Prognostic role of BNP in children undergoing surgery for congenital heart disease: analysis of prediction models incorporating standard risk factors.

BACKGROUND: The routine use of brain natriuretic peptide (BNP) in pediatric cardiac surgery remains controversial. Our aim was to test whether BNP adds information to predict risk in pediatric cardiac surgery. METHODS: In all, 587 children undergoing cardiac surgery (median age 6.3 months; 1.2-35.9 months) were prospectively enrolled at a single institution. BNP was measured pre-operatively, on every post-operative day in the intensive care unit, and before discharge. The primary outcome was major complications and length ventilator stay >15 days. A first risk prediction model was fitted using Cox proportional hazards model with age, body surface area and Aristotle score as continuous predictors. A second model was built adding cardiopulmonary bypass time and arterial lactate at the end of operation to the first model. Then, peak post-operative log-BNP was added to both models. Analysis to test discrimination, calibration, and reclassification were performed. RESULTS: BNP increased after surgery (p<0.001), peaking at a mean of 63.7 h (median 36 h, interquartile range 12-84 h) post-operatively and decreased thereafter. The hazard ratios (HR) for peak-BNP were highly significant (first model HR=1.40, p=0.006, second model HR=1.44, p=0.008), and the log-likelihood improved with the addition of BNP at 12 h (p=0.006; p=0.009). The adjunction of peak-BNP significantly improved the area under the ROC curve (first model p<0.001; second model p<0.001). The adjunction of peak-BNP also resulted in a net gain in reclassification proportion (first model NRI=0.089, p<0.001; second model NRI=0.139, p=0.003). CONCLUSIONS: Our data indicates that BNP may improve the risk prediction in pediatric cardiac surgery, supporting its routine use in this setting.

Mitral valve repair versus replacement in patients with ischaemic mitral regurgitation and depressed ejection fraction: risk factors for early and mid-term mortality†.

OBJECTIVES: Mitral valve (MV) surgery for ischaemic mitral regurgitation (IMR) in patients with depressed left ventricular ejection fraction (LVEF) is associated with poor outcomes. The optimal surgical strategy for IMR in these patients remains controversial. The objective of this study was to compare the early mortality and mid-term survival of MV repair versus MV replacement in patients with IMR and depressed LVEF undergoing coronary artery bypass grafting (CABG). METHODS: A retrospective, observational, cohort study was undertaken of prospectively collected data on 126 consecutive CABG patients with IMR and LVEF <40% undergoing either MV repair (n = 98, 78%) or MV replacement (n = 28, 22%) between July 2002 and February 2011. RESULTS: The overall mortality rate was 7.9% (n = 10). MV replacement was associated with a 4-fold increase in the risk of death compared with MV repair [17.9%, n = 5 vs 5.1%, n = 5; odds ratio (OR) 4.04, 95% confidence interval (CI) 1.08-15.1, P = 0.04]. However, after adjusting for preoperative risk factors, the type of surgical procedure was not an independent risk factor for early mortality (OR 0.1, 95% CI 0.01-31, P = 0.7). Multivariable analysis showed that preoperative LVEF (OR 0.8, 95% CI 0.6-0.9, P = 0.018), preoperative B-type natriuretic peptide (BNP) levels (OR 1.01, 95% CI 1-1.02, P = 0.025), preoperative left ventricle end-systolic diameter (OR 0.8, 95% CI 0.7-1.0, P = 0.05) and preoperative left atrial diameter (OR 1.3, 95% CI 1.0-1.6, P = 0.015) were independent risk factors of early mortality. At the median follow-up of 45 months (interquartile range 20-68 months), the mid-term survival rate was 74% in the MV repair group and 70% in the MV replacement group (P = 0.08). At follow-up, predictors of worse survival were BNP levels [hazard ratio (HR) 1.0, 95% CI 1.0-1.01, P = 0.047], preoperative renal failure (HR 4.6, 95% CI 1.1-20.3, P = 0.039) and preoperative atrial fibrillation (HR 3.3, 95% CI 1.1-10, P = 0.032). CONCLUSIONS: MV repair in CABG patients with IMR and depressed LVEF is not superior to MV replacement with regard to operative early mortality and mid-term survival.

Pantoprazole significantly interferes with antiplatelet effect of clopidogrel: results of a pilot randomized trial.

