7.1 Background and Brief History

In the last 21 years, the introduction and generalization of intravenous thrombolytic therapy (IVTT) of the stroke has been a clear advance that has benefited thousands of people. ¹ The National Institute of Neurological Diseases and Stroke (NINDS) Genentech Intravenous (IV) tPA stroke trial established the critical importance of time to treatment and led to Food and Drug Administration (FDA) approval of IV tPA to treat acute ischemic stroke (AIS) in 1996, but within a small window of 3 hours. ¹ However, in many patients (35–90%), IVTT does not achieve arterial recanalization, especially in cases of occlusion of a large cerebral vessel. For this reason, it was necessary to develop endovascular rescue procedures (ERP) as an effective therapeutic alternative to intravenous fibrinolytic treatment.

Local intra-arterial treatment began in the 1980s by administering fibrinolytic drugs directly to the thrombus through a microcatheter. ¹ Basilar artery occlusion was felt to have the worst prognosis, and this drove Zeumer et al ² to first perform basilar thrombolysis via catheter and report excellent outcomes based on historical controls.

Del Zoppo, Furlan, Higashida, and Pessin designed the Prolyse in Acute Cerebral Thromboembolism (PROACT, versions I and II) trials to demonstrate the safety, recanalization efficacy, and clinical benefit of Intraarterial (IA) r-proUK in patients with Middle Cerebral Artery (MCA) occlusion treated within 6 hours of stroke onset. ^{1 ,​ 2 ,​ 3 ,​ 4}

In 1998, the PROACT study ³ described the efficacy of administering locally and through a microcatheter, r-proUK in cerebral arterial occlusion, demonstrating high rates of recanalization and improvement clinic. The conclusion of this work stated, “Intra-arterial local rpro-UK infusion was associated with superior recanalization in acute thrombotic/thrombolitic stroke compared with placebo.”

In 1999, the results of the PROACT II study ⁴ showed “For the primary analysis, 40% of r-proUK patients and 25% of control patients had a modified Rankin score of 2 or less (P = 0,4). Mortality was 25% for the r-proUK group, and 27% for the control group. The recanalization rate was 66% for the r-proUK group, and 18% for the control group (P < .001). Intracranial hemorrhage with neurologic deterioration within 24 hours occurred in 10% of r-proUK patients and 2% of control patients (P = .06).” However, the FDA did not approve r-proUK for IA stroke therapy because of the small size and marginal significance (P=0.043) of PROACT II. ¹

Use of mechanical thrombectomy (MT) also began in the 1990s. Two UCLA inventors, Y. P. Gobin and J.P. Wensel, were involved in the design of a revolutionary device known as the Concentric Mechanical Embolus Removal in Cerebral Ischemia (MERCI) Retrieval. The MERCI Retrieval story started in the fall of 1995, when Gobin saw the need for a device that would just remove the clot and would be faster and have less risk of hemorrhage than thrombolytics. In 1996, Gobin and Wensel started in vitro studies and then animal studies. In May 2001, clinical lab safety studies began, leading to success. The first two patients treated at UCLA with the MERCI Retriever were two full Thrombolysis in Myocardial Infarction (TIMI) score 3. ⁵ The MERCI Retriever device received an FDA premarket approval in 2004 and was the first device to be used for clot removal in AIS.

In 2005, the first MERCI trial was published. ⁶ In this trial, the recanalization was achieved in 46% (69/151) of patients with intention to treat analysis and in 48% (68/141) of patients in whom the device was deployed. This rate is significantly higher than expected, using an historical control of 18% (P 0.0001). Clinically significant procedural complications occurred in 10 of 141 (7.1%) patients. Symptomatic intracranial hemorrhages were observed in 11 of 141 (7.8%) patients. Good neurologic outcomes (modified Rankin score < 2) were more frequent at 90 days in patients with successful recanalization compared with patients with unsuccessful recanalization (46% vs. 10%; relative risk [RR], 4.4; 95% CI, 2.1 to 9.3; P = 0.0001), and mortality was less (32% vs. 54%; RR, 0.59; 95% CI, 0.39 to 0.89; P = 0.01).

In 2008, the Multi MERCI Trial was published. ⁷ In this trial, 164 patients received thrombectomy, and 131 were initially treated with the L5 Retriever. Mean age ± SD was 68 ± 16 years, and baseline median (interquartile range) National Institutes of Health Stroke Scale (NIHSS) score was 19 (15 to 23). Treatment with the L5 Retriever resulted in successful recanalization in 75 of 131 (57.3%) treatable vessels and in 91 of 131 (69.5%) after adjunctive therapy (IA tPA, mechanical). Overall, favorable clinical outcomes (modified Rankin Scale 0 to 2) occurred in 36%, and mortality was 34%; both outcomes were significantly related to vascular recanalization. Symptomatic intracerebral hemorrhage occurred in 16 patients (9.8%); four (2.4%) of these were parenchymal hematoma type 2. Clinically significant procedural complications occurred in nine (5.5%) patients.

