Orally Inhaled Flecainide for Conversion of Atrial Fibrillation to Sinus Rhythm: INSTANT Phase 2 Trial.

BACKGROUND: INSTANT (INhalation of flecainide to convert recent-onset SympTomatic Atrial fibrillatioN to sinus rhyThm) was a multicenter, open-label, single-arm study of flecainide acetate oral inhalation solution (FlecIH) for acute conversion of recent-onset (≤48 hours) symptomatic atrial fibrillation (AF) to sinus rhythm. OBJECTIVES: This study investigated the efficacy and safety in 98 patients receiving a single dose of FlecIH delivered via oral inhalation. METHODS: Patients self-administered FlecIH over 8 minutes in a supervised medical setting using a breath-actuated nebulizer and were continuously monitored for 90 minutes using a 12-lead Holter. RESULTS: Mean age was 60.5 years, mean body mass index was 27.0 kg/m2, and 34.7% of the patients were women. All patients had ≥1 AF-related symptoms at baseline, and 87.8% had AF symptoms for ≤24 hours. The conversion rate was 42.6% (95% CI: 33.0%-52.6%) with a median time to conversion of 14.6 minutes. The conversion rate was 46.9% (95% CI: 36.4%-57.7%) in a subpopulation that excluded predose flecainide exposure for the current AF episode. Median time to discharge among patients who converted was 2.5 hours, and only 2 patients had experienced AF recurrence by day 5. In the conversion-no group, 44 (81.5%) patients underwent electrical cardioversion by day 5. The most common adverse events were related to oral inhalation of flecainide (eg, cough, oropharyngeal irritation/pain), which were mostly of mild intensity and limited duration. CONCLUSIONS: The risk-benefit of orally inhaled FlecIH for acute cardioversion of recent-onset AF appears favorable. FlecIH could provide a safe, effective, and convenient first-line therapeutic option. (INhalation of Flecainide to Convert Recent Onset SympTomatic Atrial Fibrillation to siNus rhyThm [INSTANT]; NCT03539302).

Acute Coronary Syndrome Subphenotypes Based on Repeated Biomarker Measurements in Relation to Long-Term Mortality Risk.

BACKGROUND: We aimed to identify patients with subphenotypes of postacute coronary syndrome (ACS) using repeated measurements of high-sensitivity cardiac troponin T, N-terminal pro-B-type natriuretic peptide, high-sensitivity C-reactive protein, and growth differentiation factor 15 in the year after the index admission, and to investigate their association with long-term mortality risk. METHODS AND RESULTS: BIOMArCS (BIOMarker Study to Identify the Acute Risk of a Coronary Syndrome) was an observational study of patients with ACS, who underwent high-frequency blood sampling for 1 year. Biomarkers were measured in a median of 16 repeated samples per individual. Cluster analysis was performed to identify biomarker-based subphenotypes in 723 patients without a repeat ACS in the first year. Patients with a repeat ACS (N=36) were considered a separate cluster. Differences in all-cause death were evaluated using accelerated failure time models (median follow-up, 9.1 years; 141 deaths). Three biomarker-based clusters were identified: cluster 1 showed low and stable biomarker concentrations, cluster 2 had elevated concentrations that subsequently decreased, and cluster 3 showed persistently elevated concentrations. The temporal biomarker patterns of patients in cluster 3 were similar to those with a repeat ACS during the first year. Clusters 1 and 2 had a similar and favorable long-term mortality risk. Cluster 3 had the highest mortality risk. The adjusted survival time ratio was 0.64 (95% CI, 0.44-0.93; P=0.018) compared with cluster 1, and 0.71 (95% CI, 0.39-1.32; P=0.281) compared with patients with a repeat ACS. CONCLUSIONS: Patients with subphenotypes of post-ACS with different all-cause mortality risks during long-term follow-up can be identified on the basis of repeatedly measured cardiovascular biomarkers. Patients with persistently elevated biomarkers have the worst outcomes, regardless of whether they experienced a repeat ACS in the first year.

