Pasquale Santangeli，Luigi Di Biase，Andrea Natale 美国圣大卫医学中心
Andrea Natale 美国德州圣大卫医学中心心律失常研究所执行医疗主任，斯坦福大学心脏病学顾问教授，凯斯西储大学临床医学副教授，加州太平洋医疗中心心脏电生理服务高级医学总监。开创了环形超声波静脉消融系统纠正心房颤动，专注于心房颤动的创新治疗。
心律vs.心率控制：药理学试验
和正常窦性心律相比，心房颤动（房颤）无疑增加卒中、心力衰竭（心衰）和死亡风险。恢复和维持窦性心律（联合血栓栓塞并发症预防）是房颤治疗的主要目的。房颤心率与心律控制争议源于“心律控制”治疗，目前使用的抗心律失常药物（AADs）尚不能持续恢复和维持窦性心律。目前控制房颤心律的长效药物未达最佳标准。房颤加拿大试验中，平均随访16个月内，仅37%接受索他洛尔和普罗帕酮治疗和65%使用胺碘酮的患者维持窦性心律。一项比较房颤心律和心率控制的药理学试验也有类似发现，使用ⅠA，ⅠC和Ⅲ类AADs治疗后无房颤的存活者获益仅分别增加21.5%，33.1%和17.4%。这些结果导致错误理解--房颤心律与心率控制等效。
关于患者实际心律的大型试验均将持续窦性心律作为患者存活的最强预测因素。房颤心律管理的随访调查（AFFIRM）试验亚组分析中，窦性心律患者比房颤患者死亡率降低约50%，其他大型多中心研究也有类似发现。有报道称AADs的使用与死亡率增加有关，可能抵消了其维持窦性心律的存活获益。AADs如能恢复和维持窦性心律，将会增加存活获益，多个研究发现房颤本身与发病率和死亡率增加有独立相关性。
心律vs.心率控制：导管消融试验
由于AADs控制心律效果欠佳，近几年开展了许多房颤心律控制的非药物治疗研究，有些比较消融和心率控制治疗。第一个试验是比较肺静脉电隔离与房室结消融和双心室起搏治疗房颤伴充血性心衰患者（PABA-CHF）研究，81例充血性心衰和症状性药物难治性房颤患者随机分别接受肺静脉电隔离或房室结消融和双心室起搏治疗。6个月时，消融组患者生活质量、运动耐力和左心室功能显著改善。该研究结果被评估心衰伴持续性房颤患者管理中导管消融和心率控制（ARC-HF）试验所复制。ARC-HF研究中，52例有充血性心衰和持续性房颤的患者被随机分至消融组或心率控制组，12个月时，和心率控制组相比，消融组峰值耗氧量（VO2）显著增加（+3.07 ml/kg/min，P=0.018），明尼苏达评分（P=0.019）和脑钠肽（BNP）（P=0.045）水平也改善。左心室射血分数（LVEF）改善无显著统计学意义（P=0.055）。
迄今共9项研究（2项随机试验，7项观察性研究）评估伴房颤和左心室功能障碍的患者行导管消融的获益。这些研究共包括354例左心室功能障碍（LVEF：35%～43%）和阵发性和持续性房颤患者。所有研究都报告随访时患者LVEF显著改善，对均数的混合随机效应meta分析发现，和基线相比，平均改善11%（P<0.001）。这些研究评估发现，房颤伴充血性心衰的心率控制治疗可改善LVEF。最近一项meta分析发现，房室结消融和双心室起搏后LVEF仅改善2.6%（95% CI：1.7%～3.4%）。
房颤伴充血性心衰患者相关试验中报道的导管消融优于心率控制到多大程度时，导管消融可适用于正常射血分数的患者仍不清楚。虽然消融对这些患者完全可能有潜在获益。正进行的对比房颤患者导管消融和AADs治疗（CABANA）试验会提供一些答案。
结论
由于房颤与血栓栓塞、心衰和死亡有独立相关性，恢复和长期维持窦性心律是房颤治疗的主要目标，药物治疗控制房颤心律效果欠佳，因此，产生了实质上等同的旨在控制房颤心室率的治疗。另一方面，侵入性手术（如导管消融）使窦性心律有效恢复，心律控制优于心率控制的获益显而易见。迄今，有证据表明，房颤伴充血性心衰患者行导管消融治疗优于心率控制。进一步研究将评估这种获益是否也适用于左心室功能正常患者。
One in four men and women above 40 years of age can expect to develop atrial fibrillation (AF) in their lifetime.1， 2The burden of AF on healthcare system is overwhelming， given its independent association with stroke and systemic thromboembolism， heart failure， and mortality.1An old controversy regarding the management of AF is whether restoring and maintaining sinus rhythm (i.e.， rhythm-control therapy) should be preferred to an approach aimed at controlling only the ventricular rate during AF (i.e.， rate-control therapy).3-6 This article will briefly review the state of the art on rhythm- versus rate-control treatment strategies for AF.