In 2008 appeared the Penumbra System (Penumbra, Inc), which supposes a sophistication of the concept of thrombectomy by aspiration. ⁸ Initially, the technique consisted of the application of continuous aspiration by means of a suction pump simultaneously with the manipulation of the thrombus, which was carried out with a conical device that mobilized in and out of the thrombus (penumbra 3D separator), thus fragmenting it. Continuous aspiration collected these fragments and thus prevented catheter obstruction. This system was approved by the FDA in 2008 and evaluated in a first study that included 125 patients treated in less than 8 hours, of which 81.6% recanalized and 11.2% presented Symptomatic intracerebral hemorrhage (SICH), although only 25% had a good prognosis. ⁹ This triggered criticism about MT and the discrepancy between recanalization and prognosis. However, a subsequent study of 157 patients showed recanalization rates of 87% and mRS ≤ 2 in 41%. ¹⁰ Further technological development has seen the development of new catheters such as 5MAX, 5MAX-ACE, ACE64 and ACE68, and no longer use the ‘penumbra 3D separator’. Thus, this technique has evolved a lot and is now known as A Direct Aspiration First Pass Technique (ADAPT). ¹¹ (This technique will be developed in another chapter).

Because successful recanalization with the MERCI Retriever was achieved in less than 60% of treatable vessels (Multi MERCI trial), ⁷ a new device was needed that was more effective. After the MERCI Retriever came the era of stents retrievers or retrievable stents.Retrievable stents were first used for thrombectomy in 2008, when C. Castaño used the Solitaire AB stent (Medtronic), which had been designed for intracranial aneurysms ¹² and had the particularity of being attached to a guide and detachable by electrolysis. Instead of detaching the stent, Castaño used it to catch the thrombus and used the guide to remove the stent with the thrombus. In June 2008, Castaño started animal studies and in November of that year treated his first patient with full TICI 3, using the Solitaire AB stent to remove the thrombus which had not been removable using the MERCI device. In 2009, he published this patient ¹³ in the first paper that describing technique. In August 2010, he published a pilot study with the first 20 cases. ¹⁴ In this study, successful revascularization, defined as TICI grade 2b or 3, was achieved in 18 of 20 (90%) treated vessels, and 16 patients showed immediate restoration of flow after stent deployment. The mean number of passes for maximal recanalization was 1.4, and the median (quartiles) time from groin puncture to recanalization was 50 (38–71) minutes. No case required adjuvant therapy after deployment of the embolectomy device, and no significant procedural events occurred. Symptomatic intracranial hemorrhage was found in two (10%) patients; four (20%) patients died during the 90-day follow-up period, and 45% of patients showed good functional outcome at 3 months (modified Rankin Scale score ≤ 2).

This study marked a turning point in the endovascular treatment of ischemic stroke. Subsequent studies confirmed the efficacy of the Solitaire stent for restoring vascular patency at a significantly higher rate than previous generation devices and techniques. ^{15 ,​ 16}

In 2012, a randomized study comparing the MERCI Retriever with the Solitaire stent was published (SWIFT Trial) ¹⁵ ; In this randomized, parallel-group, noninferiority trial, patients were enrolled from 18 sites (17 in the United States and one in France). Between February 2010, and February 2011, they randomly allocated 58 patients to the Solitaire group and 55 patients to the MERCI group. The primary efficacy outcome was achieved more often in the Solitaire group than in the MERCI group (61% vs. 24%; difference 37% [95% CI 19–53], odds ratio [OR] 4·87 [95% CI 2·14–11·10]; P (noninferiority) < .001, P (superiority) < .001). More patients had good 3-month neurologic outcome with Solitaire than with MERCI (58% vs. 33%; difference 25% [6–43], OR 2.78 [1.25–6.22]; P (noninferiority) < .001, P (superiority) = 0.02). Ninety-day mortality was lower in the Solitaire group than it was in the MERCI group (17 vs. 38; difference -21% [-39 to -3], OR 0·34 [0.14–0.81]; P (noninferiority) < .001, p(superiority)=0.02).

