AHA/ASA新卒中指南强调rtPA与远程医疗

美国心脏协会(AHA)和美国卒中学会(ASA)联合发布了最新急性缺血性卒中指南，强烈建议扩大溶栓治疗在急性缺血性卒中患者中的应用，但对机械性血栓切除装置的支持力度有限(Stroke 2013 Jan. 31 [doi:10.1161/STR.0b013e318284056a])。

根据新的Ⅰ类A级证据建议，重组组织型纤维蛋白酶原激活剂(rtPA)静脉治疗的就诊至溶栓治疗时间(door-to-needle time)应为到达医院后60分钟内。指南建议，临床医生在对所有疑似缺血性卒中患者进行rtPA治疗前，可考虑先进行无造影剂的颅脑CT或MRI和一系列血液检查，但根本上看，需在进行纤溶治疗前进行的唯一实验室检查是血糖测定，可采集指血进行测定。rtPA治疗窗口也从卒中发生后3 h延长至4.5 h，这点在AHA/ASA 2009年更新的资料(Stroke 2009;40:2945-8)中已有阐述。

Edward Jauch博士

指南主编、南卡罗来纳医科大学查尔斯顿分校急诊医学主任Edward Jauch博士表示，鉴于美国食品药品管理局(FDA)并未像欧洲药品管理局那样批准将rtPA的治疗窗口时间延长至4.5 h，因此上述建议可能会再次引发长期以来存在的有关应用rtPA治疗卒中的争议。FDA主要是基于美国的数据作出不予批准的决定，而指南是基于所有可获取的数据而制订。指南委员会还从rtPA activase(阿替普酶)生产商基因泰克公司获得了安全性数据。

第3次国际卒中试验(Lancet 2012;379:2352-63)和一项英国meta分析(Lancet 2012;379:2364-72)去年报道，症状出现后6 h内进行rtPA治疗可增加具有自理能力的存活患者比例。

新型抗凝药的诞生促使AHA/ASA增加了新的建议，即在使用达比加群(Pradaxa)等直接凝血酶抑制剂或利伐沙班(Xarelto)等直接因子Ⅹa抑制剂的患者中，静脉或动脉内使用rtPA可能有害，不建议这么做，除非专科检查结果正常或患者已停药2天以上。

Patrick D. Lyden博士

不是指南编委会成员的洛杉矶Cedars-Sinai医疗中心神经病科主任和卒中项目主任Patrick Lyden博士评论指出，减少rtPA治疗前的血液检查项目具有特别重要的意义，并且其治疗团队在同时使用rtPA和抗凝剂阿加曲班的患者中未观察到安全性问题，因此其认为指南建议有所不妥。Jauch博士对此回应表示，目前缺乏数据证明rtPA可安全应用于使用新型抗凝药的患者。用于华法林的国际标准化比值等常见血液检查项目并不记录这些药物的抗凝效果，而且目前尚不清楚有何逆转策略。

在机械性血栓切除术中，与线圈回收装置相比，支架回收装置更受青睐。指南指出，在仔细挑选的患者中，Merci栓子回收系统、Penumbra System、Solitaire FR和TREVO血栓切除装置单独使用或与纤溶剂联合使用时可有效达到再通，但尚不清楚这些装置改善患结局的作用如何。需要继续在随机试验中进一步研究。

Jauch博士表示，尽管这些装置能够非常迅速地恢复血流，但是在评估这些装置时存在的问题是，患者从发生卒中至到达导管室的时间不断增加。如果患者被多次转诊或者不能及时对患者进行评估，那么获得良好结局的几率将会降低。

远程医疗

在可行的情况下，应将患者转移至最近的初级保健卒中中心或综合卒中中心。

Bart Demaerschalk博士

凤凰城梅奥医院神经病学教授Bart M. Demaerschalk博士表示，约40%的美国人住在偏远的农村地区，无法直接到达综合卒中中心，有时甚至是通过飞机转运这些患者。患者在到达卒中中心时，治疗窗口通常已经关闭。对于这些患者，最新指南主张通过远程医疗来开展专家卒中治疗及优化静脉rtPA的应用。

