CRT可使QRS较短患者心血管死亡率翻倍

阿姆斯特丹——一项纳入809例患者的国际随机研究显示，在QRS间期＜130毫秒的严重心力衰竭患者中，接受心脏再同步治疗(CRT)者的心血管死亡率比未接受该治疗者增加1倍以上。这项研究同时发表在《新英格兰医学杂志》上(N. Engl. J. Med. 2013 [doi:10.1056/NEJMoa1306687])。


Johannes Holzmeister博士

苏黎世大学的Johannes Holzmeister博士在欧洲心脏病学会(ESC)年会上报告称，启动CRT功能的患者在主要疗效终点(全因死亡或首次因心力衰竭加重而住院)方面并未显示出优于关闭CRT功能的患者。不仅如此，在平均19个月的随访过程中，启动CRT功能组患者的全因死亡率比对照组升高了近5%(相对增加80%)，心血管死亡率也升高了5%(相对增加1倍以上)，差异均具有显著性。

印第安纳大学的电生理专家Douglas P. Zipes博士评论指出：“这是对‘CRT用于QRS仅轻度延长的患者’这一做法的致命一击。”

美国心脏病学会(ACC)和美国心脏协会(AHA)的现行建议(J. Am. Coll. Cardiol. 2013  [doi:10.1016/j.jacc2013.05.019])仅明确支持对QRS间期≥150毫秒的心力衰竭患者实施CRT，并声称CRT对于纽约心脏协会(NYHA) Ⅱ~Ⅳ级心力衰竭、左束支传导阻滞(LBBB)和QRS间期介于120~149毫秒的患者可能有用。ESC的建议则更加宽松，推荐将CRT用于窦性心律、QRS间期≥120毫秒、QRS波呈现LBBB形态、射血分数≥35%且预期可保持良好功能状态超过1年的患者(Eur. Heart J. 2012;33:1787-847)。

ESC还建议，对于QRS间期≥150毫秒的患者，无论其QRS形态如何，都应当考虑实施CRT。

似乎已经有很多QRS间期较短的患者接受了CRT治疗。Holzmeister博士在报告中引用了2008~2009年欧洲心律协会(EHRA)对全欧洲CRT患者的调查数据：在使用CRT装置的欧洲患者中，9%的QRS间期＜120毫秒，另有10%的QRS间期介于120~129毫秒(Eur. Heart J. 2009;30:2450-60)。

英国赫尔大学的心力衰竭专家John G.F. Cleland博士评论指出，有相当多的QRS间期介于120~129毫秒的患者仍在接受CRT治疗，而数据提示该治疗应当被视为“最后的手段”。尽管当前的学会建议支持对经过选择的QRS间期介于120~149毫秒的心力衰竭患者实施CRT，但很多专家认为需要为这一领域设定新的QRS标准。

“我认为CRT置入术的切点应当是150毫秒。”约翰霍普金斯大学的电生理专家Gordon F. Tomaselli博士在接受采访时指出：“QRS间期不足150毫秒的患者，尤其是在没有左束支传导阻滞的情况下，很可能不应当接受CRT，除非还存在其他的特殊情况。”

德国柏林Charitè医院的Stefan D. Anker博士评论指出：“上述结果进一步表明，我们不应当对QRS间期＜130毫秒的心力衰竭患者使用CRT装置。我认为对QRS间期介于130~149毫秒的患者使用CRT仍存在不确定性，还需要更多来自试验的疗效和安全性证据。只有对QRS间期≥150毫秒的患者是明确应当使用CRT的，可显著降低死亡率。”

超声心动图引导下心脏再同步治疗(EchoCRT)研究将809例QRS间期＜130毫秒、左心室射血分数≤35%且符合左心室不同步超声心动图标准的患者随机分组。所有患者均置入了CRT装置，其中404例患者的装置处于开动状态。这项研究从2008年8月份开始，招募工作截止于2013年3月13日，停止招募的原因是该治疗无益和可能有害。

截至停止招募时，CRT装置开动组和关闭组分别有9%和4%的患者发生了心血管死亡。

EchoCRT试验由百多力和GE Healthcare资助。Holzmeister博士报告称担任了百多力的顾问。Zipes博士报告称担任了卫生系统网络的顾问，并且是Insight Telehealth的共同所有人。Anker博士承认接受了圣裘德、雅培血管和多家其他公司的酬金。Tomaselli博士报告称无相关利益冲突。

