Sébastien Armero

Tailored clopidogrel loading dose according to platelet reactivity monitoring to prevent acute and subacute stent thrombosis.

Stent thrombosis remains a significant pitfall of percutaneous coronary intervention (PCI). A recent trial observed that an adjusted loading dose (LD) of clopidogrel according to platelet monitoring decreases the rate of major adverse cardiovascular events after PCI. We investigated if such a strategy of a tailored clopidogrel LD according to platelet reactivity monitoring could decrease the rate of stent thrombosis. This multicenter prospective randomized study included 429 patients with a low clopidogrel response after a 600-mg LD undergoing PCI. Patients were randomized to a control group (n = 214) and to a vasodilator-stimulated phosphoprotein (VASP)-guided group (n = 215). In the VASP-guided group, patients received up to 3 additional 600-mg LDs of clopidogrel to obtain a VASP index <50% before PCI. The primary end point was the rate of stent thrombosis at 1 month. Secondary end points were rates of major adverse cardiovascular events and bleeding. Patients in the 2 groups had a high body mass index and were often diabetic (control vs VASP-guided group 28 +/- 5.1 vs 27.9 +/- 4.7 kg/m(2), p = 0.8, and 39% vs 33%, p = 0.2, respectively). PCI was performed in most patients for acute coronary syndrome in the 2 groups (52.3% vs 50.7%, p = 0.8). Despite a 2,400-mg LD of clopidogrel, 8% of patients in the VASP-guided group remained low responders. The rate of stent thrombosis was significantly lower in the VASP-guided group (0.5% vs 4.2%, p <0.01). The rate of major adverse cardiovascular events was also higher in the control group (8.9% vs 0.5%, p <0.001). There was no difference in the rate of bleeding (2.8% vs 3.7%, p = 0.8). In conclusion, a tailored clopidogrel LD according to platelet reactivity monitoring decreases the rate of early stent thrombosis after PCI without increasing bleeding.

Clopidogrel Loading Dose Adjustment According to Platelet Reactivity Monitoring in Patients Carrying the 2C19*2Loss of Function Polymorphism

OBJECTIVES We aimed to investigate the biological impact of a tailored clopidogrel loading dose (LD) according to platelet reactivity monitoring in carriers of the cytochrome (CYP) 2C19*2 loss-of-function polymorphism undergoing percutaneous coronary intervention for an acute coronary syndromes. BACKGROUND CYP2C19*2 polymorphism is associated with reduced clopidogrel metabolism and a worse prognosis after percutaneous coronary intervention. METHOD A prospective multicenter study enrolling 411 patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention was performed. Platelet reactivity was measured using the vasodilator-stimulated phosphoprotein (VASP) index, and a cutoff value of ≥ 50% was used to define high on-treatment platelet reactivity (HTPR). The genetic polymorphism of CYP2C19 was determined by allele-specific polymerase chain reaction. In patients carrying CYP2C19*2 and exhibiting HTPR after a first 600-mg LD of clopidogrel, dose adjustment was performed by using up to 3 additional 600 mg LDs to obtain a VASP index <50%. RESULTS One hundred thirty-four patients (35.3%) carried at least one 2C19*2 allele (11 homozygotes [2.7%] and 123 heterozygotes [32.6%]). The VASP index in these patients was significantly higher than in homozygotic patients for the wild-type alleles (61.7 ± 18.4% vs. 49.2 ± 24.2%; p < 0.001). Of the 134 carriers of the loss-of-function polymorphism, 103 were considered to have HTPR. After a second clopidogrel LD, the VASP index was significantly decreased in these patients (69.7 ± 10.1% vs. 50.6 ± 17.6%; p < 0.0001). Finally, dose adjustment according to platelet reactivity monitoring, enabled 88% of 2C19*2 carriers exhibiting HTPR to reach a VASP index <50%. CONCLUSIONS Increased and tailored clopidogrel loading dose according to platelet reactivity monitoring overcome HTPR in carriers of the loss-of-function CYP2C19*2 polymorphism.

Rate of nuisance bleedings and impact on compliance to prasugrel in acute coronary syndromes.