对于没有专业成像设备可对疑似急性卒中患者进行颅脑CT和MRI扫描的医院，指南推荐其配备FDA或“等同机构”批准的远程放射系统。在卒中医生无法亲自到床边诊疗的情况下，还应建立远程医疗。

Demaerschalk近期进行的一项研究显示，远程医疗还具有成本效益。在建立由1个枢纽医疗中心和7个支持医院构成的远程卒中网络后发现，与常规治疗相比，每年接受静脉溶栓治疗的患者数量增加了45例，接受血管内卒中治疗的患者数量增加了20例，并且这一网络使每家医院每年约节省358,435或109,080美元(Circ. Cardiovasc. Qual. Outcomes 2013;6:18-26)。

指南作者之一、David Z. Wang博士表示，对远程医疗的重视使人认识到神经病科医生和放射科医生的短缺，并且卒中治疗并非打一针rtPA这么简单。1997年当Wang博士开始建立远程神经病学网络时，支持医院的急诊医生在诊断卒中或rtPA给药方面尚缺乏信心和经验。但经过这么多年的发展，目前一些只有20张床位的小医院也已积累了较多经验。这些位于农村地区的小型医院的医生通过电话联系枢纽医疗中心的医生，就可共同作出决定、提供权宜治疗，并将患者送至枢纽医疗中心。

多位指南委员会成员与药物和器械生产商存在利益关系。

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By: PATRICE WENDLING, Cardiology News Digital Network

Expanded use of clot-busting therapy is strongly endorsed for patients with acute ischemic stroke, while mechanical thrombectomy devices garner only lukewarm support in updated acute ischemic stroke guidelines from the American Heart Association and American Stroke Association.

The "door-to-needle time" for intravenous administration of clot-busting recombinant tissue plasminogen activator (rtPA) should be within 60 minutes from hospital arrival, according to a new class I, evidence level A recommendation.

Clinicians are advised to consider a noncontrast brain CT or MRI and a series of blood tests in all patients with suspected ischemic stroke before administering rtPA, but ultimately, the guidelines (Stroke 2013 Jan. 31 [doi:10.1161/STR.0b013e318284056a]) state that "The only laboratory result required in all patients before fibrinolytics therapy is initiated is a glucose determination; use of finger-stick measurement devices is acceptable."

The treatment window for rtPA therapy is also extended from 3 hours to 4.5 hours after stroke onset – as recommended in the AHA/ASA 2009 update on the extended time window for administration of fibrinolytic agents (Stroke 2009;40:2945-8).

"It’s clear that time is brain," lead guideline author Dr. Edward Jauch, director of emergency medicine at the Medical University of South Carolina in Charleston, said in an interview. "We are making a much greater emphasis that patients should be evaluated as quickly as possible and get treated as quickly as possible to give them the maximum opportunity for benefit."

Dr. Jauch acknowledges that the recommendations could reignite the long-standing controversy over the use of rtPA in stroke patients, particularly in light of the Food and Drug Administration’s recent decision not to expand approval of rtPA to include treatment up to 4.5 hours, as the European Medicines Agency has done.

"The FDA makes decisions largely based on American data, and we make guidelines based on all available data," he said, noting that safety data were also obtained from Genentech, maker of the rtPA activase (Alteplase).

Two European trials – the third International Stroke Trial (Lancet 2012;379:2352-63) and a British meta-analysis (Lancet 2012;379:2364-72) – reported last year that rtPA therapy within 6 hours of symptom onset increased the proportion of people who were alive and independent on follow-up.
 
Dr. Patrick Lyden, chair of neurology and director of the stroke program at Cedars-Sinai Medical Center in Los Angeles, said reducing the battery of blood tests prior to rtPA administration is particularly important and pointed out that when the FDA first approved rtPA to treat stroke on the basis of a National Institutes of Health study, it "took the research protocol and turned it into a package insert.

"It’s taken the intervening 16 years for people to do studies and realize that you don’t need to do all the things in the package insert," he said. "So the American Heart Association, for the first time, is endorsing a much more practical, a much more optimal use of tPA for stroke."

