Non-vitamin K antagonist oral anticoagulants in atrial fibrillation accompanying mitral stenosis: the concept for a trial.

Patients at thromboembolic risk with non-valvular atrial fibrillation (AF) can now be managed either with a vitamin K antagonist (VKA) or with a fixed dose of a non-VKA oral anticoagulant (NOAC), while patients with valvular AF have been restricted to VKAs on the basis of a potentially higher risk and different mechanism of thrombosis, and the lack of sufficient data on the efficacy of NOACs. The terms 'non-valvular AF' and 'valvular AF' have not been however consistently defined. 'Valvular' AF has included any valvular disorder, including valve replacement and repair. In AF with rheumatic mitral disease, observational studies strongly suggest that VKA treatment is valuable. These patients have not been included in NOAC trials, but there is also no stringent argument to have excluded them. This is at sharp variance from patients with mechanical valves, also excluded from the pivotal Phase III trial comparing warfarin with NOACs, but in whom a single Phase II trial of dabigatran etexilate against VKA treatment was stopped prematurely because of increased rates of thromboembolism as well as increased bleeding associated with dabigatran. Until more data are available, such patients should be therefore managed with VKAs. We here propose an open-label randomized trial of one of the NOACs against the best of treatment available in regions of the world in which rheumatic heart disease is still highly prevalent, aiming at showing the superiority of the NOAC used against current standard treatment

901–37 Computer Implementation of Wavelet Decomposition of Signal Averaged Electrocardiograms

Simple spectral analysis of signal averaged electrocardiograms (SAECG) has been the subject of numerous studies. However, the approaches reported so far appear inferior to the gold-standard time-domain analysis of SAECG. At the same time, the limitations of the time-domain analysis are well known and suggest that a more complex spectral analysis of SAECG will be of clinical importance. One of the possibilities for a more complex spectral analysis of SAECG is the so called Wavelet Analysis (WA) which is a time-scale technique suitable for the detection of small transient signals even if they are hidden in large waves. It is obtained by expanding the signal on a set of functions resulting from translation (time) and dilatation (scale) of a socalled “analysing wavelet”. WA provides a bidimensional representation of the signal in function of time and scale.In order to apply WA to SAECG, a special software package written in Borland Pascal has been developed. The WA of the signal s(t) is computed according to the formula Sg(a,b)=∫-∞+∞(1/√a)g(t)s(t)dt, where parameter a corresponds to the dilatation and parameter b to the time shift. The package uses the Morlet wavelet g(t)=exp(iωt) exp(-t2/2) for ω>=5.3. Empirically, 54 scales were chosen, defined by the scale parameter a=40×2-m, with m ranging from 0.95 to 3.6 with an increment of 0.05. The middle frequencies of the corresponding wavelets range from 250 to 40Hz. The package processes SAECG files in the standard ART format. To synthesise the information contained within all three wavelet transforms, a wavelet vector magnitude is obtained from the wavelets of three averaged X, Y, Z leads and computed as WM=(WX2+WY2+WZ2)1/2.The package has been employed in several studies which showed that (a) WA of SAECG is highly reproducible and (b) selected parameters of WA are superior to the time-domain analysis of SAECG when used for identification of survivors of acute myocardial infarction who are at high risk of sudden death and/or ventricular tachycardia. This comparison of WA and time domain analysis of SAECG used receiver operator and positive predictive characteristics which showed highly significant differences

Left atrial appendage closure: A new technique for clinical practice

n/

801-4 Prognostic Implications of QT and QU Interval Measures in Acute Myocardial Infarction

Prolongation of the QT interval corrected using Bazett's formula (QTc) has been reported as a marker for increased risk of arrhythmic events after acute myocardial infarction (AMI). However, the QU interval changes have not been examined. At the same time, QU interval may be of clinical significance, especially in the light of recent experimental evidence linking the U wave with the subpopulation of the so-called M cells within myocardial wall. To evaluate prognostic significance of QT and QU interval measures in AMI, we studied 512 survivors of acute phase of their first myocardial infarction. Patients with conduction defects and drugs likely to affect QT measures were noT included into the analysis. The following intervals were estimated in all the measurable leads on a standard predischarge 12-lead ECG (25 mm/sec paper speed) using a digitizing pad—mean RR, mean and max QT, and mean QU. All QT and QU intervals were subsequently corrected for heart rate using Bazett's formula. At one year follow-up, 23 patients (Group I. 19 male. mean age 58.7±8.9 years) suffered arrhythmic events (VT/VF or sudden cardiac death). This subset of patients was compared with arrhythmia-free group of 489 subjects (Group II, 385 male, mean age 56.1±9.2 years). Statistical analysis was performed using unpaired t-test and ANOVA, results are expressed as mean±SD.GroupQT meanQTc meanQT maxQTc maxQU meanQUc meanI358.7±31.5426.6±30.7396.5±38.5472.8±40.3459.5±58.7535.2±41.3II387.3±44.1423.9±24421.7±51.5467.9±79.1552.0±73.9585.7±55.1p<0.002NS0.02NS0.0010.01The significant difference in QU and QUc, but not in QT intervals persisted even after elimination of the effect of heart rate (ANOVA: p<0.007 and 0.011, respectively).ConclusionThe differences in the QT but not QU interval measures in the 2 groups can be explained by differing heart rates. Shorter QU interval seemed to identify patients at risk of arrhythmic events after AMI. The pathophysiological basis for this finding is not clear, but could be related to differences in the subpopulation of M cells within myocardial wall