Rhythm- versus rate-control: pharmacological trials
There is no question that AFindependently increases the risk of stroke， heart failure， and mortality compared to normal sinus rhythm.1， 2， 7 Accordingly， restoring and maintaining sinus rhythm (coupled with prevention of thromboembolic complications) is the main endpoint of AF treatment. The controversy on rate- versus rhythm-control for AF essentially derives from the fact that “rhythm-control” therapy， at least with currently available antiarrhythmic drugs， does not translate into a consistent restoration and maintenance of sinus rhythm.4The long-term effectiveness of currently available pharmacological agents for the rhythm-control of AF is clearly suboptimal.8In the Canadian Trial of Atrial Fibrillation， sinus rhythm was maintained in only 37% of patients receiving sotalol or propafenone at an average follow-up of 16 months， and in about 65% of those receiving amiodarone.9 Similar findings were confirmed in a pooled analysis of pharmacological trials comparing rhythm-control versus rate-control for AF， with an incremental benefit in terms of AF-free survival for antiarrhythmic drug therapy of only 21.5%， 33.1%， and 17.4% for class IA， IC， and class III agents， respectively.10 Taken together， these findings contributed to the false perception that rhythm-control and rate-control in AF are equivalent strategies.1
On the other hand， when analyzing the data from such large trials according to the patients’ actual rhythm， being consistently in sinus rhythm was confirmed as one of the most powerful predictors of survival.11In a sub-analysis of theAF Follow-up Investigation of Rhythm Management(AFFIRM) trial， patients in sinus rhythm had almost 50% lower mortality as compared to those in AF;11 similar findings have been confirmed in other large multicenter studies.12， 13In addition， use of antiarrhythmic drugs has been alsoreported to be associated with increased mortality， which possibly offsets the survival benefit of sinus rhythm maintenance.14 In conclusions， large pharmacological trials comparing rhythm- versus rate-control for AF mainly prove the inadequacy of current antiarrhythmic pharmacological agents to effectively restore and maintain sinus rhythm. On the other side， if sinus rhythm is effectively restored and consistently maintained， there is no doubt that this would translate in a survival benefit， as presence of AF per se has been independently associated with increased risk of morbidity and mortality in multiple studies.
Rhythm- versus rate-control: catheter ablation trials
Given the overall ineffectiveness of antiarrhythmic agents to achieve the ultimate endpoint of rhythm-control， namely， long-term consistent maintenance of sinus rhythm， over the last years multiple studies have investigatednon-pharmacological therapies for rhythm-control of AF.15Surprisingly， very few of these studies have been designed with the specific purpose of comparing ablative therapy versus rate-control.The first study that has formally compared the two treatment strategies was the Pulmonary Vein Antrum Isolation vs AV Node Ablation With Biventricular Pacing for Treatment of Atrial Fibrillation in Patients With Congestive Heart Failure (PABA-CHF).16In this trial， a total of 81 patients with congestive heart failure and symptomatic drug-refractory AF were randomized to either pulmonary vein isolation or atrioventricular-node ablation with backup biventricular pacing therapy， which represents an extreme form of rate-control.16 At 6 months， patients assigned to ablation were more likely to have improved quality of life， exercise tolerance and left ventricular function. The results of the PABA-CHF have been replicated in a recently published randomized trial， the Randomized Trial to Assess Catheter Ablation versus Rate Control in the Management of Persistent Atrial Fibrillation in Heart Failure (ARC-HF).17 In the ARC-HF， 52 patients with congestive heart failure and persistent AF were randomized to either ablation or rate-control. At 12 months， the peak VO2significantly increased in the ablation arm compared with rate-control (+3.07ml/kg/min， P =0.018). Catheter ablation also improved the Minnesota score (P =0.019) and BNP (P =0.045)， and showed a non-significant trend toward improved left ventricular ejection fraction (P =0.055). It bears emphasis that both the PABA-CHF and the ARC-HF adopted extensive ablation protocols aimed at targeting areas outside the pulmonary vein ostia. Although based on a relatively small number of patients， the results of the PABA-CHF and ARC-HF are totally in line with what already shown in smaller prospective series evaluating either catheter ablation or atrio-ventricular node ablation with backup pacing in patients with congestive heart failure and AF.
To date， a total of 9 studies (2 randomized trials， and 7 observational studies) have evaluated the benefit of catheter ablation in patients with AF and left ventricular dysfunction.16， 18-25These studies have included a total of 354 patients with left ventricular dysfunction (range of ejection fraction 35% to 43%) and both paroxysmal and persistent AF. Remarkably， all studies reported a significant improvement of ejection fraction at follow-up， accounting for an overall average 11% improvement (P < 0.001) compared with baseline values， when performing a pooled random effect meta-analysis of mean differences.Notably， none of the studies evaluating rate-control in AF patients with congestive heart failure has reported comparable improvements of left ventricular ejection fraction. For instance， in a recent meta-analysis， the overall improvement in left ventricular ejection fraction after atrioventricular nodal ablation and biventricular pacing was of only 2.6% (95% confidence interval， 1.7% to 3.4%).26
The extent to which the benefits of catheter ablation over rate-control reported in trials focused on AF patients with congestive heart failure might be generalized to patients with normal ejection fraction is still unclear， although it entirely plausible that ablation might translate into a substantial benefit also in these subjects.The ongoing Catheter ABlation versus ANtiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial will certainly provide some answers in this sense.
Conclusions
Restoration and long-term maintenance of sinus rhythm constitutes the major endpoint of AF treatment， given the independent association of AF with the risk of thromboembolism， heart failure and mortality. Pharmacological therapy for the rhythm-control of AF is largely ineffective in achieving stable and consistent sinus rhythm， thus resulting in a substantial equivalence with treatments aimed at controlling the ventricular rate during AF (i.e.， rate-control). On the other side， when sinus rhythm is effectively restored with invasive procedures， such as catheter ablation， the benefit of rhythm-control over rate-control becomes clearly manifest. Thus far， there is convincing evidence that catheter ablation is superior to rate-control in AF patients with congestive heart failure. Further studies will evaluate whether such benefits might extend also to patients with normal left ventricular function.
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