Time-trends and treatment gaps in the antithrombotic management of patients with atrial fibrillation after percutaneous coronary intervention: Insights from the CHUM AF-STENT Registry.

BACKGROUND: The management of atrial fibrillation and flutter (AF) patients undergoing percutaneous coronary intervention (PCI) has undergone a rapid recent evolution. In 2016, the Canadian Cardiovascular Society (CCS) published expert recommendations to help guide clinicians in balancing bleeding and thrombotic risks in these patients. HYPOTHESIS: Antithrombotic regimen prescriptions for AF patients undergoing PCI evolved after the publication of the 2016 CCS AF guidelines. METHODS: A prospective cohort of AF patients undergoing PCI with placement of a coronary stent from a single tertiary academic center was analyzed for the recommended antithrombotic regimen at discharge. Prescribing behavior was compared between three time periods (Cohort A [2010-2011]; Cohort B [2014-2015]; Cohort C [2017]) using the χ2 test. In addition, antithrombotic management in Cohorts B and C were compared to guideline-recommended therapy. RESULTS: A total of 459 patients with AF undergoing PCI were identified. Clinical and procedural characteristics were similar between cohorts, with the exception of an increase in drug-eluting stent (DES) use over time (P < .01). Overall, the rate of oral anticoagulation (OAC) increased over time (P < .01), associated with an increase in nonvitamin K OAC prescription (P < .01) and a concomitant decrease in vitamin K antagonist prescription (P < .01). Despite this, the overall rate of anticoagulation remains below what would be predicted with perfect guideline compliance (75% vs 94%, P < .01). CONCLUSION: There has been a dramatic shift in clinical practice for AF patients requiring PCI, with increases in prescription of OAC even in the context of an increase in the use of DES. However, room for further practice optimization still exists

AIM-AF: A Physician Survey in the United States and Europe.

Background Guideline recommendations are the accepted reference for selection of therapies for rhythm control of atrial fibrillation (AF). This study was designed to understand physicians' treatment practices and adherence to guidelines. Methods and Results The AIM-AF (Antiarrhythmic Medication for Atrial Fibrillation) study was an online survey of clinical cardiologists and electrophysiologists that was conducted in the United States and Europe (N=629). Respondents actively treated ≥30 patients with AF who received drug therapy, and had received or were referred for ablation every 3 months. The survey comprised 96 questions on physician demographics, AF types, and treatment practices. Overall, 54% of respondents considered guidelines to be the most important nonpatient factor influencing treatment choice. Across most queried comorbidities, amiodarone was selected by 60% to 80% of respondents. Other nonadherent usage included sotalol by 21% in patients with renal impairment; dofetilide initiation (16%, United States only) outside of hospital; class Ic agents by 6% in coronary artery disease; and dronedarone by 8% in patients with heart failure with reduced ejection fraction. Additionally, rhythm control strategies were frequently chosen in asymptomatic AF (antiarrhythmic drugs [AADs], 35%; ablation, 8%) and subclinical AF (AADs, 38%; ablation, 13%). Despite guideline algorithms emphasizing safety first, efficacy (48%) was selected as the most important consideration for AAD choice, followed by safety (34%). Conclusions Despite surveyed clinicians recognizing the importance of guidelines, nonadherence was frequently observed. While deviation may be reasonable in selected patients, in general, nonadherence has the potential to compromise patient safety. These findings highlight an underappreciation of the safe use of AADs, emphasizing the need for interventions to support optimal AAD selection

Real-world utilization of the pill-in-the-pocket method for terminating episodes of atrial fibrillation: data from the multinational Antiarrhythmic Interventions for Managing Atrial Fibrillation (AIM-AF) survey.