Antiplatelet agents are critical to prevent thrombotic events in patients with acute coronary syndromes, particularly those who undergo percutaneous coronary intervention. Prasugrel is a potent P2Y(12)-adenosine diphosphate receptor antagonist that is superior to clopidogrel in such patients. Previous studies have observed that nuisance and internal bleedings were relatively frequent in patients under clopidogrel therapy and were associated with noncompliance. Furthermore, premature drug discontinuation is associated with thrombotic recurrences. The aim of the present study was to investigate the rate of nuisance or internal bleedings in patients receiving prasugrel and its relation with compliance. This prospective multicenter study included 396 patients. Bleeding events were recorded and classified as alarming, nuisance, or internal according. Compliance with prasugrel therapy was assessed. Almost half of the patients (48.5%) were included for ST-segment elevation acute coronary syndromes. During the 1-month follow-up period, 54 patients (13.6%) had bleeding events. Most bleeding events were classified as internal or nuisance (96%). Internal and nuisance bleedings were associated with high rates of prasugrel discontinuation (16.6% and 14.7%, respectively). Nuisance and internal bleedings were significantly associated with prasugrel discontinuation in multivariate analysis (odds ratio 3.1, 95% confidence interval 1.01 to 9.2, p = 0.04). The rate of major adverse cardiovascular events was 2.3%. No relation was observed between minor bleeds, compliance, and major adverse cardiovascular events. In conclusion, in the present study, minor bleedings were common during the first month after percutaneous coronary intervention and were significantly associated with prasugrel withdrawal.

Relationship between platelet reactivity inhibition and non-CABG related major bleeding in patients undergoing percutaneous coronary intervention

Dual anti-platelet regimen has dramatically decreased the rate of thrombotic events including stent thrombosis in patients undergoing percutaneous coronary intervention (PCI) [1]. However following the report of a large inter-individual variability in response to clopidogrel loading dose (LD), several studies have demonstrated a strong relationship between the level of platelet reactivity inhibition (PRI) achieved and the occurrence of thrombotic events following PCI [2–5]. The TRITON TIMI 38 and PRINCIPLE-TIMI 44 trials have demonstrated that achieving higher levels of PR inhibition using a more potent thienopyridine, prasugrel, compared to clopidogrel was associatedwith a reduction in the rate of major adverse cardiovascular events (MACE) [6,7]. However in the TRITON TIMI 38 trial, patients randomized to receive prasugrel weremore likely to suffer from TIMI major bleedings. Together, these findings have suggested a link between platelet reactivity inhibition and major bleedings [8]. We therefore aimed to investigate the relationship between PRI following clopidogrel LD and in-hospital non-CABG related TIMI major bleedings. The study population was identified from a registry of consecutive patients who underwent PCI between January 2008 and may 2009 in our institution. Exclusion criteria were: CABG during hospital stay, coumadin use, cardiac arrest, contraindications to anti-platelet therapy, a platelet count<100 g/L, history of bleeding diathesis, balloon pump insertion, cardiogenic shock. A complete data set to allow for propensity matching. Among the 710 patients that had PCI during this time period180 had exclusion criteria and 184 had no or failed VASP measurement and were therefore also excluded from the study. Finally 346 patients were included in the present analysis: 16 with non-CABG related major TIMI bleeding in-hospital and 330 patients without during the same time period. PR was assessed by the VASodilator (Fig. 1A). Phosphoprotein index(VASP index) on blood samples collected at least 6 hours after clopidogrel loading dose and before PCI. All patients gave informed consent for the PCI procedure and the study was conducted under local ethic committee approval. The PCI was carried out according to international guidelines, using a standard technique, through the radial or femoral route [8]. The sheath was removed immediately at the end of the procedure in all cases. Percutaneous closures were used in all patients for whom femoral access was used. Routine care before and after the procedure was undertaken for all patients, including pre-treatment clopidogrel (600-mg initial bolus) 12 h before the procedure followed by 75 mg daily for at least 1 month. In addition, all patients received aspirin, 160 mg daily, for at least 1 month, with a loading dose administered 12 h before stenting. For patients with acute coronary syndromes, anticoagulation with unfractionated heparin was begun in the intensive care unit before PCI. During PCI, patients were anticoagulated with unfractionated heparin (a bolus of 40 UI/ kg and additional heparin to achieve an activated clotting time of 250–300 s).

Impact of P2Y12-ADP receptor polymorphism on the efficacy of clopidogrel dose-adjustment according to platelet reactivity monitoring in coronary artery disease patients.

