Subcutaneous or Transvenous Defibrillator Therapy.pdf

To the Editor: We inquire about the adjudication of shocks in the Prospective Randomized Comparison of Subcutaneous and Transvenous Implantable Cardioverter Defibrillator Therapy (PRAETORIAN) trial conducted by Knops and colleagues (Aug. 6 issue). Of the 83 patients in the subcutaneous implantable cardioverter–defibrillator (ICD) group who had shocks labeled as “appropriate,” 11 had shocks for ventricular tachycardia below the cutoff of 180 beats per minute solely because of oversensing of cardiac signals. For example, ventricular tachycardia at a rate of 150 beats per minute could be sensed as 300 beats per minute. Although the device ultimately terminated an arrhythmia in these 11 patients, oversensing can lead to the highly undesirable outcome of shocks while the patient is awake.

致编者：我们在由Knops及其同事进行的皮下和经皮植入式心脏复律除颤器疗法（PRAETORIAN）的前瞻性随机比较（8月6日发行）中询问了电击的裁决。 在皮下植入式心脏复律除颤器（ICD）组的83例患者中，电击标记为“适当”，其中11例因心电信号过快而使心动过速低于每分钟180次跳动。 例如，以每分钟150次的速度心室性心动过速可被感测为每分钟300次。 尽管该设备最终在这11名患者中终止了心律不齐，但是在患者清醒时，过度感应可能会导致极不希望的电击结果。

The authors acknowledge that these shocks may have been occasionally clinically desirable but they also could be considered to be unnecessary. They cite a post hoc analysis of the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) that showed a strong association between any shocks and higher mortality, and the Multicenter Automatic Defibrillator Implantation Trial (MADIT)–Reduce Inappropriate Therapy (MADITRIT), which showed that permissive high-rate programming markedly reduced shocks and decreased mortality. These analyses cited by Knops et al. indicate that shocks for slower ventricular tachycardias are inappropriate because they are both painful and associated with increased mortality.

作者承认，这些电击有时在临床上可能是合乎需要的，但也可以认为是不必要的。 他们引用了一项关于心脏衰竭试验中突然心脏死亡的事后分析（SCD-HeFT），该分析显示了任何电击和更高的死亡率之间的紧密联系，以及多中心自动除颤器植入试验（MADIT）–减少了不适当的疗法（MADITRIT）， 这表明允许的高速率编程显着减少了电击并降低了死亡率。 这些分析由Knops等人引用。 提示对于慢速室性心动过速的电击是不合适的，因为它们既痛苦又与死亡率增加相关。

In the original trial protocol (available with the full text of the article at NEJM.org), Knops et al. defined appropriate shocks as those for ventricular tachycardia at a rate of more than 180 beats per minute. We estimate that if approximately half of these oversensed ventricular tachycardias had been labeled as inappropriate, noninferiority would not have been met.

在原始的试验方案中（可在NEJM.org上找到本文的全文），Knops等人将适当的电击定义为以每分钟180次以上的速度进行的室性心动过速。 我们估计，如果将这些过度感知的室性心动过速中大约一半标记为不适当，那么就不会满足非自卑感。

To the Editor: The PRAETORIAN trial involved a smaller cohort of patients with better-preserved ventricular function and intraventricular conduction than those in previous trials of implantable defibrillators. In this trial, the subcutaneous ICD was not significantly inferior to a standard transvenous ICD.

致编者：与以前的植入式除纤颤器试验相比，PRAETORIAN试验涉及的一小群患者，其心室功能和脑室内传导得到更好的保护。 在该试验中，皮下ICD并不明显低于标准的静脉ICD。

Sudden death can result from ventricular tachycardia or ventricular fibrillation or from asystole; the transvenous ICD can address any of these by cardioversion, defibrillation, antitachycardia pacing, or standard pacing. The subcutaneous ICD has only two of these four capabilities and addresses only ventricular tachycardia or ventricular fibrillation, not asystole. Cardiac arrest is often asystolic, particularly when ventricular function is severely impaired or if conduction is disturbed.

