Watchman装置试验达到安全性终点

旧金山——美国心脏病学会(ACC)2013年会一开始就不太顺利，原计划在开幕式全体会议上报告的备受期待的PREVAIL试验，即有关Watchman装置预防房颤患者血栓栓塞事件的首个最新临床试验，在最后时刻却因试验主办方违反新闻保密要求而被迫取消。

在ACC前主席、美国梅奥医院的David R. Holmes Jr.博士原定发言时间前几个小时，波士顿科学公司的一名员工在投资者新闻通告中提前公布了PREVAIL试验的结果，因此ACC不得不取消这次发言。

这种Watchman装置采用的是伞形自膨胀镍钛记忆合金结构，杆上有锚钩和一层可渗透的织物覆盖物。它通过经房间隔导管操作置入。这种装置的设计目的是封堵左心耳以预防房颤患者大约80%~90%的卒中事件，这类事件被认为是左心耳中形成的血栓所致。

鉴于这种Watchman装置有望取代终身口服抗凝治疗，PREVAIL(Watchman左心耳封堵装置治疗房颤患者相对于华法林长期治疗的前瞻性随机评估)试验曾一度被视为这次大会的焦点。美国食品药品管理局(FDA)考虑到之前PROTECT AF试验中出现的一些问题，要求波士顿科学公司提供更多的安全性数据，于是又开展了这项试验。

在近期更新的涉及707例患者的PROTECT AF试验中，平均随访2.3年后 Watchman组不良事件的发生率约为每100患者-年5.5例大出血、心包积液或装置栓塞事件，而华法林治疗组约为每100患者-年3.6例，提示装置治疗与风险增加53%相关。另一方面，由卒中、全身性栓塞或心血管死亡组成的主要疗效终点的发生率在Watchman组约为每100患者-年3例，而对照组约为每100患者-年4.3例，提示风险下降29%(Circulation 2013;127:720-9)。

PREVAIL试验纳入了来自美国41家医院的407例房颤患者，以2:1的比例将患者随机分配至接受Watchman装置或华法林治疗。虽然该试验的研究者拒绝了在高规格的ACC大会上发言，不过也公布了一些试验数据。

Watchman装置的置入操作由心脏介入科医生和电生理科医生共同完成。由于操作上的改进，PREVAIL试验中的置入成功率达到了95.1%，显著高于PROTECT AF试验中90.9%的成功率。新手施术医生的操作成功率和并发症发生率与有经验的医生相似。

PREVAIL试验设计了多个试验终点。主要安全性终点为死亡、缺血性卒中、全身性栓塞或需要重大干预的装置相关并发症的7天复合发生率，这在Watchman组中约为2.2%。

一个疗效终点是卒中、全身性栓塞或心血管死亡的18个月复合发生率，这在两个治疗组中都约为每100患者-年0.064例。虽然发生率相同，但该终点没能达到非劣性的统计学标准。

另一个疗效终点是术后7天直至18个月内缺血性卒中或全身性栓塞的发生率，这在Watchman组中约为每100患者-年0.025例，在对照组中约为每100患者-年0.02例，达到了非劣性标准。


Gordon Tomaselli博士

即将离任的美国心脏学会(AHA)主席Gordon Tomaselli博士(没有参与Watchman试验)在接受采访时说，他认为PREVAIL试验还不能说服我们用这种装置来取代广大房颤患者人群的终身抗凝治疗。

作为美国约翰霍普金斯大学医学教授/心脏科主任的Tomaselli博士说：“我预计FDA医疗器械委员会很可能会建议FDA只批准该装置较窄的适应证范围：仅用于那些有理由不能接受抗凝治疗的患者。”他估计在其自身临床实践中大约有5%~10%的房颤患者属于这种类型，其不能接受抗凝治疗的原因是出血风险高或者已经在使用华法林或其他抗凝剂期间出现过栓塞。

Tomaselli博士声明无相关经济利益冲突。Holmes博士在这种Watchman技术上存在经济利益关系。

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By: BRUCE JANCIN, Cardiology News Digital Network

SAN FRANCISCO – The annual meeting of the American College of Cardiology got off to a rocky start as the first late-breaking clinical trial in the opening plenary session – the eagerly anticipated PREVAIL study of the Watchman device for prevention of thromboembolic events in patients with atrial fibrillation – was removed from the program at the last minute because of a news embargo violation by the study sponsor. 

