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Ivabradine for chronic heart rate control in persistent atrial fibrillation. Design of the BRAKE-AF project.
Fontenla, A, López-Gil, M, Tamargo-Menéndez, J, Matía-Francés, R, Salgado-Aranda, R, Rey-Blas, JR, Miracle-Blanco, Á, Mejía-Martínez, E, Pastor-Fuentes, A, Toquero-Ramos, J, et al
Revista espanola de cardiologia (English ed.). 2020;(5):368-375
Abstract
INTRODUCTION AND OBJECTIVES Ivabradine is an inhibitor of the If channel, the main determinant of the pacemaker function of the sinus node. The drug has been approved for the treatment of angina and heart failure. There is some evidence of its role as an inhibitor of atrial-ventricular node (AVN) conduction. The aim of the BRAKE-AF project is to assess ivabradine use for rate control in atrial fibrillation (AF). METHODS A multicenter, randomized, parallel, open-label, noninferiority phase III clinical trial will be conducted to compare ivabradine vs digoxin in 232 patients with uncontrolled permanent AF despite beta-blockers or calcium channel blockers. The primary efficacy endpoint is the reduction in daytime heart rate measured by 24-hour Holter monitoring at 3 months. This clinical trial will be supported by an electrophysiological study of the effect of ivabradine on the action potential of the human AVN. To do this, an experimental model will be used with Chinese hamster ovarium cells transfected with the DNA encoding the expression of the t channels involved in this action potential and recording of the ionic currents with patch clamp techniques. RESULTS New data will be obtained on the effect of ivabradine on the human AVN and its safety and efficacy in patients with permanent AF. CONCLUSIONS The results of the BRAKE-AF project might allow inclusion of ivabradine within the limited arsenal of drugs currently available for rate control in AF. CLINICAL TRIAL REGISTRATION http://www.clinicaltrials.gov. Identifier: NCT03718273.
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Efficacy and safety of flecainide for ventricular arrhythmias in patients with Andersen-Tawil syndrome with KCNJ2 mutations.
Miyamoto, K, Aiba, T, Kimura, H, Hayashi, H, Ohno, S, Yasuoka, C, Tanioka, Y, Tsuchiya, T, Yoshida, Y, Hayashi, H, et al
Heart rhythm. 2015;(3):596-603
Abstract
BACKGROUND Andersen-Tawil syndrome (ATS) is an autosomal dominant genetic or sporadic disorder characterized by ventricular arrhythmias (VAs), periodic paralyses, and dysmorphic features. The optimal pharmacological treatment of VAs in patients with ATS remains unknown. OBJECTIVE We evaluated the efficacy and safety of flecainide for VAs in patients with ATS with KCNJ2 mutations. METHODS Ten ATS probands (7 females; mean age 27 ± 11 years) were enrolled from 6 institutions. All of them had bidirectional VAs in spite of treatment with β-blockers (n = 6), but none of them had either aborted cardiac arrest or family history of sudden cardiac death. Twenty-four-hour Holter recording and treadmill exercise test (TMT) were performed before (baseline) and after oral flecainide therapy (150 ± 46 mg/d). RESULTS Twenty-four-hour Holter recordings demonstrated that oral flecainide treatment significantly reduced the total number of VAs (from 38,407 ± 19,956 to 11,196 ± 14,773 per day; P = .003) and the number of the longest ventricular salvos (23 ± 19 to 5 ± 5; P = .01). At baseline, TMT induced nonsustained ventricular tachycardia (n = 7) or couplets of premature ventricular complex (n = 2); treatment with flecainide completely (n = 7) or partially (n = 2) suppressed these exercise-induced VAs (P = .008). In contrast, the QRS duration, QT interval, and U-wave amplitude of the electrocardiogram were not altered by flecainide therapy. During a mean follow-up of 23 ± 11 months, no patients developed syncope or cardiac arrest after oral flecainide treatment. CONCLUSION This multicenter study suggests that oral flecainide therapy is an effective and safe means of suppressing VAs in patients with ATS with KCNJ2 mutations, though the U-wave amplitude remained unchanged by flecainide.
