Mathieu Pankert

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.

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.

Comparison of Platelet Reactivity and Clopidogrel Response in Patients ≤75 Years Versus >75 Years Undergoing Percutaneous Coronary Intervention for Non–ST-Segment Elevation Acute Coronary Syndrome

Specific data about the clopidogrel response in elderly patients are lacking. The present study was performed to compare the platelet reactivity and clopidogrel response between patients aged > 75 years and < 75 years undergoing percutaneous coronary intervention for non-ST-segment elevation acute coronary syndrome. A total of 689 patients were enrolled, including 162 patients aged > 75 years and 527 younger patients. All patients received a loading dose of 600 mg clopidogrel followed by 150 mg/day. Post-treatment platelet reactivity was assessed by adenosine diphosphate 10 μmol/L-induced platelet aggregation and the specific pharmacologic response to clopidogrel by the platelet reactivity index vasoactive stimulated phosphoprotein. High post-treatment platelet reactivity was defined as adenosine diphosphate 10 μmol/L-induced platelet aggregation >70%. Clinical events were recorded during 1 month of follow-up. The patients > 75 years old had a greater rate of both ischemic and bleeding complications (p = 0.04 and p = 0.03, respectively). The post-treatment platelet reactivity in response to both the loading and the maintenance clopidogrel dose was greater in patients > 75 years old than in the younger patients: 50 ± 17% versus 45 ± 17% (p = 0.002) and 57 ± 15% versus 53 ± 16% (p = 0.0005), respectively. The rate of high post-treatment platelet reactivity was significantly greater in patients aged > 75 years after 600 mg and 150 mg clopidogrel: 14% versus 9% (p = 0.04) and 23% versus 15% (p = 0.02), respectively. In contrast, the pharmacologic response to clopidogrel was not impaired in patients > 75 years after loading and maintenance doses: 43 ± 21% versus 46 ± 21% (p = 0.17) and 38 ± 18% versus 39 ± 18% (p = 0.55), respectively. In conclusion, patients aged > 75 years have an impaired prognosis after acute coronary syndrome. They display greater post-treatment platelet reactivity. However, this greater platelet reactivity does not seem to be related to an impaired specific response to clopidogrel.

Impact of Obesity and the Metabolic Syndrome on Response to Clopidogrel or Prasugrel and Bleeding Risk in Patients Treated After Coronary Stenting

This study aimed to analyze the impact of body mass index (BMI) and the metabolic syndrome (MS) on responses to clopidogrel or prasugrel and bleeding risk after acute coronary syndrome. The study included 1,542 consecutive patients who underwent coronary stenting (287 clopidogrel 75 mg, 868 clopidogrel 150 mg, and 387 prasugrel 10 mg). Platelet reactivity was assessed 1 month after discharge using platelet reactivity index vasodilator stimulated phosphoprotein (PRI VASP). Three hundred thirty-six patients (21.8%) were obese (BMI ≥30), and we observed higher platelet reactivity associated with higher BMI across thienopyridine regimens. Incidence of high on-treatment platelet reactivity (PRI VASP >50%) was higher in obese than nonobese patients (p <0.05 for all regimens). Conversely, incidence of low on-treatment platelet reactivity with prasugrel therapy (PRI VASP <20%) was lower in obese than nonobese patients: 13% (12 of 93) versus 33% (97 of 294); odds ratio 0.30, 95% confidence interval 0.16 to 0.58; p <0.001. Accordingly, incidence of Bleeding Academic Research Consortium bleeding complications was higher in nonobese than in obese patients: 10% (119 of 1,206) versus 6% (20 of 336); odds ratio 1.7, 95% confidence interval 1.1 to 2.8; p = 0.03. This impaired response was only observed in obese patients with the MS, and obese with the MS had significantly higher platelet reactivity than other obese patients with all regimens (p <0.01). Obese patients without the MS had no significant difference in platelet reactivity compared with nonobese patients. In conclusion, the present study confirmed that BMI has a strong impact on response to clopidogrel and prasugrel with higher incidence of high on-treatment platelet reactivity, lower incidence of low on-treatment platelet reactivity, and lower bleeding complication in obese patients. However, among obese patients, the presence of the MS strongly affects response to antiplatelet agents, indicating that the metabolic status might be a better predictor of platelet inhibition than BMI.