INTRODUCTION High on-treatment platelet reactivity (HTPR) after clopidogrel loading dose (LD) is associated with a high risk of thrombotic events after percutaneous coronary intervention(PCI). We have demonstrated that HTPR could be overcome in the majority of cases using LD adjustment resulting in an improved clinical outcome. However this strategy failed in nearly 10% of patients with HTPR. We aimed to determine if P2Y12-ADP receptor polymorphisms were associated with failed dose adjustment. MATERIAL AND METHOD Forty-three patients undergoing PCI were included in this prospective study. A VASP index >or=50% after a 600 mg LD of clopidogrel defined HTPR. Dose adjustment was performed according to PR monitoring to reach a VASP index <50%. Genetic polymorphism of the P2Y12-ADP receptor was determined by direct sequencing. RESULTS Patients with successful dose-adjustment (SDA) (n=33) and failed (FDA) (n=10) dose-adjustment groups were compared. The 2 groups were similar in terms of cardiovascular risk factors including diabetes mellitus (SDA vs FDA: 42 vs 20%; p=0.3). The prevalence of the H2 allele of the P2Y12-ADP receptor was also similar between the 2 groups (p=0.3). The H2 allele was found in 6 patients which are all included in the SDA group. After the first 600 mg loading dose of clopidogrel, patients carrying at least one H2 allele had similar VASP index compared to those carrying two copies of the wild type allele (H1) (SDA vs FDA: 44.9+/-14.9 vs 43.5+/-10%; p=0.8). CONCLUSION The present study suggests that the H2 allele of the P2Y12-ADP receptor is not involved in clopidogrel failed dose adjustment according to platelet reactivity monitoring.

Intra-individual variability in clopidogrel responsiveness in coronary artery disease patients under long term therapy

Clopidogrel responsiveness (CR) following a loading dose (LD) predicts thrombotic events after percutaneous coronary interventions (PCI). Some of the mechanisms involved in large inter-individual variability in CR may be varied. We therefore postulated that there may be an intra-individual variability in CR. Two hundred and one patients receiving long-term therapy with aspirin and clopidogrel after drug-eluting stents PCI were prospectively included in this monocentre study along with any patient re-admitted within 12 months post-PCI. Platelet reactivity (PR) inhibition was assessed by the vasodilator phosphoprotein (VASP) index following a 600 mg loading dose of clopidogrel on each admission to determine CR (VASP 1 during the first admission and VASP 2 during re-admission). DeltaVASP = VASP 2 –VASP 1 was used to study intra-individual variability in CR. We observed that the response to a 600 mg LD of clopidogrel was poorly correlated within an individual (kappa = 0.33; p < 0.001 (n = 201)). Although most patients had increased platelet inhibition at the time of readmission, 35.3% of patients exhibited a decreased platelet inhibition despite chronic clopidogrel therapy and a 600 mg reload. Quartiles analysis of DeltaVASP demonstrated that insulin-treated diabetes was associated with decreased CR over time (p = 0.03). In addition to the large inter-individual variability in clopidogrel responsiveness, there is large intra-individual variability. Decreased clopidogrel responsiveness despite long-term clopidogrel therapy could be a trigger for recurrent thrombotic events.

Impact of loading dose adjustment on platelet reactivity in homozygotes of the 2C19 2 loss of function polymorphism

The cytochromes 2 C19 2* loss of function polymorphism has recently been shown to be associated with decreased platelet reactivity (PR) inhibition after clopidogrel loading dose (LD) and an excess in thrombotic events following percutaneous coronary intervention (PCI). We aimed to investigate if an optimal PR inhibition could be obtained in patients homozygotes for this alleles using adjusted LD of clopidogrel according to platelet reactivity monitoring. Post-treatment PR was measured using the VASP index. Dose adjustment was performed in order to obtain a PR <50% using additional clopidogrel LD. Direct sequencing was used to select homozygotes for CYP 2C19 2* alleles. Six patients with the loss of function polymorphism were recruited. The mean VASP index was 53.7 ± 16.2% after the first LD of clopidogrel. Four patients had a VASP index >50% and were therefore considered to have high on treatment PR. Using up to 3 additional 600 mg LD of clopidogrel we were able to obtain a VASP <50% in all these patients. The present study is the first to suggest that in homozygotes for CYP 2C19 2* loss of function polymorphism, increased loading dose of 55 clopidogrel is efficient to obtain an optimal level PR inhibition in patients undergoing PCI.

