Most sufferers with heart disease cannot be cured. The purpose of intelligent care is the prolongation of life, the diminution of suffering, and the increase in the mental and physical efficiency of the patient.

— Samuel Levine, Clinical Heart Disease Fourth Edition, Saunders, 1951

Antiarrhythmic drugs have been and will remain the mainstay of the chronic therapy of patients who have cardiac arrhythmias. A retrospective study in the United States reported a tripling of antiarrhythmic drug prescriptions from 2004 to 2016.¹ Antiarrhythmic drugs are expected to have reliable efficacy with well described, manageable risks to obtain regulatory approval. However, efficient use of these drugs in clinical practice requires in-depth knowledge of their diverse and complicated pharmacology, careful patient selection, and scrupulous surveillance. In addition, as Levine discussed, we need to have realistic expectations of efficacy; antiarrhythmic drugs are used to improve symptoms but, as with many of our therapies, they are not curative.

For decades, clinicians who treated patients with cardiac arrhythmias had a highly limited armamentarium. Digoxin, long known to treat dropsy, was also known to slow the ventricular response to atrial fibrillation (AF) and prevent other supraventricular arrhythmias via its vagally mediated inhibition of AV nodal conduction. It was joined by beta-adrenergic and L-type calcium channel blockers in the later 20th century for similar indications. Candidates for direct suppression of atrial or ventricular arrhythmia were sparse, with quinidine, procainamide, and lidocaine the only choices until the late 1970s when several candidate drugs were brought forward. A wave of clinical trials supported the approval of new sodium channel–blocking agents, including disopyramide, encainide, flecainide, ethmozine, and propafenone. These drugs were limited either by their potential for ventricular proarrhythmia or heart failure. A few of them survived to present day use, but they are restricted to carefully defined patient subsets. For example, we learned from CAST (Cardiac Arrhythmia Suppression Trial) that drugs with potent effects on the fast sodium current were associated with a high mortality when administered to patients with ischemic heart disease, a recent myocardial infarction, and frequent premature ventricular complexes.² In the post-CAST era, flecainide and propafenone are widely used for suppression of paroxysmal AF in patients with no structural heart disease, and recent data suggest they may be used in patients with minimal coronary artery disease.³ Mexiletine, a lidocaine congener, has also maintained clinical usage for niche ventricular indications including treatment of torsade de pointes in patients resistant to intravenous magnesium. Tocainide, another lidocaine congener, had limited use for ventricular arrhythmia suppression mostly due to the rare occurrence of neutropenia.

The success of amiodarone in suppressing a variety of cardiac arrhythmias led to interest in drugs that affected potassium currents thus prolonging ventricular repolarization in addition to multichannel blockade. Amiodarone was studied in many clinical trials, illustrating consistent efficacy, albeit protean toxicity that if not recognized, caused morbidity and mortality. Dronedarone, a modified amiodarone molecule without the iodine moiety, was developed to preserve amiodarone’s high efficacy and safety in patients with impaired left ventricular function, without replicating its arcane pharmacology and its several side effects.⁴ Dronedarone has modest efficacy and is contraindicated in patients with advanced heart failure but has the advantages of outpatient initiation and no need for dose titration. In ATHENA (A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg BID for the Prevention of Cardiovascular Hospitalizations or Death From Any Cause in Patients With Atrial Fibrillation/Flutter), dronedarone was the first antiarrhythmic to improve cardiovascular outcomes in a large prospective placebo-controlled trial. Though the exact mechanism for this benefit has not been elucidated, the results of ATHENA raised the bar for future antiarrhythmic drug approval by the FDA and limited interest from industry due to the high cost of performing such trials. Sotalol and dofetilide have been used mostly for atrial arrhythmia indications but with the liability of QT prolongation and torsades de pointes that mandate in-hospital initiation.

The lack of understanding of the precise pathogenesis of the arrhythmias for which pharmacologic therapy was prescribed necessarily limited efficacy by not permitting application of drugs with a definable effect on the substrate. The advent of catheter ablation for supraventricular arrhythmias, and device treatment for malignant ventricular arrhythmias led to a declining interest in drug development. Paradoxically, new treatment technology led to an increased need to treat residual arrhythmia in patients who fail ablation or have frequent implantable cardioverter defibrillator discharges. In addition, not all patients are candidates for invasive treatment, therefore antiarrhythmic drug treatment has maintained an important role in clinical practice.

