【争论】普萘洛尔 vs美托洛尔：治疗长QT间期综合征（LQTS）哪家强？

关键信息

该研究纳入1530例长QT间期综合征（LQTS）患者，基因型包括LQT1和LQT2型。研究比较了4种普通β-受体阻滞剂（阿替洛尔、美托洛尔、普萘洛尔和纳多洛尔）减少心血管事件的效果。研究结果显示，在降低首次心血管事件方面，4种β-受体阻滞剂对LQT1基因型患者的效果类似；不过对于LQT2基因型患者，只有纳多洛尔可显著降低风险。首次心血管事件发作后，普萘洛尔降低后续心血管事件风险效果最小。

以上结果提示，特定β-受体阻滞剂预防首次心血管事件的效果可能会受患者基因型影响。

专家评论

帕威亚大学Peter J Schwartz 教授

美国心脏病学会杂志最近刊登了一篇研究不同β-阻滞剂治疗LQTS效果的文章及相关社论。文章和社论的作者均是LQTS治疗经验丰富的心脏病专家，表达的观点却完全相反。对这种罕见疾病经验有限的执业医生可能会因此有所顾虑。这种争议是由这篇社论的作者和我在2012年发表的一篇文章引发；文章报告，和普萘洛尔和纳多洛尔治疗相比，美托洛尔治疗时突破性事件更多。

Moss等人的文章是基于国际LQTS数据库的数据。这个数据库于1979年创立，Moss和我都是其联合创始人，我完全知晓这个数据库的优势和弱点。这里的大部分数据来自在美国各处执业的医生，他们治疗和随访的LQTS患者数量非常有限。这会影响风险评估、数据收集质量的均一性，以及选用β-受体阻滞剂的种类和剂量，尤其是剂量受到的影响，医生通常会出于心动过缓的顾虑而过分降低处方剂量。

该文章中，患者的年龄值得注意。开始应用普萘洛尔的年龄为11±11岁：很明显，应用这种药物的患者也包括非常年幼的儿童和婴儿，任何治疗对于他们而言都是风险最大、反应最小。首次发现LQTS和病况最严重的患者选用β-受体阻滞剂时也会选择普萘洛尔。比较而言，应用美托洛尔的患者群体完全不同，其平均年龄为24±10岁；在20~30岁之间首次接受治疗的患者大都是较轻缓的LQTS，否则在15岁之前就应该有症状。作者指出，他们统计分析时“校正”了这一点和其他临床参数，不过差异仍非常明显。例如，普萘洛尔治疗组中一小部分患者QT间期非常长，这无疑会影响治疗失败的数目，不过因为样本数量高达679，平均值并不会因此改变。有一种因素不能校正，即医生的风险认知。在对非常年幼和症状性儿童治疗时，医生很有可能选择使用被认为最有效的β-受体阻滞剂，即普萘洛尔和阿替洛尔；但是，对于20多岁时出现首次昏厥的年轻成人，医生更倾向于使用其他β-受体阻滞剂，如美托洛尔和阿替洛尔。我这里列举的一些想法在社论中也有提及。

Wilde和Ackerman给出的一个观点值得仔细思考。他们指出，应用普萘洛尔时出现的复发，半数在用药最初6个月内发生，6个月后所有β-阻滞剂的曲线趋势相似。再次思考后会发现，尽管这个研究纳入了多达1530例的患者，首次心血管事件后应用美托洛尔治疗1年以上的患者实际仅有13例。

Wilde和Ackerman对这篇文章的其他许多方面也提出了质疑，不过其总结最具临床意义：“对于将患者由普萘洛尔转至阿替洛尔时出现致死或近乎致死的事件，我们两个都有现实经验；所以不会轻易接受这个研究中另3种药物明显优于普萘洛尔的观点。” 我也有直接经验，几例患者应用普萘洛尔或纳多洛尔多年并无症状，转而应用美托洛尔几天或几周内就出现心脏骤停或猝死。

1971年以来，我自己治疗的LQTS患者远超1000例，大多数仍定期回来进行临床评估，所以我能够直接核查治疗的效果。一些用奇特数据支持的医疗建议与常识和临床经验相悖，我不会因此动摇自己的想法。我很明确自己现在说的内容非常科学，如果我的孙辈受累于LQTS，我会使用普萘洛尔或纳多洛尔为他们治疗，肯定不会用美托洛尔或阿替洛尔。

TAKE-HOME MESSAGE

In a study of 1530 long QT syndrome (LQTS) patients with LQT1 and LQT2 genotype, the efficacy of common β-blockers (atenolol, metoprolol, propranolol, and nadolol) in reducing cardiac events was compared. The efficacy of all four β-blockers was comparable for reducing the risk for a first cardiac event overall as well as in patients with LQT1 genotype. However, for those with LQT2 genotype, only nadolol showed a significant reduction in risk. Following the first cardiac event, propranolol was the least effective in reducing the risk for subsequent cardiac events.