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A prospective survey in European Society of Cardiology member countries of atrial fibrillation management: baseline results of EURObservational Research Programme Atrial Fibrillation (EORP-AF) Pilot General Registry.
Lip, GY, Laroche, C, Dan, GA, Santini, M, Kalarus, Z, Rasmussen, LH, Oliveira, MM, Mairesse, G, Crijns, HJ, Simantirakis, E, et al
Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2014;(3):308-19
Abstract
AIMS: Given the advances in atrial fibrillation (AF) management and the availability of new European Society of Cardiology (ESC) guidelines, there is a need for the systematic collection of contemporary data regarding the management and treatment of AF in ESC member countries. METHODS AND RESULTS We conducted a registry of consecutive in- and outpatients with AF presenting to cardiologists in nine participating ESC countries. All patients with an ECG-documented diagnosis of AF confirmed in the year prior to enrolment were eligible. We enroled a total of 3119 patients from February 2012 to March 2013, with full data on clinical subtype available for 3049 patients (40.4% female; mean age 68.8 years). Common comorbidities were hypertension, coronary disease, and heart failure. Lone AF was present in only 3.9% (122 patients). Asymptomatic AF was common, particularly among those with permanent AF. Amiodarone was the most common antiarrhythmic agent used (∼20%), while beta-blockers and digoxin were the most used rate control drugs. Oral anticoagulants (OACs) were used in 80% overall, most often vitamin K antagonists (71.6%), with novel OACs being used in 8.4%. Other antithrombotics (mostly antiplatelet therapy, especially aspirin) were still used in one-third of the patients, and no antithrombotic treatment in only 4.8%. Oral anticoagulants were used in 56.4% of CHA2DS2-VASc = 0, with 26.3% having no antithrombotic therapy. A high HAS-BLED score was not used to exclude OAC use, but there was a trend towards more aspirin use in the presence of a high HAS-BLED score. CONCLUSION The EURObservational Research Programme Atrial Fibrillation (EORP-AF) Pilot Registry has provided systematic collection of contemporary data regarding the management and treatment of AF by cardiologists in ESC member countries. Oral anticoagulant use has increased, but novel OAC use was still low. Compliance with the treatment guidelines for patients with the lowest and higher stroke risk scores remains suboptimal.
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Effects of intravenous nicorandil on the mid-term prognosis of patients with acute heart failure syndrome.
Ishihara, S, Koga, T, Kaseda, S, Nyuta, E, Haga, Y, Fujishima, S, Ishitsuka, T, Sadoshima, S
Circulation journal : official journal of the Japanese Circulation Society. 2012;(5):1169-76
Abstract
BACKGROUND Acute heart failure syndrome (AHFS) remains a major clinical challenge because of its poor prognosis. Nicorandil, a hybrid compound of a potassium-channel opener and nitric oxide donor, has been reported to improve the prognosis of ischemic heart disease. We sought to evaluate the effect of intravenous nicorandil on the mid-term prognosis of AHFS. METHODS AND RESULTS A total of 402 consecutive patients who were hospitalized for AHFS were divided into 2 groups according to the use of intravenous nicorandil: 78 patients in the Nicorandil group and 324 patients in the Control group. During the 180-day follow-up, death or rehospitalization for heart failure occurred in 7 patients in the Nicorandil group (9.0%) and in 75 patients (23.2%) in the Control group. Event-free survival rates were significantly higher in the Nicorandil group than in the Control group (P=0.006). Multivariate Cox hazard analysis revealed that age (hazard ratio (HR)=1.066, P<0.0001), systolic blood pressure (HR=0.983, P=0.0023), New York Heart Association class III/IV (HR=6.550, P<0.0001), log creatinine (HR=3.866, P=0.0106), and use of intravenous nicorandil (HR=0.179, P<0.0001) were significant predictive factors for the occurrence of death or rehospitalization for heart failure. CONCLUSIONS Intravenous nicorandil treatment from the urgent phase of AHFS may improve the prognosis.
