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Background: Oral activated factor XI (FXIa) inhibitors may modulate coagulation to prevent thromboembolic events without substantially increasing bleeding. We explored the pharmacodynamics, safety, and efficacy of the oral FXIa inhibitor asundexian for secondary prevention after acute myocardial infarction (MI). Methods: We randomized 1601 patients with recent acute MI to oral asundexian 10, 20, or 50 mg or placebo once daily for 6 to 12 months in a double-blind, placebo-controlled, phase 2, dose-ranging trial. Patients were randomized within 5 days of their qualifying MI and received dual antiplatelet therapy with aspirin plus a P2Y12 inhibitor. The effect of asundexian on FXIa inhibition was assessed at 4 weeks. The prespecified main safety outcome was Bleeding Academic Research Consortium type 2, 3, or 5 bleeding comparing all pooled asundexian doses with placebo. The prespecified efficacy outcome was a composite of cardiovascular death, MI, stroke, or stent thrombosis comparing pooled asundexian 20 and 50 mg doses with placebo. Results: The median age was 68 years, 23% of participants were women, 51% had ST-segment–elevation MI, 80% were treated with aspirin plus ticagrelor or prasugrel, and 99% underwent percutaneous coronary intervention before randomization. Asundexian caused dose-related inhibition of FXIa activity, with 50 mg resulting in >90% inhibition. Over a median follow-up of 368 days, the main safety outcome occurred in 30 (7.6%), 32 (8.1%), 42 (10.5%), and 36 (9.0%) patients receiving asundexian 10 mg, 20 mg, or 50 mg, or placebo, respectively (pooled asundexian versus placebo: hazard ratio, 0.98 [90% CI, 0.71–1.35]). The efficacy outcome occurred in 27 (6.8%), 24 (6.0%), 22 (5.5%), and 22 (5.5%) patients assigned asundexian 10 mg, 20 mg, or 50 mg, or placebo, respectively (pooled asundexian 20 and 50 mg versus placebo: hazard ratio, 1.05 [90% CI, 0.69–1.61]). Conclusions: In patients with recent acute MI, 3 doses of asundexian, when added to aspirin plus a P2Y12 inhibitor, resulted in dose-dependent, near-complete inhibition of FXIa activity without a significant increase in bleeding and a low rate of ischemic events. These data support the investigation of asundexian at a dose of 50 mg daily in an adequately powered clinical trial of patients who experienced acute MI. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04304534; URL: https://www.clinicaltrialsregister.eu/ctr-search/search ; Unique identifier: 2019-003244-79.

BACKGROUND Direct-acting oral anticoagulant use for stroke prevention in atrial fibrillation is limited by bleeding concerns. Asundexian, a novel, oral small molecule activated coagulation factor XIa (FXIa) inhibitor, might reduce thrombosis with minimal effect on haemostasis. We aimed to determine the optimal dose of asundexian and to compare the incidence of bleeding with that of apixaban in patients with atrial fibrillation. METHODS In this randomised, double-blind, phase 2 dose-finding study, we compared asundexian 20 mg or 50 mg once daily with apixaban 5 mg twice daily in patients aged 45 years or older with atrial fibrillation, a CHA2DS2-VASc score of at least 2 if male or at least 3 if female, and increased bleeding risk. The study was conducted at 93 sites in 14 countries, including 12 European countries, Canada, and Japan. Participants were randomly assigned (1:1:1) to a treatment group using an interactive web response system, with randomisation stratified by whether patients were receiving a direct-acting oral anticoagulant before the study start. Masking was achieved using a double-dummy design, with participants receiving both the assigned treatment and a placebo that resembled the non-assigned treatment. The primary endpoint was the composite of major or clinically relevant non-major bleeding according to International Society on Thrombosis and Haemostasis criteria, assessed in all patients who took at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT04218266, and EudraCT, 2019-002365-35. FINDINGS Between Jan 30, 2020, and June 21, 2021, 862 patients were enrolled. 755 patients were randomly assigned to treatment. Two patients (assigned to asundexian 20 mg) never took any study medication, resulting in 753 patients being included in the analysis (249 received asundexian 20 mg, 254 received asundexian 50 g, and 250 received apixaban). The mean age of participants was 73·7 years (SD 8·3), 309 (41%) were women, 216 (29%) had chronic kidney disease, and mean CHA2DS2-VASc score was 3·9 (1·3). Asundexian 20 mg resulted in 81% inhibition of FXIa activity at trough concentrations and 90% inhibition at peak concentrations; asundexian 50 mg resulted in 92% inhibition at trough concentrations and 94% inhibition at peak concentrations. Ratios of incidence proportions for the primary endpoint were 0·50 (90% CI 0·14-1·68) for asundexian 20 mg (three events), 0·16 (0·01-0·99) for asundexian 50 mg (one event), and 0·33 (0·09-0·97) for pooled asundexian (four events) versus apixaban (six events). The rate of any adverse event occurring was similar in the three treatment groups: 118 (47%) with asundexian 20 mg, 120 (47%) with asundexian 50 mg, and 122 (49%) with apixaban. INTERPRETATION The FXIa inhibitor asundexian at doses of 20 mg and 50 mg once daily resulted in lower rates of bleeding compared with standard dosing of apixaban, with near-complete in-vivo FXIa inhibition, in patients with atrial fibrillation. FUNDING Bayer.

