Author + information
- †Department of Cardiology, Heart Failure Research Centre, Academic Medical Centre, Amsterdam, the Netherlands
- ‡Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia
- §Departments of Medicine, Pediatrics, and Molecular Pharmacology and Experimental Therapeutics/Divisions of Cardiovascular Diseases and Pediatric Cardiology and the Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota
- ↵∗Reprint requests and correspondence:
Dr. Arthur A.M. Wilde, Department of Cardiology, Heart Failure Research Centre, Academic Medical Centre, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands.
The most common primary inherited arrhythmia syndrome is the congenital long QT syndrome (LQTS). Prolonged QT interval on the electrocardiogram (ECG) is the signature feature of this disease, which is associated with an increased propensity to (arrhythmogenic) syncope and sudden death. The diagnosis is mainly based on the QT interval corrected for heart rate (QTc), but a clinical scoring system (the Schwartz score), which combines molecular genetic testing and several clinical and electrocardiographic parameters, also plays a role (1). Management of patients with LQTS, whose risk is predominantly determined by their QTc on the baseline ECG and by prior expressivity, involves life-style modifications (including avoidance of QT-prolonging drugs) and antiadrenergic therapy, either by β-blockers (class 1 recommendation in all symptomatic patients and also in asymptomatic patients with QTc ≥470 ms) or by left cardiac sympathetic denervation (class 1 recommendations in “high risk patients in whom β-blockers are either not effective in preventing syncope/arrhythmias, not tolerated, not accepted or contraindicated and/or in whom implantable cardioverter-defibrillator treatment is contraindicated or refused”) (1).
The central role of β-blockers in LQTS has been established since the 1970s (2,3). It is, however, known that breakthrough cardiac events (BCEs) occur, particularly in previously symptomatic patients who are receiving β-blocker treatment (3–8). Multiple factors are involved in an eventual favorable response, the most important of which are the dosage and type of β-blocker. Indeed, differences in the pharmacodynamics and pharmacokinetics of various β-blockers (including their lipophilicity) are well known. Moreover, secondary to the selectivity of β-blockers for different subtypes of β-adrenergic receptors, adverse effects are frequent, along with consequent dose adjustments (9,10). Prospective studies comparing the efficacy of different β-blockers have not been performed, so answers to the highly relevant clinical question, “Is one β-blocker superior to another?” rely completely on retrospective analysis in available cohorts.
This issue of the Journal contains the largest analysis of this type published so far. It compares the relative efficacies of the most commonly prescribed β-blockers (nadolol, propranolol, atenolol, and metoprolol) in 1,530 patients from the LQTS Registry based in Rochester, New York (11). In the overall cohort, all β-blockers seem equally effective in reducing the risk of a first cardiac event. In the subcohort of patients with LQTS1 (n = 379), no β-blocker was superior, whereas in LQTS2 (n = 406), nadolol was slightly more effective than other β-blockers. In patients with at least one BCE while taking β-blockers, propranolol appears to be the least effective drug (11).
These data are in agreement with our earlier retrospective analysis in 207 patients with LQTS1 and 176 patients with LQTS2 that showed equal prophylactic efficacy of the 4 β-blockers in asymptomatic patients and high efficacy of nadolol in both LQT1 and LQT2 in patients with and without symptoms (8). However, in the Registry’s symptomatic group, metoprolol and atenolol are superior to propranolol (11), whereas in our previous study, propranolol was superior (8).
That propranolol is the least effective β-blocker in symptomatic patients in the present study is unexpected. In addition to its β-blocker activity, propranolol also reduces the QTc, thereby providing another risk-reducing mechanism of action (8). The authors’ argument that “this (i.e., QTc shortening) has not been our experience with β-blockers in general (11)” is not surprising because in the 2000 study (3), all β-blockers were lumped together; however, not all β-blockers (by virtue of the presence or absence of late sodium current blocking efficacy) would be expected to shorten the QTc (12).