BACKGROUND: The CYP2C19*2 polymorphism is significantly associated with residual platelet reactivity (RPR) and maybe a major confounding factor in studies evaluating pharmacological interactions with clopidogrel. OBJECTIVES: We sought to evaluate the influence of a proton pump inhibitor (PPI), pantoprazole, indicated as relatively less influent than other PPIs, on the antiplatelet effect of clopidogrel, considering a stratification of the population for the presence of cytochrome 2C19*2 polymorphism. METHODS: 105 patients with ST elevation myocardial infarction (STEMI), treated with percutaneous coronary angioplasty (PCI) and who received dual antiplatelet therapy, were randomized between pantoprazole (n=54) or ranitidine (n=51). RPR was evaluated by Platelet Function Analyzer-100 (PFA-100) with collagen-epinephrine (CEPI) and collagene-ADP (CADP) cartridges and by light transmitted aggregometry with 10 µM adenosin diphosphate (ADP) and 1mM arachidonic acid (AA), on 5 (T0) and 30 (T1) days after PCI. RESULTS: Demographic, clinical and procedural data and the prevalence of CYP2C19*2 polymorphism were similar between the two groups. Not statistically differences were observed for CEPI-CT and for the maximal aggregation (MA) values with AA stimulus at both times. We observed a significant increase in MA values with ADP in PPI group at T0 (p=0.01) and T1 (p=0.03). At the multiple regression analysis PPI use remained significantly associated with ADP-MA both at T0 (p=0.05) and T1 (p=0.03). CONCLUSIONS: This is the first documentation in a randomized trial, after correction for the bias of CYP2C19*2 polymorphism, that pantoprazole increases the ADP-MA in patients treated with dual antiplatelet therapy.

Von Willebrand factor antigen predicts response to double dose of aspirin and clopidogrel by PFA-100 in patients undergoing primary angioplasty for ST elevation myocardial infarction.

Von Willebrand factor (VWF) is an emerging risk factor in acute coronary syndromes. Platelet Function Analyzer (PFA-100) with Collagen/Epinephrine (CEPI) is sensitive to functional alterations of VWF and also identifies patients with high on-treatment platelet reactivity (HPR). The objective of this study was to verify the effect of double dose (DD) of aspirin and clopidogrel on HPR detected by PFA-100 and its relation to VWF and to its regulatory metalloprotease ADAMTS-13. Between 2009 and 2011 we enrolled 116 consecutive patients with ST elevation myocardial infarction undergoing primary PCI with HPR at day 5 after PCI. Patients recruited were then randomized between a standard dose (SD, n = 58) or DD of aspirin and clopidogrel (DD, n = 58), maintained for 6 months follow-up. Blood samples for PFA-100, light transmittance aggregometry, and VWF/ADAMTS-13 analysis were collected after 5, 30, and 180 days (Times 0, 1, and 2). At Times 1 and 2 we observed a significantly higher CEPI closure times (CT) in DD as compared to SD (P < 0.001). Delta of CEPI-CT (T1 - T0) was significantly related to VWF (P < 0.001) and inversely related to ADAMTS-13 (0.01). Responders had a significantly higher level of VWF at T0. Finally, in a multivariate model analysis, VWF and ADAMTS-13 in resulted significant predictors of CEPI-CT response (P = 0.02). HRP detected by PFA-100 in acute myocardial infarction is reversible by DD of aspirin and clopidogrel; the response is predicted by basal levels of VWF and ADAMTS-13. PFA-100 may be a useful tool to risk stratification in acute coronary syndromes given its sensitivity to VWF.

Relationships between optical aggregometry (type born) and flow cytometry in evaluating ADP-induced platelet activation.

BACKGROUND: Platelet response to activating agents is used to monitor the efficacy of anti-aggregation therapies. The aim of our study has been to demonstrate the existence of relationships between early events of ADP-induced platelet activation, measured by flow cytometry and platelet-rich plasma aggregation, quantified by optical aggregometry. METHODS: We evaluated peripheral blood of 12 donors. The following parameters were quantified by cytometry after stimulation with adenosine diphosphate (ADP) (0.5, 1, 2, 5, 10, 20 muM): CD62P (P-selectin) and PAC-1 expression, and cytosolic Ca(2+) mobilization. Aggregation was measured by optical aggregometry. We also studied 13 patients, undergoing coronary stenting, treated with aspirin (before procedure) or with aspirin plus clopidogrel (after procedure). We evaluated CD62P and PAC-1 expression, aggregation, and vasodilator-stimulated phopshoprotein phosphorylation (platelet reactivity index, PRI). RESULTS: Flow procedures were more sensitive than aggregometry, with a lowest interindividual variability. Linear relationships existed in donors between CD62P expression and Ca(2+) mobilization (P < 0.0001), and between aggregation and Ca(2+) mobilization (P < 0.0001). Linear relationships existed between aggregation and CD62P expression, as percentage (P < 0.0001), or relative fluorescence intensity (RFI) (P < 0.0001). Exponential equations related aggregation and PAC-1 expression, as percentage (P < 0.0001), or RFI (P < 0.0001). Linear relationships between aggregation and CD62P expression (as percentage) existed in the patients before (P = 0.0022) and after procedure (P = 0.0020). Exponential relationships between aggregation and PAC-1 expression (as percentage) existed before (P = 0.0012) and after procedure (P = 0.0024). Linear correlations related aggregation response predicted on CD62P expression, and measured aggregation inhibition after clopidogrel (P = 0.0013) as well as predicted aggregation and PRI inhibition (P = 0.0031). CONCLUSIONS: Tight relationships between aggregation and cytometric quantification of platelet markers in whole blood, in particular CD62P, allow to predict aggregation response to ADP from flow data in patients treated with aspirin alone or with aspirin plus clopidogrel.