Editor's Note: This Article of the Month is based on Chockalingam P, Girardengo G, Johnson JN et al. Not All Beta-Blockers Are Equal in the Management of Long QT Syndrome Types 1 and 2: Higher Recurrence of Events Under Metoprolol. J Am Coll Cardiol 2012. 60;2092-9.

Summary

Although a number of approaches (e.g., beta blockers, permanent pacing, left cervicothoracic sympathectomy, ICD implantation) have been proposed as therapeutic options for patients with the congenital long QT syndromes (LQTS), beta blocker therapy has served as the mainstay of treatment for the majority of these patients.^1-4 Furthermore, the published guidelines recommended an ICD only for LQTS patients who experience syncope or VT while taking a beta blocker (class IIa indication, level of evidence B).⁵ However, there is a paucity of data on both the differential electrophysiological and clinical effects of the available beta blockers.^6-8 In this retrospective study the authors present data upon the electrocardiographic and clinical effects of propranolol, nadalol, and metoprolol among patients with LQT1 and LQT2.⁹

Methods

In this study, 382 patients with genetically confirmed isolated LQTS 1 or 2 were analyzed to determine potential differences in electrocardiographic and clinical outcomes when treated with standard doses of propranolol, nadolol, or metoprolol. The ECG reading physicians were blinded to treatment choice. The QT interval was calculated according to standard criteria and the QTc was determined using Bazett's formula. The QTc was considered normal if < 450 msec, borderline if between 451-480 msec, and abnormal if > 480 msec. Breakthrough cardiac events (BCEs) included syncope, aborted sudden death, an ICD shock, and sudden death.

Results

Baseline Clinical Characteristics: Baseline demographic, clinical, and electrocardiographic differences were noted. LQT1 was more common among propranolol and nadolol treated patients (p<0.001). The metoprolol treated patients were older (p<0.001). Female gender was more common in the metoprolol treated group (p=0.03). The baseline QTc was longer in the propranolol treated group (p=0.03).

On-Therapy QTc Changes: The overall reduction in QTc was greater among propranolol treated patients than among patients treated with either nadolol (p=0.004) or metoprolol (p=0.003). This reduction in QTc derived entirely from a decrease in the QTc among patients with a baseline abnormal QTc, in whom the shortening in the QTc was greater with propranolol than with either nadolol or metoprolol (p=0.04) since the change in QTc was comparable in all three beta blocker groups with a normal or borderline baseline QTc (p=0.8). Furthermore, among a small group of patients who were switched from propranolol to metoprolol, the QTc on metoprolol was significantly longer than on propranolol (p=0.004). There were no differences in QTc changes between the LQT1 and LQT2 groups.

On-Therapy Clinical Outcomes: In follow-up there were no BCEs among the asymptomatic patients. Among symptomatic patients BCEs (all secondary to syncope) were less common in the propranolol (8%) and nadolol (7%) groups than in the metoprolol group (29%), (p=0.018). Patients who experienced BCEs had less QTc shortening than patients without BCEs (p=0.02). Furthermore, among patients who were symptomatic at baseline, LQT2 patients had more BCEs (24.4%) than LQT1 patients (7.1%), (p=0.02).

Conclusion:

In this retrospective study several potentially significant findings manifest. Patients with a prolonged QTc at baseline had a greater shortening in the QTc with propranolol than with either nadolol or metoprolol. All BCEs in follow-up were observed among patients who were symptomatic at the time of their baseline evaluation. In follow-up, the risk reduction for a BCE was correlated with greater QTc shortening on beta blocker therapy. Finally, metoprolol provided less protection against BCEs than did either propranolol or nadolol.

Perspective:

Despite the methodological flaws and limitations of this study (e.g. retrospective design, baseline demographic and clinical differences among the patient groups, failure to control for treatment differences across the groups), the findings raise several very important therapeutic considerations for clinicians caring for patients with the congenital LQTS. Although clinicians often view beta blockers as similar in their pharmacological characteristics, electrocardiographic manifestations, electrophysiologic properties, and clinical efficacy, it has been established that there are a number of important differences among beta blockers. The findings of this study provide evidence in support of the hypothesis that not all beta blockers are equal in their electrocardiographic effects upon the QTc and their ability to provide protection against potentially serious arrhythmic events.

Pharmacological and electrophysiological differences among beta adrenergic blocking agents include their selectivity, their lipophilicity, and thus their ability to cross the blood-brain barrier, their sodium channel blocking capacity, and their elimination half-life. Compared to metoprolol, propranolol is non-selective, has greater lipophilicity, and different effects on the sodium channels. Propranolol has a strong effect on the late non-inactivating Na⁺ current as well as an effect on the peak Na⁺ current, while nadolol has a weak effect on the latter current but no effect on the former current, and metoprolol has no effect on either current.^10,11 These electrophysiological effects of propranolol on the Na⁺ current probably produce the secondary effects on the QTc that may in turn account for its enhanced clinical efficacy when compared to metoprolol for the treatment of congential LQTS.

Questions about potential differences in intrinsic clinical benefits between the individual beta blockers when used to treat patients with the congenital LQTS have been raised by a number of authors. Some studies have shown a differential clinical effect between different agents.⁶ Others have suggested differential effects between the different beta blockers based upon specific LQT mutations.^8,12-14 Alternative studies have shown no discernable difference in outcome among the employed agents.^3,7 Unfortunately, the small number of evaluated patients and the lack of a robust research design has limited the conclusions that can be drawn from these studies.

Specifically the results of this study suggest that among patients with genetically documented, symptomatic LQT1 or LQT2 and an abnomal baseline QTc (i.e. a QTc > 480 msec.), proranolol is more likely to shorten the QTc than either nadolol or metoprolol, and that either propranolol or nadolol are more likely to reduce the risk of a life-threatening arrhythmic event. Given the observed improvement in the QT interval with propranolol and the improved clinical outcomes with propranolol or nadolol, clinicians should give strong consideration to the preferential use of propranolol or possibly nadolol, as first line beta blocker therapy, in this patient population. Although these preliminary findings are intriguing they are far from definitive. They demonstrate the need for additional study, which at a minimum should include an assessment among patients enrolled in a larger registry.¹⁵

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References

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9. Chockalingam P, Girardengo G, Johnson JN et al. Not All Beta-Blockers Are Equal in the Management of Long QT Syndrome Types 1 and 2: Higher Recurrence of Events Under Metoprolol. J Am Coll Cardiol 2012;60:2092-9.
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13. Barsheshet A, Goldenberg I, O-Uchi J, et al. Mutations in cytoplasmic loops of the KCNQ1 channel and the risk of life-threatening events: implications for mutation-specific response to beta-blocker therapy in type 1 long-QT syndrome. Circulation 2012;125:1988-96.
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Keywords: Adrenergic beta-Antagonists, Long QT Syndrome, Syncope

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