Treatment of elderly patients with non-ST-elevation myocardial infarction: the nationwide POPular age registry.

OBJECTIVE: We describe the current treatment of elderly patients with non-ST-elevation myocardial infarction (NSTEMI) enrolled in a national registry. METHODS: The POPular AGE registry is a prospective, multicentre study of patients ≥ 75 years of age presenting with NSTEMI, performed in the Netherlands. Management was at the discretion of the treating physician. Cardiovascular events consisted of cardiovascular death, myocardial infarction and ischaemic stroke. Bleeding was classified according to the Bleeding Academic Research Consortium (BARC) criteria. RESULTS: A total of 646 patients were enrolled between August 2016 and May 2018. Median age was 81 (IQR 77-84) years and 58% were male. Overall, 75% underwent coronary angiography, 40% percutaneous coronary intervention, and 11% coronary artery bypass grafting, while 49.8% received pharmacological therapy only. At discharge, dual antiplatelet therapy (aspirin and P2Y12 inhibitor) was prescribed to 56.7%, and 27.4% received oral anticoagulation plus at least one antiplatelet agent. At 1­year follow-up, cardiovascular death, myocardial infarction or stroke had occurred in 13.6% and major bleeding (BARC 3 and 5) in 3.9% of patients. The risk of both cardiovascular events and major bleeding was highest during the 1st month. However, cardiovascular risk was three times as high as bleeding risk in this elderly population, both after 1 month and after 1 year. CONCLUSIONS: In this national registry of elderly patients with NSTEMI, the majority are treated according to current European Society of Cardiology guidelines. Both the cardiovascular and bleeding risk are highest during the 1st month after NSTEMI. However, the cardiovascular risk was three times as high as the bleeding risk.

Use of loop diuretics in patients with chronic heart failure: an observational overview.

INTRODUCTION: This study aimed to evaluate the use and dose of loop diuretics (LDs) across the entire ejection fraction (EF) spectrum in a large, 'real-world' cohort of chronic heart failure (HF) patients. METHODS: A total of 10 366 patients with chronic HF from 34 Dutch outpatient HF clinics were analysed regarding diuretic use and diuretic dose. Data regarding daily diuretic dose were stratified by furosemide dose equivalent (FDE)>80 mg or ≤80 mg. Multivariable logistic regression models were used to assess the association between diuretic dose and clinical features. RESULTS: In this cohort, 8512 (82.1%) patients used diuretics, of which 8179 (96.1%) used LDs. LD use was highest among HF with reduced EF (HFrEF) patients (81.1%) followed by HF with mild-reduced EF (76.1%) and HF with preserved ejection fraction EF (73.8%, p<0.001). Among all LDs users, the median FDE was 40 mg (IQR: 40-80). The results of the multivariable analysis showed that New York Heart Association classes III and IV and diabetes mellitus were one of the strongest determinants of an FDE >80 mg, across all HF categories. Renal impairment was associated with a higher FDE across the entire EF spectrum. CONCLUSION: In this large registry of real-world HF patients, LD use was highest among HFrEF patients. Advanced symptoms, diabetes mellitus and worse renal function were significantly associated with a higher diuretic dose regardless of left ventricular ejection fraction.

Conservative versus Invasive Strategy in Elderly Patients with Non-ST-Elevation Myocardial Infarction: Insights from the International POPular Age Registry.

This registry assessed the impact of conservative and invasive strategies on major adverse clinical events (MACE) in elderly patients with non-ST-elevation myocardial infarction (NSTEMI). Patients aged ≥75 years with NSTEMI were prospectively registered from European centers and followed up for one year. Outcomes were compared between conservative and invasive groups in the overall population and a propensity score-matched (PSM) cohort. MACE included cardiovascular death, acute coronary syndrome, and stroke. The study included 1190 patients (median age 80 years, 43% female). CAG was performed in 67% (N = 798), with two-thirds undergoing revascularization. Conservatively treated patients had higher baseline risk. After propensity score matching, 319 patient pairs were successfully matched. MACE occurred more frequently in the conservative group (total population 20% vs. 12%, adjHR 0.53, 95% CI 0.37-0.77, p = 0.001), remaining significant in the PSM cohort (18% vs. 12%, adjHR 0.50, 95% CI 0.31-0.81, p = 0.004). In conclusion, an early invasive strategy was associated with benefits over conservative management in elderly patients with NSTEMI. Risk factors associated with ischemia and bleeding should guide strategy selection rather than solely relying on age.