Usefulness of Index of Microcirculatory Resistance to detect microvascular dysfunction as a potential mechanism of stress-induced cardiomyopathy (tako-tsubo syndrome)

A 76 year-old womanwas admitted for suspected Non-ST segment elevation Acute Coronary Syndrome with EKG modifications in anterior leads (Fig. 1) and troponin elevation. She suffered from acute chest pain for 30 min after sudden emotional stress. She had no previous significant medical history and no identified cardiovascular risk factors. The echocardiography revealed anterior wall hypokinesia with reduced left ventricular systolic function. After medical treatment, she underwent coronary angiography via right radial access showing no significant angiographic stenosis but ventriculography revealed akinesia of the middle and apical segments with hyperkinesia at the base, suggestive of stress-induced cardiomyopathy (Fig. 2). To assess the underlying physiopathology, we decided to perform measure of the Index of Microcirculatory Resistance (IMR) in the Left Anterior Descending (LAD) artery using the intracoronary pressure/temperature sensor-tipped guide wire (Radi pressure wire Certus-Radi, Saint-Jude Medical). Maximal hyperemia was achieved by infusion of 140 μg/kg/min of adenosine via the femoral vein. Mean transit time (Tmn) at baseline and maximal hyperemia were derived from thermodilution curves. Simultaneous recordings of mean aortic pressure (Pa, from the guiding catheter) and mean distal coronary pressure (Pd, from the distal pressure sensor) were also made at baseline and maximal hyperemia. IMR was calculated from the ratio of the mean distal coronary pressure at maximal hyperemia to the

Transradial approach and subclavian wired temporary pacemaker to increase safety of alcohol septal ablation for treatment of obstructive hypertrophic cardiomyopathy: The TRASA trial

BACKGROUND Alcohol septal ablation (ASA) is a therapeutic catheter-based option and an alternative to surgical myectomy in the treatment of patients with hypertrophic obstructive cardiomyopathy. Although the safety of the ASA procedure has been consistently improved, a temporary transvenous pacemaker is recommended for at least 48h postprocedure, with several drawbacks, including the risk of cardiac perforation and infection, and the absence of any fixation mechanism. In addition, femoral artery catheterization has resulted in a concomitant increase in bleedings and iatrogenic femoral artery injuries. AIMS To evaluate and validate the feasibility of less invasive management of ASA using the transradial approach and a subclavian wired temporary pacemaker. METHODS To avoid transfemoral temporary pacing, we used a subclavian bipolar active-fixation permanent pacing lead, stitched to the skin and connected to a desterilized recuperation pacemaker. The day before discharge, if there was no high-degree atrioventricular block, the pacemaker lead was removed. In all patients, we used the right radial access and the left main was cannulated with a 6F Judkins left 3.5 guiding catheter. RESULTS Thirty consecutive patients were prospectively and successfully included in our study. No complication was observed during the hospital stay, neither access-site nor stimulation-lead related. CONCLUSIONS Our study shows the feasibility and safety of a transradial approach and a subclavian wired temporary pacemaker. The reduction in periprocedural complications offered by this strategy reflects the less invasive nature of ASA, without increasing the cost and complexity of the procedure.

Safety and effectiveness of the association ezetimibe-statin (E-S) versus high dose rosuvastatin after acute coronary syndrome: the SAFE-ES study.