Predictors of B-type natriuretic peptide and left atrial volume index in patients with preserved left ventricular systolic function: An echocardiographic-catheterization study

BACKGROUND B-type natriuretic peptide (BNP) and left atrial volume index (LAVi) are used as surrogate measures for global myocardial function and are recommended for the diagnosis of heart failure with normal ejection fraction. Little is known, however, about predictors in patients with preserved systolic function. AIMS To identify factors that influence the relation of BNP and left atrial size to invasively determined left ventricular end-diastolic pressure in stable patients with preserved left ventricular systolic function. METHODS Fifty-nine consecutive patients were included prospectively. Clinical, biological, Doppler echocardiographic and invasive variables were collected simultaneously. RESULTS BNP was predicted independently by left ventricular ejection fraction, diastolic function and age (p<0.05). LAVi was predicted independently by left ventricular mass index and invasive left ventricular end-diastolic pressure (p<0.01). BNP predicted increased left ventricular end-diastolic pressure greater than 16 mmHg (p=0.004); the optimal cut-off value was 33 pg/mL (area under the receiver-operating characteristic curve [AUC] 0.74 [0.6-0.84], p<0.001, sensitivity 72%, specificity 70%). LAVi predicted increased left ventricular end-diastolic pressure (p<0.001); the optimal cut-off value for LAVi was 26 mL/m(2) (AUC 0.87 [0.75-0.94], p<0.001; sensitivity 85%, specificity 80%). Unlike BNP (p=0.1), LAVi performed well in patients with abnormal relaxation at mitral filling (p<0.01). CONCLUSION BNP is influenced by age in stable patients with preserved systolic function and should be interpreted cautiously. LAVi is a powerful surrogate for invasively determined left ventricular end-diastolic pressure regardless of age and mitral filling.

Non-invasive coronary angiography for patients with acute atypical chest pain discharged after negative screening including maximal negative treadmill stress test. A prospective study

UNLABELLED Among patients admitted in the emergency department for acute atypical chest pain those with an acute coronary syndrome (ACS) who are mistakenly discharged home have high mortality. A recent retrospective study has demonstrated that multislice computed tomography (MSCT) coronary angiography could improve triage of these patients. We aimed to prospectively confirm these data on patients with a negative screening including maximal treadmill stress. PATIENTS 30 patients discharged from the emergency department after negative screening for an ACS were included. All patients underwent MSCT angiography of the coronary artery. Patients with coronary atheroma on MSCT had an invasive coronary angiography to confirm these findings. RESULTS Seven patients (23%) had obstructive coronary artery disease on MSCT. Invasive coronary angiography (ICA) confirmed the diagnosis in all patients. CONCLUSION In patients with no previously known coronary artery disease admitted to the emergency department with atypical acute chest pain and discharged after negative screening, including maximal treadmill stress test, MSCT coronary angiography is useful for the diagnosis of obstructive coronary artery disease.

Early and late outcomes of clopidogrel and Coumadin combination for patients on oral anticoagulants undergoing coronary stenting

BACKGROUND In patients under oral anticoagulant requiring percutaneous coronary intervention (PCI) with stent implantation, the optimal association between aspirin, clopidogrel and oral anticoagulant (OAC) remains cumberstome. Triple therapy and dual therapy using aspirin and OAC have been evaluated and are associated with a high frequency of major bleedings. The combination of clopidogrel and OAC has never been evaluated. OBJECTIVE We aimed to investigate the safety and efficacy of clopidogrel and OAC in patients requiring OAC undergoing PCI for acute coronary syndrome. METHODS A monocenter retrospective study was undertaken between 2000 and 2006 and included all patients undergoing PCI with stent implantation on OAC. On discharge dual therapy with clopidogrel and OAC was prescribed. The primary end-point was the frequency of major TIMI bleedings. Secondary end-points were major cardiovascular event (MACE). Results are reported as rate of events with 95% confidence intervals (CI). RESULTS Two hundreds and nine patients were followed for 71 +/- 22 months. The indication for oral anticoagulation was atrial fibrillation in 80% of patients, a valvular prothesis in 18% and a history of pulmonary embolism in 5%. The rate (95%CI) of major bleeding was 2.4% (0.9%-5.8%) 2.87% (1.17%-6.44%) and 3.8% (1.79%-7.68%) at 1 month, 12 months and 71 months respectively, which represent 8 events among which 2 were fatal. The MACE rate (95%CI) was low: 0% at one month, 3.8% (1.79%-7.68%) at 12 months and 24.4% (19.07%-30.65%) at 71 months of follow up. Only one stent thrombosis was recorded at the ninth month. The overall rate of death was 9.5% (6.28%-14.32%) among which 2.87% (1.17%-6.44%) were of cardiovascular origin. CONCLUSION The use of clopidogrel and OAC combination in patients on OAC undergoing coronary stenting is safe and efficient at the short-term. At the long-term, this combination is probably not safe, with a relatively high incidence of fatal stroke.