Jean-Baptiste Vignalou

Clinical, Angiographic, and Genetic Factors Associated With Early Coronary Stent Thrombosis

CONTEXT Despite dual antiplatelet therapy, stent thrombosis remains a devastating and unpredictable complication of percutaneous coronary intervention (PCI). OBJECTIVE To perform a sequential analysis of clinical and genetic factors associated with definite early stent thrombosis. DESIGN, SETTING, AND PARTICIPANTS Case-control study conducted in 10 centers in France between January 2007 and May 2010 among 123 patients undergoing PCI who had definite early stent thrombosis and DNA samples available, matched on age and sex with 246 stent thrombosis-free controls. MAIN OUTCOME MEASURE Accuracy of early stent thrombosis prediction by 23 genetic variants. RESULTS Among the 23 genetic variants investigated in 15 different genes, the significant determinants of early stent thrombosis were CYP2C19 metabolic status (adjusted odds ratio [OR], 1.99; 95% CI, 1.47-2.69), ABCB1 3435 TT genotype (adjusted OR, 2.16; 95% CI, 1.21-3.88), and ITGB3 PLA2 carriage (adjusted OR, 0.52; 95% CI, 0.28-0.95). Nongenetic independent correlates were acuteness of PCI (adjusted OR, 3.05; 95% CI, 1.54-6.07), complex lesions (American College of Cardiology/American Heart Association type C) (adjusted OR, 2.33; 95% CI, 1.40-3.89), left ventricular function less than 40% (adjusted OR, 2.25; 95% CI, 1.09-4.70), diabetes mellitus (adjusted OR, 1.82; 95% CI, 1.02-3.24), use of proton pump inhibitors (adjusted OR, 2.19; 95% CI, 1.29-3.75), and higher clopidogrel loading doses (adjusted OR, 0.73; 95% CI, 0.57-0.93). The discriminative accuracy of the clinical-only model was similar to that of a genetic-only model (area under the curve, 0.73 [95% CI, 0.67-0.78] vs 0.68 [95% CI, 0.62-0.74], respectively; P = .34). A combined clinical and genetic model led to a statistically significant increase in the discriminatory power of the model compared with the clinical-only model (area under the curve, 0.78 [95% CI, 0.73-0.83] vs 0.73 [95% CI, 0.67-0.78]; P = .004). CONCLUSIONS This case-control study identified 3 genes (CYP2C19, ABCB1, and ITGB3) and 2 clopidogrel-related factors (loading dose and proton pump inhibitors) that were independently associated with early stent thrombosis. Future studies are needed to validate the prognostic accuracy of these risk factors in prospective cohorts.

Switching Acute Coronary Syndrome Patients From Prasugrel to Clopidogrel

OBJECTIVES This study sought to assess the consequences of switching prasugrel to clopidogrel on platelet inhibition and clinical outcomes after an acute coronary syndrome (ACS). BACKGROUND Many ACS patients are switched from prasugrel to clopidogrel within the recommended 1-year duration of treatment. METHODS Platelet reactivity was measured with the VerifyNow P2Y(12) assay (Accumetrics, San Diego, California) in 300 ACS patients treated for 15 days with prasugrel 10 mg. Patients displaying low on-treatment platelet reactivity (LPR) and/or at high risk of bleeding were switched to clopidogrel 75 mg and tested again 15 days later. The rate of patients with high on-treatment platelet reactivity (HPR), P2Y(12) reaction units (PRU) >208, and LPR (PRU <0) were evaluated before and after the switch. Bleeding and ischemic events were also recorded. RESULTS On a regimen of prasugrel 10 mg, the rate of patients with LPR was 45.6% (n = 137), whereas 4.3% (n = 13) had HPR. A group of 31 patients (10.3%) was switched to clopidogrel 75 mg, of whom 29 had LPR (93.5%) on a regimen of prasugrel. On-treatment platelet reactivity (PRU) increased from 14 ± 4 on a regimen of prasugrel to 155 ±15 on a regimen of clopidogrel (p = 0.0001), resulting in a much lower rate of patients with LPR (9.7%). The rate of patients with HPR increased from 0% with prasugrel to 29% (n = 9) with clopidogrel. The rate of minor bleeding decreased after the switch from 32.2% to 9.7%; p = 0.03. CONCLUSIONS An LPR is frequent in patients treated with prasugrel 10 mg. Early switching from prasugrel 10 mg to clopidogrel 75 mg reduces the number of patients with LPR and minor bleeding events but unmasks a group of nonresponders to clopidogrel with unknown consequences on clinical outcomes.

