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Objective: Balancing bleeding risk and stroke risk in patients with atrial fibrillation (AF) is a common challenge. Though several bleeding risk scores exist, most have not included patients on direct oral anticoagulants (DOACs). We aimed at developing a novel bleeding risk score for patients with AF on oral anticoagulants (OAC) including both vitamin K antagonists (VKA) and DOACs., Methods: We included patients with AF on OACs from a prospective multicenter cohort study in Switzerland (SWISS-AF). The outcome was time to first bleeding. Bleeding events were defined as major or clinically relevant non-major bleeding. We used backward elimination to identify bleeding risk variables. We derived the score using a point score system based on the β-coefficients from the multivariable model. We used the Brier score for model calibration (<0.25 indicating good calibration), and Harrel's c-statistics for model discrimination., Results: We included 2147 patients with AF on OAC (72.5% male, mean age 73.4 ± 8.2 years), of whom 1209 (56.3%) took DOACs. After a follow-up of 4.4 years, a total of 255 (11.9%) bleeding events occurred. After backward elimination, age > 75 years, history of cancer, prior major hemorrhage, and arterial hypertension remained in the final prediction model. The Brier score was 0.23 (95% confidence interval [CI] 0.19-0.27), the c-statistic at 12 months was 0.71 (95% CI 0.63-0.80)., Conclusion: In this prospective cohort study of AF patients and predominantly DOAC users, we successfully derived a bleeding risk prediction model with good calibration and discrimination., (© 2021 International Society on Thrombosis and Haemostasis.)

Background: Intraventricular conduction disturbances are associated with an increased risk of adverse cardiovascular outcomes. However, data about factors associated with intraventricular conduction disturbances are sparse. We aimed to identify the clinical factors associated with intraventricular conduction disturbances in the general population., Methods: Cross-sectional study in a sample of 3704 participants (age range 45-86 years, 55.2% women). Intraventricular conduction disturbances were defined as QRS > 110 ms on electrocardiograms, and classified into right bundle branch block (RBBB), left bundle branch block (LBBB), left anterior fascicular block (LAFB) and non-specific intraventricular conduction disturbances (NIVCD)., Results: The number of participants, the resulting prevalence (square brackets) and 95% CI (round brackets) of intraventricular conduction disturbances and subtypes (RBBB, LBBB, LAFB and NIVCD) were 187 [5.1% (4.4-5.8%)], 103 [2.9%, (2.3-3.4%)], 29 [0.8% (0.6-1.1%)], 31 (0.9% [0.6-1.2%]), and 47 [1.3% (0.9-1.7)], respectively. Multivariable logistic regression identified male sex [odds ratio and (95% CI): 2.55 (1.34-4.86)] and increasing age (p-value for trend <0.001) as being associated with RBBB; hypertension [3.08 (1.20-7.91)] and elevated NT-proBNP [3.26 (1.43-7.41)] as being associated with LBBB; elevated NT-proBNP [3.14 (1.32-7.46)] as being associated with LFAB; and male sex [5.97 (1.91-18.7)] and increased height [1.31 (1.06-1.63)] as being associated with NIVCD., Conclusion: In a sample of the Swiss middle-aged population, the clinical factors associated with intraventricular conduction disturbances differed according to the intraventricular conduction disturbances subtype: male sex and ageing for RBBB; hypertension and elevated NT-proBNP for LBBB; elevated NT-proBNP for LAFB; and male sex and increased height for NIVCD., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: A longer QTc interval has been associated with more adverse cardiovascular events and death in the general population. Little evidence is available on these relationships among patients with atrial fibrillation (AF)., Methods: We performed a prospective observational multicenter cohort study of 1413 patients with AF. A resting 12‑lead electrocardiogram (ECG) was performed at baseline. QT interval was corrected for heart rate using the Bazett formula (QTc). Endpoints for this study included hospitalizations for congestive heart failure (CHF), a combination of cardiovascular death, myocardial infarction, stroke, systemic arterial embolism (MACE) and all-cause mortality., Results: Mean age of our population was 68±12years and 420 (30%) participants were female. Median QTc was 432ms (interquartile range 409; 457). The mean follow-up time was 3.6±1.5years. After multivariable adjustment, there was a linear increase in risk with increasing QTc interval for incident CHF (hazard ratio (HR) per 1-SD increase in QTc 1.3 [95% CI 1.1; 1.6], p=0.008), MACE (HR 1.2 [1.0; 1.4], p=0.02) and all-cause mortality (HR 1.3 [1.0; 1.6], p=0.002). Results were consistent whether or not patients were in sinus rhythm on the baseline ECG (HR for CHF 1.7 versus 1.3, p interaction 0.08; HR for MACE 1.3 versus 1.2, p interaction 0.9; HR for all-cause mortality 1.4 versus 1.4, p interaction 0.9)., Conclusions: In this large well-characterized cohort of AF patients, QTc interval was independently associated with adverse outcomes. These results were independent of the rhythm on the baseline ECG., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Evaluation of syncope remains often unstructured. The aim of the study was to assess the effectiveness of a standardized protocol designed to improve the diagnosis of syncope., Methods: Consecutive patients with syncope presenting to the emergency departments of two primary and tertiary care hospitals over a period of 18 months underwent a two-phase evaluation including: 1) noninvasive assessment (phase I); and 2) specialized tests (phase II), if syncope remained unexplained after phase I. During phase II, the evaluation strategy was alternately left to physicians in charge of patients (control), or guided by a standardized protocol relying on cardiac status and frequency of events (intervention). The primary outcomes were the diagnostic yield of each phase, and the impact of the intervention (phase II) measured by multivariable analysis., Results: Among 1725 patients with syncope, 1579 (92%) entered phase I which permitted to establish a diagnosis in 1061 (67%) of them, including mainly reflex causes and orthostatic hypotension. Five-hundred-eighteen patients (33%) were considered as having unexplained syncope and 363 (70%) entered phase II. A cause for syncope was found in 67 (38%) of 174 patients during intervention periods, compared to 18 (9%) of 189 during control (p<0.001). Compared to control periods, intervention permitted diagnosing more cardiac (8%, vs 3%, p=0.04) and reflex syncope (25% vs 6%, p<0.001), and increased the odds of identifying a cause for syncope by a factor of 4.5 (95% CI: 2.6-8.7, p<0.001). Overall, adding the diagnostic yield obtained during phase I and phase II (intervention periods) permitted establishing the cause of syncope in 76% of patients., Conclusion: Application of a standardized diagnostic protocol in patients with syncope improved the likelihood of identifying a cause for this symptom. Future trials should assess the efficacy of diagnosis-specific therapy.

