Cardiology Department, Hospital Universitario Quironsalud Madrid, Madrid, Spain; Cardiology Department. Complejo Hospitalario Ruber Juan Bravo, Madrid, Spain; Research Institute Hospital Universitario 12 de Octubre (I+12), Madrid, Spain.
Pharmacology and Toxicology Department, School of Medicine, Universidad Complutense de Madrid, Madrid Spain.
Heart Rhythm. 2023 Jun;20(6):822-830. doi: 10.1016/j.hrthm.2023.02.012.
Pharmacological options for rate control in atrial fibrillation are scarce. Ivabradine was postulated to reduce the ventricular rate in this setting.
The objectives of this study were to evaluate the mechanism of inhibition of atrioventricular conduction produced by ivabradine and to determine its efficacy and safety in atrial fibrillation.
The effects of ivabradine on atrioventricular node and ventricular cells were studied by in vitro whole-cell patch-clamp experiments and mathematical simulation of human action potentials. In parallel, a multicenter, randomized, open-label, phase III clinical trial compared ivabradine with digoxin for uncontrolled permanent atrial fibrillation despite β-blocker or calcium channel blocker treatment.
Ivabradine 1 μM inhibited "funny" current and rapidly activating delayed rectifier potassium channel current by 28.9% and 22.8%, respectively (P < .05). The sodium channel current and L-type calcium channel current were reduced only at 10 μM. Ivabradine slowed the firing frequency of a modeled human atrioventricular node action potential by 10.6% and induced a minimal prolongation of ventricular action potential. Thirty-five (51.5%) patients were randomized to ivabradine and 33 (49.5%) to digoxin. The mean daytime heart rate decreased by 11.6 beats/min (-11.5%) in the ivabradine arm (P = .02) vs 19.6 (-20.6%) in the digoxin arm (P < .001), although the noninferiority margin of efficacy was not met (Z = -1.95; P = .97). The primary safety end point occurred in 3 patients (8.6%) on ivabradine and in 8 (24.2%) on digoxin (P = .10).
Ivabradine produced a moderate rate reduction in patients with permanent atrial fibrillation. The inhibition of funny current in the atrioventricular node seems to be the main mechanism responsible for this reduction. Compared with digoxin, ivabradine was less effective, was better tolerated, and had a similar rate of serious adverse events.
在心房颤动中，用于控制心率的药物选择有限。伊伐布雷定被认为可以降低这种情况下的心室率。
本研究的目的是评估伊伐布雷定对房室结传导的抑制机制，并确定其在心房颤动中的疗效和安全性。
通过在体全细胞膜片钳实验和人类动作电位的数学模拟研究了伊伐布雷定对房室结和心室细胞的影响。同时，一项多中心、随机、开放标签、III 期临床试验比较了伊伐布雷定与地高辛在β受体阻滞剂或钙通道阻滞剂治疗后仍无法控制的永久性心房颤动中的疗效。
伊伐布雷定 1 μM 分别抑制“有趣”电流和快速激活延迟整流钾通道电流 28.9%和 22.8%（P<.05）。仅在 10 μM 时才会减少钠通道电流和 L 型钙通道电流。伊伐布雷定使模型人类房室结动作电位的发放频率减慢 10.6%，并引起心室动作电位的最小延长。35 例（51.5%）患者被随机分配至伊伐布雷定组，33 例（49.5%）被分配至地高辛组。伊伐布雷定组日间平均心率下降 11.6 次/分（-11.5%）（P=.02），地高辛组下降 19.6 次/分（-20.6%）（P<.001），但疗效的非劣效性边界未达到（Z=-1.95；P=.97）。伊伐布雷定组有 3 例（8.6%）和地高辛组有 8 例（24.2%）发生主要安全性终点事件（P=.10）。
伊伐布雷定可使永久性心房颤动患者的心率适度降低。房室结中“有趣”电流的抑制似乎是这种降低的主要机制。与地高辛相比，伊伐布雷定疗效较低，耐受性较好，严重不良事件发生率相似。
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