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Reducing elevated heart rate in patients with multiple organ dysfunction syndrome by the I (f) (funny channel current) inhibitor ivabradine : MODI (f)Y trial.
Nuding, S, Ebelt, H, Hoke, RS, Krummenerl, A, Wienke, A, Müller-Werdan, U, Werdan, K
Clinical research in cardiology : official journal of the German Cardiac Society. 2011;(10):915-23
Abstract
BACKGROUND Heart rate (HR) is of relevant prognostic value not only in the general population and patients with cardiovascular disease, but also in critically ill patients with multiple organ dysfunction syndrome (MODS). An elevated HR in MODS patients is associated with a worse prognosis. Beta-blocker (BB) administration has been shown to reduce mortality in MODS. In most cases, negative inotropic effects prevent administration of BBs in MODS patients. In this trial we investigate, whether the "funny current" (I (f)) channel inhibitor ivabradine is able and apt to reduce pathologically elevated HR in MODS patients. We hypothesize that critically ill patients could derive particular benefit from the specific HR-lowering agent ivabradine. METHODS MODI (f)Y is a prospective, single centre, open label, randomized, controlled two arms, phase II-trial to evaluate the potential of ivabradine to reduce an elevated HR in MODS patients. The primary end point is the proportion of patients with a reduction of HR by at least 10 beats per minute (bpm) within 4 days. This trial will randomize 70 patients (men and women, aged ≥18 years) with newly diagnosed MODS, with an elevated HR (sinus rhythm with HR ≥90 bpm) and contraindications to BB therapy. Treatment period will last for 4 days. All patients will be followed for 6 months. RESULTS The first patient was randomized on May 21, 2010. CONCLUSIONS The MODI (f)Y trial is the first application of ivabradine as a pure heart rate reducing agent in MODS patients.
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Effects of quinidine on the action potential duration restitution property in the right ventricular outflow tract in patients with brugada syndrome.
Ashino, S, Watanabe, I, Kofune, M, Nagashima, K, Ohkubo, K, Okumura, Y, Mano, H, Nakai, T, Kunimoto, S, Kasamaki, Y, et al
Circulation journal : official journal of the Japanese Circulation Society. 2011;(9):2080-6
Abstract
BACKGROUND On a cellular level, Brugada syndrome has been attributed to a deep phase 1 notch and subsequent shallow and prolonged repolarization in the right ventricular outflow tract (RVOT). A sodium channel mutation that leads to early inactivation of the late sodium current has been identified in some patients. Thus, drugs that inhibit the transient outward current (I(to)) responsible for the phase 1 notch and/or enhance the late sodium current might suppress arrhythmic events in patients with Brugada syndrome. The effects of quinidine gluconate, a potent inhibitor of I(to), on RVOT action potential duration (APD) restitution kinetics in patients with Brugada syndrome were evaluated. METHODS AND RESULTS Programmed ventricular stimulation was performed in 9 Brugada syndrome patients by delivering up to 3 extrastimuli from the right ventricular apex and RVOT. RVOT monophasic action potentials (MAPs) were recorded before and after intravenous administration of quinidine (n=6) or ibutilide (n=3). All patients had inducible ventricular fibrillation (VF) before drug administration. Both quinidine and ibutilide increased steady-state and minimum RVOT MAP duration during programmed stimulation. Quinidine decreased the maximum slope of the RVOT APD restitution curve and VF could not be induced after administration of quinidine in 5 of the 6 patients. CONCLUSIONS Quinidine appears to suppress the induction of VF by increasing RVOT MAP duration and decreasing the maximum slope of the restitution curve.
