Safety of intravenous ivabradine in acute ST-segment elevation myocardial infarction patients treated with primary percutaneous coronary intervention: a randomized, placebo-controlled, double-blind, pilot study.

AIMS: Rapid heart rate lowering may be attractive in acute ST-segment elevation myocardial infarction (STEMI). Accordingly we studied the effect of intravenous ivabradine on heart rate in this setting. METHODS AND RESULTS: This was a multicenter randomized double-blind placebo-controlled trial: patients aged 40-80 years were randomized after successful primary percutaneous coronary intervention (PCI) performed within 6 h of STEMI symptom onset. Patients were in sinus rhythm and with heart rate >80 bpm and systolic blood pressure >90 mm Hg. They were randomly assigned (2:1 ratio) to intravenous ivabradine (n=82) (5 mg bolus over 30 s, followed by 5 mg infusion over 8 h) or matching placebo (n=42). The primary outcome measure was heart rate and blood pressure. In both groups, heart rate was reduced over 8 h, with a faster and more marked decrease on ivabradine than placebo (22.2 ± 1.3 vs 8.9 ± 1.8 bpm, p<0.0001). After treatment discontinuation, heart rate was similar in both groups. Throughout the study, there was no difference in blood pressure between groups. There was no difference in cardiac biomarkers (creatine kinase (CK-MB), troponin T and troponin I). On echocardiography performed at baseline and post treatment (median 1.16 days), final left ventricular volumes were lower in the ivabradine group both for left ventricular end-diastolic volume (LVEDV) (87.1 ± 28.2 vs 117.8 ± 21.4 ml, p=0.01) and left ventricular end-systolic volume (LVESV) (42.5 ± 19.0 versus 59.1 ± 11.3 ml, p=0.03) without differences in volume change or left ventricular ejection fraction. CONCLUSION: This pilot study shows that intravenous ivabradine may be used safely to slow the heart rate in STEMI. Further studies are needed to characterize its effect on infarct size, left ventricular function and clinical outcomes in this population.

Effect of paraoxonase-1 polymorphism on clinical outcomes in patients treated with clopidogrel after an acute myocardial infarction.

Paraoxonase-1 (PON1) Q192R polymorphism was recently suggested to determine per se clopidogrel response on major cardiovascular events (MACEs). We assessed the impact of PON1, CYP2C19, and ABCB1 polymorphisms on MACE in clopidogrel-treated acute myocardial infarction (AMI) patients (N = 2,210), including those undergoing percutaneous coronary intervention (PCI) (n = 1,538). PON1 polymorphism was not associated with increased risk of in-hospital death and MACEs at 1 year (adjusted hazard ratio (HR) 1.03, 95% confidence interval (CI) 0.66-1.61 and adjusted HR 0.77, 95% CI 0.42-1.41 for QQ versus RR in all and PCI patients, respectively). The presence of two CYP2C19 loss-of-function (LOF) alleles was associated with the risk of in-hospital death and MACEs at 1 year in the overall population (adjusted odds ratio (OR) 3.67, 95% CI 1.05-12.80 and adjusted HR 1.96, 95% CI 1.08-3.54) and in PCI patients (adjusted OR 6.87, 95% CI 2.52-18.72 and adjusted HR 3.06, 95% CI 1.47-6.41). Unlike CYP2C19 polymorphism, PON1 (Q192R) polymorphism is not a major pharmacogenetic contributor of clinical response to clopidogrel in AMI patients.

Use of recombinant factor VIIa (NovoSeven(®)) in 8 patients with ongoing life-threatening bleeding treated with fondaparinux.

BACKGROUND: Fondaparinux has a favourable efficacy-safety profile but if major bleeding occurs, reversal of antithrombotic treatment is challenging. We present clinical and biological observations from patients treated with rFVIIa for bleeding under fondaparinux. METHODS: Fondaparinux-treated patients with bleeding (>10% haematocrit decrease) and cardiovascular collapse were eligible. Patients received a single 90 µg/kg bolus rFVIIa. Clinical success was defined as clinical bleeding control without thrombotic complication. A biological criterion of successful antagonization was defined as a >100% increase in peak thrombin generation (C(max)). RESULTS: 8 patients were treated (5 ACS, 3 VTE). Patients received aspirin and clopidogrel (n = 5), eptifibatide (n = 2), fluindione (n = 5). In addition to standard haemostatic methods, all patients received rFVIIa and transfusion. Clinical progression was favourable in 4, with bleeding clinically controlled in <6 h. 1 patient died. Biological success was observed in 4 patients with lowest baseline anti-Xa (0.67-0.92 U/L); ¾ had clinical success. In patients with baseline anti-Xa >1.0 U/L (1.14-1.62 U/L), increase in C(max) was low; ¾ had no clinical bleeding control. CONCLUSION: This series is the largest describing rFVIIa use to control bleeding in patients under fondaparinux. rVFIIa was considered efficient in 50%, suggesting inefficacy in the context of elevated anti-Xa.

