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Tirofiban is a glycoproteine (GP) IIb/IIIa receptor antagonist, which inhibits platelet-platelet aggregation and is a potential adjunctive antithrombotic treatment in patients with acute coronary syndromes (ACS) or high-risk percutaneous coronary interventions (PCI). It is administered intravenously as a bolus followed by continuous infusion. However, the dosage recommendations in the United States (US) and European Union (EU) differ considerably. Furthermore, in routine clinical practice, deviations from the recommendations may occur. The objective of the present study was to investigate the impact of different alterations on tirofiban plasma concentrations in US and EU administration regimens and to give suggestions for delay management in clinical practice. We therefore mathematically simulated the effects of different bolus-infusion delays and infusion interruptions in different scenarios according to the renal function. Here, we provide a systematic assessment of concentration patterns of tirofiban in the US versus EU dosage regimens. We show that differences between the two regimens have important effects on plasma drug levels. Furthermore, we demonstrate that deviations from the proper administration mode affect the concentration of tirofiban. Additionally, we calculated the optimal dosage of a second bolus to rapidly restore the initial concentration without causing overdosage. In conclusion, differences in tirofiban dosing regimens between the U.S and EU and potential infusion interruptions have important effects on drug levels that may impact on degrees of platelet inhibition and thus antithrombotic effects. Thus, the findings of our modelling studies may help to explain differences in clinical outcomes observed in previous clinical trials on tirofiban. [ABSTRACT FROM AUTHOR]

Background: Periprocedural uninterrupted anticoagulation for catheter ablation of atrial fibrillation (AF) became standard after positive results of vitamin K antagonist (VKA) trials. Previous studies of uninterrupted direct oral anticoagulants (DOACs) vs. VKA have given controversial results. We thus aimed to elucidate the risk/benefit ratio of uninterrupted DOAC vs. VKA during catheter ablation of AF in an updated meta-analysis of randomised controlled trials (RCTs). Methods: Online databases were searched for RCTs comparing uninterrupted DOAC to VKA in patients undergoing catheter ablation of AF. Data from retrieved studies were analysed in a comprehensive meta-analysis. Primary safety outcome was major bleeding; primary efficacy outcome was stroke or transient ischaemic attack (TIA). Secondary outcomes included a composite of major bleeding and stroke or TIA, minor bleeding, acute cerebral lesions on magnetic resonance imaging (MRI), and mortality. Results: Six eligible RCTs comprising 2,369 patients were included. There were no significant differences in DOAC vs. VKA concerning the rates of major bleeding (2.2% vs. 3.8%; odds ratio (OR) 0.69, 95% confidence interval (CI) 0.30-1.56; p=.37) and stroke or TIA (0.2% vs. 0.2%; OR 0.97, CI 0.20-4.72; p=.97). Pooled meta-analysis of secondary outcomes revealed no significant differences (OR 0.73, p=.49 for composite of major bleeding and stroke or TIA; OR 1.08, p=.52 for minor bleeding; OR 1.12, p=.59 for acute cerebral lesions on MRI; and OR 0.60, p=.64 for all-cause mortality). Conclusion: Our meta-analysis suggests that uninterrupted DOAC is not superior to VKA in patients undergoing catheter ablation of AF with comparable rates of major bleeding and stroke. [ABSTRACT FROM AUTHOR]

Aims: To evaluate whether CMR-derived RV assessment can facilitate risk stratification among patients undergoing transcatheter mitral valve repair (TMVR). Background: In patients undergoing TMVR, only limited data exist regarding the role of RV function. Previous studies assessed the impact of pre-procedural RV dysfunction stating that RV failure may be associated with increased cardiovascular mortality after the procedure. Methods: Sixty-one patients underwent CMR, echocardiography and right heart catheterization prior TMVR. All-cause mortality and heart failure hospitalizations were assessed during 2-year follow-up. Results: According to RV ejection fraction (RVEF) <46%, 23 patients (38%) had pre-existing RV dysfunction. By measures of RV end-diastolic volume index (RVEDVi), 16 patients (26%) revealed RV dilatation. Nine patients (15%) revealed both. RV dysfunction was associated with increased right and left ventricular volumes as well as reduced left ventricular (LV) ejection fraction (all p<0.05). During follow-up, 15 patients (25%) died and additional 14 patients (23%) were admitted to hospital due to heart failure symptoms. RV dysfunction predicted all-cause mortality even after adjustment for LV function. Similarly, RVEDVi was a predictor of all-cause mortality even after adjustment for LVEDVi. Kaplan-Meier survival analysis unraveled that, among patients presenting with CMR indicative of both, RV dysfunction and dilatation, the majority (78%) experienced an adverse event during follow-up (p<0.001). Conclusion: In patients undergoing TMVR, pre-existing RV dysfunction and RV dilatation are associated with reduced survival, in progressive additive fashion. The assessment of RV volumes and function by CMR may aid in risk stratification prior TMVR in these high-risk patients. [ABSTRACT FROM AUTHOR]

