Bradycardia and atrial fibrillation in patients with stable coronary artery disease treated with ivabradine: an analysis from the SIGNIFY study

Fox, Kim; Ford, Ian; Steg, Philippe Gabriel; Tardif, Jean‐Claude; Tendera, Michał; Ferrari, Roberto

doi:10.1093/eurheartj/ehv451

Cited by 34 publications

(27 citation statements)

References 13 publications

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“…However, Martin et al have conducted a Meta analysis of five randomized trials with ivabradine, and reported a 15% increase in the relative risk of developing AF in patients receiving ivabradine. Another study performed by Fox et al showed that the incidence of emergent AF on ivabradine treatment group was similar with that of the placebo group (2.2% per year ivabradine vs 1.5% per year placebo) in patients with stable coronary artery disease. Ivabradine was also found to decrease the sinoatrial functions while inhibiting the I f current, and thus increase the risk of AF, which was in contrast to our results.…”

Section: Discussionmentioning

confidence: 77%

Long‐term treatment with ivabradine in transgenic atrial fibrillation mice counteracts hyperpolarization‐activated cyclic nucleotide gated channel overexpression

Wang

Yang

et al. 2018

Cardiovasc electrophysiol

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Introduction: Recent studies have demonstrated that ivabradine (IVA), is a selective inhibitor of funny current (If) and exerts antiarrhythmic effects in the settings of various diseases such as heart failure and myocardial ischemia. However, little is known regarding the effects of long-term IVA treatment on I f current and hyperpolarization-activated cyclic nucleotide gated (HCN) channel overexpression. Methods and Results:We investigated both the I f current and HCN channel expression in wild-type (WT) mice and transgenic (TG) atrial fibrillation (AF) mice (heart-specific overexpressing of (pro) renin receptor TG mice) and examined the effects of IVA on the I f current and HCN channel expression, and whether those effects were sufficient to prevent an AF episode. Compared with WT mice, the I f current density (at −170 mV: TG, −39.6 ± 4.6 pA/pF; WT, −26.9 ± 3.0 pA/pF; P < 0.001) and activation kinetics (V 1/2 : TG, −109.45 ± 1.35 mV; WT, −128.20 ± 1.65 mV), as well as HCN2 and HCN4 messenger RNA expression and HCN4 protein expression were significantly increased in the atrial myocytes of TG mice. After 4 months of IVA treatment (7 mg/kg per day orally) the effects of IVA on TG AF mice were accompanied by the inhibition of upregulation of HCN2 and HCN4 protein expression in atrial tissue, and then resulted in a uniform I f loss of function. Furthermore, we observed that ivabradine significantly decreased the incidence of AF in the TG mice (41.2% in TG mice, 16.7% in TG + IVA mice; P < 0.01).Conclusion: IVA reduced the incidence of AF in mice, and the antiarrhythmic effects of IVA are not limited to heart rate reduction, as they partially counteract HCN overexpression and reverse electrophysiological cardiac remodeling by attenuating I f gain-of-function. K E Y W O R D S atrial fibrillation, funny current, hyperpolarization-activated cyclic nucleotide gated channels, Ivabradine, transgenic mice J Cardiovasc Electrophysiol. 2019;30:242-252. wileyonlinelibrary.com/journal/jce 242 |

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Section: Discussionmentioning

confidence: 77%

Long‐term treatment with ivabradine in transgenic atrial fibrillation mice counteracts hyperpolarization‐activated cyclic nucleotide gated channel overexpression

Wang

Yang

et al. 2018

Cardiovasc electrophysiol

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“…Показано, что на фоне оптимальной терапии снижение ЧСС ниже 70 уд/мин за счет дополнительного назначения ивабрадина ассоциировалось со снижением риска развития фатальных и нефатальных коронарных катастроф на 36% и необходимости в реваскуляризации на 30% (p=0,001). Тем не менее, по данным исследования SIGNIFY [15], проведенного на 18 тыс. пациентов в 2014 г. при отсутствии проявлений недостаточности кровообращения аргументации в пользу улучшения прогноза не получено.…”

Section: Discussionunclassified

Possibilities of Combination of Beta-blockers and Ivabradine in Patients with Stable Angina Pectoris