[Evaluation of management of infarction in the Franche Comté province by the use of the Franche Comté Cardiology Registry, May 2005-May 2006]. / L'évaluation des pratiques professionnelles pour la prise en charge des infarctus en Franche-Comté. Expérience d'une évaluation à l'échelle régionale par l'utilisation des données du registre franc-comtois de cardiologie, mai 2005-mai 2006.

RATIONALE: The management of acute infarction often necessitates a network of organisation between different centres, thus making it the object of an evaluation of professional practices (EPP). We report the experience in the Franche Comté province of an EPP at a regional level in the management of infarction. METHODS: All of the patients admitted to 10 of the 11 centres in the region were included in a prospective survey. Quality indicators for acute and chronic care were defined, as well as scores, on the basis of use of treatments specified in guidelines. RESULTS: Between May 2005 and May 2006, 1,170 patients were admitted. The patients' risk levels and quality scores were calculated. The rate of use of the quality indicators was higher in our survey than that observed in all of the published studies, except for the use of betablockers. The quality of care could therefore be considered as highly satisfactory. Comparison between the centres revealed some differences. Even after adjustment for the risk score on admission, the quality score for acute care was related to mortality at 1 month. CONCLUSIONS: An EPP is possible for the management of infarction, on a regional scale such as in the province of Franche Comté. The acute quality score turned out to be an independent factor for mortality. The indicators showed that the quality of care was highly satisfactory, even though more progress could be made in the prescription of betablockers.

Predictive value of admission hyperglycaemia on mortality in patients with acute myocardial infarction.

RATIONALE AND AIM: In patients with an acute myocardial infarction, admission hyperglycaemia (AH) is a major risk factor for mortality. However, the predictive value of AH, when the risk score and use of guidelines-recommended treatments are considered, is poorly documented. METHODS: The first fasting plasma glucose levels after admission, risk level, guidelines-recommended treatment use and 1-year mortality were recorded. Patients with first fasting glucose level after admission > 7.7 mmo/l were considered to have AH. RESULTS: Three hundred and twenty patients with ST segment elevation myocardial infarction (STEMI) and 404 with non-ST segment elevation myocardial infarction (NSTEMI) were included. One hundred and seventy-five (24%) patients had pre-existing diabetes (diabetes group), 154 (21%) had AH (AH+ group) and the remainding 395 (55%) had neither diabetes nor AH (AH- group). The Global Registry of Acute Coronary Events (GRACE) risk score was lower in the AH- group, but the use of guidelines-recommended treatment was comparable in all groups. At 1 year, the mortality rate was higher in the AH+ group compared with the AH- group (18.8 vs. 6.1%, P < 0.01) and similar to that in the diabetes group (18.8 vs. 16.6%, P = NS). The relation between glycaemic status and mortality remained strong [AH+ vs. AH-, OR = 3.0 (1.5, 6.0) and diabetes vs. AH-, OR = 3.6 (1.7, 6.6)] after adjustment for the GRACE risk score [OR = 2.4 (1.8, 3.1) per 10% increase] and for treatment score [OR = 0.7 (0.6, 0.8) per 10% increase]. CONCLUSIONS: In patients without a history of diabetes, the presence of AH indicates an increased risk of 1-year mortality, similar to that of patients with diabetes, even when the risk score and use of guidelines-recommended treatment are controlled for.

[Chronic renal failure: an independent factor of mortality after myocardial infarction]. / L'insuffisance rénale chronique, facteur de risque indépendant de mortalité après un infarctus aigu.

PURPOSE: The prognostic significance of glomerular filtration rate (GFR) was studied in a registry of 754 patients admitted for myocardial infarction in Franche Comté; 333 of them had STEMI. PATIENTS AND METHODS: One-year mortality was 11.5%: 2.3% in the group with normal GFR, 9.4% in the group with moderate renal failure, and 24.2% in the group with severe renal failure. GFR increased the prognostic value of conventional risk scores. CONCLUSION: Chronic renal failure therefore appears as a major independent predictor of mortality after myocardial infarction.

[Predictive factors of restenosis: what changes with "active" stents?]. / Les facteurs prédictifs de la resténose: quels changements avec les stents << actifs >> ?

