, 10 clinical trials comprising 4213 randomized patients were identified. Compared to standard antiplatelet therapy, the intensified protocol was associated with a significant reduction in cardiovascular mortality, ST and myocardial infarction (p<0.01 for all). There was no difference in the rate of major bleeding events between intensified and standard groups (p=0.44). Although the observed effects regarding mortality, ST and bleeding were not heterogeneous, meta-regression analysis revealed that the net clinical benefit of the intensified treatment significantly depended on the risk of ST with standard-dose clopidogrel (p=0.023). ConclusionIntensifying antiplatelet therapy on the basis of platelet reactivity testing reduces cardiovascular mortality and ST after PCI; however, the net benefit of this approach depends on the risk of ST with standard-dose clopidogrel.

Recovery of Platelet Function After Discontinuation of Prasugrel or Clopidogrel Maintenance Dosing in Aspirin-Treated Patients With Stable Coronary Disease: The Recovery Trial

The goal of this study was to assess the offset of the antiplatelet effects of prasugrel and clopidogrel. Guidelines recommend discontinuing clopidogrel at least 5 days and prasugrel at least 7 days before surgery. The pharmacodynamic basis for these recommendations is limited. Aspirin-treated patients with coronary artery disease were randomly assigned to either prasugrel 10 mg or clopidogrel 75 mg daily for 7 days. Platelet reactivity was measured before study drug administration and for up to 12 days during washout. The primary endpoint was the cumulative proportion of patients returning to baseline reactivity after study drug discontinuation. A total of 56 patients were randomized; 54 were eligible for analysis. Platelet reactivity was lower 24 h after the last dose of prasugrel compared with clopidogrel. After prasugrel, ≥75% of patients returned to baseline reactivity by washout day 7 compared with day 5 after clopidogrel. Recovery time was dependent on the level of platelet reactivity before study drug exposure and the initial degree of platelet inhibition after study drug discontinuation but not on treatment assignment. Recovery time after thienopyridine discontinuation depends on the magnitude of on-treatment platelet inhibition, resulting, on average, in a more delayed recovery with prasugrel compared with clopidogrel. The offset of prasugrel was consistent with current guidelines regarding the recommended waiting period for surgery after discontinuation. (Prasugrel/Clopidogrel Maintenance Dose Washout Study; NCT01014624).

Primary percutaneous revascularization using coronary stent in a patient with acute mesenteric ischemia.

Acute mesenteric ischemia (AMI) is an uncommon disorder with serious morbidity and mortality caused by acute obstruction of the intestinal vessels. The obstruction is generally due to cardiac thromboembolism or, less frequently, by the acute thrombosis on an existing atherosclerotic plaque. The most commonly involved vessel is the superior mesenteric artery (SMA).Surgical revascularization and resection is still the treatment of choice. Although percutaneous transluminal revascularization has been found to be as effective as surgical revascularization in chronic mesenteric ischemia, there is not enough evidence in literature for its use in acute cases. A 70-year-old female patient presented to our emergency department with an ongoing abdominal pain of 12-hour duration, nausea, vomiting and palpitation. She had a previous medical history of cerebrovascular accident (CVA), hypertension, chronic obstructive pulmonary disease, type 2 diabetes mellitus and atrial fibrillation (AF). She was under treatment with aspirin and warfarin for CVA and AF. On physical examination, the blood pressure was 80/50 mmHg and pulse rate 142 per minute. The heart sounds were normal and rhonchus was heard over bilateral lungs fields. The abdomen was tender and rebound pain was present. ECG was normal except for AF with high ventricular response. Laboratory results showed normal values of ALT, AST, amylase, lipase and troponin I, but leukocyte count and CRP were high (leukocyte: 20200/mm3, CRP: 237 mg/L). Her INR was 2.4. On abdominal computed tomography, diffuse increased wall thickness of the ileum and mesenteric edema were seen, and acute mesenteric ischemia was confirmed. Because of the patient’s clinical conditions, accompanying systemic diseases and the extended ischemia of the intestines, surgical mortality was considered very high. Percutaneous transluminal angioplasty was contemplated as is carried out in acute myocardial infarction. After obtaining written informed consent from the patient, celiac angiography was performed via the right femoral artery approach. A 100% occlusion was seen in the proximal SMA (Figure 1). Right Judkins catheter was used to engage the ostium of the SMA. The total occlusion was crossed with the floppy guide wire. After predilatation with a 2.75×30 mm balloon, two bare metal coronary stents of 4.5×24 mm and 4.5×20 mm were implanted end to end at 18 atm (Figure 2). A good distal flow was achieved (Figure 3). In addition to antibiotic and antiarrhythmic medications, heparin infusion was started. Clopidogrel loading and maintenance doses of 600 mg and 75 mg and acetyl salicylic acid 300 mg were also prescribed. Abdominal pain began to subside dramatically after the procedure and disappeared completely after one week. At the two-month follow-up, the intestinal functions have recovered and tomography taken at the 3-month follow-up showed that the SMA was patent and the thickness of the intestinal wall had returned to normal. Figure 1. Totally occluded superior mesenteric artery Figure 2. Implanting the stent Figure 3. Superior mesenteric artery angiogram after stenting Acute mesenteric ischemia is a rare disorder with serious morbidity and mortality caused by acute obstruction of the intestinal vessels. The obstruction is generally due to cardiac thromboembolism or, less frequently, by acute thrombosis on an existing atherosclerotic plaque. Although abdominal pain is severe in the early phase, tenderness is typically absent on initial physical examination. With ongoing ischemia and intestinal tissue damage, tenderness appears. Thus, the diagnosis is often made late. As ischemia has already occurred by the time of diagnosis, the treatment of choice is surgery, and the resection of the bowels is often inevitable. Successful angioplasty or stenting of mesenteric artery in the absence of intestinal necrosis have been reported in literature (1, 2). Percutaneous transluminal angioplasty has been found to be as effective as surgical treatment (3, 4). However, in acute cases, timely diagnosis and revascularization before necrosis is often impossible. As a result, stenting of acute occlusion is not widespread. In the literature, only a few cases of early diagnosis with successful thrombectomy and angioplasty have been reported (5–7). In our patient, the diagnosis was made early and successful angioplasty and stenting was carried out because of severe comorbidity. In short, mesenteric ischemia has high morbidity and mortality despite treatment. Primary angioplasty and stenting before intestinal necrosis may be life-saving, especially in patients at high surgical risk.

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].

019 Effect of increased maintenance dose of clopidogrel in cardiovascular outpatients and influence of the cytochrome P450 2C19 *2 allele on clopidogrel responsiveness

019 Effect of increased maintenance dose of clopidogrel in cardiovascular outpatients and influence of the cytochrome P450 2C19 *2 allele on clopidogrel responsiveness