新型取栓器可提高卒中治疗效果

《柳叶刀》(Lancet)8月26日发表且同时在欧洲心脏病学会(ESC)2012年会上公布的两项随机对照临床研究显示，两种“下一代”新型机械性血流恢复装置(或称取栓器)有望改善组织型纤溶酶原激活剂(tPA)治疗失败或不适合接受tPA治疗的卒中患者的预后。

Jeffrey L. Saver博士

在SWIFT研究中，加州大学洛杉矶分校的Jeffrey L. Saver博士及其同事于2010年2月~2011年2月从18个中心入选符合以下标准的患者：急性缺血性卒中伴中至重度神经功能障碍，血管造影证实大脑近端动脉闭塞，适合在症状出现后8 h内通过血栓切除术予以治疗。该研究对新型取栓器Solitaire与第一代取栓器Merci进行了比较。结果显示，Solitaire组大脑近端动脉闭塞的成功再通率显著高于Merci组。Solitaire 组58例患者所有可治疗血管的血流达到心肌缺血溶栓(TIMI)量表2~3级(主要终点)的几率是Merci组55例患者的近5倍[61% vs. 24%；优势比(OR) = 4.87]。此外，与Merci组相比，Solitaire组90天神经功能预后良好的患者比例更高(58% vs. 33%；OR = 2.78)，并且装置治疗次数也较少(平均1.7次vs. 2.2次)。两组的总体装置相关和手术相关不良事件发生率无显著差异。在校正年龄和至治疗时间后发现，Solitaire组90天死亡率较低(OR = 0.29)。

研究者总结指出，这些结果表明，对急性缺血性卒中患者进行血管内再通时，可考虑使用Solitaire进行初始治疗(Lancet 2012 Aug. 26 [doi: 10.1016/S0140-6736(12)61384-1])。

Raul G. Nogueira博士

在TREVO 2研究中，亚特兰大埃默里大学的Raul G. Nogueira博士及其同事在2011年2月至2011年12月间从26个中心入选符合以下标准的患者：出现导致显著临床缺陷的急性卒中症状，血管造影证实大脑近端动脉闭塞，适合在症状出现后8 h内接受血管内治疗。该研究对新型Trevo Retriever(类似于Solitaire的支架样装置)与Merci取栓器进行了比较。该研究将成功再通(主要终点)定义为脑梗死溶栓(TICI)评分≥2，这与SWIFT研究稍有区别。

结果显示，Trevo组88例患者的成功再通几率明显高于Merci组90例患者(86% vs. 60%；OR=4.22)。此外，与Merci组相比，Trevo组需接受任何类型辅助治疗的患者比例较低(18% vs. 31%；OR=0.49)，并且辅助治疗后，达到≥TICI 2级再灌注的患者比例较高。Trevo组90天功能预后良好的患者比例也高于Merci组(40% vs. 22%；OR=2.39)。两组在主要安全终点(装置和手术相关复合事件)方面无显著差异，但Merci组的血管穿孔发生率是Trevo组的10倍。两组的30天和90天死亡率也相似。

研究者指出，尽管TREVO 2研究未对Trevo装置与单纯药物治疗进行比较，但与前期的PROACT II研究相比，TREVO 2研究的结果令人鼓舞。在TREVO 2研究中，尽管患者的年龄较大、基线国立卫生研究院卒中量表评分较高、近端闭塞病变及难治性闭塞病变数量更多，但Trevo组临床预后良好的患者比例与PROACT II研究中的尿激酶原组相同。因此，TREVO 2研究结果支持将Trevo Retriever用于比较血管内治疗与单纯药物治疗的前瞻性随机研究(Lancet 2012 Aug. 26 [doi: 10.1016/S0140-6736(12)61299-9])。