For many years, restenosis was the major limiting factor of coronary angioplasty, even since the systematic use of stents. Numerous scientific publications have aimed to define the predictive factors of this phenomenon. Factors such as diabetes, the size of the treated artery, the use of stents or not, the length of the lesion, lesion located on the proximal left anterior descending artery, the degree of residual stenosis post-angioplasty (assessed by angiography or by intravascular ultrasound) have all been evoked as being classically related to restenosis. However, our perception of the restenosis phenomenon has been dramatically changed by the demonstration of the efficacy and security of active stents. Even in so-called "at risk" populations, the use of active stents is rarely followed by restenosis. In this way, the classic risk factors for restenosis have now become arguments in favour of the implantation of an active stent. As long as budgetary constraints limit the use of active stents to patients said to be "at risk of restenosis", this population, quite paradoxically, will have a more favourable outcome than so-called "low risk" patients, in whom "ordinary" non-active stents will continue to be used.

[Enzyme calibrators: principle and practical use]. / Le calibrage en enzymologie clinique: principe, conditions d'application et résultats.

Results of catalytic activities of enzymes are highly dependent on the measurement procedures and on local conditions. Thus, only poorly marked improvement of interlaboratory comparability of results have been observed in clinical enzymology. To solve this problem, SFBC and IFCC have proposed to use "validated enzyme calibrators". Standardised operating procedures adapted to 37 C have been developed by IFCC for the most commonly used enzymes in clinical chemistry, and will be soon published. Reference materials which have been certified with these SOPs can be used as calibrators for a set of measurement methods which exhibit the same analytical specificity. Calibrators must be commutable, a property that must be checked experimentally. It is possible to produce stable and commutable materials for the calibration of a set of methods. Interest of this approach has been demonstrated for several enzymes. Results of two studies presented here show that the comparison of results to the upper limit of reference ranges does not improve the interlaboratory comparability of results in contrast to the calibration of different methods by a common calibrator which allowed to reach an interlaboratory CV close to 4% for ALT and gammaGT.

False lumen patency as a predictor of late outcome in aortic dissection.

Aortic dissection (AD) is a disease with a high-risk of mortality. Late deaths are often related to complications in nonoperated aortic segments. Between 1984 and 1996, we retrospectively analyzed the data of 109 patients with acute AD (81 men and 28 women; average age 61 +/- 14 years). All imaging examinations were reviewed, and a magnetic resonance imaging examination was performed at the time of the study. Aortic diameters were measured on each aortic segment. Predictive factors of mortality were determined by Cox's proportional hazard model, in univariate and multivariate analyses, using BMDP statistical software. Follow-up was an average of 44 +/- 46 months (range 24 to 164). Actuarial survival rates were 52%, 46%, and 37% at 1, 5, and 10 years, respectively, for type A AD versus 76%, 72%, and 46% for type B AD. Predictors of late mortality were age >70 years and postoperative false lumen patency of the thoracic descending aorta (RR 3.4, 95% confidence intervals 1.20 to 9.8). Descending aorta diameter was larger when false lumen was patent (31 vs 44 mm; p = 0.02) in type A AD. Furthermore, patency was less frequent in operated type A AD when surgery had been extended to the aortic arch. Thus, patency of descending aorta false lumen is responsible for progressive aortic dilation. In type A AD, open distal repair makes it possible to check the aortic arch and replace it when necessary, decreases the false lumen patency rate, and improves late survival.

[Harmonization of practices: application to the measurement of enzymatic activities used in prevention, screening, diagnosis and therapeutic monitoring]. / Harmonisation des pratiques: application à la mesure d'activités enzymatiques utilisées en prévention, dépistage, diagnostic et surveillance thérapeutique.

The large metrological variation (CV, about 25%) observed between laboratories, at the national French level, for the measurement of enzymatic activities results in a loss of efficiency in using laboratory results. Current data show that the standardisation of methods is insufficient to solve this problem and needs to be completed by an harmonisation of the practices including the use of a common reference (calibrator). The present work, carried out by the joint working group between laboratories of the Centres for Periodic Health Examination and the French Society of Clinical Biology (SFBC), deals mainly with the feasibility and evaluation of the improvement of the consistency of the results. Twenty laboratories participated in this study. Five independent surveys were conducted during an height month period. Two enzymes were selected because of their clinical importance and their interest in prevention, screening, diagnosis or epidemiology: ALT (alanine aminotransferase) and GGT (gamma-glutamyltransferase). In each survey three kinds of samples i.e. control sera, candidate calibrators and human serum pools, each of them at two levels of activity (one physiological and the other pathological) were measured in duplicate. The low intra-laboratory imprecision and the high degree of the standardisation of used methods, due to an important effort previously done in this field, permitted to consider a common calibration. The stability and mainly the commutability, i.e. the ability for the candidate calibrator to show a behaviour similar to that of human samples towards the used methods, allowed to reduce the inter-laboratory variation by a half to two third-fold, reaching a coefficient of variation < 5% similar to those observed for cholesterolemia or glycemia. This level of consistency should permit to use common reference limits and common decision limits, after validation of this approach in real practice. The consequences of the harmonisation of practices, extended to the all laboratories, exceed largely the scope of this study. The reduction of the uncertainty and a better approach of the accuracy for the measurement of enzymatic activities should led to a real benefit for the patients in terms of prevention, screening, diagnosis or therapeutic monitoring and consequently for the public health.

