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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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Low-dose Magnesium Sulfate Versus High Dose in the Early Management of Rapid Atrial Fibrillation: Randomized Controlled Double-blind Study (LOMAGHI Study).
Bouida, W, Beltaief, K, Msolli, MA, Azaiez, N, Ben Soltane, H, Sekma, A, Trabelsi, I, Boubaker, H, Grissa, MH, Methemem, M, et al
Academic emergency medicine : official journal of the Society for Academic Emergency Medicine. 2019;(2):183-191
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OBJECTIVES We aim to determine the benefit of two different doses magnesium sulfate (MgSO4 ) compared to placebo in rate control of rapid atrial fibrillation (AF) managed in the emergency department (ED). METHODS We undertook a randomized, controlled, double-blind clinical trial in three university hospital EDs between August 2009 and December 2014. Patients > 18 years with rapid AF (>120 beats/min) were enrolled and randomized to 9 g of intravenous MgSO4 (high-dose group, n = 153), 4.5 g of intravenous MgSO4 (low-dose group, n = 148), or serum saline infusion (placebo group, n = 149), given in addition to atrioventricular (AV) nodal blocking agents. The primary outcome was the reduction of baseline ventricular rate (VR) to 90 beats/min or less or reduction of VR by 20% or greater from baseline (therapeutic response). Secondary outcome included resolution time (defined as the elapsed time from start of treatment to therapeutic response), sinus rhythm conversion rate, and adverse events within the first 24 hours. RESULTS At 4 hours, therapeutic response rate was higher in low- and high-MgSO4 groups compared to placebo group; the absolute differences were, respectively, 20.5% (risk ratio [RR] = 2.31, 95% confidence interval [CI] = 1.45-3.69) and +15.8% (RR = 1.89, 95% CI = 1.20-2.99). At 24 hours, compared to placebo group, therapeutic response difference was +14.1% (RR = 9.74, 95% CI = 2.87-17.05) with low-dose MgSO4 and +10.3% (RR = 3.22, 95% CI = 1.45-7.17) with high-dose MgSO4 . The lowest resolution time was observed in the low-dose MgSO4 group (5.2 ± 2 hours) compared to 6.1 ± 1.9 hours in the high-dose MgSO4 group and 8.4 ± 2.5 hours in the placebo group. Rhythm control rate at 24 hours was significantly higher in the low-dose MgSO4 group (22.9%) compared to the high-dose MgSO4 group (13.0%, p = 0.03) and the placebo group (10.7%). Adverse effects were minor and significantly more frequent with high-dose MgSO4 . CONCLUSIONS Intravenous MgSO4 appears to have a synergistic effect when combined with other AV nodal blockers resulting in improved rate control. Similar efficacy was observed with 4.5 and 9 g of MgSO4 but a dose of 9 g was associated with more side effects.
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Efficacy and safety of nicorandil on perioperative myocardial injury in patients undergoing elective percutaneous coronary intervention: results of the PENMIPCI trial.
Ye, Z, Lu, H, Su, Q, Long, M, Li, L
Drug design, development and therapy. 2018;:2591-2599
Abstract
BACKGROUND Previous studies have indicated that nicorandil can reduce perioperative myocardial injury (PMI) in patients undergoing elective percutaneous coronary intervention (ePCI), but this conclusion is still controversial. Additionally, studies reporting on the safety of nicorandil are lacking. Therefore, we performed this prospective study to evaluate the efficacy and safety of nicorandil on PMI in patients undergoing ePCI. METHODS One hundred and forty-six patients with coronary heart disease (CHD) scheduled to undergo ePCI were randomly assigned to the nicorandil group (n=74) or control group (n=72). The primary outcomes were the change in cardiac troponin T (cTnT) and creatine kinase-MB (CK-MB) at 12 and 24 hours after surgery. The secondary outcome was the incidence of major adverse cardiac events (MACE), which was a composite of cardiac death, nonfatal myocardial infarction, new heart failure or coronary revascularization. RESULTS There was no difference in age (54.76±5.93 vs 56.35±5.22) between the nicorandil group and the control group. In addition, no differences were observed in the cTnT and CK-MB levels between the two groups at admission (all P⩾0.05). Compared with those in the control group, the cTnT (0.15±0.12 vs 0.12±0.10 at 12 hours and 0.17±0.12 vs 0.13±0.10 at 24 hours) and CK-MB (15.35±8.23 vs 12.31±7.93 at 12 hours and 13.63±8.87 vs 11.13±5.71 at 24 hours) levels in the nicorandil group were significantly decreased after surgery (all P⩽0.05). Furthermore, nicorandil did not increase the incidence of MACE in the nicorandil group compared with the control group (12.16% vs 12.50%). CONCLUSIONS Nicorandil can reduce PMI in patients undergoing ePCI and does not increase the incidence of MACE. CLINICAL TRIAL REGISTRATION URL: http://www.chictr.org.cn/. Unique Identifier: ChiCTR-IOR-17012056.