专家点评：EchoCRT证实了CRT的危险性

EchoCRT的结果与我们近期针对5项由美敦力资助的试验中3,782例接受CRT治疗的心力衰竭患者的meta分析结果非常一致。结果显示，QRS间期是CRT对并发症和死亡率影响的强预测因素。

这项meta分析的结果证实，CRT对有轻~重度心力衰竭症状、窦性心律且QRS间期≥140毫秒的患者是有益的，对于这些患者而言，CRT是标准治疗。结果还显示，在QRS间期缩短至140毫秒以下后，CRT的获益减少。QRS间期介于130~139毫秒的患者属于一个灰色地带。假如他们需要除颤器，置入CRT装置是有意义的，但是假如不打算置入任何装置，那么继续尝试药物治疗很可能是比CRT更好的选择。


John G.F. Cleland博士

我会避免对QRS间期＜130毫秒的患者进行CRT，现在EchoCRT的结果显示出了CRT对此类患者有害的证据。在QRS间期介于120~129毫秒的患者中，很多已开始使用CRT装置，尽管获益的几率很低。这可能是一种最后的治疗手段，只有当你用尽了所有其他办法都不奏效时才能用它。

这项meta分析还显示出，QRS间期是CRT结局的唯一独立预测因素(Eur. Heart J. 2013 [doi:10.1093/eurheartj/eht290])。QRS形态——不论是否有左束支传导阻滞——并不是与QRS间期相关的显著因素。EchoCRT结果还显示，超声心动图用于诊断左心室不同步性时并不能识别出可从CRT中获益的窄QRS间期亚组患者。

点评专家John G.F. Cleland博士是英国赫尔大学的内科学教授。他担任了百多力、圣裘德和美敦力的顾问。

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By: MITCHEL L. ZOLER, Cardiology News Digital Network

AMSTERDAM – Patients with severe heart failure and a narrow QRS duration who received cardiac resynchronization therapy had more than twice the rate of cardiovascular deaths as patients who did not undergo active CRT treatment in a multinational randomized study with 809 patients.

The study’s enrollment criteria focused on patients with a QRS duration of less than 130 msec, and in this group active CRT produced no benefit, compared with the CRT function turned off in control patients for the study’s primary efficacy endpoint of death from any cause or first hospitalization for worsening heart failure.
 
In addition, during an average 19 months’ follow-up, patients in the CRT-on group had an all-cause death rate nearly five percentage points above the controls, an 80% relatively increased hazard, and a cardiovascular death rate also five percentage points above the controls, a greater than two-fold relative hazard, Dr. Johannes Holzmeister said at the annual congress of the European Society of Cardiology.

Both increased hazard rates were statistically significant and were a "surprising, unexpected finding," said Dr. Holzmeister, a cardiologist at the University of Zurich.

"This is the final nail in the coffin for CRT in patients with only slightly-prolonged QRS," commented Dr. Douglas P. Zipes, a professor and electrophysiologist at Indiana University in Indianapolis.

Existing recommendations from the American College of Cardiology and American Heart Association (J. Am. Coll. Cardiol. 2013 [doi:10.1016/j.jacc2013.05.019]) restrict unequivocal endorsement of CRT to heart failure patients with a QRS duration of at least 150 msec and say that CRT can be useful for patients with New York Heart Association class II, III, or IV heart failure, left bundle branch block (LBBB), and a QRS duration of 120-149 msec. Recommendations from the European Society of Cardiology are more permissive, calling CRT recommended for patients in sinus rhythm with a QRS duration of at least 120 msec, LBBB morphology on their QRS wave, and an ejection fraction of at least 35% who are expected to remain in good functional status for more than 1 year (Eur. Heart J. 2012;33:1787-847).

The ESC recommendations also say that CRT should be considered in patients with a QRS duration of at least 150 msec, irrespective of their QRS morphology.

It seems like many patients with shorter QRS durations have been receiving CRT treatment. During his report at the meeting, Dr. Holzmeister cited data from a 2008-2009 European-wide survey of CRT patients by the European Heart Rhythm Association, which showed that, 4-5 years ago, 9% of patients in Europe who received a CRT device had a QRS duration of less than 120 msec and another 10% of the CRT recipients had durations of 120-129 msec (Eur. Heart J. 2009;30:2450-60).