Bei der Mehrheit der Kranken mit einem Vorhofflimmern ist eine wirksame Thromboembolie-Prophylaxe die wichtigste therapeutische Massnahme. In den aktuellen Leitlinien wird empfohlen, eine orale Antikoagulation mit Nicht-Vitamin-K-abhängigen oralen Antikoagulantien durchzuführen, wobei eine sorgfältige Individualisierung indiziert ist. Besonders eine Mehrfachhemmung der Blutgerinnung mit oralen Antikoagulantien und Plättchenhemmern stellt ein erhebliches Blutungsrisiko dar. Neben der An-tikoagulation können verschiedene Interventionen (Verschluss des linken Vorhofohrs, Katheterablation) sowie Antiarrhythmika in Betracht gezogen werden.

The use of electroanatomical mapping can facilitate the identification of the ideal cryoablation site by providing a three-dimensional map of the earliest activation site. Combined use of the cryoablation technology with electroanatomical mapping can further increase the precision and safety of the procedure by applying test applications at a lower energy level.

High-density three-dimensional (3D) mapping of the pulmonary vein (PV)-left atrial (LA) junction was performed to characterize spontaneous PV activity in humans.The activation patterns of ectopic beats and of the initial 2 seconds of atrial fibrillation (AF) from the PVs were analyzed using a 64-poles basket catheter. A focal mechanism was defined as a discrete site of early and centrifugal activation. Continuous activity was considered as an activation coveringor = 80% of the tachycardia beat-to-beat cycle length within the mapping field. In 35 patients, 123 spontaneous focal ectopic beats that did not induce AF and 95 that did induce AF were mapped. The mean coupling interval of ectopic discharges not inducing AF was 281 +/- 70 msec versus 236 +/- 90 msec for ectopies initiating AF (Por = 0.01). The first ectopic activity of all 218 arrhythmogenic events showed exclusively a focal mechanism. During the 95 episodes of AF initiation, one or two ectopic beats from the PVs initiated AF in the LA in 39%, a stable focal tachycardia was recorded in 14%, continuous activity with important changes in cycle length (35 +/- 15 msec) suggestive of decremental or fibrillatory conduction was found in 18%, and in 29% the activation pattern could not be classified. No stable and sustained reentrant circuit could be identified by our mapping tool in the PV-LA junction.Arrhythmogenic activity from PVs in humans is predominantly due to discrete focal activity.

Abnormal baseline electrocardiograms (ECGs) are common in patients with isolated left ventricular noncompaction (IVNC). Whether certain electrocardiographic parameters are associated with a poor clinical outcome, however, remains elusive. The present study was therefore designed to comprehensively assess the predictive value of baseline ECG findings in patients newly diagnosed with IVNC.74 patients diagnosed with IVNC were included in the analysis. During follow-up, 8 patients (11%) died of a cardiovascular cause or underwent heart transplantation (primary outcome measure). On univariate analysis, several variables, including repolarization abnormalities (ST segment elevation/depression, T-wave inversion) in the inferior leads (5-year estimator: 67.1 ± 10.7% vs. 98 ± 2.2%; P = 0.001), an increase in PQ- (hazard ratio (HR) 1.032, P=0.004) and QTc-duration (HR 1.037, P=0.001), were predictive of cardiovascular death or heart transplantation. On multivariate analysis, only PQ- and QTc-duration and the presence of repolarization abnormalities in the inferior leads remained significantly predictive of a poor outcome.PQ duration, QTc duration, and repolarization abnormalities in the inferior leads are independently predictive of a poor prognosis in IVNC. Further prospective studies are required to conclusively investigate the usefulness of baseline ECG parameters for risk stratification in patients with IVNC.