The arrival of new classes of anticoagulants has prompted the AHA/ASA to add a new recommendation that the use of intravenous or intra-arterial rtPA in patients taking direct thrombin inhibitors like dabigatran (Pradaxa) or direct factor Xa inhibitors like rivaroxaban (Xarelto) "may be harmful" and is not recommended unless specialized testing is normal, or the patient has been off the drug for more than 2 days.

"I think that’s overreaching; I don’t think the data support that," said Dr. Lyden, who was not a member of the guidelines writing committee. He added that his team has had "no safety issues whatsoever" when administering the anticoagulant argatroban in patients on rtPA.

Dr. Jauch counters that data are lacking to support the safety of rtPA in patients on the new anticoagulants. Common blood tests – such as the international normalized ratio used for warfarin – do not register the anticoagulant effects of these drugs and reversal strategies are not yet known.

"As a community, we have a ways to go to figure out the optimal way to manage stroke in patients who come in on these drugs," he said.

When mechanical thrombectomy is pursued, stent retrievers are generally preferred to coil retrievers. The guidelines acknowledge that the Merci embolus retrieval system, Penumbra System, Solitaire FR, and TREVO thrombectomy devices "can be useful" in achieving recanalization alone or in combination with fibrinolytics in carefully selected patients, but that "their ability to improve patient outcomes has not been established" and continued study in randomized trials is warranted.

While these devices can restore blood flow very quickly, part of the problem in evaluating them is that the time from when the patient develops their stroke to when they get to the catheterization lab continues to increase, Dr. Jauch said.

"One of the challenges we have is, yes, we have a great device and if you happen to have your stroke on the cath table, you’re in great luck," he said. "But if you transfer multiple times or there’s a delay in getting the patient evaluated sufficiently, then it diminishes the chance of getting a good outcome."

Telemedicine comes of age

If feasible, patients should be transported to the closest available certified primary care stroke center or comprehensive stroke center, which in some cases may involve air transport or hospital bypass.

An estimated 40% of Americans, however, live in remote or rural areas without direct access to a comprehensive stroke center. For these patients, the updated guidelines emphasize the use of telemedicine to extend expert stroke care and optimize the use of intravenous rtPA, said guideline coauthor Dr. Bart M. Demaerschalk, professor of neurology at Mayo Clinic in Phoenix, which serves as a hub for 12 hospitals across Arizona with limited or no neurologic support.

"Even if air transport is available, the patients generally arrive when the respective treatment window is already closed," he said. "So telemedicine often means the difference between no treatment whatsoever, which is the usual case, and treatment."

The guidelines recommend teleradiology systems approved by the FDA or "an equivalent organization" for sites without in-house imaging expertise for prompt review of brain CT and MRI scans in patients with suspected acute stroke. When it’s not physically possible for a stroke team physician to be at the bedside, telemedicine should also be established so that more hospitals can potentially meet the criteria to become acute stroke-ready hospitals and primary stroke hospitals.

Telemedicine may also be cost effective, according to a recent study coauthored by Dr. Demaerschalk. It reports that a telestroke network model with one hub and seven spoke hospitals would result in 45 more patients getting intravenous thrombolysis and 20 more getting endovascular stroke therapies per year compared with usual care, and was associated with an estimated annual cost savings of $358,435 or $109,080 for each spoke hospital (Circ. Cardiovasc. Qual. Outcomes 2013;6:18-26).

Fellow guideline coauthor Dr. David Z. Wang, who has established one of the largest teleneurology networks in the country with 27 spoke hospitals in the OSF St. Francis Medical Center’s stroke network in Peoria, Ill., said the emphasis on telemedicine recognizes that there is a shortage of neurologists and radiologists, and that stroke care isn’t always as simple as giving a shot of rtPA. When they first started the teleneurology network in 1997, emergency physicians did not feel comfortable diagnosing stroke or giving rtPA. Over the years, however, things began to change as these hospitals, some as small as 20 beds, gained more experience with teleneurology, including feedback on the final diagnosis.

"Our hospitals in these smaller, rural areas, they all feel very comfortable now making a diagnosis," he said. "They make a phone call to us and jointly make a decision, offer treatment expediently and then ship them over to our center. The mentality has changed ... we’re providing better care."

Many guidelines committee members had financial ties with drug manufacturers and device makers.