Impact of red blood cell transfusion on platelet activation and aggregation in healthy volunteers: results of the TRANSFUSION study †

AIMS The underlying mechanisms leading to recurrent ischaemic events or mortality after red blood cell (RBC) transfusion in anaemic acute coronary syndrome patients are poorly understood. The aim of this paper is to determine whether RBC transfusion increases platelet activation and aggregation. METHODS AND RESULTS In vitro transfusions (n = 45) were performed by the addition of RBCs obtained from transfusion packs to fresh whole blood provided by healthy volunteers. Residual platelet aggregation (RPA) and maximal platelet aggregation (MPA) were assessed before and after in vitro transfusion using light transmission aggregometry performed with four different agonists. Flow cytometry was used for the measurement of P-selectin expression and vasodilatator-stimulated phosphoprotein (VASP) platelet reactivity index (PRI). To control for the effect of haemoconcentration, the same experiments were repeated after hematocrit adjustment using volunteers platelet poor plasma. Transfusion increased platelet aggregation as measured by RPA with ADP 5 µM (57.7 ± 25 vs. 65.7 ± 24%; P = 0.03) or Collagen 2 µg/mL (59.4 ± 28 vs. 69.7 ± 24%; P = 0.03). There were no significant differences with Arachidonic Acid 1.25 mM or Epinephrine 20 µM and results were similar when MPA was considered. Platelet activation was also increased by transfusion as confirmed by an elevation of P-selectin expression induced by 20 µM ADP (12.2 ± 18 vs. 23.9 ± 18%; P = 0.002) or 50 µM ADP (15.4 ± 18.6 vs.26.8 ± 21.2%; P = 0.004) and an increase in VASP PRI (77.8 ± 6 vs. 81.9 ± 3%; P = 0.03). These effects were all independent of hematocrit. CONCLUSION Red blood cell transfusion increases platelet activation and aggregation in vitro in healthy volunteers. This effect might be mediated through the P2Y(12) activation pathway.

Coronary Revascularization in the Diabetic Patient

An asymptomatic and sedentary 58-year–old man with moderate overweight (body mass index, 29 kg/m2) and controlled hypertension was referred for a stress test. The patient had a highly positive stress test, with significant ST segment depression and tightening chest pain 2 minutes after the start of the exercise (40 Watts) followed by nonsustained ventricular tachycardia at rest. The physician hospitalized the patient into the coronary care unit for further evaluation. The echocardiogram was considered normal, without wall motion abnormalities, and serial troponin measurements remained normal. The patient was scheduled for next day coronary angiogram. In the morning, the laboratory evaluation included a fasting blood glucose value of 135 mg/dL, with a hemoglobin A1C of 7.4%, resulting in the likely diagnosis of previously unknown type 2 diabetes mellitus. Renal function was normal. The coronary angiogram showed a right-sided dominant coronary anatomy, with a focal lesion (75%) of the mid right coronary artery and with a fractional flow reserve (FFR) measured at 0.65. There were 2 focal and severe lesions in the left anterior descending artery (LAD), 1 proximal (95%) just before the first diagonal branch, which had also an intermediate ostial lesion, and 1 less tight lesion downstream (70%). FFR was not performed on the LAD because of the critical nature of the proximal lesion. The circumflex artery was a small artery without major branches. How would you manage this patient? ### Diabetes Mellitus and Coronary Artery Disease Cardiovascular disease is the leading cause of morbidity and mortality in people with diabetes mellitus. Patients with diabetes mellitus have a 2- to 4-fold increase in risk of developing cardiovascular disease than those without diabetes mellitus, and also a 2- to 5-fold increase in mortality attributable to cardiovascular disease when compared with age- and sex-matched nondiabetic persons.1 Accelerated atherogenesis, blood abnormalities (altered platelet function, inflammation, hypofibrinolysis, and hypercoagulability), …