Chronic right ventricular apical (RVA) pacing has been associated with increased risk of heart failure and adverse outcome. The acute effects of RVA pacing on three-dimensional (3D) ventricular function and mechanical dyssynchrony are not well known. We performed a real-time 3D echocardiographic (RT3DE) study to assess global and regional left ventricular function during RVA pacing.Twenty-six patients with implanted cardiac devices and normal intrinsic atrioventricular conduction were included in the study. RT3DE was performed during intrinsic sinus rhythm and during RVA pacing. Quantification of global and regional left ventricular function was performed offline by time-volume analysis of 16 myocardial segments. Time to reach minimum regional volume was calculated for each segment as a percentage of the cardiac cycle. The systolic dyssynchrony index (SDI) was defined as the standard deviation of these time periods. Longitudinal function was assessed by time-volume analysis of apical, midventricular, and basal segments.During RVA pacing, a reversed apical-to-basal longitudinal contraction sequence was observed in 58% of all patients. RVA pacing was associated with increased left ventricular (LV) dyssynchrony (SDI increase from 4.4 ± 2.2% to 6.3 ± 2.4%, P = 0.001) and reduced LV ejection fraction (decrease from 53 ± 13% to 47 ± 14%, P = 0.05).RT3DE assessment of LV function provides evidence that pacing from the RVA results in acute alterations in LV contraction sequence and increased LV dyssynchrony. Further studies are warranted to assess the potential of RT3DE to identify patients who might be at increased risk of pacing-induced heart failure or who might benefit from alternate-site or multisite pacing.

To assess the effect of intra-arterial magnesium on the radial artery during transradial cardiac catheterization.Transradial coronary angiography has become popular in the last decade and offers several advantages over transfemoral angiography. Radial artery spasm is a major limitation of this approach, and a vasodilatory cocktail is usually given. The aim of this study was to examine the effect of magnesium sulphate on the radial artery during cardiac catheterization.This was a prospective, double-blind, randomized trial of 86 patients undergoing radial catheterization. Patients were randomized to receive magnesium sulphate (150 mg) or verapamil (1 mg) into the radial sheath. Radial dimensions were assessed using Doppler ultrasound. The primary endpoint of the study was a change in radial artery diameter following administration. Secondary endpoints included operator-defined radial artery spasm and patient pain.Following administration of the study drug, there was an increase in radial artery diameter in both groups (p0.01), although the increase seen was greater in the group receiving magnesium (magnesium 0.36 +/- 0.03 mm; verapamil 0.27 +/- 0.03 mm; p0.05). Administration of verapamil resulted in a fall in mean arterial pressure (MAP) (change in MAP -6.6 +/- 1.4 mmHg; p0.01), whereas magnesium did not have a hemodynamic effect. Severe arm pain (pain score5) was observed in 14 (30%) patients receiving verapamil and 9 (27%) receiving magnesium (p = NS).This study demonstrates that magnesium is a more effective vasodilator when compared to verapamil, with a reduced hemodynamic effect, and is equally effective at preventing radial artery spasm. As such, the use of this agent offers distinct advantages over verapamil during radial catheterization.

What is already known about this subject • Furosemide is an effective diuretic, but its absorption may be too slow to allow oral treatment in certain patients. What this study adds • In healthy volunteers, sublingual administration is associated with a higher Cmax, a higher bioavailability and a more accentuated initial natriuretic response than oral furosemide. Sublingual administration may offer advantages over oral administration of furosemide in certain clinical situations. Background In patients with decompensated heart failure, absorption of orally administered furosemide may be delayed, possibly leading to impaired pharmacodynamic effects. Sublingual administration may represent an alternative in such situations. Methods In a crossover study including 11 healthy men, 20 mg furosemide was administered intravenously, orally and sublingually on three different days. Pharmacokinetics and pharmacodynamics were assessed from repeated blood and urine samples. Results Compared with oral administration, sublingual administration was associated with 43% higher Cmax[difference 215 ng ml−1, 95% confidence interval (CI) 37, 392], a higher urinary recovery (8.9 vs. 7.3 mg, difference 1.6 mg, 95% CI 0.3, 2.9), an 28% higher AUC (difference 328 ng h−1 ml−1, 95% CI 24, 632) and a higher bioavailability of furosemide (59 vs. 47%, difference 12.0%, 95% CI −1.2, 25.2). Sodium excretion was higher after sublingual compared with oral administration (peak excretion rate 1.8 vs. 1.4 mmol min−1, P

Pulmonary artery rupture is a rare but often fatal complication of right heart catheterization. We present a case of a ruptured pulmonary artery caused by a Cournand catheter in a high-risk patient with pulmonary hypertension on oral anticoagulation with successful emergency embolization with gelatine foam. Catheter Cardiovasc Interv 2004;61:317–319. © 2004 Wiley-Liss, Inc.