A Boston Scientific employee triggered the ACC action by releasing PREVAIL results in an investors’ newsletter several hours before the study’s scheduled presentation by Dr. David R. Holmes Jr., professor of medicine at the Mayo Clinic in Rochester, Minn., and a former ACC president.
     
The Watchman device is an umbrella-like, self-expanding nitinol frame with anchors and a permeable fabric cover. It is deployed via a transseptal catheter-based approach. The device is designed to seal off the left atrial appendage to help prevent the estimated 80%-90% of strokes in patients with atrial fibrillation that are believed to be caused by emboli formed in the left atrial appendage.

PREVAIL (Prospective Randomized EVAluation of the Watchman left atrial appendage closure device In patients with atrial fibrillation versus Long-term warfarin therapy) had been expected to be a meeting highlight, given the Watchman’s potential as an alternative to lifelong oral anticoagulation. The study was conducted in response to a Food and Drug Administration request for additional safety data because of concerns raised in the earlier PROTECT AF trial.

In a recent update of the 707-patient PROTECT AF, the adverse event rate after a mean of 2.3 years of follow-up was 5.5 cases of major bleeding, pericardial effusion, or device embolization per 100 patient-years in the Watchman arm and 3.6 per 100 patient-years in the warfarin-treated control arm, for a 53% increase in risk with device therapy.

On the other hand, the primary treatment efficacy endpoint comprised of stroke, systemic embolization, or cardiovascular death occurred at a rate of 3 cases per 100 patient-years in the Watchman group compared to 4.3 per 100 patient-years in the control group, representing a 29% reduction in risk (Circulation 2013;127:720-9).

The PREVAIL trial involved 407 patients with atrial fibrillation who were randomized 2-to-1 at 41 U.S. centers to the Watchman device or warfarin therapy. Study investigators, denied the high-profile ACC forum, nonetheless made the data available.

The Watchman was implanted both by interventional cardiologists and electrophysiologists. As a result of procedural refinements, the implant success rate in PREVAIL was 95.1%, significantly better than the 90.9% rate in PROTECT AF. New operators had procedural success and complication rates similar to experienced ones.

PREVAIL featured multiple study endpoints. The primary safety endpoint, the 7-day composite rate of death, ischemic stroke, systemic embolism, or device-related complications requiring major interventions, was 2.2% in device recipients.  

One efficacy endpoint, the 18-month combined rate of stroke, systemic embolism, or cardiovascular death, occurred at a rate of 0.064 cases per 100 patient-years in both study arms in PREVAIL. Despite the identical rates, this endpoint didn’t meet the statistical criterion for noninferiority.

Another efficacy endpoint, the rate of ischemic stroke or systemic embolism after 7 days and continuing out to 18 months, occurred at a rate of 0.025 cases per 100 patient-years in the Watchman group and 0.02 cases per 100 patient-years in controls, which did meet the noninferiority standard.

In an interview, American Heart Association immediate past-president Dr. Gordon Tomaselli, who was not involved in the Watchman trials, said he doesn’t think they establish a persuasive case for the device as an alternative to lifelong anticoagulation in the broad population of patients with atrial fibrillation.

“My prediction is the FDA device panel will probably recommend approval with a narrow indication: for patients who have a reason that they can’t be anticoagulated,” said Dr. Tomaselli, professor of medicine and chief of the division of cardiology at Johns Hopkins University, Baltimore.

He estimated that 5%-10% of patients with atrial fibrillation in his own practice fall into that category, either because they are at high bleeding risk or they have developed an embolism while on warfarin or another anticoagulant.

Dr. Tomaselli reported having no financial conflicts. Dr. Holmes has a financial interest in the Watchman technology.