AIMS: Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice. Episodes may stop spontaneously (paroxysmal AF); may terminate only via intervention (persistent AF); or may persist indefinitely (permanent AF) (see European and American guidelines, referenced below, for more precise definitions). Recently, there has been renewed interest in an approach to terminate AF acutely referred to as 'pill-in-the-pocket' (PITP). The PITP is recognized in both the US and European guidelines as an effective option using an oral antiarrhythmic drug for acute conversion of acute/recent-onset AF. However, how PITP is currently used has not been systematically evaluated. METHODS AND RESULTS: The recently published Antiarrhythmic Interventions for Managing Atrial Fibrillation (AIM-AF) survey included questions regarding current PITP usage, stratified by US vs. European countries surveyed, by representative countries within Europe, and by cardiologists vs. electrophysiologists. This manuscript presents the data from this planned sub-study. Our survey revealed that clinicians in both the USA and Europe consider PITP in about a quarter of their patients, mostly for recent-onset AF with minimal or no structural heart disease (guideline appropriate). However, significant deviations exist. See the Graphical abstract for a summary of the data. CONCLUSION: Our findings highlight the frequent use of PITP and the need for further physician education about appropriate and optimal use of this strategy

The Response of Paroxysmal Supraventricular Tachycardia to Overdrive Atrial and Ventricular Pacing:

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75015/1/j.1540-8167.1993.tb01227.x.pd

Maternal melatonin: Effective intervention against developmental programming of cardiovascular dysfunction in adult offspring of complicated pregnancy

Funder: British Heart Foundation; Id: http://dx.doi.org/10.13039/501100000274Abstract: Adopting an integrative approach, by combining studies of cardiovascular function with those at cellular and molecular levels, this study investigated whether maternal treatment with melatonin protects against programmed cardiovascular dysfunction in the offspring using an established rodent model of hypoxic pregnancy. Wistar rats were divided into normoxic (N) or hypoxic (H, 10% O2) pregnancy ± melatonin (M) treatment (5 μg·ml−1.day−1) in the maternal drinking water. Hypoxia ± melatonin treatment was from day 15–20 of gestation (term is ca. 22 days). To control for possible effects of maternal hypoxia‐induced reductions in maternal food intake, additional dams underwent pregnancy under normoxic conditions but were pair‐fed (PF) to the daily amount consumed by hypoxic dams from day 15 of gestation. In one cohort of animals from each experimental group (N, NM, H, HM, PF, PFM), measurements were made at the end of gestation. In another, following delivery of the offspring, investigations were made at adulthood. In both fetal and adult offspring, fixed aorta and hearts were studied stereologically and frozen hearts were processed for molecular studies. In adult offspring, mesenteric vessels were isolated and vascular reactivity determined by in‐vitro wire myography. Melatonin treatment during normoxic, hypoxic or pair‐fed pregnancy elevated circulating plasma melatonin in the pregnant dam and fetus. Relative to normoxic pregnancy, hypoxic pregnancy increased fetal haematocrit, promoted asymmetric fetal growth restriction and resulted in accelerated postnatal catch‐up growth. Whilst fetal offspring of hypoxic pregnancy showed aortic wall thickening, adult offspring of hypoxic pregnancy showed dilated cardiomyopathy. Similarly, whilst cardiac protein expression of eNOS was downregulated in the fetal heart, eNOS protein expression was elevated in the heart of adult offspring of hypoxic pregnancy. Adult offspring of hypoxic pregnancy further showed enhanced mesenteric vasoconstrictor reactivity to phenylephrine and the thromboxane mimetic U46619. The effects of hypoxic pregnancy on cardiovascular remodelling and function in the fetal and adult offspring were independent of hypoxia‐induced reductions in maternal food intake. Conversely, the effects of hypoxic pregnancy on fetal and postanal growth were similar in pair‐fed pregnancies. Whilst maternal treatment of normoxic or pair‐fed pregnancies with melatonin on the offspring cardiovascular system was unremarkable, treatment of hypoxic pregnancies with melatonin in doses lower than those recommended for overcoming jet lag in humans enhanced fetal cardiac eNOS expression and prevented all alterations in cardiovascular structure and function in fetal and adult offspring. Therefore, the data support that melatonin is a potential therapeutic target for clinical intervention against developmental origins of cardiovascular dysfunction in pregnancy complicated by chronic fetal hypoxia

International trends in clinical characteristics and oral anticoagulation treatment for patients with atrial fibrillation: Results from the GARFIELD-AF, ORBIT-AF I, and ORBIT-AF II registries.