室性心动过速或室颤或心搏停止可导致猝死； 静脉ICD可以通过心脏复律，除颤，心动过速起搏或标准起搏来解决。 皮下ICD仅具有这四种功能中的两种，并且仅解决室性心动过速或室颤，而无心律失常。 心脏骤停通常是收缩期的，特别是当心室功能严重受损或传导受到干扰时。

The implantation of a device is not a cure but rather the start of a course of therapy. The cost should be calculated from the time of implantation to death. Our local best price for a transvenous ICD equates to approximately $8,600 in U.S. dollars; the subcutaneous ICD costs approximately $15,000. These devices have a projected battery longevity of 15.4 and 7.3 years, respectively, for a corresponding yearly cost of approximately $560 and $2,050. A higher price demands demonstration of clinical superiority; the current subcutaneous ICD offers half the work for thrice the wage.

植入设备不是治愈方法，而是治疗过程的开始。 费用应从植入到死亡的时间计算。 我们当地静脉ICD的最优惠价格约为8,600美元。 皮下ICD的费用约为15,000美元。 这些设备的预计电池寿命分别为15.4年和7.3年，相应的年成本分别约为560美元和2,050美元。 更高的价格要求证明其具有临床优势； 当前的皮下ICD提供了一半工资的一半工作。

To the Editor: Knops and colleagues report that subcutaneous ICDs were noninferior to transvenous ICDs with respect to device-related complications and inappropriate shocks. We have concerns about their trial design.

致编者：诺普斯及其同事报告说，就器械相关并发症和不适当的电击而言，皮下ICD不亚于经静脉ICD。 我们担心他们的试用设计。

First, noninferiority testing should assess efficacy for interventions with superior safety or interventions that offer an obvious benefit, such as convenience. With regard to subcutaneous ICDs, the evaluation of superiority for safety outcomes (e.g., inappropriate shocks and complications) or noninferiority for efficacy (e.g., shock efficacy and mortality) would have been more informative. The testing of noninferiority for safety outcomes risks acceptance of a therapy of uncertain and potentially inferior efficacy.

首先，非劣效性测试应评估具有较高安全性的干预措施或提供明显好处（如便利性）的干预措施的功效。 对于皮下ICD，安全性结果的优越性（例如，不适当的电击和并发症）或疗效的劣等性（例如，电击的功效和死亡率）的评估将更具参考价值。 安全性非劣效性测试可能会导致接受不确定且潜在劣质疗效的治疗方法。

Second, the choice of composite for the primary outcome is debatable. Subcutaneous ICDs led to fewer complications and more inappropriate shocks than transvenous ICDs, as expected.The combination of these two outcomes trending in opposite directions for subcutaneous ICDs and transvenous ICDs decreased the betweengroup difference and increased the likelihood of a finding of noninferiority. Thus, we recommend interpreting the two components of the primary composite outcome of this trial separately when assessing the risks and benefits of choosing a subcutaneous ICD instead of a transvenous ICD.

其次，对于主要结果的复合材料选择尚有争议。 与预期的相比，皮下ICD导致的并发症更少，而不适当的电击的发生率也高于经皮ICD。皮下ICD和经皮ICD两种结果趋势相反的趋势相结合，减少了组间差异，增加了发现非劣势性的可能性。 因此，在评估选择皮下ICD而非静脉ICD的风险和收益时，我们建议分别解释该试验的主要综合结果的两个组成部分。

To the Editor: The PRAETORIAN trial conducted by Knops et al. showed noninferiority of the subcutaneous ICD to the transvenous ICD with respect to device-related complications or inappropriate shocks in patients who had a class I or IIa indication for an ICD but no requirement for pacing. In this trial, 43% of the patients had a first-generation device and 57% had a secondgeneration device (Table S3 in the Supplementary Appendix, available with the full text of the article at NEJM.org). Since there is a lower incidence of inappropriate shocks with the second-generation subcutaneous ICD than with the first-generation subcutaneous ICD, it would be informative to provide a comparative analysis of the cumulative incidence of inappropriate shocks with the two devices.