ESC CardioMed

Reprinted with permission from: Eur Heart J. 2018; 19: 959–961Reprinted with permission from: Eur Heart J. 2018; 19: 959–96

The RACE to the EAST. In pursuit of rhythm control therapy for atrial fibrillation-a dedication to Harry Crijns

The RACE trial was one of the first landmark trials to establish whether restoring and maintaining sinus rhythm could reduce morbidity and mortality in patients with atrial fibrillation (AF). Its neutral outcome shaped clinical decision-making for almost 20 years. However, there were two important treatment-related factors associated with mortality of rhythm control therapy at that time: One was safety of antiarrhythmic drug therapy, and the other one withdrawal of anticoagulation after restoration of sinus rhythm. Both concerns have been overcome, and, moreover, important knowledge considering the importance of time for the treatment of AF has been gained. These insights led to the concept of the EAST-AFNET 4 trial, and after more than two decades in the pursuit of ongoing therapeutic improvement, early rhythm control therapy has demonstrated to reduce a composite of cardiovascular death, stroke, and hospitalization for worsening of HF or acute coronary syndrome, by 21% (first primary outcome, absolute reduction 1.1 per 100 patient-years). For this entire period, Harry Crijns characterized the treatment of AF patients, and contributed decisively to realizing the benefit of rhythm control therapy. It is almost easier to list the clinical trials without Harry's involvement than to list those which he co-designed and led

Global Prospective Safety Analysis of Rivaroxaban.

BACKGROUND: The efficacy of direct oral anticoagulants (DOACs) for stroke prevention in patients with atrial fibrillation (AF) has been established in clinical trials. However, well-conducted, prospective, real-world observational studies of the safety and effectiveness of DOACs are needed. OBJECTIVES: This study sought to assess the real-world safety profile of rivaroxaban through a pooled analysis of patients with AF enrolled in the XANTUS (Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation) program worldwide. METHODS: A pre-planned pooled analysis of the XANTUS, XANAP (Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation in Asia), and XANTUS-EL (Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation in Latin America and EMEA Region) registries was performed. Patients with AF newly starting rivaroxaban for stroke prevention were followed for 1 year. Primary outcomes were treatment-emergent major bleeding, adverse events (AEs)/serious AEs, and all-cause death. Secondary outcomes included treatment-emergent thromboembolic events and nonmajor bleeding. Major outcomes were centrally adjudicated. RESULTS: Overall, 11,121 patients were included (mean age 70.5 ± 10.5 years; female 42.9%). Comorbidities included heart failure (21.2%), hypertension (76.2%), and diabetes (22.3%). Event rates were: events/100 patient-years: major bleeding 1.7 (95% confidence interval [CI]: 1.5 to 2.0; lowest: Latin America 0.7; highest: Western Europe, Canada, and Israel 2.3); all-cause death 1.9 (95% CI: 1.6 to 2.2; lowest: Eastern Europe 1.5; highest: Latin America, Middle East, and Africa 2.7); and stroke or systemic embolism 1.0 (95% CI: 0.8 to 1.2; lowest: Latin America 0; highest: East Asia 1.8). One-year treatment persistence was 77.4% (lowest: East Asia 66.4%; highest: Eastern Europe 84.4%). CONCLUSIONS: This large, prospective, real-world analysis in 11,121 patients from 47 countries showed low bleeding and stroke rates in rivaroxaban-treated patients with AF, with low treatment discontinuation in different regions of the world. Results were broadly consistent across regions. (Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation [XANTUS]; NCT01606995; Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation in Latin America and EMEA Region [XANTUS-EL]; NCT01800006; and Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation in Asia [XANAP]; NCT01750788)

Evolving quality standards for large-scale registries: the GARFIELD-AF experience.