Кашталап

Barbarash

Sedykh

et al. 2019

Racionalʹnaâ farmakoterapiâ v kardiologii

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Aim. To evaluate the therapeutic efficacy of a combination of ivabradine and beta-blockers (BAB) in patients with stable angina, initially taking only BAB and not reaching the target heart rate (HR) due to the risk of hypotension.Material and methods. A prospective observational post-registration study was performed at the Research Institute for Complex Issues of Cardiovascular Diseases. The study included 50 patients with stable angina pectoris (diagnosed by coronary angiography in combination with clinical manifestations of angina of functional class II-III according to the Canadian classification) and an initial sinus rhythm with a heart rate of more than 70 beats per minute. These patients have already taken BAB. Heart rate, the number of angina attacks, nitrate intake and quality of life indicators according to the questionnaire were evaluated as criteria for therapeutic efficacy.Results. Taking the study drug in combination with BAB led to a significant decrease the average heart rate at rest by 20%, as well as after a six-minute walk test (TLC) in most patients (p<0.050), and a decrease in the total number of angina attacks per week from 5 to less than 1 (p<0.050) and the frequency of nitrate intake for the relief of angina attacks from 58% to 20% (p=0.001). Therapy with ivabradine (Bravadin) was well tolerated by patients: there were no adverse events in the observed sample of patients, patients had a high adherence to treatment (100% of the contents of handed out blisters were used). During the 3 months of follow-up, according to the EQ-5D-5L quality of life questionnaire, patients improved their perception of their own health level (p<0.050), the number of patients experiencing mild (p=0.034) and strong (p=0.041) mobility limitations decreased; strong (p=0.024) restriction in self-care, mild (p=0.041) and strong (p=0.024) restriction of daily activities, mild manifestation of pain (p=0.009) and mild anxiety (p=0.027) also were reduced compared with the initial questionnaires.Conclusion. Ivabradine (Bravadin) in addition to BAB is an effective and safe antianginal therapy for the prevention of angina attacks by reducing the initially high heart rate in patients with angina pectoris of functional class II-III.

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“…60 When only emergent atrial fibrillation in SIGNIFY was considered, 74% of patients had no history of atrial fibrillation, and most cases were paroxysmal. 58 Although the incidence of the primary composite end point and stroke was comparable for those who developed atrial fibrillation on ivabradine and on placebo in SIGNIFY, this analysis lacked power, and a detectable downstream harm may manifest only when a large population can be analyzed for a longer duration.…”

Section: Adverse Eventsmentioning

confidence: 97%

“…Fortunately, no association was found between emergent bradycardia (HR <50 bpm) and the primary SIGNIFY end point, either in the total population or in those with activity-limiting angina. 58 Given the worse prognosis for patients with HF and atrial fibrillation compared with those with HF alone, the 1.5% absolute risk increase in atrial fibrillation over 28 months with ivabradine therapy (0.7% yearly absolute increased risk) in SIGNIFY is striking. 45,59 In the pooled analysis from SHIFT and BEAUTIFUL with baseline HR ≥70 bpm, there was a similar 1.7% increase in the absolute risk of atrial fibrillation (P<0.001) with ivabradine.…”

Section: Adverse Eventsmentioning

confidence: 99%

Ivabradine

Psotka

Teerlink

2016

Circulation

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Abstract-Ivabradine is approved to reduce hospitalizations for patients with symptomatic heart failure, reduced ejection fraction, and persistently elevated heart rate despite otherwise maximal medical therapy. However, the eligible patient population is a small fraction of those with heart failure overall. This review summarizes the major clinical evidence supporting the use of ivabradine, identifies and discusses areas of uncertainty from the clinical trial data, helps describe the population most likely to benefit, and attempts to place ivabradine within the multifaceted treatment scheme currently used for patients with heart failure and reduced ejection fraction.

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Bradycardia and atrial fibrillation in patients with stable coronary artery disease treated with ivabradine: an analysis from the SIGNIFY study

Abstract: ISRCTN61576291.

Cited by 34 publications

References 13 publications

Long‐term treatment with ivabradine in transgenic atrial fibrillation mice counteracts hyperpolarization‐activated cyclic nucleotide gated channel overexpression

Long‐term treatment with ivabradine in transgenic atrial fibrillation mice counteracts hyperpolarization‐activated cyclic nucleotide gated channel overexpression

Possibilities of Combination of Beta-blockers and Ivabradine in Patients with Stable Angina Pectoris

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