Background: Patients with chronic kidney disease (CKD) and atrial fibrillation have increased risks for stroke and bleeding under oral anticoagulation (OAC). We investigated an alternative therapy of percutaneous left atrial appendage occlusion (LAAO) in CKD patients in this study. Methods: Consecutive patients undergoing LAAO were included in a retrospective analysis and stratified for kidney function into CKD/Non-CKD groups (cutoff eGFR 60 ml/min). Procedural characteristics, in-hospital and follow-up events were analysed and compared between groups. Results: LAAO was performed in 146 patients (81 CKD; 65 Non-CKD), mean follow-up was 391 days. Groups differed in eGFR (40.1 (CKD) vs. 75.1 (Non-CKD) ml/min) and CHA2DS2VASc scores (4.65 ± 1.3 (CKD) vs. 4.06 ± 1.4 (Non-CKD)). Procedural success was 98.6%, contrast-induced acute kidney injury was significantly more frequent in CKD patients (11.1% vs. 0%; p =.004). Follow-up mortality was higher in CKD (10.5/100 PY vs. 4.2/100 PY; p =.156). Follow-up stroke rates were 2.3/100 (CKD) patient-years (PY) and 1.4/100 PY (Non-CKD) (p = 1.000), corresponding to a relative risk reduction (RRR) of 60% (all), 68% (CKD) and 71% (Non-CKD) compared to expected stroke rates. Follow-up major bleeding rates were 3.5/100 PY (CKD) and 4.2/100 PY (Non-CKD), corresponding to RRR of 57% (all), 61% (CKD) and 53% (Non-CKD) compared to OAC. Conclusions: Left atrial appendage occlusion shows comparable efficacy for stroke and bleeding prevention in CKD and Non-CKD patients. CKD patients experience more adverse events during follow-up and a significantly increased risk for periprocedural contrast-induced acute kidney injury. [ABSTRACT FROM AUTHOR]

Background and purpose: The National Cardiovascular Data Registry (NCDR) risk scores for mortality, bleeding and acute kidney injury (AKI) are accurate outcome predictors of coronary catheterization procedures in North American populations. However, their application in German clinical practice remained elusive and we thus aimed to verify their use. Methods: NCDR scores for mortality, bleeding and AKI and corresponding clinical outcomes were retrospectively assessed in patients undergoing catheterization for ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI) or for elective coronary procedures at a German Heart Center from 2014 to 2017. Risk model performance was assessed using receiver-operating-characteristic curves (discrimination) and graphical analysis/logistic regression (calibration). Results: A total of 1637 patients were included, procedures were performed for STEMI (565 patients, 34.5%), NSTEMI (572 patients, 34.9%) and elective purposes (500 patients, 30.5%); 6% (13% of STEMI and 5% of NSTEMI patients) presented in cardiogenic shock and 3% with resuscitated cardiac arrest. Radial access was used in 38% of procedures and cross-over was necessary in 5%; PCI was performed in 60% of procedures. In-hospital mortality was 6.3% (STEMI 14.5%; NSTEMI 3.7%; elective 0%) and major bleedings occurred in 5.6% (STEMI 10.6%; NSTEMI 5.4%; elective 0.2%); AKI was detected in 18.1% of patients (STEMI 23.7%; NSTEMI 27.3%; elective 1.4%), amounting to KDIGO stage I/II/III in 11.5%/3.5%/3.2%. NCDR risk models discriminated very well for mortality [AUC 0.93 with 95% confidence interval (CI) 0.91–0.95] and well for major bleeding (AUC 0.82, CI 0.78–0.86) and any AKI (AUC 0.83, CI 0.81–0.86). Discrimination in the subgroup of patients with PCI was comparable (mortality: AUC 0.90; major bleeding: AUC 0.78; any AKI: AUC 0.79). However, calibration showed considerable underestimation of mortality and AKI in high-risk patients, while major bleeding was consistently overestimated (Hosmer–Lemeshow p < 0.02 for all outcomes). Conclusions: The NCDR risk models showed excellent performance in discriminating high-risk from low-risk patients in contemporary German interventional cardiology. Model calibration for adverse event probability prediction, however, is limited and demands recalibration, especially in high-risk patients. [ABSTRACT FROM AUTHOR]