由于SWIFT研究和TREVO 2研究对再灌注和良好神经功能预后的定义不同，因此无法比较Solitaire取栓器和Trevo取栓器。然而，这两者均已在美国和欧洲常规应用，并且安全性等同或优于Merci取栓器，目前为止的结果表明这两者有望显著改善药物治疗无效的卒中患者的预后。

SWIFT研究获Solitaire生产商Covidien/ev3资助。TREVO 2研究获Trevo生产商Stryker Neurological资助。许多研究者声明与这两家公司和其他卒中血管内治疗公司存在利益关系。

随刊述评：重大进展

霍恩斯坦神经科学中心及密歇根州立大学人类医学院的Philip B. Gorelick博士表示，尽管这两项研究的样本量较少，但试验过程严谨，而且提供了有关机械性取栓器用于急性缺血性卒中的疗效和安全性的高水平证据，代表了该领域的重要进展。未来有必要探讨侧枝循环或血栓特点是否对疗效有影响。这些新一代的取栓器的优效性可能与术中保留了血栓和血管壁的结构完整性有关。此外，未来有关这些及其他更新型取栓器的随机研究还应考虑与重组tPA比较或辅助应用重组tPA，或与新一代的溶栓剂(如去氨普酶和替奈普酶)比较(Lancet 2012 Aug. 26 [doi: 10.1016/S0140-6736(12)61302-6])。

Gorelick博士声明是去氨普酶DIAS研究的临床协调中心的联合总监，并因此获得相应酬金。

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By: SHARON WORCESTER, Cardiology News Digital Network

Two novel "next generation" mechanical flow restoration devices, or "clot retrievers," show promise for improving the treatment of stroke patients who fail or aren’t eligible for treatment with tissue plasminogen activator, according to findings from separate randomized controlled clinical trials.

In the SWIFT (Solitaire With the Intention of Thrombectomy) trial, the new Solitaire flow restoration device, a self-expanding stent retriever designed to restore blood flow in patients with ischemic stroke due to a large intracranial vessel occlusion, proved significantly more likely to successfully recanalize occlusions of the proximal cerebral arteries than did the Merci retriever, a first-generation mechanical thrombectomy device approved for use in 2004. The results showed that 58 patients treated with the Solitaire device had nearly fivefold greater odds of meeting the primary end point of a Thrombolysis in Myocardial Ischemia (TIMI) scale 2 or 3 flow in all treatable vessels than did 55 patients treated with the Merci retriever (61% vs. 24%; odds ratio, 4.87).

In another trial called TREVO 2, 88 patients treated with the new Trevo Retriever, a stentlike device similar to the Solitaire device, had greater than fourfold higher odds of successful revascularization than did 90 patients treated with the Merci retriever (86% vs. 60%; OR, 4.22). This trial used a slightly different definition of successful recanalization than did the SWIFT trial, defining it as a Thrombolysis in Cerebral Infarction (TICI) score of 2 or greater.

The findings of both trials were published Aug. 26 in the Lancet and were simultaneously presented at the annual congress of the European Society of Cardiology.

Dr. Jeffrey L. Saver of the University of California, Los Angeles, and his colleagues enrolled patients in the SWIFT trial at 18 sites between February 2010 and February 2011, if they had acute ischemic stroke with moderate to severe neurological deficits and angiographically confirmed occlusions of the proximal cerebral arteries, that were treatable by thrombectomy within 8 hours of symptom onset.

In addition to the greater likelihood of achieving the primary end point, the Solitaire patients were more likely to have good 90-day neurological outcomes (58% vs. 33%; OR, 2.78), and to require fewer passes with the device (mean of 1.7 vs. 2.2 passes), the investigators said (Lancet 2012 Aug. 26 [doi: 10.1016/S0140-6736(12)61384-1]).

Furthermore, the frequency of total device-related and procedure-related adverse events did not differ between the two groups, and the 90-day mortality rate was lower in the Solitaire group (OR, 0.29 after adjusting for age and time to treatment), the investigators said.