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Efficacy of Flecainide in the Treatment of Catecholaminergic Polymorphic Ventricular Tachycardia: A Randomized Clinical Trial.
Kannankeril, PJ, Moore, JP, Cerrone, M, Priori, SG, Kertesz, NJ, Ro, PS, Batra, AS, Kaufman, ES, Fairbrother, DL, Saarel, EV, et al
JAMA cardiology. 2017;(7):759-766
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IMPORTANCE Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal genetic arrhythmia syndrome characterized by polymorphic ventricular tachycardia with physical or emotional stress, for which current therapy with β-blockers is incompletely effective. Flecainide acetate directly suppresses sarcoplasmic reticulum calcium release-the cellular mechanism responsible for triggering ventricular arrhythmias in CPVT-but has never been assessed prospectively. OBJECTIVE To determine whether flecainide dosed to therapeutic levels and added to β-blocker therapy is superior to β-blocker therapy alone for the prevention of exercise-induced arrhythmias in CPVT. DESIGN, SETTING, AND PARTICIPANTS This investigator-initiated, multicenter, single-blind, placebo-controlled crossover clinical trial was conducted from December 19, 2011, through December 29, 2015, with a midtrial protocol change at 10 US sites. Patients with a clinical diagnosis of CPVT and an implantable cardioverter-defibrillator underwent a baseline exercise test while receiving maximally tolerated β-blocker therapy that was continued throughout the trial. Patients were then randomized to treatment A (flecainide or placebo) for 3 months, followed by exercise testing. After a 1-week washout period, patients crossed over to treatment B (placebo or flecainide) for 3 months, followed by exercise testing. INTERVENTIONS Patients received oral flecainide or placebo twice daily, with the dosage guided by trough serum levels. MAIN OUTCOMES AND MEASURES The primary end point of ventricular arrhythmias during exercise was compared between the flecainide and placebo arms. Exercise tests were scored on an ordinal scale of worst ventricular arrhythmia observed (0 indicates no ectopy; 1, isolated premature ventricular beats; 2, bigeminy; 3, couplets; and 4, nonsustained ventricular tachycardia). RESULTS Of 14 patients (7 males and 7 females; median age, 16 years [interquartile range, 15.0-22.5 years]) randomized, 13 completed the study. The median baseline exercise test score was 3.0 (range, 0-4), with no difference noted between the baseline and placebo (median, 2.5; range, 0-4) exercise scores. The median ventricular arrhythmia score during exercise was significantly reduced by flecainide (0 [range, 0-2] vs 2.5 [range, 0-4] for placebo; P < .01), with complete suppression observed in 11 of 13 patients (85%). Overall and serious adverse events did not differ between the flecainide and placebo arms. CONCLUSIONS AND RELEVANCE In this randomized clinical trial of patients with CPVT, flecainide plus β-blocker significantly reduced ventricular ectopy during exercise compared with placebo plus β-blocker and β-blocker alone. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01117454.
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Impact of treatment crossovers on clinical outcomes in the rate and rhythm control strategies for atrial fibrillation: Insights from the AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) trial.