Misguided advice to pharma that predicted the demise of drug treatment led to the abandonment of potentially productive lines of research. In addition, once bitten by the CAST bug, and sullied by the unexpected harm wreaked by antiarrhythmic drugs in vulnerable patient populations, regulators made an active decision that antiarrhythmic drug development programs would require proof that new agents don’t increase morbidity or mortality. Outcome studies would be of such magnitude or expense that most pharmaceutical companies were loath to launch new development programs. No antiarrhythmic drug has been approved by the FDA since dronedarone in 2009. Consequently, many potentially useful drugs, such as a ranolazine–dronedarone combination for AF prevention, vernakalant for AF termination, and azimilide for implantable cardioverter defibrillator shock prevention, were relegated to the drug graveyard.

We are left with a limited panel of drugs that are frequently used at an inappropriately low dose, and prematurely discontinued for any arrhythmia recurrence in favor of ablation or device treatment. Curiously, the most toxic and least understood drug of all, amiodarone, has emerged as the go-to option for AF, even though it was never approved for this indication and is often used outside guideline recommendations by nonexpert physicians who are unfamiliar with the need for multicomponent surveillance to avoid life-threatening and cumulative toxicity.

Adjuvant pharmacological therapy for patients after ablation or device implantation remains an unmet medical need. AF ablation is ineffective in upwards of one-third of patients and antiarrhythmic drugs are often prescribed postablation. More than one-half of patients with implantable cardioverter defibrillators are also taking an antiarrhythmic drug. Exactly how to apply pharmacologic therapy to these patients is poorly understood because no drug has been well studied in this population and no drug has safety and efficacy sufficient to garner a labeled indication for adjuvant treatment.

No matter what the pundits say, doctors need new drugs to treat patients who have cardiac arrhythmias. It has been 14 years since a new antiarrhythmic drug of any kind has been approved in the United States and we have been forced to use old and flawed drugs. Fortunately, interest has not been completely extinguished. As one of us (PRK) summarized in a Circulation article, antiarrhythmic drug development continues, focusing on new methods of delivery of conventional agent (eg, intranasal antiarrhythmic drugs), as well as new chemical entities with novel mechanisms of action.⁵

It is axiomatic that every component of the treatment of cardiac arrhythmias would be served with a better understanding of their pathophysiology. Applying pulmonary vein lesions in all patients with AF will be as unsuccessful as treating all patients with any antiarrhythmic agent.

The position that we do not need new antiarrhythmic drugs is wrong and poorly serves our discipline and our patients. The advances we have made in imaging and mapping should be applied more aggressively as we search for new chemical entities. We vigorously endorse pragmatic trial designs that will permit drug development without breaking the bank on large outcome trials. This might include better use of patient reported outcomes and health care utilization, and conditional approvals contingent on adequately designed and executed postmarketing registries including genetic profiling. We also must do a better job of teaching our fellows how and when to use antiarrhythmic drugs in concert with nonpharmacologic treatments.

History has taught us that the successful treatment of patients with any complex medical problem requires flexibility and individualization as well as perseverance. We hope that these important lessons will serve as rationale for expanding the search for new, better, and affordable drugs for the treatment of patients with cardiac arrhythmias.

None.

Disclosures Dr Kowey serves as consultant to Medtronic, Incarda, Glaxo Smith Kline, Milestone, Acesion, Novartis, Sanofi, Huya, Janssen, Abbvie, and Cardurion. Dr Naccarelli serves as consultant to Medtronic, Sanofi, InCarda, Acesion, and Glaxo Smith Kline.

The American Heart Association celebrates its 100th anniversary in 2024. This article is part of a series across the entire AHA Journal portfolio written by international thought leaders on the past, present, and future of cardiovascular and cerebrovascular research and care. To explore the full Centennial Collection, visit https://www.ahajournals.org/centennial.

The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

For Sources of Funding and Disclosures, see page 803.