Aims: Registries have the potential to capture treatment practices and outcomes in populations beyond the constraints of clinical trial settings. The value of data obtained depend critically upon robust quality standards (including source data verification [SDV] and training); features that are commonly absent from registries. This article outlines the quality standards developed for Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF). Methods and Results: GARFIELD-AF comprises ∼57 000 patients prospectively recruited over 6.5 years in 35 countries in five successive cohorts. The registry employs a combination of remote and onsite monitoring to ascertain completeness and accuracy of records and by design, SDV is performed on 20% of cases (i.e. ∼11 400 patients). Four performance measures for ranking sites according to data quality and other performance indicators were evaluated (including data quality for 13 quantifiable variables, late data locking, number of missing critical variables, and history of poor data quality from the previous monitoring phase). These criteria facilitated the identification of sites with potentially suboptimal data quality for onsite monitoring. During early phases of the registry, critical variables for data checking were also identified. SDV using these variables (partial SDV in 902 patients) showed similar concordance to SDV of all fields (110 patients): 94.4% vs. 93.1%, respectively. This standard formed the baseline against which ongoing quality improvements were assessed, facilitating corrective action on data quality issues. In consequence, concordance was improved in the next monitoring phase (95.6%; n = 1172). Conclusion: The quality standards in GARFIELD-AF have the potential to inform a future 'reference' for registries

Causes of death in patients with atrial fibrillation anticoagulated with rivaroxaban:a pooled analysis of XANTUS

Aims: Anticoagulation can prevent stroke and prolong lives in patients with atrial fibrillation (AF). However, anticoagulated patients with AF remain at risk of death. The aim of this study was to investigate the causes of death and factors associated with all-cause and cardiovascular death in the XANTUS population. Methods and results: Causes of death occurring within a year after rivaroxaban initiation in patients in the XANTUS programme studies were adjudicated by a central adjudication committee and classified following international guidance. Baseline characteristics associated with all-cause or cardiovascular death were identified. Of 11 040 patients, 187 (1.7%) died. Almost half of these deaths were due to cardiovascular causes other than bleeding (n = 82, 43.9%), particularly heart failure (n = 38, 20.3%) and sudden or unwitnessed death (n = 24, 12.8%). Fatal stroke (n = 8, 4.3%), which was classified as a type of cardiovascular death, and fatal bleeding (n = 17, 9.1%) were less common causes of death. Independent factors associated with all-cause or cardiovascular death included age, AF type, body mass index, left ventricular ejection fraction, hospitalization at baseline, rivaroxaban dose, and anaemia. Conclusion: The overall risk of death due to stroke or bleeding was low in XANTUS. Anticoagulated patients with AF remain at risk of death due to heart failure and sudden death. Potential interventions to reduce cardiovascular deaths in anticoagulated patients with AF require further investigation, e.g. early rhythm control therapy and AF ablation. Trial registration numbers: NCT01606995, NCT01750788, NCT0180000

A Randomized Active-Controlled Study Comparing the Efficacy and Safety of Vernakalant to Amiodarone in Recent-Onset Atrial Fibrillation

ObjectivesThis randomized double-blind study compared the efficacy and safety of intravenous vernakalant and amiodarone for the acute conversion of recent-onset atrial fibrillation (AF).BackgroundIntravenous vernakalant has effectively converted recent-onset AF and was well tolerated in placebo-controlled studies.MethodsA total of 254 adult patients with AF (3 to 48 h duration) eligible for cardioversion were enrolled in the study. Patients received either a 10-min infusion of vernakalant (3 mg/kg) followed by a 15-min observation period and a second 10-min infusion (2 mg/kg) if still in AF, plus a sham amiodarone infusion, or a 60-min infusion of amiodarone (5 mg/kg) followed by a maintenance infusion (50 mg) over an additional 60 min, plus a sham vernakalant infusion.ResultsConversion from AF to sinus rhythm within the first 90 min (primary end point) was achieved in 60 of 116 (51.7%) vernakalant patients compared with 6 of 116 (5.2%) amiodarone patients (p < 0.0001). Vernakalant resulted in rapid conversion (median time of 11 min in responders) and was associated with a higher rate of symptom relief compared with amiodarone (53.4% of vernakalant patients reported no AF symptoms at 90 min compared with 32.8% of amiodarone patients; p = 0.0012). Serious adverse events or events leading to discontinuation of study drug were uncommon. There were no cases of torsades de pointes, ventricular fibrillation, or polymorphic or sustained ventricular tachycardia.ConclusionsVernakalant demonstrated efficacy superior to amiodarone for acute conversion of recent-onset AF. Both vernakalant and amiodarone were safe and well tolerated in this study. (A Phase III Superiority Study of Vernakalant vs Amiodarone in Subjects With Recent Onset Atrial Fibrillation [AVRO]; NCT00668759