Maan, A, Zhang, Z, Qin, Z, Wang, Y, Dudley, S, Dabhadakar, K, Refaat, M, Mansour, M, Ruskin, JN, Heist, EK
Pacing and clinical electrophysiology : PACE. 2017;(7):770-778
Abstract
We investigated the rates and reasons for crossover to alternative treatment strategies and its impact on mortality in patients who were enrolled in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial. Over a mean follow-up period of 3.5 years, 842 patients underwent crossover to the alternative treatment arms in AFFIRM. The rate of crossover from rhythm to rate control (594/2,033, 29.2%) was more frequent than the rate of crossover from rate to rhythm control (248/2,027, 12.2%, P < 0.0001). The leading reasons for crossover from rhythm to rate control were failure to achieve or maintain sinus rhythm (272/594, 45.8%) and intolerable adverse effects (122/594, 20.5%). In comparison, the major reasons for crossover from rate to rhythm control were failure to control atrial fibrillation symptoms (159/248, 64.1%) and intolerable adverse effects (9/248, 3.6%). This difference in crossover pattern was statistically significant (P < 0.0001). There was a significantly decreased risk of all-cause mortality (adjusted HR: 0.61, 95% CI: 0.48-0.78, P < 0.0001) and cardiac mortality (adjusted hazard ratio [HR]: 0.61, 95% confidence interval [CI]: 0.43-0.88, P = 0.008) in the subgroup of patients who crossed over from rhythm to rate control as compared to those who continued in rhythm control. There was a nonsignificant trend toward decreased all-cause (adjusted HR: 0.76, 95% CI: 0.53-1.10, P = 0.14) and cardiac mortality (adjusted HR: 0.70, 95% CI: 0.42-1.18, P = 0.18) in patients who crossed over from rate to rhythm control as compared to those who continued rate control.
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Troponin I levels in permanent atrial fibrillation-impact of rate control and exercise testing.
Horjen, AW, Ulimoen, SR, Enger, S, Norseth, J, Seljeflot, I, Arnesen, H, Tveit, A
BMC cardiovascular disorders. 2016;:79
Abstract
BACKGROUND High-sensitivity troponin I (hs-TnI) and troponin T (hs-TnT) are moderately correlated and independently related to outcome in atrial fibrillation (AF). Rate controlling therapy has been shown to reduce hs-TnT, however the potential impact on hs-TnI levels, and whether this differs from the effects on hs-TnT, has not been investigated previously. METHODS Sixty patients with stable, permanent AF without heart failure or known ischemic heart disease were included in a randomised crossover study (mean age 71 ± 9 years, 18 women). Diltiazem 360 mg, verapamil 240 mg, metoprolol 100 mg, and carvedilol 25 mg were administered once daily for three weeks, in a randomised sequence. At baseline and on the last day of each treatment period, hs-TnI was measured at rest and after a maximal exercise test and compared to hs-TnT. RESULTS Hs-TnI and hs-TnT correlated moderately at baseline (rs = 0.582, p < 0.001). All drugs reduced both the resting and the peak exercise levels of hs-TnI compared with baseline (p < 0.001 for all). The decline in resting hs-TnI and hs-TnT values relative to baseline levels was similar for all drugs except for verapamil, which reduced hs-TnI more than hs-TnT (p = 0.017). Levels of hs-TnI increased significantly in response to exercise testing at baseline and at all treatment regimens (p < 0.001 for all). The relative exercise-induced increase in hs-TnI was significantly larger compared to hs-TnT at baseline (p < 0.001), on diltiazem (p < 0.001) and on verapamil (p = 0.001). CONCLUSIONS In our population of stable, permanent AF patients, all four rate control drug regimens reduced hs-TnI significantly, both at rest and during exercise. The decline in hs-TnI and hs-TnT levels associated with beta-blocker and calcium channel blocker treatment was similar, except for a larger relative decrease in hs-TnI levels following verapamil treatment. TRIAL REGISTRATION www.clinicaltrials.gov ( NCT00313157 ).
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Increased Heart Rate Is Associated With Higher Mortality in Patients With Atrial Fibrillation (AF): Results From the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF).