Circulation is available at www.ahajournals.org/journal/circ

大多数心脏病患者无法治愈。智能护理的目的是延长患者的生命、减少痛苦、提高患者的身心效率。

— Samuel Levine，《临床心脏病》第四版，Saunders，1951 年

抗心律失常药物已经并将继续是心律失常患者长期治疗的支柱。美国的一项回顾性研究报告称，从 2004 年到 2016 年，抗心律失常药物处方量增加了两倍^。1抗心律失常药物预计具有可靠的疗效，且风险描述清楚、可控，从而获得监管部门的批准。然而，在临床实践中有效使用这些药物需要深入了解其多样化和复杂的药理学、仔细的患者选择和严格的监测。此外，正如莱文所讨论的，我们需要对功效有现实的期望；抗心律失常药物用于改善症状，但与我们的许多疗法一样，它们没有疗效。

几十年来，治疗心律失常患者的临床医生的医疗设备非常有限。地高辛长期以来一直被认为可以治疗水肿，还可以减缓心室对房颤 (AF) 的反应，并通过其迷走神经介导的房室结传导抑制来预防其他室上性心律失常。20 世纪后期，β-肾上腺素能药物和 L 型钙通道阻滞剂也加入了它的行列，用于类似的适应症。直接抑制房性或室性心律失常的候选药物很少，奎尼丁、普鲁卡因酰胺和利多卡因是唯一的选择，直到 20 世纪 70 年代末提出了几种候选药物。一波临床试验支持了新型钠通道阻滞剂的批准，包括丙吡胺、恩卡尼、氟卡尼、乙莫嗪和普罗帕酮。这些药物因其潜在的室性致心律失常或心力衰竭而受到限制。其中一些保留至今，但仅限于仔细定义的患者子集。例如，我们从 CAST（心律失常抑制试验）中了解到，对患有缺血性心脏病、近期心肌梗死和频繁发生室性早搏的患者服用对快钠电流有效的药物会导致高死亡率。²在后 CAST 时代，氟卡尼和普罗帕酮广泛用于抑制无器质性心脏病患者的阵发性 AF，最近的数据表明它们可用于患有轻微冠状动脉疾病的患者。³美西律是一种利多卡因同系物，也一直在临床上用于特定心室适应症，包括治疗对静脉注射镁剂耐药的患者的尖端扭转型室性心动过速。托卡尼是另一种利多卡因同系物，在抑制室性心律失常方面的用途有限，主要是因为中性粒细胞减少症很少发生。

胺碘酮在抑制多种心律失常方面的成功引起了人们对影响钾电流的药物的兴趣，从而除了多通道阻滞之外还延长了心室复极。胺碘酮在许多临床试验中进行了研究，显示出一致的疗效，尽管其毒性多种多样，如果不加以认识，会导致发病率和死亡率。决奈达隆是一种不含碘部分的改良胺碘酮分子，旨在保持胺碘酮对左心室功能受损患者的高效性和安全性，而不会重复其神秘的药理学和多种副作用。⁴决奈达隆疗效有限，晚期心力衰竭患者禁用，但其优点是可在门诊开始使用，无需调整剂量。在 ATHENA（一项安慰剂对照、双盲、平行组试验，评估决奈达隆 400 mg BID 对于预防心房颤动/扑动患者心血管住院或任何原因死亡的功效）中，决奈达隆是第一种抗心律失常药物。在一项大型前瞻性安慰剂对照试验中改善心血管结局。尽管这种益处的确切机制尚未阐明，但 ATHENA 的结果提高了 FDA 未来抗心律失常药物批准的门槛，并且由于进行此类试验的成本高昂，业界的兴趣有限。索他洛尔和多非利特主要用于房性心律失常适应症，但具有导致 QT 间期延长和尖端扭转型室速的可能性，需要在医院内开始使用。

对药物治疗所针对的心律失常的精确发病机制缺乏了解，由于不允许使用对底物具有明确作用的药物，必然会限制疗效。用于室上性心律失常的导管消融术和用于恶性室性心律失常的装置治疗的出现导致人们对药物开发的兴趣下降。矛盾的是，新的治疗技术导致对消融失败或频繁植入式心脏复律除颤器放电的患者治疗残余心律失常的需求增加。此外，并非所有患者都适合侵入性治疗，因此抗心律失常药物治疗在临床实践中一直保持着重要作用。