致编辑：Knops等人进行的PRAETORIAN试验。 在I级或IIa级ICD指示但无需起搏的患者中，在与器械相关的并发症或不适当的电击方面，皮下ICD优于经静脉ICD。 在该试验中，43％的患者使用第一代设备，57％的患者使用第二代设备（补充附录中的表S3，该文章的全文可在NEJM.org上找到）。 由于与第一代皮下ICD相比，第二代皮下ICD发生不适当电击的几率较低，因此，对这两种设备对不适当电击的累积发生率进行比较分析将是有益的。

In addition, considering the greater battery longevity of second-generation subcutaneous ICDs, longer-term follow-up in this trial might show superiority of second-generation subcutaneous ICDs with respect to device-related complications. Finally, several patients in the subcutaneous ICD group underwent an upgrade to a cardiac resynchronization therapy defibrillator (CRT-D) during the median 4-year follow-up (Table S4 of the article). Accordingly, it appears likely that a device upgrade to a CRT-D within several years may have been warranted in some patients in the subgroup of patients with a low left ventricular ejection fraction (<35%), high New York Heart Association class (III or IV), and wide QRS duration (≥120 msec). This finding may suggest that the exclusion criteria of this trial were incomplete.

此外，考虑到第二代皮下ICD具有更长的电池寿命，因此该试验的长期随访可能显示出第二代皮下ICD在与器械相关的并发症方面的优越性。 最后，在中位的4年随访期间，皮下ICD组的几名患者接受了心脏再同步治疗除颤器（CRT-D）的升级（文章表S4）。 因此，在左心室射血分数低（<35％），纽约心脏协会等级高（III）的患者亚组中的某些患者中，似乎有必要在几年内将设备升级为CRT-D。 或IV）和宽QRS持续时间（≥120毫秒）。 这一发现可能表明该试验的排除标准不完整。

The authors reply: As noted by Mandrola et al., the definitions of appropriate and inappropriate shocks in the PRAETORIAN trial were changed early in the course of the trial. This change took place in July 2011 (4 months after enrollment began), when our trial transitioned from its initial single-center pilot phase to become a multicenter trial. The original definition of an “appropriate” shock included shock therapy for ventricular tachycardia of more than 180 beats per minute; the revised definition included “shock therapy for ventricular tachycardia.” The rate cutoff of 180 beats per minute was removed from the definition to allow for variations in programming zones and to be consistent with definitions in other large ICD trials. Since any ventricular tachycardia could be clinically relevant, the definition of shocks used in the SCD-HeFT and the MADIT trials was also used in the PRAETORIAN trial. In the SCDHeFT, “ICD shocks that followed the onset of ventricular tachycardia or ventricular fibrillation were considered to be appropriate.” In the MADIT trials, inappropriate therapy was defined as “therapy delivered for nonventricular tachyarrhythmias.”Since the causal association between ICD therapy, including antitachycardia pacing, and death in these trials is uncertain and complex, these citations do not suggest that shock therapy for slower ventricular tachycardia is inappropriate.

作者回答：正如曼德罗拉等人指出的那样，PRAETORIAN试验中适当和不适当电击的定义在试验过程的早期就已更改。这项变更发生在2011年7月（注册开始后的4个月），当时我们的试验从最初的单中心试验阶段过渡到多中心试验。 “适当的”电击的最初定义包括每分钟心律超过180次的室速的电击治疗。修订后的定义包括“休克治疗室性心动过速”。从定义中删除了每分钟180次心跳的截止频率，以允许编程区域中的变化，并与其他大型ICD试验中的定义保持一致。由于任何室性心动过速都可能与临床相关，因此在SCD-HeFT和MADIT试验中使用的电击定义在PRAETORIAN试验中也使用。在SCDHeFT中，“在发生室性心动过速或心室纤颤后发生的ICD休克被认为是适当的。”在MADIT试验中，不适当的治疗被定义为“针对非室性快速性心律失常的治疗”。由于ICD治疗（包括抗心动过速起搏）与死亡之间的因果关系尚不确定且复杂，因此这些引用并不意味着休克疗法的治疗速度较慢室性心动过速是不合适的。