Production and certification of an enzyme reference material for adenosine deaminase 1 (BCR 647).

BACKGROUND: We describe the preparation of a lyophilised reference material containing purified human adenosine deaminase 1 and the certification of its catalytic concentration. METHODS: The enzyme was purified from human erythrocytes. RESULTS: The enzyme was >99% pure on polyacrylamide gel electrophoresis. Only trace amounts (<0.4%) of alanine aminotransferase, aspartate aminotransferase and L-lactate dehydrogenase were detected in the purified fraction. The purified adenosine deaminase had a molar mass of 41600 g/mol and an isoelectric pH at 4.7, 4.85 and 5.0. The material was prepared by diluting the purified adenosine deaminase in a matrix containing 50 mmol/l Tris-HCl buffer pH 7.4 and 30 g/l human serum albumin; dispensing in vials and freeze-drying. The batch was homogeneous and the predicted loss of adenosine deaminase activity per year on the basis of accelerated degradation studies was 0.006% at -20 degrees C and 0.04% at 4 degrees C. The certified value for adenosine deaminase catalytic concentration in the reconstituted reference material is (2.55+/-0.09) microkat/l when measured by the method that uses adenosine as substrate and glutamate dehydrogenase as auxiliary enzyme at 37 degrees C. CONCLUSIONS: The material can be used to verify the comparability of results from different laboratories, for intra-laboratory quality control, or for calibration of the adenosine deaminase catalytic concentration measurements.

Lack of agreement between left ventricular volumes and ejection fraction determined by two-dimensional echocardiography and contrast cineangiography in postinfarction patients.

OBJECTIVE: To assess the agreement between left ventricular (LV) volumes and ejection fraction (EF) determined by two-dimensional echocardiography (2-D echo) and by cineangiography in postinfarction patients. DESIGN: LV end-diastolic and end-systolic volumes indexed (EDVI and ESVI) to body surface area as well as EF were determined by both methods in all patients. SETTING: Multicenter trial conducted in five university hospitals. PATIENTS: 63 patients, 61 male, two female, mean age 55.5 +/- 10.4 years, suffering from a recent myocardial infarction. Eighty-one pairs of measurements were available. METHODS: The results of biplane 2-D echo measures, using apical four-chamber (4C) and two-chamber (2C) views were compared to those of a 30 degrees right anterior oblique cineangiography projection, using either the apical method of discs or the area-length 2-D echo method. Moreover, eyeball EF was estimated at 2-D echo and cineangiography, and was compared to the conventional methods. The agreement between results was assessed by the Bland and Altman method. RESULTS: The agreement between 2-D echo and cineangiography results was poor. Mean differences (MD) were -21.8 (EDVI, ml/m(2)), -9.5 (ESVI, ml/m(2)), and -0.9 (EF, %), respectively for 2-D echo method of discs versus cineangiography, and -23.2, -9.3, and -5.7 for area-length 2-D echo versus cineangiography. For EF (%), MD was -3.6 for eyeball cineangiography versus cineangiography, -1.3 for eyeball 2-D echo versus method of discs, and +0.30 for eyeball 2-D echo versus area-length 2-D echo, respectively. Two-dimensional echo is likely to underestimate LV volumes compared to cineangiography, especially for largest volumes. Even for EF, discrepancies are large, with a lack of agreement of 21%-25% between conventional methods, but agreement is better between eyeball EF and usual methods. CONCLUSIONS: Even with modern echocardiographic devices, agreement between 2-D echo and cineangiography-derived LV volumes and EF remains moderate, and both methods must not be considered interchangeable in clinical practice.

Apolipoproteins E and C-III in apo B- and non-apo B-containing lipoproteins in middle-aged women from the Stanislas cohort: effect of oral contraceptive use and common apolipoprotein E polymorphism.