FXIII-A Leu34 genetic variant in premature coronary artery disease: A genotype – phenotype case control study

The FXIII-A Leu34 genetic variant increases and accelerates fibrin stabilisation; however, its association with premature coronary artery disease (CAD) and thrombotic events remains controversial. FXIII Val34Leu genotype was determined in 242 young individuals (<45 years old) who survived a myocardial infarction (MI) and 242 healthy controls matched for age and gender. We evaluated its effect on long-term clinical outcome defined as a composite of cardiovascular death, recurrent MI and urgent revascularisation. In addition, fibrin clot stiffness (elastic modulus or EM) and response to rt-PA-mediated fibrinolysis (fibrinolysis rate) were measured ex vivo using the Hemodyne analyser and confocal microscopy as surrogate endpoint. FXIII-A Leu34 genetic variant was not associated with premature CAD (adj. odds ratio 0.83 [0.49-1.4]) nor did it influence clinical outcome in patients, during a median follow-up of 6.3 (± 2.4) years. Patients produced stiffer fibrin clots (median [IQR] EM = 20.3 [14.9-28.1] vs. 12.8 [9.6-17.1] kdynes/cm²; p<0.0001) and displayed reduced response to fibrinolysis with lower fibrinolysis rate (6.7 [3.4-11.0] vs. 9.0 [5.0-16.7] sec-¹ x 10(-4); p<0.0001) than healthy controls. Carriage of factor XIII-A Leu34 led to a stepwise decrease in fibrinolysis rate with a significant gene-dose-effect in patients (7.7 [4.1-12.2] vs. 4.8 [3.0-8.5] vs. 4.3 [2.4-8.1] sec-¹ x 10(-4), for wild-type, heterozygous and homozygous, p for trend = 0.003) and a non-significant trend in controls (p = 0.01). In conclusion, FXIII-A Leu34 is a polymorphism which provides a strong resistance to fibrinolysis with a gene-dose effect, but does not relate to premature CAD or to recurrent coronary events in this study.

005 ST-elevation myocardial infarction admission during “ON-” versus “OFF-” hours: is there an impact on outcome for primary PCI?

Background It has been suggested that delays, quality and outcome of reperfusion therapy provided to ST-Elevation Myocardial Infarction (STEMI) patients during OFF-hours (nights and weekend) are worse than during ON-hours (day working hours). Methods We studied 736 consecutive STEMI patients transferred for primary percutaneous intervention (PCI) to a single large volume urban Primary PCI center. Characteristics and clinical outcome of patients admitted during ON-hours (Monday through Friday 8 am-6 pm) were compared to OFF-hours patients (admitted during night shifts and weekends). Clinical outcome was 1 year death and death or MI. Results STEMI patients undergoing primary PCI were admitted more frequently during OFF-hours (n = 449; 61.1%) than ON-hours (n = 287; 38.9%), with no major differences in characteristics or treatment between the two groups. Use of radial approach and the rate of stenting during PCI was 83.3% and 86.1% in ON-hours patients vs. 88.2%.and 88.1% in OFF-hours patients. There was no impact of time of admission on in-hospital mortality before or after adjustment for baseline characteristics OR 1.54; CI [0.71–3.35]. Time from symptom onset to first medical contact was shorter during OFF-hours than ON-hours (105 min [50–225] vs. 114 min [60–367]; p = 0.06). Time from first medical contact to sheath insertion was also identical between the 2 groups (101 min [80–155] and 105 min [78–155]; p = 0.61 respectively). Time to TIMI 3 flow and duration of procedure were also similar. At one year, all cause mortality and the composite end point of death or MI was 8.3% and 12.2% for OFF-hours patients vs. 7.0% and 10,8% in ON-hours patients, p = 0.4 and p = 0.3 respectively. Conclusion In a well-organized urban STEMI network, were 61% of patients referred for primary PCI are admitted during “OFF” hours, admission time does not impact quality of care or outcomes. Download : Download full-size image Death or MI after one year of follow-up