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High index of microcirculatory resistance level after successful primary percutaneous coronary intervention can be improved by intracoronary administration of nicorandil.
Ito, N, Nanto, S, Doi, Y, Sawano, H, Masuda, D, Yamashita, S, Okada, K, Kaibe, S, Hayashi, Y, Kai, T, et al
Circulation journal : official journal of the Japanese Circulation Society. 2010;(5):909-15
Abstract
BACKGROUND Although microvascular dysfunction following percutaneous coronary intervention (PCI) can be evaluated with the index of microcirculatory resistance (IMR), no method of treatment has been established. We hypothesized that intracoronary administration of nicorandil can improve IMR after successful primary PCI in patients with ST-segment elevation myocardial infarction (STEMI). METHODS AND RESULTS In 40 patients with first STEMI after successful primary PCI, IMR was measured using PressureWire(TM) Certus (St. Jude Medical, MN, USA). In 20 of the patients (Group N), IMR was measured at baseline and after intracoronary nicorandil (2 mg/10 ml). In the other 20 patients (Control), IMR was measured at baseline, after intracoronary saline (10 ml) and after intracoronary nicorandil (2 mg/10 ml). In Group N, IMR significantly decreased after intracoronary nicorandil (median IMR, 27.7-18.7 U, P<0.0001). In the Control group, IMR did not change after saline administration (median IMR, 24.3-23.8 U, P=0.8193), but was significantly decreased after intracoronary nicorandil (median IMR, 23.8-14.9 U, P<0.0001). Next, all 40 patients were divided into subgroups by tertile of baseline IMR. In those with intermediate to high IMR (baseline IMR > or =21), intracoronary nicorandil significantly decreased IMR, although it did not change IMR in those with low IMR (baseline IMR <21). CONCLUSIONS High IMR levels in patients with STEMI after successful primary PCI can be improved by intracoronary administration of nicorandil.
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Magnesium sulfate versus placebo for paroxysmal atrial fibrillation: a randomized clinical trial.
Chu, K, Evans, R, Emerson, G, Greenslade, J, Brown, A
Academic emergency medicine : official journal of the Society for Academic Emergency Medicine. 2009;(4):295-300
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Abstract
OBJECTIVES The objective was to investigate the efficacy of magnesium sulfate (MgSO4) in decreasing the ventricular rate in emergency department (ED) patients presenting with new-onset, rapid atrial fibrillation (AF). METHODS A double-blinded, placebo-controlled randomized clinical trial was conducted in an adult university hospital. Patients aged > or =18 years with AF onset of less than 48 hours and a sustained ventricular rate of >100 beats/min were randomized to either intravenous (IV) MgSO4 10 mmol or normal saline (NSal). Rhythm and instantaneous heart rate as measured by the monitor were recorded at baseline and every 15 minutes for 2 hours after starting the trial drug. Heart rate and rhythm were compared at 2 hours. A multilevel modeling analysis was performed to adjust for differences in baseline heart rate and any additional treatment and to examine changes in heart rate over time. RESULTS Twenty-four patients were randomized to MgSO4 and 24 to NSal. Baseline heart rate was lower in the MgSO4 group (mean +/- standard deviation [+/-SD] = 125 +/- 24 vs. 140 +/- 21 beats/min]. One and 3 patients in the MgSO4 and NSal groups, respectively, were given another antiarrhythmic or were electrically cardioverted within 2 hours after starting the trial drug. Heart rate (mean +/- SD) at 2 hours in both MgSO4 (116 +/- 30 beats/min) and NSal groups (114 +/- 31 beats/min) decreased below their respective baseline levels. However, the rate of heart rate decrease across time did not differ between groups (p = 0.124). The proportion of patients who converted to sinus rhythm 2 hours post-trial drug did not differ (MgSO4 8.7% vs. NSal 25.0%, p = 0.25). CONCLUSIONS This study was unable to demonstrate a difference between IV MgSO4 10 mmol and saline placebo for reducing heart rate or conversion to sinus rhythm at 2 hours posttreatment in ED patients with AF of less than 48 hours duration.
