Proarrhythmic Safety of Repeat Doses of Mirabegron in Healthy Subjects: A Randomized, Double-Blind, Placebo-, and Active-Controlled Thorough QT Study

Malik, Marek; Gelderen, E. Marcel van; Lee, J H; Kowalski, Donna; Yen, Mark; Goldwater, Ronald; Mujais, Salim; Schaddelee, Marloes; Koning, P de; Kaibara, Atsunori; Moy, Selina; Keirns, James J.

doi:10.1038/clpt.2012.181

Cited by 128 publications

(151 citation statements)

References 37 publications

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“…As previously published (25), the clinical study providing the baseline recordings was ethically approved and conformed with the principles outlined in the Declaration of Helsinki. All study subjects gave written informed consent.…”

Section: Methodsmentioning

confidence: 99%

“…Data were obtained from a previously published study (25) that enrolled 176 female healthy subjects and 176 male healthy subjects. Table 1 shows the descriptive characteristics of the population.…”

Section: Methodsmentioning

confidence: 99%

“…Using previously published quality assurance techniques (12,24,25), QT and RR intervals were measured in repeated 10-s ECG segments of each baseline recording. In addition to segments that corresponded to per-protocol study time points, the segments were also selected based on heart rate scans of the entire recording to obtain wide ranges of heart rates (25). For the same purpose, the per-protocol baseline study time points included repeated postural provocation maneuvers (25).…”

Section: Methodsmentioning

confidence: 99%

“…Since the design of accurate individual QT rate corrections depends on accurate mathematical description of baseline QT/RR relationship (9), it has been proposed to fit different nonlinear models to the data of different individuals, which, in essence, means to classify the curvatures of the QT/RR patterns into several distinct categories (10,12). While this technology has been used successfully in studies of electrocardiographic drug effects (24,25), it does not deal with the problem of the QT/RR curvature fully (26). Instead of classification into different ad hoc-selected categories, technology is needed to describe the curvatures of QT/RR patterns on a continuous numeric scale.…”

mentioning

confidence: 99%

“…With this in mind, we used data of a previous study (25) that obtained repeated Holter recordings in hundreds of healthy subjects to propose numeric measurements of the curvatures of QT/RR patterns and to compare them between healthy women and men since many other aspects of normal cardiac electrophysiology are sex dependent (32).…”

mentioning

confidence: 99%

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QT/RR curvatures in healthy subjects: sex differences and covariates

Malik

Hnatkova²,

Kowalski

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Data of a large clinical study were used to investigate how much are the QT/RR patterns in healthy subjects curved and whether these curvatures differ between women and men. Daytime drug-free 12-lead Holter recordings were repeated 4 times in each of 176 female healthy subjects and 176 male healthy subjects aged 32.7 Ϯ 9.1 yr. In each of the subjects, up to 1,440 carefully verified QT interval measurements were obtained with QT/RR hysteresis-corrected RR intervals. Individual subject data were used to fit the following regression equation: QT ϭ ϩ (␦/␥)(1 Ϫ RR ␥ ) ϩ ε, where QT and RR are QT and RR measurements (in s), is regression intercept, ␦ is the QT/RR slope, ␥ is the QT/RR curvature and provides the lowest regression residual, and ε represents normally distributed zero-centered errors. The bootstrap technique showed the intrasubject reproducibility of QT/RR slopes and curvatures. In women and men, QT/RR curvatures were 0.544 Ϯ 0.661 and 0.797 Ϯ 0.706, respectively (P ϭ 0.0006). The corresponding QT/RR slopes were 0.158 Ϯ 0.030 and 0.139 Ϯ 0.023, respectively (P Ͻ 0.0001). QT/RR curvatures were related to QT/RR slopes but not to individually corrected mean QTc intervals or individual QT/RR hysteresis profiles. The individual heart rate correction formula derived from the curvilinear regression provided a significantly lower intrasubject variability of QTc interval than individual optimisation of linear or log-linear QT/RR heart rate corrections. The QT/RR curvature can be reliable measured and expressed numerically. The corresponding heart rate correction formula provides more compact data than the previously proposed approaches. There are substantial sex differences in QT/RR patterns. Women have a QT/RR pattern that is not only steeper than men but also more curved.QT/RR curvature profile; intrasubject stability; intersubject differences; QT heart rate correction THE DEPENDENCY of the duration of ventricular repolarization on the underlying heart rate is well known. It is also known that it is related to a similar dependency of action potential durations (7) that shows regional differences within the ventricular myocardium (23). Similarly, delayed adaptation of action potential durations after abrupt changes in stimulation rates are well known (8). The intracellular mechanism underlying the repolarization dependency and thus the pattern of the QT/RR relationship are not completely understood and have been subject of both animal and modeling experiments of ionic currents (11,19,22). Why the QT/RR relationship and adaptation exhibits substantial intersubject differences with intrasubject stability (3, 27) is not known. Further studies of the phenomenon require appropriate tools for the description of the relationship.A number of studies (5, 6, 10, 16) assessed the slope of the QT/RR relationship in long-term Holter recordings and investigated its meaning as a clinical characteristic. The majority of these studies investigated the relationship by means of linear regression between simultaneously measured QT a...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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QT/RR curvatures in healthy subjects: sex differences and covariates