009 - Red Blood Cell Transfusion Increase Platelet Aggregation: a potential mechanism for increased mortality in transfused patients

Background Erythrocytes transfusion is an independent risk factor for recurrent ischemic events and mortality in patients suffering from acute coronary syndrome. There is no evidence regarding the underlying mechanism of such association. Aim We hypothesized that red blood cell transfusion would activate platelet aggregation and we sought to identify which are the pathway involved in this activation process. Methods Healthy volunteers (n=15) provided blood samples that were mixed with red blood cell (tRBC) obtained from transfusion packs. We explored platelet activation using light transmission agregometry with four different agonist (ADP, Arachidonic Acid (AA), Collagen and Epinephrin) in 10 volunteers and with flow cytometry for P-selectin and VASP in 5 volunteers. Measures were obtained at baseline (whole blood from healthy volunteers), after in vitro transfusion with a 1:4 ratio of tRBC and after in vitro transfusion with a 1:4 ratio of tRBC and hematocrit adjustement with platelet poor plasma. All experiment were performed in duplicates. Results Theses are preliminary results from the ongoing TRANSFUSION study. Numerical values are given in table 1. 1/ RBC transfusion activates platelet aggregation thought ADP and AA pathway. 2/ This effect was confirmed by increase in P-Selectin platelet content with flow cytometry and is independent of an increase in hematocrit. 3/ P2Y12 activation pathways is involved with an increase in VASP. Conclusions Red Blood Cell transfusion activates platelet thought ADP and AA pathway in healthy volunteers. This may explain the independent association between transfusion and recurrent ischemic events including mortality in ACS patients. Results of tRBC induced platelet aggregation n=10 n=5 Technique Aggregometry (Residual Platelet Aggregation %) P-Selection % PRI (%) Agonist ADP AA Collagen Epinephrin 20μM ADP 50μm ADP VAS P Baseline 58,0 79,5 61,6 65,0 33,6 40,2 68,4 After tRBC (no adjustement) 70,3 89,1 72,5 59,6 50,5 56,4 83,9 After tRBC (adjusted with PPP) 48,1 54,5 74,8 p value 0,03 * 0,04 * 0,13 0,15 ND ND ND ND=not done *

020 - Transfer Time is not a major determinant of in-hospital mortality in Primary PCI when performed in a well organized urban network

Aim In STEMI, controversial data exist on the relative importance of patient-dependent time (Symptom-Onset (SO) to first medical contact (FMC)) and Transfer Time (TT=time from FMC to sheath insertion). We assessed the impact of TT on in-hospital (IH) mortality in a well organized urban network using Mobile Intensive Care Units (MICU). Methods In a web-based registry (e-PARIS), we evaluated delay in care of 705 consecutive STEMI patients transferred to the Pitie-Salpetriere cath-lab for primary PCI. Results Population was 63±14 y/o, 75.6% were male, 46.9% had anterior MI, 16.7% were in Killip class 2, and 3.8% had out-of-hospital cardiac arrest. Abciximab was used in 82.4%, radial approach in 87.7% and stenting in 89.7% of patients. Median time (IQR) from SO to FMC was 110 (248) min (102 (190) min when FMC was MICU and 160 (381) min when FMC was a referring hospital, p 2 hours of SO) (fig). After adjustment for baseline characteristics, TT was not associated with mortality anymore suggesting that the sicker patients had the longest TT. Conclusions The association between TT and early mortality is strongly dependent on patients’ characteristics and time to presentation. After adjustment for these parameters, TT does not appear to be a major contributor of IH mortality in a well organized urban network for primary PCI. Improving time-to-first medical contact may be more critical. Download : Download full-size image