Serially measured high-sensitivity cardiac troponin T, N-terminal-pro-B-type natriuretic peptide, high-sensitivity C-reactive protein, and growth differentiation factor 15 for risk assessment after acute coronary syndrome: the BIOMArCS cohort.

AIMS: Evidence regarding the role of serial measurements of biomarkers for risk assessment in post-acute coronary syndrome (ACS) patients is limited. The aim was to explore the prognostic value of four, serially measured biomarkers in a large, real-world cohort of post-ACS patients. METHODS AND RESULTS: BIOMArCS is a prospective, multi-centre, observational study in 844 post-ACS patients in whom 12 218 blood samples (median 17 per patient) were obtained during 1-year follow-up. The longitudinal patterns of high-sensitivity cardiac troponin T (hs-cTnT), N-terminal-pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hs-CRP), and growth differentiation factor 15 (GDF-15) were analysed in relation to the primary endpoint (PE) of cardiovascular mortality and recurrent ACS using multivariable joint models. Median age was 63 years, 78% were men and the PE was reached by 45 patients. The average biomarker levels were systematically higher in PE compared with PE-free patients. After adjustment for 6-month post-discharge Global Registry of Acute Coronary Events score, 1 standard deviation increase in log[hs-cTnT] was associated with a 61% increased risk of the PE [hazard ratio (HR) 1.61, 95% confidence interval (CI) 1.02-2.44, P = 0.045], while for log[GDF-15] this was 81% (HR 1.81, 95% CI 1.28-2.70, P = 0.001). These associations remained significant after multivariable adjustment, while NT-proBNP and hs-CRP were not. Furthermore, GDF-15 level showed an increasing trend prior to the PE (Structured Graphical Abstract). CONCLUSION: Longitudinally measured hs-cTnT and GDF-15 concentrations provide prognostic value in the risk assessment of clinically stabilized patients post-ACS. CLINICAL TRIAL REGISTRATION: The Netherlands Trial Register. Currently available at URL https://trialsearch.who.int/; Unique Identifiers: NTR1698 and NTR1106.

Heart failure treatment in patients with and without obesity with an ejection fraction below 50.

BACKGROUND: The aim of this study was to assess heart failure (HF) treatment in patients with and without obesity in a large contemporary real-world Western European cohort. METHODS: Patients with a left ventricular ejection fraction (LVEF) <50% and available information on body mass index (BMI) were selected from the CHECK-HF registry. The CHECK-HF registry included chronic HF patients in the period between 2013 and 2016 in 34 Dutch outpatient clinics. Patients were divided into BMI categories. Differences in HF medical treatment were analysed, and multivariable logistic regression analysis (dichotomized as BMI <30 kg/m2 and ≥30 kg/m2 ) was performed. RESULTS: Seven thousand six hundred seventy-one patients were included, 1284 (16.7%) had a BMI ≥30 kg/m2 , and 618 (8.1%) had a BMI ≥35 kg/m2 . Median BMI was 26.4 kg/m2 . Patients with obesity were younger and had a higher rate of comorbidities such as diabetes mellitus, hypertension and obstructive sleep apnoea (OSAS). Prescription rates of guideline-directed medical therapy (GDMT) increased significantly with BMI. The differences were most pronounced for mineralocorticoid receptor antagonists (MRAs) and diuretics. Patients with obesity more often received the guideline-recommended target dose. In multivariable logistic regression, obesity was significantly associated with a higher likelihood of receiving ≥100% of the guideline-recommended target dose of beta-blockers (OR 1.34, 95% CI 1.10-1.62), renin-angiotensin system (RAS)-inhibitors (OR 1.34, 95% CI 1.15-1.57) and MRAs (OR 1.40, 95% CI 1.04-1.87). CONCLUSIONS: Guideline-recommended HF drugs are more frequently prescribed and at a higher dose in patients with obesity as compared to HF patients without obesity.