Atrial fibrillation (AF) is the most common cardiac arrhythmia in the world. We aimed to provide comprehensive data on international patterns of AF stroke prevention treatment. METHODS: Demographics, comorbidities, and stroke risk of the patients in the GARFIELD-AF (n=51,270), ORBIT-AF I (n=10,132), and ORBIT-AF II (n=11,602) registries were compared (overall N=73,004 from 35 countries). Stroke prevention therapies were assessed among patients with new-onset AF (≤6 weeks). RESULTS: Patients from GARFIELD-AF were less likely to be white (63% vs 89% for ORBIT-AF I and 86% for ORBIT-AF II) or have coronary artery disease (19% vs 36% and 27%), but had similar stroke risk (85% CHA2DS2-VASc ≥2 vs 91% and 85%) and lower bleeding risk (11% with HAS-BLED ≥3 vs 24% and 15%). Oral anticoagulant use was 46% and 57% for patients with a CHA2DS2-VASc=0 and 69% and 87% for CHA2DS2-VASc ≥2 in GARFIELD-AF and ORBIT-AF II, respectively, but with substantial geographic heterogeneity in use of oral anticoagulant (range: 31%-93% [GARFIELD-AF] and 66%-100% [ORBIT-AF II]). Among patients with new-onset AF, non-vitamin K antagonist oral anticoagulant use increased over time to 43% in 2016 for GARFIELD-AF and 71% for ORBIT-AF II, whereas use of antiplatelet monotherapy decreased from 36% to 17% (GARFIELD-AF) and 18% to 8% (ORBIT-AF I and II). CONCLUSIONS: Among new-onset AF patients, non-vitamin K antagonist oral anticoagulant use has increased and antiplatelet monotherapy has decreased. However, anticoagulation is used frequently in low-risk patients and inconsistently in those at high risk of stroke. Significant geographic variability in anticoagulation persists and represents an opportunity for improvement

GARFIELD-AF: risk profiles, treatment patterns and 2-year outcomes in patients with atrial fibrillation in Germany, Austria and Switzerland (DACH) compared to 32 countries in other regions worldwide.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is a worldwide non-interventional study of stroke prevention in patients with non-valvular AF. METHODS AND RESULTS: 52,080 patients with newly diagnosed AF were prospectively enrolled from 2010 to 2016. 4121 (7.9%) of these patients were recruited in DACH [Germany (n = 3567), Austria (n = 465) and Switzerland (n = 89) combined], and 47,959 patients were from 32 countries in other regions worldwide (ORW). Hypertension was most prevalent in DACH and ORW (85.3% and 75.6%, respectively). Diabetes, hypercholesterolaemia, carotid occlusive disease and vascular disease were more prevalent in DACH patients vs ORW (27.6%, 49.4%, 5.8% and 29.0% vs 21.7%, 40.9%, 2.8% and 24.5%). The use of non-vitamin K antagonist oral anticoagulants (NOACs) increased more in DACH over time. Management of vitamin K antagonists was suboptimal in DACH and ORW (time in therapeutic range of INR ≥ 65% in 44.6% and 44.4% of patients or ≥ 70% in 36.9% and 36.0% of patients, respectively). Adjusted rates of cardiovascular mortality and MI/ACS were higher in DACH while non-haemorrhagic stroke/systemic embolism was lower after 2-year follow-up. CONCLUSIONS: Similarities and dissimilarities in AF management and clinical outcomes are seen in DACH and ORW. The increased use of NOAC was associated with a mismatch of risk-adapted anticoagulation (over-and-undertreatment) in DACH. Suboptimal control of INR requires educational activities in both regional groups. Higher rates of cardiovascular death in DACH may reflect the higher risk profile of these patients and lower rates of non-haemorrhagic stroke could be associated with increased NOAC use

Single Doses up to 800 mg of E-52862 Do Not Prolong the QTc Interval--A Retrospective Validation by Pharmacokinetic-Pharmacodynamic Modelling of Electrocardiography Data Utilising the Effects of a Meal on QTc to Demonstrate ECG Assay Sensitivity.