Oral contraceptive (OC) use and common apo E polymorphism are well known to modify serum lipid and lipoprotein concentrations. The combined effect of OC use and apo E genotype on the concentration of apo E or apo C-III in apo B- (apo E-LpB or apo C-III-LpB) or in non-apo B-containing lipoparticles (apo E-Lp-non-B or apo C-III-Lp-non-B) are unknown. Our study comprised 613 women, aged 30-45 years, genotyped for common apo E polymorphism and who differed in their combined low-dose OC consumption. The concentrations of apo C-III, apo C-III-LpB and apo C-III-Lp-non-B were significantly higher in OC users than in non-users by 13, 23 and 8% respectively, without significant interaction with the apo E genotype. The concentrations of apo E and apo E-Lp-non-B were significantly lower (differences being -14% and -31% respectively) in OC users than in controls whereas the apo E-LpB concentration was significantly higher (+19%), resulting in a redistribution of apo E from Lp-non-B towards LpB. Total apo E and apo E-Lp-non-B concentrations were higher in subjects carrying the epsilon2 allele and lower in those with the epsilon4 allele when compared to epsilon3/epsilon3 subjects (P < 0.001). The opposite held for the apo E- LpB concentration (P < 0.05). The main finding is the significant interaction between apo E genotype and OC use (P < 0.01) on apo E-Lp-non-B concentration, the epsilon4 carriers showing the smallest differences between OC users and non-users in comparison with the epsilon2 or epsilon3/epsilon3 carriers. These results suggest that the common apo E polymorphism can modulate the OC use effect.

Cytomegalovirus, Chlamydia pneumoniae, and Helicobacter pylori IgG antibodies and restenosis after stent implantation: an angiographic and intravascular ultrasound study.

OBJECTIVE: To determine the impact of previous infection with cytomegalovirus, Chlamydia pneumoniae, and Helicobacter pylori on neointimal proliferation after coronary angioplasty with stent implantation. DESIGN: The study population was made up of 180 patients who had stent implantation in a native coronary artery with systematic angiographic and intravascular ultrasound (IVUS) follow up at six months. Quantitative coronary angiography was used to assess the late lumen loss. The mean area of neointimal tissue within the stent and the ratio of neointimal tissue to stent area were assessed from IVUS images. Previous cytomegalovirus, C pneumoniae, and H pylori infection was identified by IgG antibody determination. RESULTS: Previous cytomegalovirus infection was detected in 50% of the population, previous C pneumoniae in 18%, and previous H pylori in 33%. Mean (SD) reference diameter was 2.94 (0.48) mm and mean minimum lumen diameter after stent implantation was 2.45 (0.42) mm. At six months, the mean late loss was 0.74 (0.50) mm, the mean neointimal tissue area was 3.8 (1.7) mm(2), and the average ratio of neointimal tissue area to stent area was 45 (18)%. None of these variables of restenosis was linked to any of the three infectious agents. By multivariate analysis, lesion length was the variable best correlated with mean neointimal tissue area, the ratio of neointimal tissue to stent area, and late loss, explaining respectively 31%, 39%, and 8% of their variability. CONCLUSIONS: Previous infection with cytomegalovirus, C pneumoniae, or H pylori was not a contributing factor in the process of restenosis after stent implantation.

Intracoronary stent implantation under intracoronary ultrasound guidance with aspirin and ticlopidine therapy.

OBJECTIVE: To observe the immediate angiographic and intravascular ultrasound (IVUS) results and their effects on one month clinical outcomes in forty-one patients who submitted to coronary stent deployment with IVUS guidance. METHODS: All patients were allocated to coronary stent implantation with high inflation pressure. After good angiographic results (< 20% residual stenosis), all patients underwent IVUS and higher-pressure dilatation would be necessary if criteria for optimal coronary stent implantation were not met. The optimal criterion of IVUS for stent implantation was the ratio of intrastent lumen cross-sectional area to the average of the proximal and distal reference lumen cross-sectional areas > or = 80%. All patients had aspirin and ticlopidine therapy on the day of angioplasty and during the one month follow-up period. RESULTS: Optimal criteria of IVUS were obtained without any further intrastent dilatation in twenty-five patients but intrastent higher-pressure dilatation was performed in fourteen patients whose ultrasound results did not reach the criteria. In these patients, we increased the minimal intrastent lumen area 25.7% (P < 0.05). Thirty-five patients (90%) had good minimal intrastent lumen area of IVUS. There were no deaths, myocardial infarction, acute stent thrombosis or need for revascularization during the study and the one month follow-up. CONCLUSIONS: Intracoronary stent deployment under IVUS guidance, including combining aspirin and ticlopidine therapy, had beneficial ultrasound results and good clinical outcomes after one month follow-up.