"On the basis of these results, when endovascular recanalization is done in patients with acute ischemic stroke, initial treatment with Solitaire might be a future treatment of choice," they concluded.

Dr. Raul G. Nogueira of Emory University in Atlanta and his colleagues enrolled patients in the TREVO 2 trial at 26 sites between February 2011 and December 2011, if they had acute onset of stroke symptoms leading to significant clinical deficits, angiographically proven occlusion of a proximal intracranial artery, and eligibility for endovascular therapy within 8 hours of symptom onset.

In addition to the greater likelihood of achieving the primary end point, the Trevo patients were less likely to require adjunctive treatment of any kind (18% vs. 31%; OR, 0.49), and after adjunctive interventions, the rate of TICI 2 or greater reperfusion was higher in the Trevo patients, the investigators said (Lancet 2012 Aug. 26 [doi: 10.1016/S0140-6736(12)61299-9]).

The Trevo patients also were more likely to have good 90-day functional outcomes (40% vs. 22%; OR, 2.39).

No significant differences were seen between the Trevo and Merci patients with respect to the primary safety end point (a composite of multiple device- and procedure-related events), although vessel perforations were 10 times more common with the Merci device, the investigators reported.

Mortality was also similar in both groups at 30 and 90 days.

The investigators noted that although the Trevo device was not compared with medical treatment alone in this study, the findings are encouraging when considered in the context of those from studies of the Trevo predecessor – PROACT II. In the current study, patients treated using the Trevo Retriever achieved the same rate of good clinical outcomes as reported in a pro-urokinase group in the PROACT II trial despite older age, higher baseline National Institutes of Health Stroke Scale score, more proximal occlusions, and more refractory occlusions.

"Our results are therefore encouraging and support the use of the Trevo Retriever in a prospective randomized trial of endovascular therapy against medical treatment alone," the investigators concluded.

As for how the Solitaire and Trevo devices compare with each other, no conclusions can be drawn from SWIFT and TREVO 2 because the two studies used different definitions of reperfusion and good neurological outcomes. However, the devices, both of which have been cleared for general use in the United States and Europe, appear to have a similar or better safety profile than the Merci retriever, and the results thus far suggest that "significant improvement could be forthcoming in stroke patients for whom drug treatment is ineffective," according to a Lancet press statement.

The SWIFT trial was funded by Covidien/ev3, the maker of the Solitaire device. TREVO 2 was funded by Stryker Neurological, the maker of Trevo. Many of the investigators disclosed conflicts of interest involving Covidien/ev3 Neurovascular or Stryker Neurological, as well as other manufacturers of endovascular therapies for stroke.

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Trials Are Major Steps Forward

Despite modest sample sizes, the "carefully done" SWIFT and TREVO 2 trials begin to answer the call for high-level evidence about the efficacy and safety of mechanical clot retrieval devices in acute ischemic stroke, Dr. Philip B. Gorelick wrote in an editorial accompanying the Lancet articles.

"It will be interesting to learn, on the basis of future non-primary analyses, whether collateral flow patterns or clot characteristics elucidate propensity for treatment response," he said (Lancet 2012 Aug. 26 [doi: 10.1016/S0140-6736(12)61302-6]).

He also stated that the "mechanistic basis for superiority" of these next-generation devices might relate to retention of structural integrity of the clot and vessel wall during the procedure.

"Future randomized trials of these and other, newer devices will need to take into account comparison or complementary treatment with rt-PA [recombinant tissue plasminogen activator], or with newer-generation thrombolytics such as desmoteplase and tenecteplase," he said.

Meanwhile, SWIFT and TREVO 2 represent major steps forward, and pave the way for new treatment options, as well as for further validation by additional study, he said.

DR. GORELICK is with the Hauenstein Neuroscience Center and Michigan State University College of Human Medicine in Grand Rapids. He disclosed that he receives remuneration as co-director of the clinical coordinating center for the DIAS trial that involves desmoteplase.