向制药公司提出的错误建议预测了药物治疗的消亡，导致了潜在生产线研究的放弃。此外，一旦受到 CAST 病毒的影响，并因抗心律失常药物对弱势患者群体造成的意外伤害而受到玷污，监管机构就做出了积极的决定，即抗心律失常药物开发计划需要证明新药不会增加发病率或死亡率。结果研究的规模或费用如此之大，以至于大多数制药公司都不愿意启动新的开发计划。自 2009 年决奈达隆以来，FDA 尚未批准任何抗心律失常药物。因此，许多潜在有用的药物，例如用于预防 AF 的雷诺嗪 - 决奈达隆组合、用于终止 AF 的维那卡兰以及用于预防植入式心律转复除颤器休克的阿齐利特，都被归入了毒品墓地。

我们只剩下有限的一组药物，这些药物经常以不适当的低剂量使用，并且因心律失常复发而过早停药，转而采用消融或装置治疗。奇怪的是，胺碘酮是所有药物中毒性最大且最不为人所知的药物，它已成为治疗 AF 的首选药物，尽管它从未被批准用于该适应症，并且经常由不熟悉该需求的非专业医生在指南建议之外使用用于多成分监测以避免危及生命和累积毒性。

消融或装置植入后患者的辅助药物治疗仍然是一个未满足的医疗需求。房颤消融对三分之一以上的患者无效，消融后通常会开具抗心律失常药物。超过一半的植入式心脏复律除颤器患者同时服用抗心律失常药物。确切地如何对这些患者应用药物治疗尚不清楚，因为没有药物在这一人群中得到充分研究，也没有药物的安全性和有效性足以获得辅助治疗的标签适应症。

无论专家怎么说，医生都需要新药来治疗心律失常患者。自从美国批准任何一种新的抗心律失常药物以来，已经有 14 年了，我们被迫使用旧的和有缺陷的药物。幸运的是，兴趣还没有完全消失。正如我们之一 (PRK) 在《循环》文章中所总结的那样，抗心律失常药物的开发仍在继续，重点关注传统药物（例如鼻内抗心律失常药物）的新递送方法，以及具有新颖作用机制的新化学实体。⁵

不言而喻，心律失常治疗的每一个组成部分都需要更好地了解其病理生理学。对所有 AF 患者应用肺静脉损伤与使用任何抗心律失常药物治疗所有患者一样不成功。

我们不需要新的抗心律失常药物的立场是错误的，并且不利于我们的学科和我们的患者。当我们寻找新的化学实体时，我们应该更积极地应用我们在成像和绘图方面取得的进步。我们大力支持务实的试验设计，这将使药物开发无需在大型结果试验中花费太多。这可能包括更好地利用患者报告的结果和医疗保健利用，以及根据充分设计和执行的上市后登记（包括基因分析）进行有条件批准。我们还必须更好地教导我们的同事如何以及何时使用抗心律失常药物与非药物治疗相结合。

历史告诉我们，成功治疗患有任何复杂医疗问题的患者都需要灵活性、个体化以及毅力。我们希望这些重要的经验教训将成为扩大寻找新的、更好的、负担得起的药物来治疗心律失常患者的基础。

没有任何。

Kowey博士担任 Medtronic、Incarda、Glaxo Smith Kline、Milestone、Acesion、Novartis、Sanofi、Huya、Janssen、Abbvie 和 Cardurion 的顾问。Naccarelli 博士担任 Medtronic、Sanofi、InCarda、Acesion 和 Glaxo Smith Kline 的顾问。

美国心脏协会将于 2024 年庆祝成立 100 周年。本文是国际思想领袖撰写的整个 AHA 期刊系列文章的一部分，内容涉及心脑血管研究和护理的过去、现在和未来。要探索完整的百年纪念收藏，请访问 https://www.ahajournals.org/centennial。

本文表达的观点不一定代表编辑或美国心脏协会的观点。

有关资金来源和披露信息，请参阅第 803 页。

流通量可在 www.ahajournals.org/journal/circ 上获取