Given the potential impact of therapeutic switches on the basis of either study, it is critically important to attempt to understand the cause or causes of these discrepancies. First, the two studies did not define the symptomatic group in the same way. In our previous study (i.e., the Chockalingam study), the symptomatic patient group was defined as symptomatic before β-blocker therapy. In this group, the first event that occurred during β-blocker therapy is counted. In contrast, in the present (Rochester, New York) study, the event rate is studied in individuals who already experienced 1 cardiac event while taking β-blocker therapy (i.e., 1 BCE) and, thus, second and subsequent events are counted. This latter group is probably more seriously affected. From Figure 1 in their article (11), it can be concluded that almost 50% of BCEs occur within the first 6 months after therapy initiation. In this respect, in contrast to the Chockalingam study, the Rochester, New York database included patients who were diagnosed before 1 year of age. It is very likely that this cohort, generally accepted to be at a very high risk (13), is started most frequently on liquid propranolol 3 to 4 times a day (14). Indeed, in this cohort (as well as in our study), the age at which propranolol was started was younger, and the rapid recurrence of BCEs in almost half of the propranolol-treated patients with BCEs in the current study may reflect the impact of this subcohort, in which virtually all therapy fails (in terms of BCEs) (13). After the first 6 months, the curves no longer deviate. An additional argument for differences in the groups is the mean age of 24 ± 10 years in the metoprolol subgroup (11), which virtually excludes the presence of very young children.
Furthermore, in the current study, the comparable mean QTc values in all groups does not preclude potential differences in the numbers of other high-risk (with very long QTc) patients included in the 4 subgroups. An increased number of such patients in the propranolol-treated group could easily contribute to a higher event rate. The lack of these data, critical for the correct interpretation of the study, is not compensated for by the current paper’s complex statistical analysis.
In both studies (8,11), no corrections were made for including multiple members from single families. Pharmacokinetic properties of various β-blockers also rely, in part, on genetic factors (e.g., related to metabolism), and within given families, these factors could determine whether β-blocker therapy has favorable or detrimental effects. Overrepresentation of such families in either group could skew the results.
In conclusion, the data from both registries clearly underline the well-known beneficial effect of β-blocker therapy in LQTS. There is agreement that nadolol, unfortunately not available in every country (including the Netherlands), is probably one of the more effective drugs for this condition. The role of propranolol, the most widely prescribed drug (3,11), is now disputed, particularly in symptomatic patients. At present, retrospective analysis is the only tool available to address the issue of whether the β-blocker propranolol should now be deemed inferior to the β1-selective β-blockers metoprolol and atenolol.
Great caution must be exercised before rendering such a conclusion and, as a result, choosing to switch a patient’s LQTS treatment program from propranolol to metoprolol or atenolol. These retrospective studies have inherent limitations (e.g., lack of randomization; reliability of the data, potentially even more so if the physicians in charge of the registry do not see all the patients themselves; compliance). Furthermore, we are not aware of a single center (among the largest LQTS centers throughout the world) directly managing the care of hundreds of patients with LQTS in which atenolol or metoprolol is the β-blocker of choice. Instead, virtually every LQTS specialty center has arrived at an experiential preference for nadolol or propranolol.
Because both of us have real-world experience with lethal or near-lethal events after switching patients from propranolol to atenolol or metoprolol, it will not be easy to accept the apparent superiority of the latter drugs over propranolol, as suggested by the present study. Although we and other investigators advocate propranolol (and nadolol) over metoprolol and atenolol (15), solid, irrefutable data are lacking. Accordingly, we should realize that individual experience should not prevail over sound scientific data.
Hence, the current analysis is of significant importance and should motivate each of us to compare and extend our data in further detail and try to discover the β-blocker truth for our patients. However, it does not seem that the truth will emerge from a randomized prospective trial. Given the overall low event rate during β-blocker therapy, to enroll the huge number of patients necessary, such a trial would have to be conducted on a worldwide scale. Moreover, strongly held experiential views may preclude the participation of some of the largest LQTS centers that, in the name of “the best interest of the patient is the only interest to be considered,” may find it difficult to have their patients randomized to either atenolol or metoprolol.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Wilde is a member of the scientific advisory boards of Transgenomics and Sorin. Dr. Ackerman is a consultant for Boston Scientific, Gilead Sciences, Medtronic, and St. Jude Medical. Dr. Ackerman and the Mayo Clinic also receive royalties from Transgenomics for their FAMILION-LQTS and FAMILION-CPVT genetic tests. The authors acknowledge support from the Netherlands CardioVascular Research Initiative (CVON-PREDICT project), the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development, and the Royal Netherlands Academy of Sciences. Dr. Ackerman’s research is supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program.
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