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The usefulness of 99mTc-sestaMIBI thyroid scan in the differential diagnosis and management of amiodarone-induced thyrotoxicosis.
Piga, M, Cocco, MC, Serra, A, Boi, F, Loy, M, Mariotti, S
European journal of endocrinology. 2008;(4):423-9
Abstract
BACKGROUND Amiodarone-induced thyrotoxicosis (AIT) is caused by excessive hormone synthesis and release (AIT I) or a destructive process (AIT II). This differentiation has important therapeutic implications. PURPOSE To evaluate (99m)Tc-sestaMIBI (MIBI) thyroid scintigraphy in addition to other diagnostic tools in the diagnosis and management of AIT. SUBJECTS AND METHODS Thyroid and (99m)Tc-MIBI scintigraphies were performed in 20 consecutive AIT patients, along with a series of biochemical and instrumental investigations (measurement of thyrotrophin, free thyroid hormones and thyroid autoantibodies; thyroid colour-flow Doppler sonography (CFDS) and thyroid radioiodine uptake (RAIU)). RESULTS On the basis of instrumental and laboratory data (excluding thyroid (99m)Tc-MIBI scintigraphy) and follow-up, AIT patients could be subdivided into six with AIT I, ten with AIT II and four with indefinite forms of AIT (AIT Ind). (99m)Tc-MIBI uptake results were normal/increased in all the six patients with AIT I and absent in all the ten patients with AIT II. The remaining four patients with AIT Ind showed low, patchy and persistent uptake in two cases and in the other two evident MIBI uptake followed by a rapid washout. MIBI scintigraphy was superior to all other diagnostic tools, including CFDS (suggestive of AIT I in three patients with AIT II and of AIT II in three with AIT Ind) and RAIU, which was measurable in all patients with AIT I, and also in four out of the ten with AIT II. CONCLUSION Thyroid MIBI scintigraphy may be proposed as an easy and highly effective tool for the differential diagnosis of different forms of AIT.
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Efficacy of pulmonary vein isolation in paroxysmal atrial fibrillation patients with a Brugada electrocardiogram.
Yamada, T, Yoshida, Y, Tsuboi, N, Murakami, Y, Okada, T, McElderry, HT, Yoshida, N, Doppalapudi, H, Epstein, AE, Plumb, VJ, et al
Circulation journal : official journal of the Japanese Circulation Society. 2008;(2):281-6
Abstract
BACKGROUND Medical therapy of atrial fibrillation (AF) can be challenging in patients with Brugada electrocardiograms (ECGs). The purpose of this study was to investigate the efficacy of pulmonary vein (PV) isolation (PVI) in AF patients with Brugada ECGs. METHODS AND RESULTS PVI was performed in 6 consecutive patients exhibiting Brugada ECGs (type I in 1, type II in 4, and type III in 1) at baseline. In all patients exhibiting type II or III Brugada ECGs but 1, the administration of sodium-channel blockers converted those ECG patterns to a type I. Five of 6 (83%) patients were free of symptomatic AF without any antiarrhythmic drugs after the first procedure. In the 1 remaining patient with AF recurrence and newly developed atrial tachycardia (AT), the residual conduction gaps of the 3 previously isolated PVs and a focal AT originating from the mitral isthmus were eliminated in the 2nd session. Finally, during the follow-up period (11+/-6 months) after the last procedure, all patients were free of any symptomatic atrial arrhythmias without any antiarrhythmic drugs. No other complications occurred. CONCLUSIONS Because of the concerns of proarrhythmias with antiarrhythmic drugs, PVI may be an effective strategy for highly symptomatic patients with AF who have a Brugada ECG pattern.