Malik

Hnatkova²,

Kowalski

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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β3 adrenergic agonist treatment in chronic pulmonary hypertension associated with heart failure (SPHERE‐HF): a double blind, placebo‐controlled, randomized clinical trial

García

Blanco

García‐Lunar

et al. 2022

European J of Heart Fail

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Pulmonary hypertension (PH) associated with left heart disease is an increasingly prevalent problem, orphan of targeted therapies, and related to a poor prognosis, particularly when pre-and post-capillary PH combine. The current study aimed to determine whether treatment with the selective β3 adrenoreceptor agonist mirabegron improves outcomes in patients with combined pre-and post-capillary PH (CpcPH).

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Cardiovascular Safety of the β₃‐Adrenoceptor Agonist Mirabegron and the Antimuscarinic Agent Solifenacin in the SYNERGY Trial

White

Chapple

Gratzke

et al. 2018

The Journal of Clinical Pharma

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There have been concerns that treatment of overactive bladder with β -adrenoceptor agonists may potentially have detrimental cardiovascular (CV) side effects. We evaluated the CV safety of mirabegron, a β -adrenoceptor agonist, alone and in combination therapy with the antimuscarinic agent solifenacin. The SYNERGY trial was a multinational, multicenter, randomized, double-blind, parallel-group, placebo and active-controlled phase 3 trial. Patients were randomized to receive solifenacin 5 mg + mirabegron 50 mg (combination 5 + 50 mg), solifenacin 5 mg + mirabegron 25 mg (combination 5 + 25 mg), solifenacin 5 mg monotherapy, mirabegron 25 mg monotherapy, mirabegron 50 mg monotherapy, or placebo for a 12-week double-blind treatment period. A total of 3398 patients were included in the study. Mean changes from baseline to the end of therapy in ECG parameters were similar across treatment groups, although there was an increase in heart rate of 1 beat/minute in the mirabegron treatment groups. There were no clinically meaningful differences in change from baseline in QTcF between monotherapies and placebo and between monotherapies and combination therapy. There were very few major CV events: 1 of 853 (0.1%) with a nonfatal myocardial infarction in the combination 5 + 25 mg group, 2 of 848 (0.2%) with a nonfatal stroke in the combination 5 + 50 mg group, and no events in the other groups. This CV safety analysis of the combination of mirabegron and solifenacin showed rates of CV events comparable with those for monotherapy treatments based on assessments of vital signs, electrocardiograms, and adjudicated CV events.

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Proarrhythmic Safety of Repeat Doses of Mirabegron in Healthy Subjects: A Randomized, Double-Blind, Placebo-, and Active-Controlled Thorough QT Study

Cited by 128 publications

References 37 publications

QT/RR curvatures in healthy subjects: sex differences and covariates

QT/RR curvatures in healthy subjects: sex differences and covariates

β3 adrenergic agonist treatment in chronic pulmonary hypertension associated with heart failure (SPHERE‐HF): a double blind, placebo‐controlled, randomized clinical trial

Cardiovascular Safety of the β₃‐Adrenoceptor Agonist Mirabegron and the Antimuscarinic Agent Solifenacin in the SYNERGY Trial

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Proarrhythmic Safety of Repeat Doses of Mirabegron in Healthy Subjects: A Randomized, Double-Blind, Placebo-, and Active-Controlled Thorough QT Study

Cited by 128 publications

References 37 publications

QT/RR curvatures in healthy subjects: sex differences and covariates

QT/RR curvatures in healthy subjects: sex differences and covariates

β3 adrenergic agonist treatment in chronic pulmonary hypertension associated with heart failure (SPHERE‐HF): a double blind, placebo‐controlled, randomized clinical trial

Cardiovascular Safety of the β3‐Adrenoceptor Agonist Mirabegron and the Antimuscarinic Agent Solifenacin in the SYNERGY Trial

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Cardiovascular Safety of the β₃‐Adrenoceptor Agonist Mirabegron and the Antimuscarinic Agent Solifenacin in the SYNERGY Trial