Background: Previous randomized controlled trials (RCT) failed to demonstrate benefits of patent foramen ovale (PFO) closure (PFO-C) over medical therapy (MT) for secondary prevention of cryptogenic ischemic stroke. Three recently published RCTs, however, turned out positive for PFO-C and warrant an updated meta-analysis.Methods: Data from all available RCTs on PFO-C vs. MT for secondary prevention of cryptogenic ischemic stroke up until October 2017 were abstracted and analyzed in a comprehensive meta-analysis. Clinical efficacy outcomes were recurrent stroke, recurrent TIA, and their combination; safety outcomes were mortality, major bleeding, venous thromboembolism (VTE), and new-onset atrial fibrillation/flutter (NOAF).Results: Five trials including a total of 3440 patients were included in the meta-analysis. PFO-C significantly reduced recurrent stroke [odds ratio (OR) 0.41, 95% confidence interval (CI) 0.19-0.90; p = 0.03] and the combination of recurrent stroke + TIA (OR 0.53, CI 0.36-0.80; p = 0.002) compared to MT; recurrent TIA alone showed no differences (OR 0.77; CI 0.51-1.14; p = 0.19). NOAF was significantly more frequent after PFO-C (OR 5.75, CI 3.09-10.70; p < 0.00001). Mortality (OR 0.80, CI 0.39-1.67), major bleeding (OR 0.96, CI 0.48-1.92), and VTE (OR 2.45, CI 0.75-7.99) remained neutral. Trials with superior patient selection for PFO-C showed advantageous results compared to MT.Conclusions: PFO-C after cryptogenic ischemic stroke is safe and effective to reduce the risk of recurrent stroke and recurrent stroke + TIA, albeit with an increased risk for NOAF. [ABSTRACT FROM AUTHOR]

Background: Sudden cardiac death (SCD) is frequent in patients with heart failure due to dilated cardiomyopathy (DCM). Implantable cardioverter/defibrillator (ICD) device therapy is currently used for primary prevention. However, publication of the DANISH trial has recently given reason for doubt, showing no significant improvement in all-cause mortality in comparison to contemporary medical therapy. Methods: We performed a meta-analysis of all randomized controlled trials comparing ICD therapy to medical therapy (MT) for primary prevention in DCM. The primary outcome was all-cause mortality; secondary analyses were performed on sudden cardiac death, cardiovascular death and non-cardiac death. Results: Five trials including a total of 2992 patients were included in the pooled analysis. Compared to contemporary medical treatment there was a significant mortality reduction with ICD device therapy [odds ratio (OR) 0.77, 95% confidence interval (CI) 0.64-0.93; p = 0.006]. SCD was decreased significantly (OR 0.43, CI 0.27-0.69; p = 0.0004), while cardiovascular death and non-cardiac death showed no differences. Sensitivity analyses showed no influence of amiodarone therapy on overall results. Analysis of MT details revealed the DANISH population to adhere the most to current guideline recommendations. In addition, it was the only study including a substantial amount of CRT devices (58%). Conclusions: Our meta-analysis of all available randomized evidence shows a survival benefit of ICD therapy for primary prevention in DCM. DANISH results suggest an attenuation of this ICD advantage when compared to contemporary medical and cardiac resynchronization therapy. Until larger trials have confirmed this finding, ICD therapy should remain the recommendation for primary prevention of SCD in DCM. [ABSTRACT FROM AUTHOR]

Background: Prasugrel is more effective than clopidogrel in reducing platelet aggregation in acute coronary syndromes. Data available on prasugrel reloading in clopidogrel treated patients with high residual platelet reactivity (HRPR) i.e. poor responders, is limited. Objectives: To determine the effects of prasugrel loading on platelet function in patients on clopidogrel and high platelet reactivity undergoing percutaneous coronary intervention for acute coronary syndrome (ACS). Patients: Patients with ACS on clopidogrel who were scheduled for PCI found to have a platelet reactivity ≥40 AUC with the Multiplate Analyzer, i.e. “poor responders” were randomised to prasugrel (60 mg loading and 10 mg maintenance dose) or clopidogrel (600 mg reloading and 150 mg maintenance dose). The primary outcome measure was proportion of patients with platelet reactivity <40 AUC 4 hours after loading with study medication, and also at one hour (secondary outcome). 44 patients were enrolled and the study was terminated early as clopidogrel use decreased sharply due to introduction of newer P2Y12 inhibitors. Results: At 4 hours after study medication 100% of patients treated with prasugrel compared to 91% of those treated with clopidogrel had platelet reactivity <40 AUC (p = 0.49), while at 1 hour the proportions were 95% and 64% respectively (p = 0.02). Mean platelet reactivity at 4 and 1 hours after study medication in prasugrel and clopidogrel groups respectively were 12 versus 22 (p = 0.005) and 19 versus 34 (p = 0.01) respectively. Conclusions: Routine platelet function testing identifies patients with high residual platelet reactivity (“poor responders”) on clopidogrel. A strategy of prasugrel rather than clopidogrel reloading results in earlier and more sustained suppression of platelet reactivity. Future trials need to identify if this translates into clinical benefit. Trial Registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