BACKGROUND Statin therapy is a cornerstone therapy for secondary prevention after acute coronary syndrome (ACS). However, the use of these drugs can be limited by side effects, mainly muscular pain. Ezetimibe is a newer lipid-lowering agent, with fewer side effects. AIMS The present study was designed to compare a commercially available association of ezetimibe and simvastatin (E-S) to high dose Rosuvastatin on cholesterol and muscular enzyme levels and occurrence of muscular pain. METHODS All consecutive ACS statin-naïve patients with LDL cholesterol (LDL-C)>100mg/dL randomly received either high dose statin (Rosuvastatin 20mg) or E-S 10/40-mg. All patients had one-month follow-up with biological testing and clinical examination. We compared the two groups on the biological efficiency and incidence of muscular pain. RESULTS One hundred and twenty-eight patients were randomized; 64 received E-S and 64 Rosuvastatin. In the two groups, the lowering of LDL-C level (Δ=51%) at one month was significant (P<0.01) without any difference in the rate of lowering on LDL-C or HDL-C suggesting that E-S is as effective as high dose Rosuvastatin (P=0.77 and P=0.99). The rate of patients reaching the objective of LDL-C<100mg/dL (45%) and LDL-C<70mg/dL (51%) was not different in the two clusters (P=0.65). Incidence of muscular pain was 15% higher in patients treated with Rosuvastatin (P=0.01) without any difference on CPK level (P=0.6). CONCLUSION Using an association of E-S in an effective alternative strategy to high dose Rosuvastatin with a lower incidence of muscular pain, which might impact adherence to medication after ACS.

High Radiation Exposure of the Imaging Specialist During Structural Heart Interventions With Echocardiographic Guidance

Echocardiography plays a new critical role during structural heart interventions (SHIs), although fluoroscopy remains an indispensable tool [(1,2)][1]. Exposure to radiation by staff is directly proportional to the dose the patient receives in interventional cardiology and is affected by higher mean

Role of Antiplatelet Therapy in Secondary Prevention of Acute Coronary Syndrome

Cardiovascular disease is one of the major causes of death in developed countries, mainly related to coronary artery disease and its acute complications. Platelets play a great role in the pathogenesis of acute thrombotic events of coronary artery disease when silent chronic disease becomes acutely symptomatic. Platelet importance in coronary artery disease and pathophysiology of acute events support the large benefit of antiplatelet agents for both acute management of ACS and secondary prevention. Recent developments in oral antiplatelet therapy raised questions about the choice of the molecules, the use of single or double therapy, and the optimal dosing and duration of treatment. The present review aims to provide a current appraisal of antiplatelet therapy use after ACS and to summarize available scientific evidence for an optimal use of antiplatelet agents in daily practice, including the new P2Y12 blockers.

Early versus delayed invasive strategy for intermediate‐ and high‐risk acute coronary syndromes managed without P2Y12 receptor inhibitor pretreatment: Design and rationale of the EARLY randomized trial

According to recent literature, pretreatment with a P2Y12 ADP receptor antagonist before coronary angiography appears no longer suitable in non–ST‐segment elevation acute coronary syndrome (NSTE‐ACS) due to an unfavorable risk–benefit ratio. Optimal delay of the invasive strategy in this specific context is unknown. We hypothesize that without P2Y12 ADP receptor antagonist pretreatment, a very early invasive strategy may be beneficial. The EARLY trial (Early or Delayed Revascularization for Intermediate‐ and High‐Risk Non–ST‐Segment Elevation Acute Coronary Syndromes?) is a prospective, multicenter, randomized, controlled, open‐label, 2‐parallel‐group study that plans to enroll 740 patients. Patients are eligible if the diagnosis of intermediate‐ or high‐risk NSTE‐ACS is made and an invasive strategy intended. Patients are randomized in a 1:1 ratio. In the control group, a delayed strategy is adopted, with the coronary angiography taking place between 12 and 72 hours after randomization. In the experimental group, a very early invasive strategy is performed within 2 hours. A loading dose of a P2Y12 ADP receptor antagonist is given at the time of intervention in both groups. Recruitment began in September 2016 (n = 558 patients as of October 2017). The primary endpoint is the composite of cardiovascular death and recurrent ischemic events at 1 month. The EARLY trial aims to demonstrate the superiority of a very early invasive strategy compared with a delayed strategy in intermediate‐ and high‐risk NSTE‐ACS patients managed without P2Y12 ADP receptor antagonist pretreatment.