With regard to the comments of Gallagher et al.: more ICDs were implanted in the PRAETORIAN trial than in the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial, the MADIT-II trial, and the SCD-HeFT. Also, a median ejection fraction of 30% overall is not a well-preserved ejection fraction, and the 81% of patients with a primary prevention indication in our trial had a mean ejection fraction of 28% — well below the mean ejection fraction of 32% in the AVID trial. Our trial showed no betweengroup difference in the numbers of patients with sudden cardiac death; this finding suggests that asystolic cardiac arrest was not frequent. Moreover, the subcutaneous ICD supplies post-shock pacing for up to 30 seconds. Finally, Gallagher et al. refer to costs associated with the subcutaneous ICD. However, a thorough cost-efficacy analysis should compare both the costs of the implant itself and implantation of the device and the costs of device-related complications and hospitalizations. For example, our trial showed 50% fewer device infections in the subcutaneous ICD group than in the transvenous ICD group. Treatment for a patient with an infected ICD costs more than £20,000 (approximately $27,500 in U.S. dollars) in the United Kingdom and more than $40,000 in the United States.

关于加拉格尔等人的评论：PRAETORIAN试验中植入的ICD比抗心律失常对植入式除颤器（AVID）试验，MADIT-II试验和SCD-HeFT试验要多。此外，总体射血分数中位数为30％并不是保存良好的射血分数，在我们的试验中有81％的一级预防适应症患者的平均射血分数为28％，远低于平均射血分数32 AVID试用版中的％。我们的试验表明，心脏猝死的患者人数之间没有组间差异。这一发现表明心脏收缩停搏并不常见。此外，皮下ICD可提供长达30秒的电击后起搏。最后，加拉格尔等指与皮下ICD相关的费用。但是，全面的成本效益分析应该比较植入物本身和装置的植入成本以及与装置相关的并发症和住院治疗的成本。例如，我们的试验显示，皮下ICD组的器械感染比经静脉ICD组的器械感染少50％。在英国，对感染了ICD的患者进行治疗的费用超过20,000英镑（约合27,500美元），而在美国则超过40,000美元。

The PRAETORIAN trial investigated the difference in safety outcomes between the transvenous ICD and the subcutaneous ICD, since efficacy was established in previous trials.Noninferiority and superiority analyses for the primary end point were scheduled and performed. Kim et al. correctly point out that inappropriate shocks and complications have diverging trends. However, we did not anticipate this divergence in our design.The PRAETORIAN-XL trial, a substudy of the PRAETORIAN trial, is under way to assess these outcomes separately in the prolonged follow-up period (an additional 4 years).

PRAETORIAN试验调查了静脉ICD和皮下ICD的安全性结果之间的差异，因为先前的试验已经确定了疗效，并计划并进行了主要终点的非劣效性和优越性分析。 Kim等正确指出，不适当的电击和并发症有不同的趋势。 但是，我们并未预料到设计会出现这种差异。PRAETORIAN-XL试验是PRAETORIAN试验的子研究，目前正在评估延长随访时间（额外4年）中的这些结果。

We agree with Sato and Nojiri that a large percentage of the subcutaneous ICDs in the PRAETORIAN trial were first-generation devices, which have a higher incidence of inappropriate shocks than later-generation devices. Follow-up is under way to investigate end points with newer algorithms and later-generation devices.

我们同意佐藤和Nojiri的观点，在PRAETORIAN试验中，大部分皮下ICD是第一代设备，与后代设备相比，不当电击的发生率更高。 正在进行后续工作，以使用较新的算法和下一代设备来研究端点。