Open-Label, Multicenter Study of Flecainide Acetate Oral Inhalation Solution for Acute Conversion of Recent-Onset, Symptomatic Atrial Fibrillation to Sinus Rhythm.

BACKGROUND: Oral and intravenous flecainide is recommended for cardioversion of atrial fibrillation. In this open-label, dose-escalation study, the feasibility of delivering flecainide via oral inhalation (flecainide acetate inhalation solution) for acute conversion was evaluated. We hypothesized that flecainide delivered by oral inhalation would quickly reach plasma concentrations sufficient to restore sinus rhythm in patients with recent-onset atrial fibrillation. METHODS: Patients (n=101) with symptomatic atrial fibrillation (for ≤48 hours) self administered flecainide acetate inhalation solution using a nebulizer (30 mg [n=10], 60 mg [n=22], 90 mg [n=21], 120 mg [n=19], and 120 mg in a formulation containing saccharin [n=29]). Electrocardiograms and flecainide plasma concentrations were obtained, cardiac rhythm using 4-hour Holter was monitored, and adverse events were recorded. RESULTS: Conversion rates increased with dose and with the maximum plasma concentrations of flecainide. At the highest dose, 48% of patients converted to sinus rhythm within 90 minutes from the start of inhalation. Among patients who achieved a maximum plasma concentration >200 ng/mL, the conversion rate within 90 minutes was 50%; for those who achieved a maximum plasma concentration <200 ng/mL, it was 24%. Conversion was rapid (median time to conversion of 8.1 minutes from the end of inhalation), and conversion led to symptom resolution in 86% of the responders. Adverse events were typically mild and transient and included: cough, throat pain, throat irritation; at the highest dose with the formulation containing saccharin, these adverse events were reported by 41%, 14%, and 3% of patients, respectively. Cardiac adverse events consistent with those observed with oral and intravenous flecainide were uncommon and included postconversion pauses (n=2), bradycardia (n=1), and atrial flutter with 1:1 atrioventricular conduction (n=1); none required treatment, and all resolved without sequelae. CONCLUSIONS: Administration of flecainide via oral inhalation was shown to be safe and to yield plasma concentrations of flecainide sufficient to restore sinus rhythm in patients with recent-onset atrial fibrillation. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03539302.

Age differences in contemporary treatment of patients with chronic heart failure and reduced ejection fraction.

BACKGROUND: Elderly patients are underrepresented in clinical trials but comprise the majority of heart failure patients. Data on age-specific use of heart failure therapy are limited. The European Society of Cardiology heart failure guidelines provide no age-specific treatment recommendations. We investigated practice-based heart failure management in a large registry at heart failure outpatient clinics. DESIGN AND METHODS: We studied 8351 heart failure with reduced ejection fraction patients at 34 Dutch outpatient clinics between 2013 and 2016. The mean age was 72.3 ± 11.8 years and we divided age into three categories: less than 60 years (13.9%); 60-74 years (36.0%); and 75 years and over (50.2%). RESULTS: Elderly heart failure with reduced ejection fraction patients (≥75 years) received significantly fewer beta-blockers (77.8% vs. 84.2%), renin-angiotensin system inhibitors (75.2% vs. 89.7%), mineralocorticoid receptor antagonists (50.6% vs. 59.6%) and ivabradine (2.9% vs. 9.3%), but significantly more diuretics (88.1% vs. 72.6%) compared to patients aged less than 60 years (Pfor all trends < 0.01). Moreover, the prescribed target dosages were significantly lower in elderly patients. Also, implantable cardioverter defibrillator (18.9% vs. 44.1%) and cardiac resynchronisation therapy device (14.6% vs. 16.7%) implantation rates were significantly lower in elderly patients. A similar trend in drug prescription was observed in patients with heart failure with mid-range ejection fraction as in heart failure with reduced ejection fraction. CONCLUSION: With increasing age, heart failure with reduced ejection fraction patients less often received guideline-recommended medication prescriptions and also in a lower dosage. In addition, a lower percentage of implantable cardioverter defibrillator and cardiac resynchronisation therapy device implantation in elderly patients was observed.