In October 2013, a prospective, multicenter, single-arm study of MT using Solitaire Flow Restoration in AIS was published (STAR trial). ¹⁶ A total of 202 patients were enrolled across 14 comprehensive stroke centers in Europe, Canada, and Australia. The median age was 72 years; 60% were female patients. The median National Institute of Health Stroke Scale (NIHSS) was 17. Most proximal intracranial occlusion was the internal carotid artery in 18%, and the middle cerebral artery in 82%. Successful revascularization was achieved in 79.2% of patients. Device and procedure-related severe adverse events were found in 7.4%. Favorable neurologic outcome (mRS ≤ 2) was found in 57.9%. The mortality rate was 6.9%. Intracranial hemorrhagic transformation was found in 18.8% of patients; 1.5% were symptomatic.

Recently, several clinical trials (MR CLEAN, ¹⁷ EXTEND IA, ¹⁸ ESCAPE, ¹⁹ SWIFT PRIME, ²⁰ REVASCAT ²¹ )have demonstrated that thrombectomy with a retrievable stent in patients with AIS with large artery occlusion safely increases the rate of functional independence, with scientific evidence Class 1, Level A.

After these five extensive randomized studies (discussed in other chapters of this book) were published, a great number of related meta-analysis studies appeared almost simultaneously, all demonstrating the effectiveness of MT as a treatment for AIS resulting from proximal occlusion in the anterior territory.

Because proximal occlusions were so epidemiologically relevant (17–42% of AIS admissions), scientists devoted their efforts to proving that these techniques could be employed beyond the established time limits. In this way, the universe of potential patients to be rescued from this devastating disease could enlarge considerably.

Two recent trials, the long-awaited Diffusion Weighted Imaging [DWI] or Computerized Tomography Perfusion [CTP] Assessment with Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention with Trevo (DAWN) trial ¹ , and The Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3( DEFUSE 3), ² have increased the time limit for endovascular treatment of AIS from 6 hours up to 24 hours in selected cases. Both trials were terminated early for efficacy due to the clear benefit for treated patients.

The DEFUSE 3 study was a multicenter, randomized, open label trial which included patients with proximal MCA or internal carotid artery (ICA) occlusion, an initial infarct size of less than 70 ml, and a ratio of ischemic tissue volume on perfusion imaging to infarct volume of 1.8 or more. One hundred eighty-two patients were randomized to medical therapy plus endovascular therapy, or medical therapy alone. The endovascular group showed better functional score at 90 days (OR, 2.77; P < 0.001) and much higher functional independence (45% vs. 17%, P < 0.001). No difference was observed for adverse effects ² .

The DAWN Trial, on the other hand, included patients with the same occlusion sites, but last seen well between 6 and 24 hours earlier, and who had a clinical mismatch between severity of the deficit and infarct volume. Two hundred six patients were enrolled and were randomized to endovascular plus standard treatment or standard treatment alone. The specified endpoint of utility-weighted modified Rankin scale at 3 months was 2 points higher in the endovascular arm (IC 95%, 1.1 to 3.0; P = > 0.999), and functional independence at 3 months or 90 days was 49% in the thrombectomy group as compared with 13% in the control group (P = >0.999). No difference in complication rate was observed ¹ .

The combined findings of both trials constitute very strong evidence in favor of treatment beyond the 6-hour limit, up to 24 hours. Further evidence will be necessary to determine whether imaging mismatch evidence is necessary or can improve patient selection for the most benefit. We also believe incorporation of CTP in most centers’ protocols as a standard for evaluation of AIS patients will not add significant delay and will aid in decision-making. This will be especially important in those cases in which a longer period has passed since last seen well.

7.2 Mechanical Thrombectomy Techniques

The goal of any treatment modality for AIS is to restore perfusion of ischemic tissue to improve the patient’s functional prognosis. Recanalization of occlusion has been associated with improved prognosis; however, recanalization alone is not sufficient and requires the reperfusion of the cerebral parenchyma to achieve a good prognosis. ²²

In the past, many techniques were used to try to reperfusion the brain, to remove the thrombus and open the arteries, but none of them could prove its effectiveness.At present there are basically three techniques of MT in use which are showing their effectiveness:

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  Proximal: Acting on the proximal part of the thrombus. This group includes the suction systems, or ADAPT, and will be discussed in another chapter.

  
  
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  Distal: Once the occlusion is crossed, the force is deployed and applied to the distal parts of the thrombus, and according to the length of the device, this force is also exerted on the medial and proximal portions of the thrombus. This group includes devices with stent, brush, basket, interlinked cage forms, etc., based on the initial stent retriever (Solitaire). In this chapter we will develop this technique.

  
  
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  A combination of these two, technically known as Solumbra technique.