Steinberg, BA, Kim, S, Thomas, L, Fonarow, GC, Gersh, BJ, Holmqvist, F, Hylek, E, Kowey, PR, Mahaffey, KW, Naccarelli, G, et al
Journal of the American Heart Association. 2015;(9):e002031
Abstract
BACKGROUND Most patients with atrial fibrillation (AF) require rate control; however, the optimal target heart rate remains under debate. We aimed to assess rate control and subsequent outcomes among patients with permanent AF. METHODS AND RESULTS We studied 2812 US outpatients with permanent AF in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation. Resting heart rate was measured longitudinally and used as a time-dependent covariate in multivariable Cox models of all-cause and cause-specific mortality during a median follow-up of 24 months. At baseline, 7.4% (n=207) had resting heart rate <60 beats per minute (bpm), 62% (n=1755) 60 to 79 bpm, 29% (n=817) 80 to 109 bpm, and 1.2% (n=33) ≥110 bpm. Groups did not differ by age, previous cerebrovascular disease, heart failure status, CHA2DS2-VASc scores, renal function, or left ventricular function. There were significant differences in race (P=0.001), sinus node dysfunction (P=0.004), and treatment with calcium-channel blockers (P=0.006) and anticoagulation (P=0.009). In analyses of continuous heart rates, lower heart rate ≤65 bpm was associated with higher all-cause mortality (adjusted hazard ratio [HR], 1.15 per 5-bpm decrease; 95% CI, 1.01 to 1.32; P=0.04). Similarly, increasing heart rate >65 bpm was associated with higher all-cause mortality (adjusted HR, 1.10 per 5-bpm increase; 95% CI, 1.05 to 1.15; P<0.0001). This relationship was consistent across endpoints and in a broader sensitivity analysis of permanent and nonpermanent AF patients. CONCLUSIONS Among patients with permanent AF, there is a J-shaped relationship between heart rate and mortality. These data support current guideline recommendations, and clinical trials are warranted to determine optimal rate control. CLINICAL TRIAL REGISTRATION URL: http://clinicaltrials.gov/. Unique identifier: NCT01165710.
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Rate-control drugs affect variability and irregularity measures of RR intervals in patients with permanent atrial fibrillation.
Corino, VD, Ulimoen, SR, Enger, S, Mainardi, LT, Tveit, A, Platonov, PG
Journal of cardiovascular electrophysiology. 2015;(2):137-41
Abstract
INTRODUCTION Irregularity measures have been suggested as risk indicators in patients with atrial fibrillation (AF); however, it is not known to what extent they are affected by commonly used rate-control drugs. We aimed at evaluating the effect of metoprolol, carvedilol, diltiazem, and verapamil on the variability and irregularity of the ventricular response in patients with permanent AF. METHODS AND RESULTS Sixty patients with permanent AF were part of an investigator-blind cross-over study, comparing 4 rate-control drugs (diltiazem, verapamil, metoprolol, and carvedilol). We analyzed five 20-minute segments per patient: baseline and the 4 drug regimens. On every segment, heart rate (HR) variability and irregularity of RR series were computed. The variability was assessed as standard deviation, pNN20, pNN50, pNN80, and rMSSD. The irregularity was assessed by regularity index, approximate (ApEn), and sample entropy. A significantly lower HR was obtained with all drugs, the HR was lowest using the calcium channel blockers. All drugs increased the variability of ventricular response in respect to baseline (as an example, rMSSD: baseline 171 ± 47 milliseconds, carvedilol 229 ± 58 milliseconds; P < 0.05 vs. baseline, metoprolol 226 ± 66 milliseconds; P < 0.05 vs. baseline, verapamil 228 ± 84; P < 0.05 vs. baseline, diltiazem 256 ± 87 milliseconds; P < 0.05 vs. baseline and all other drugs). Only β-blockers significantly increased the irregularity of the RR series (as an example, ApEn: baseline 1.86 ± 0.13, carvedilol 1.92 ± 0.09; P < 0.05 vs. baseline, metoprolol 1.93 ± 0.08; P < 0.05 vs. baseline, verapamil 1.86 ± 0.22 ns, diltiazem 1.88 ± 0.16 ns). CONCLUSION Modification of AV node conduction by rate-control drugs increase RR variability, while only β-blockers affect irregularity.