Background: S9788 is a triazineaminopiperidine derivative capable of reversing multidrug resistance (MDR) in vitro. In preclinical models S9788 was several fold more potent MDR inhibitor than verapamil or cyclosporine. At P-glycoprotein (Pgp) blocking concentrations, S9788 appeared to have only very little toxicity., Patients and Methods: In a two step phase I trial we treated 39 patients with refractory cancer with S9788 and bolus doxorubicin. The steps differed mainly in the S9788 infusion duration; in the first part 23 patients received the MDR-reversing drug S9788 over 30 minutes, in the second step of the study 16 patients were administered S9788 over 150 minutes. The doses of S9788 were escalated in cohorts of three patients up to a dose level (DL) of 96 mg/m2 on the 30 minutes infusion, and to 144 mg/m2 on the 150 minutes infusion. The pharmacokinetics of S9788 were determined., Results: With the 30-minute infusion schedule symptomatic cardiac arrhythmia were found to be dose limiting. In all patients at the highest DL transient cardiac repolarization prolongation with a long QT-interval on ECG was demonstrated. With the 150-minute administration schedule, S9788 could be escalated up to 144 mg/m2 without subjective toxicity. However, transient QT prolongation was present in all patients. A third degree AV-block and a QT increase of about 40% occurred at the highest DL. Asymptomatic torsade de pointe (DL 96 mg/m2) was demonstrated on Holter recording in one patient. Theses repolarization disturbances with QT increase were considered dose limiting toxicity and the trial was closed. No arrhythmia related death was noted. Pharmacokinetics were similar with both infusion schedules with a mean alpha half life of 11.3 and 13.2 minutes, for the 30-minute and 150-minute infusion, and a terminal half life of 13.5 and 15 hours, respectively. QTc prolongation duration appeared to be dose-dependent., Conclusions: With the tested infusion schedules, cardiac toxicity, in particular AV-blocks and QT prolongation, leading to ventricular arrhythmia and torsade de pointe, are the dose limiting toxicities of S9788. Our experience together with the observation of asymptomatic torsade de pointe in two other phase 1 trials of S9788 infused over six hours precluded the further clinical development of S9788.

Infection of a cardiac pacemaker and its electrodes is one of the most serious complications after implantation of a pacemaker, as it can be life-threatening and constitutes an absolute indication for complete withdrawal of the implanted material which, up until recently, could only be performed by thoracotomy or sternotomy with or without cardiopulmonary bypass. A new transvenous technique for complete removal of the infected pacemaker system has been recently described. We report 5 cases of infected pacemaker systems in which this technique was used successfully allowing withdrawal of 10 electrodes and thereby avoiding the need for a major surgical operation.