We Know What the Cardiac Surgeon Did During Last Hybrid Arrhythmia Procedure.

Superior vena cava (SVC) is an important source of origin of atrial fibrillation (AF) triggers other than a pulmonary vein. Because of the proximity of SVC-aorta ganglionic plexi to the SVC and the extension of myocardium in the SVC from the right atrium, SVC frequently becomes an important source of ectopic beats initiating AF. The potential complications of SVC isolation may include sinus node injury. Sinus node isolation was observed in a patient who had undergone previous surgical isolation of SVC for AF, while attempting to ablate endocardially, near the superior part of interatrial septum for an atrial tachycardia.

Influence of the hospital environment and presence of the physician on the white-coat effect.

OBJECTIVE: To determine the separate contribution of the physician and the hospital environment to differences between home (HBP) and office BP (OBP). METHODS: For 3 consecutive days, 65 hypertensive patients measured their HBP. OBP was determined with the same device by the physician. A higher OBP than HBP was regarded as white-coat effect (WCE), whereas lower OBP than HBP was regarded masked effect. OBP was measured automatically before, during and after the presence of the physician. The physician effect was the BP rise caused by the entrance of physician. The WCE minus the physician effect was regarded the hospital's contribution to the BP differences (hospital effect). We assessed the magnitudes of the hospital effect and the physician effect in determining the WCE. Furthermore, we assessed the correlation of these BP phenomena with each other, and with clinical variables. RESULTS: The WCE consisted of 4.6/-1.7 ±â€Š9.9/10.9 mmHg hospital effect and of 4.4/3.4 ±â€Š6.6/3.3 mmHg PE. The masked effect consisted of a substantially larger hospital effect (19.6/9.4 ±â€Š12.7/9.5 mmHg) than physician effect (4.6/3.0 ±â€Š6.4/3.9 mmHg). Physician effect did not correlate with systolic or diastolic WCE or masked effect (r = -0.05 to 0.08, P > 0.39). In regression analysis, age, baseline mean arterial pressure and BMI were not significantly associated with WCE (all P values >0.4). CONCLUSION: BP differences between home and office can largely be attributed to the hospital environment rather than to the entrance of the physician. The physician-related BP effect is not related to differences of HBP and OBP.

Coronary spasm during cardiac electrophysiological study following isoproterenol infusion.

Sudden cardiac death (SCD) remains the leading cause of death in industrialized world. The majority of SCD is caused by ventricular fibrillation associated with structural and/or ischemic heart disease. Ventricular fibrillation represents the final common pathway for SCD and, thus, is an attractive target for ablation. According to class I recommendation level of evidence A, an implantable cardioverter defibrillator (ICD) should be implanted for such patients [1]. Other than programmed electrical extrastimulus technique, isoproterenol infusion is commonly used in invasive cardiac electrophysiology labs for arrhythmia induction. We hereby report a rare case of transient coronary spasm during isoproterenol infusion for ventricular tachycardia induction testing.

Management Of Pulmonary Vein Stenosis Following Catheter Ablation Of Atrial Fibrillation.

There is limited literature available regarding PV (pulmonary vein) stenosis management. Starting from its incidence, subsequent follow up using imaging technologies to monitor the success and the way of managing different groups pose varied opinions. However, with newer technological advancements and better understanding of mechanism of the atrial fibrillation ablation, the incidence of PV stenosis secondary to catheter ablation is declining. This paper highlights the current trends and future of management of PV stenosis secondary to catheter ablation for atrial fibrillation.