Objectives: This study was designed to identify the multivariate effect of clinical risk factors on high on-treatment platelet reactivity (HPR) and 12 months major adverse events (MACE) under treatment with aspirin and clopidogrel in patients undergoing non-urgent percutaneous coronary intervention (PCI). Methods: 739 consecutive patients with stable coronary artery disease (CAD) undergoing PCI were recruited. On-treatment platelet aggregation was tested by light transmittance aggregometry. Clinical risk factors and MACE during one-year follow-up were recorded. An independent population of 591 patients served as validation cohort. Results: Degree of on-treatment platelet aggregation was influenced by different clinical risk factors. In multivariate regression analysis older age, diabetes mellitus, elevated BMI, renal function and left ventricular ejection fraction were independent predictors of HPR. After weighing these variables according to their estimates in multivariate regression model, we developed a score to predict HPR in stable CAD patients undergoing elective PCI (PREDICT-STABLE Score, ranging 0-9). Patients with a high score were significantly more likely to develop MACE within one year of follow-up, 3.4% (score 0-3), 6.3% (score 4-6) and 10.3% (score 7-9); odds ratio 3.23, P=0.02 for score 7-9 vs. 0-3. This association was confirmed in the validation cohort. Conclusions: Variability of on-treatment platelet function and associated outcome is mainly influenced by clinical risk variables. Identification of high risk patients (e.g. with high PREDICT-STABLE score) might help to identify risk groups that benefit from more intensified antiplatelet regimen. Additional clinical risk factor assessment rather than isolated platelet function-guided approaches should be investigated in future to evaluate personalized antiplatelet therapy in stable CAD-patients. [ABSTRACT FROM AUTHOR]

Antiplatelet therapy is the cornerstone of the treatment for patients with coronary artery disease (CAD). Dual therapy with clopidogrel and aspirin is currently the standard treatment after percutaneous coronary interventions. However, despite the use of clopidogrel, a considerable number of patients continue to suffer major adverse cardiac events. There is a growing degree of evidence supporting high on-treatment platelet reactivity (HPR) as a predictive factor for recurrent ischemic complications. Numerous studies have shown an interindividual variability of responsiveness to clopidogrel and aspirin, which is one of the reasons for HPR. There is yet to be established an assay for antiplatelet drug response as the gold standard. This paper provides a background to the current controversies surrounding the issue of testing for the effectiveness of antiplatelet therapy and reviews the various genetic and phenotype-based laboratory tests to measure aspirin and clopidogrel response and their correlation with clinical outcomes. On the basis of the current evidence and trying to be cost-effective, testing should be considered on a case-by-case basis, especially in patients who present with an acute coronary syndrome or stent thrombosis. In the case of stable CAD, we think that testing might be helpful in particular risk groups of patients to avoid ischemic or bleeding complications. [ABSTRACT FROM AUTHOR]

Background: Chronic inflammation promotes atherosclerosis in cardiovascular disease and is a major prognostic factor for patients undergoing percutaneous coronary intervention (PCI). Macrophage migration inhibitory factor (MIF) is involved in the progress of atherosclerosis and plaque destabilization and plays a pivotal role in the development of acute coronary syndromes (ACS). Little is known to date about the clinical impact of MIF in patients with symptomatic coronary artery disease (CAD). Methods and Results: In a pilot study, 286 patients with symptomatic CAD (n = 119 ACS, n = 167 stable CAD) undergoing PCI were consecutively evaluated. 25 healthy volunteers served as control. Expression of MIF was consecutively measured in patients at the time of PCI. Baseline levels of interleukin 6 (IL-6), "regulated upon activation, normal T-cell expressed, and secreted" (RANTES) and monocyte chemoattractant protein-1 (MCP-1) were measured by Bio-Plex Cytokine assay. C-reactive protein (CRP) was determined by Immunoassay. Patients with ACS showed higher plasma levels of MIF compared to patients with stable CAD and control subjects (median 2.85 ng/mL, interquartile range (IQR) 3.52 versus median 1.22 ng/mL, IQR 2.99, versus median 0.1, IQR 0.09, p<0.001). Increased MIF levels were associated with CRP and IL-6 levels and correlated with troponin I (TnI) release (spearman rank coefficient: 0.31, p<0.001). Patients with ACS due to plaque rupture showed significantly higher plasma levels of MIF than patients with flow limiting stenotic lesions (p = 0.002). Conclusion: To our knowledge this is the first study, demonstrating enhanced expression of MIF in ACS. It is associated with established inflammatory markers, correlates with the extent of cardiac necrosis marker release after PCI and is significantly increased in ACS patients with "culprit" lesions. Further attempts should be undertaken to characterize the role of MIF for risk assessment in the setting of ACS. [ABSTRACT FROM AUTHOR]