The efficacy of certain β-blockers to prevent first cardiac events may be influenced by patient genotype.

Expert Comment

The Journal of the American College of Cardiology has recently published an article1 and an accompanying editorial2 addressing the efficacy of different beta blockers in the treatment of the long QT syndrome (LQTS). Interestingly—because both were written by cardiologists very experienced in LQTS—the article and the editorial provide opposite views. This could be disconcerting for the practicing clinician with limited experience in this uncommon disease. This controversy was stimulated by a 2012 article in which the editorialists and I reported an excess of breakthrough events in patients with LQTS treated with metoprolol compared with propranolol and nadolol.

The article by Moss’s group is based on data from the International LQTS Registry. As a proud co-founder of the registry with Dr. Moss in 1979,4 I fully appreciate its strengths and weaknesses. Most of its data come from physicians scattered throughout the United States who follow, at most, a handful of patients with LQTS. This can affect the risk assessment, the uniformity in the quality of the data collection, and the choice, and especially the dose (which is often too low due to concerns of bradycardia), of beta blockers.

In the article, the age of the patients provides useful insights.1 Propranolol was started at 11 ± 11 years: clearly, it was also initiated in very young children and infants, the subgroup at highest risk and the least responsive to any therapy. Propranolol is also the beta blocker used in the first identified and most seriously affected cases. In contrast, metoprolol was used in a completely different age group (mean age, 24 ± 10 years); patients who are first treated between the ages of 20 and 30 years almost invariably have less severe forms of LQTS (otherwise most would have become symptomatic in the first 15 years of life). The authors indicated that they “adjusted” statistically for this and other clinical parameters, but the differences are written on the wall and, for instance, a small percentage of very long QT intervals in the propranolol-treated group could easily impact the number of failures while not altering the mean value due to a sample size of 679. One factor that cannot be adjusted for statistically is the perception of risk by clinicians. Doctors treating very young and symptomatic children are likely to use the beta blockers regarded as the most effective, namely propranolol and nadolol; whereas, for young adults with a first syncope in their 20s, physicians be more inclined to use other beta blockers, such as metoprolol and atenolol. Some of these considerations were raised in the editorial.2

One point made by Wilde and Ackerman is worthy of a careful look. They noted that, in Figure 1, half of the recurrences with propranolol occurred during the first 6 months, after which the curves of all beta blockers become similar. A second look also reveals that, even though the study impressively boasts 1530 patients, the actual number of those on metoprolol with data beyond just 1 year of treatment after the first cardiac event on beta blockers is only 13.

Wilde and Ackerman question many other aspects of the article, but it is their conclusion that provides the most clinically relevant message: “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.” I also have direct knowledge of several cases of patients who, after having been free of symptoms for many years on either propranolol or nadolol, suffered cardiac arrest or sudden death within days or weeks from having been shifted to metoprolol.

Since 1971, I have personally treated well over 1000 patients with LQTS, and most continue to return for periodic clinical evaluation, which allows me to verify directly the effect of therapy. I will not be swayed by fancy statistics suggesting medical actions that go against common sense and clinical experience. I know that what I say now is not very scientific, but if my grandchildren were affected by LQTS, I would treat them with either propranolol or nadolol; most certainly not with metoprolol or atenolol.

Journal of the American College of Cardiology

Efficacy of Different Beta-Blockers in the Treatment of Long QT Syndrome

J Am Coll Cardiol 2014 Sep 30;64(13)1352-1358, A Abu-Zeitone, DR Peterson, B Polonsky, S McNitt, AJ Moss

This abstract is available on the publisher's site.

Access this abstract now

Copyright © 2014 Elsevier Inc. All rights reserved.

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