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Pulmonary vein triggers play an important role in the initiation of atrial flutter: Initial results from the prospective randomized Atrial Fibrillation Ablation in Atrial Flutter (Triple A) trial.
Schneider, R, Lauschke, J, Tischer, T, Schneider, C, Voss, W, Moehlenkamp, F, Glass, A, Diedrich, D, Bänsch, D
Heart rhythm. 2015;(5):865-71
Abstract
BACKGROUND The incidence of atrial fibrillation (AF) after ablation of a cavotricuspid isthmus (CTI)-dependent atrial flutter (AFL) is high. OBJECTIVE The purpose of this study was to test the hypothesis that AFL and AF may be initiated by pulmonary vein triggers. This prospective randomized trial tested the efficacy of a standalone pulmonary vein isolation (PVI) in patients with AFL but without AF. METHODS Patients with AFL but without documented AF were randomly assigned to 1 of 3 treatment groups: (1) antiarrhythmic drugs (AAD), (2) CTI ablation, or (3) circumferential PVI. The primary end-point was defined as any recurrent atrial tachyarrhythmia and the secondary end-point as recurrence of AFL. In case of tachyarrhythmia recurrence in the PVI group, a second PVI was performed to close gaps in the ablation lines. RESULTS Of the 60 patients, 17 were randomized to AAD, 23 to CTI ablation, and 20 to PVI. During follow-up of 1.42 ± 0.83 years, 14 of 17 patients (82.4%) in the AAD group, 14 of 23 patients (60.9%) in the CTI group, and 2 of 20 patients (10%) in the PVI group reached the primary end-point (P <.001) after a mean of 1.4 PVI procedures per patient. AFL reoccurred in 9 patients (52.9.%) in the AAD group, in 2 patients (8.7%) in the CTI group, and after a single PVI in 3 patients (15%) in the PVI group (P = .003). After closure of gaps, 1 patient (5%) in the PVI group presented with recurrent AFL. CONCLUSION Pulmonary vein triggers play an important role in AFL. PVI can prevent the recurrence of AFL, even without CTI ablation.
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Diltiazem vs. Metoprolol in the Management of Atrial Fibrillation or Flutter with Rapid Ventricular Rate in the Emergency Department.
Fromm, C, Suau, SJ, Cohen, V, Likourezos, A, Jellinek-Cohen, S, Rose, J, Marshall, J
The Journal of emergency medicine. 2015;(2):175-82
Abstract
BACKGROUND Diltiazem (calcium channel blocker) and metoprolol (beta-blocker) are both commonly used to treat atrial fibrillation/flutter (AFF) in the emergency department (ED). However, there is considerable regional variability in emergency physician practice patterns and debate among physicians as to which agent is more effective. To date, only one small prospective, randomized trial has compared the effectiveness of diltiazem and metoprolol for rate control of AFF in the ED and concluded no difference in effectiveness between the two agents. OBJECTIVE Our aim was to compare the effectiveness of diltiazem with metoprolol for rate control of AFF in the ED. METHODS A convenience sample of adult patients presenting with rapid atrial fibrillation or flutter was randomly assigned to receive either diltiazem or metoprolol. The study team monitored each subject's systolic and diastolic blood pressures and heart rates for 30 min. RESULTS In the first 5 min, 50.0% of the diltiazem group and 10.7% of the metoprolol group reached the target heart rate (HR) of <100 beats per minute (bpm) (p < 0.005). By 30 min, 95.8% of the diltiazem group and 46.4% of the metoprolol group reached the target HR < 100 bpm (p < 0.0001). Mean decrease in HR for the diltiazem group was more rapid and substantial than that of the metoprolol group. From a safety perspective, there was no difference between the groups with respect to hypotension (systolic blood pressure < 90 mm Hg) and bradycardia (HR < 60 bpm). CONCLUSIONS Diltiazem was more effective in achieving rate control in ED patients with AFF and did so with no increased incidence of adverse effects.