Substantial numbers of patients continue to receive CRT treatment with a QRS duration of 120-129 msec, a treatment that the data indicate should be a "last resort," said Dr. John G.F. Cleland, professor of medicine and a heart failure specialist at the University of Hull (England).

Although existing society recommendations sanction CRT for selected heart failure patients with a QRS duration of 120-149 msec, many experts have become convinced that the field needs a new set of QRS criteria.

"I think the cutoff for CRT implantation should be 150 msec," said Dr. Gordon F. Tomaselli, professor of cardiology and an electrophysiologist at Johns Hopkins University in Baltimore. "Patients with a QRS duration of less than 150 msec, particularly without left bundle branch block, should probably not get CRTs unless some special circumstances are present," he said in an interview.

"This reinforces the conclusion that we should not use CRT devices in heart failure patients with a QRS duration of less than 130 msec," commented Dr. Stefan D. Anker, professor and cardiologist at Charitè Hospital in Berlin and designated discussant for Dr. Holzmeister’s talk at the meeting. Dr. Anker called CRT use in patients with QRS durations of 130-149 msec uncertain and in need of more evidence for efficacy and safety from trials. "What is certain is that in patients with a QRS of 150 msec or greater there is a strong mortality reduction with CRT," he said.

The Echocardiography Guided Cardiac Resynchronization Therapy (EchoCRT) study randomized 809 patients with a QRS duration of less than 130 msec and left ventricular ejection fraction of 35% or less, and also required that patients meet criteria for having left-ventricular dyssynchrony detected by echocardiography. All patients received a CRT device, which was turned on in 404 patients. The study began in August 2008, and enrollment stopped on March 13, 2013, because of futility and a potential for harm.

At that time, cardiovascular deaths had occurred in 9% of patients with their CRT turned on and in 4% of those with the device turned off. Concurrent with Dr. Holzmeister’s report at the meeting, an article with the results was published online (N. Engl. J. Med. 2013 [doi:10.1056/NEJMoa1306687]).

The EchoCRT trial was sponsored by Biotronik and GE Healthcare. Dr. Holzmeister said that he has been a consultant to Biotronik. Dr. Zipes said that he has been a consultant to Health System Networks and consults for and is a co-owner of Insight Telehealth. Dr. Anker said that he has received fees and honoraria from St. Jude, Abbott Vascular, and several other drug and device companies. Dr. Tomaselli said that he had no disclosures.

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EchoCRT confirms CRT’s dangers

The results from EchoCRT fit well with the results of a meta-analysis that my associates and I recently ran on data from 3,782 heart failure patients treated with CRT in five trials sponsored by Medtronic. The results showed that QRS duration was a powerful predictor of the effects of CRT on morbidity and mortality.

The meta-analysis results confirmed the benefit of CRT in patients with mild, moderate, or severe heart failure symptoms, in sinus rhythm, and with a QRS duration of at least 140 msec, and in these patients CRT is standard of care. The results also showed that the benefits from CRT diminish as the QRS duration goes below 140 msec. Patients with a QRS duration of 130-139 msec are in a gray zone. If they need a defibrillator, then making it a CRT device makes sense, but if no device implant is planned then continued attempts at medical treatment are probably better than going to CRT.

I would avoid CRT in patients with a QRS of less than 130 msec, and now the EchoCRT results show evidence of harm in these patients. A lot of patients with a QRS duration of 120-129 msec have been receiving CRT devices when the chances of benefit are small. This might be a treatment of last resort, but only when you have exhausted all the other treatment alternatives.

The meta-analysis also showed that QRS duration was the only independent predictor of CRT outcomes (Eur. Heart J. 2013 [doi:10.1093/eurheartj/eht290]). QRS morphology – whether or not there is a left bundle branch block – was not a significant factor relative to QRS duration. The EchoCRT results also showed that echocardiography used to diagnose left-ventricular dyssynchrony failed to identify a subgroup of patients with a narrow QRS duration who benefited from CRT.

Dr. John G.F. Cleland is professor of medicine at the University of Hull (England). He has been a consultant to Biotronik, St. Jude, and Medtronic. He made these comments in an interview.