BACKGROUND: E-52862 is a Sigma-1 receptor antagonist (S1RA) currently under investigation as a potential analgesic medicine. We successfully applied a concentration-effect model retrospectively to a four-way crossover Phase I single ascending dose study and utilized the QTc shortening effects of a meal to demonstrate assay sensitivity by establishing the time course effects from baseline in all four periods, independently from any potential drug effects. METHODS: Thirty two healthy male and female subjects were included in four treatment periods to receive single ascending doses of 500 mg, 600 mg or 800 mg of E-52862 or placebo. PK was linear over the dose range investigated and doses up to 600 mg were well tolerated. The baseline electrocardiography (ECG) measurements on Day-1 were time-matched with ECG and pharmacokinetic (PK) samples on Day 1 (dosing day). RESULTS: In this conventional mean change to time-matched placebo analysis, the largest time-matched difference to placebo QTcI was 1.44 ms (90% CI: -4.04, 6.93 ms) for 500 mg; -0.39 ms (90% CI: -3.91, 3.13 ms) for 600 mg and 1.32 ms (90% CI: -1.89, 4.53 ms) for 800 mg of E-52862, thereby showing the absence of any QTc prolonging effect at the doses tested. In addition concentration-effect models, one based on the placebo corrected change from baseline and one for the change of QTcI from average baseline with time as fixed effect were fitted to the data confirming the results of the time course analysis. CONCLUSION: The sensitivity of this study to detect small changes in the QTc interval was confirmed by demonstrating a shortening of QTcF of -8.1 (90% CI: -10.4, -5.9) one hour and -7.2 (90% CI: -9.4, -5.0) three hours after a standardised meal. TRIAL REGISTRATION: EU Clinical Trials Register EudraCT 2010 020343 13

Rationale and design of the NODE-303 study: evaluating the safety of symptom-prompted, self-administered etripamil for paroxysmal supraventricular tachycardia episodes in real-world settings.

BACKGROUND: Paroxysmal supraventricular tachycardia (PSVT) is a common episodic arrhythmia characterized by unpredictable onset and burdensome symptoms including palpitations, dizziness, chest pain, distress, and shortness of breath. Treatment of acute episodes of PSVT in the clinical setting consists of intravenous adenosine, beta-blockers, and calcium channel blockers (CCBs). Etripamil is an intranasally self-administered L-type CCB in development for acute treatment of AV-nodal dependent PSVT in a nonmedical supervised setting. METHODS: This paper summarizes the rationale and study design of NODE-303 that will assess the efficacy and safety of etripamil. In the randomized, double-blinded, placebo-controlled, Phase 3 RAPID trial, etripamil was superior to placebo in the conversion of single PSVT episodes by 30 minutes post initial dose when administered in the nonhealthcare setting; this study required a mandatory and observed test dosing prior to randomization. The primary objective of NODE-303 is to evaluate the safety of symptom-prompted, self-administered etripamil for multiple PSVT episodes in real-world settings, without the need for test dosing prior to first use during PSVT. Secondary endpoints include efficacy and disease burden. Upon perceiving a PSVT episode, the patient applies an electrocardiographic monitor, performs a vagal maneuver, and, if the vagal maneuver is unsuccessful, self-administers etripamil 70 mg, with an optional repeat dose if symptoms do not resolve within 10 minutes after the first dose. A patient may treat up to four PSVT episodes during the study. Adverse events are recorded as treatment-emergent if they occur within 24 hours after the administration of etripamil. RESULTS: Efficacy endpoints include time to conversion to sinus rhythm within 30 and 60 minutes after etripamil administration, and the proportion of patients who convert at 3, 5, 10, 20, 30, and 60 minutes. Patient-reported outcomes are captured by the Brief Illness Perception Questionnaire, the Cardiac Anxiety Questionnaire, the Short Form Health Survey 36, the Treatment Satisfaction Questionnaire for Medication and a PSVT survey. CONCLUSIONS: Overall, these data will support the development of a potentially paradigm-changing long-term management strategy for recurrent PSVT