Intra-arterial Therapy for Acute Ischemic Stroke

Fig. 4.1

Evolution of IA therapy trials over time. More positive trials with newer devices and technology over time. Positive trials: Circles at the upper border, Negative trials: Circle at the lower border, Results pending: Circle in the middle. Escape results announced to the participating sites investigators as favoring IA without pending the full publication (Endovascular Stroke Trials Halted for Benefit. Can be found at http://www.medscape.com/viewarticle/835040. Last accessed January 7, 2015). Permission from Stroke, Neurointerventional and Neurocritical Care (SNN) research center. ozaidat@hotmail.com

These clinical and technical advances were incorporated into the design of “MR CLEAN” interventional AIS therapy randomized clinical trial [9]. The MR Clean results demonstrated an overwhelming clinical and angiographic efficacy of mechanical approach added to standard of care over standard of care alone when initiated within 6 h from symptoms onset [9].

In this chapter, we provide an overview of intra-arterial AIS therapy [10].

The Basis for Intra-arterial Therapy

The intra-arterial approach to acute ischemic stroke has emerged as an adjuvant or stand-alone therapeutic modality for AIS. Local intra-arterial therapy (IAT) offers some advantages over systemic thrombolysis (See Table 4.1 for advantages and disadvantages of IAT).

Table 4.1

Pros and Cons of IAT for AIS

Pros	Cons
Superior to IV-rtPA for stroke due to large artery occlusion (MR CLEAN 2014, Escape 2015^a, Extend IA trials^a)	Embolization into new territory
Expanded time window to 6 h from symptoms onset	Downstream distal embolization
Efficacious for large vessel occlusion and fibrinolysis resistant clots	Tortuous anatomy in elderly stroke patients
Smaller dose or no fibrinolytic agents	Access complication and vessel injury
Higher rate of complete recanalization	24/7 specialized team and tertiary care center needs
Faster recanalization time

^aResults not yet published or presented but trials prematurely stopped due to reportedly highly favorable benefit of IAT

First, it can expand the treatment time window beyond 3 or 4.5 h. The time window has been safely expanded to 8 h and 24 h in anterior and posterior circulation, respectively, using IAT [11–14]. Second, IAT provides faster and more efficient recanalization for clot loads that are large or resistant to enzymatic degradation [15]. One study evaluated the recanalization rate in consecutive IV-rtPA treated AIS patients based on the clot size using ultrathin computerized tomography of the head to assess the length of hyper-dense MCA sign (clot size) [15]. The study demonstrated that with IV-rtPA, short clots (length <5 mm) were highly likely to be dissolved completely, whereas for longer clots (8 mm in size or greater), recanalization was very unlikely and was observed in <1 % of cases, as illustrated in Fig. 4.2 [15].

Fig. 4.2

Probability of occluded vessel recanalization by intravenous thrombolysis is very low (<5 %) when thrombus length approaches 8 mm. Reproduced from: Wolters Kluwer Health, Stroke, The Importance of Size: Successful Recanalization by Intravenous Thrombolysis in Acute Anterior Stroke Depends on Thrombus Length, Christian H. Riedel, Philip Zimmermann, Ulf Jensen-Kondering, Robert Stingele, Günther Deuschl, Olav Jansen, Dec 31, 1969, Vol 42, Issue 6

Third, beside the length and size of the clot, its composition such fibrin and platelet rich white clot, or clots rich with calcium or cholesterol crystals may render themselves resistant to both local and system fibrinolysis (versus red clots composed mainly from erythrocytes) and the need for mechanical retrieval devices ensues [16].

Given the above rationale and evidence, IAT became the logical next area of major research emphasis in AIS management to accelerate reperfusion, particularly in patients with large vessel occlusion secondary to large size clot.

Intra-arterial Chemical Thrombolysis Approach

The first attempt of IAT was the use of a local fibrinolytic agent delivered via microcatheter directly into the clot (Fig. 4.1). The pharmacological advances and newer fibrinolytic agents may lead to higher use in the future for both IV and IA thrombolysis. For example, development of a more specific agent that can be administered as a single bolus with more specificity to fibrin may reduce the time required for administration and the risk of intracranial hemorrhage (Fig. 4.3, depicting thrombolysis pathway).

Fig. 4.3

Fibrinolysis pathway

The main advantage of local intra-arterial fibrinolytic therapy is the ability to infuse smaller doses of the thrombolytic drugs locally, within or in a close proximity to the thrombus. In theory, this direct delivery of the thrombolytic agent to the thrombus can increase the chance of recanalization, decrease the risk of hemorrhage by providing a higher concentrated dose into the clot and using a smaller total dose. Moreover, in comparison to other IAT technique; it is technically easier to perform (i.e., tracking a soft and small diameter microcatheter to the face of the clot is easier). However, it is less effective than mechanical thrombectomy, and takes longer to complete (due to the slow IA infusion rate).

Different fibrinolytic agents can be used with varying targets, and rates of specificity and sensitivity to thrombus components, for example some are more specific for Plasminogen, versus Plasmin versus fibrin, while others may be more resistant to inhibitory pathways than others (Fig. 4.3). The most commonly used agent for IAT in clinical practice is rtPA. However, Urokinase and Prourokinase have been also used in clinical studies.

The Prolyse in Acute Cerebral Thromboembolism (PROACT Trial) is the first double-blinded, randomized, placebo-controlled study of fibrinolytic agents delivered intra-arterially by microcatheter in AIS and was published in 1998 [17]. The study aimed to test the safety and efficacy of the intra-arterially delivered thrombolytic agent (Prourokinase) versus placebo in AIS patients with angiographically proven proximal middle cerebral artery (MCA) occlusion. Patients who displayed a 0–1 grade MCA occlusion on the Thrombolysis in Acute Myocardial Infarction (TIMI) scale (see Table 4.2 for TIMI scoring) were enrolled in the trial.

Table 4.2

Thrombolysis in myocardial infarction (TIMI) scale (Established by the national heart, lung and blood institute in 1983 to measure myocardial reperfusion. The scale since then has been widely adopted for use in the cerebral circulation and has been used in the PROACT Trial, MERCI, MULTI MERCI, PENUMBRA PIVOTAL, SWIFT, and the START trials)

TIMI score	Definition
0-Complete occlusion	There is no antegrade flow beyond the point of occlusion.
I-Penetration without perfusion	Perfusion past the initial occlusion, however the is contrast stagnation without distal branch filling.
II-Partial perfusion	Perfusion past the initial occlusion, however the contrast rate of entry or rate of clearance rate delayed when compared to unaffected vessels.
III-Complete perfusion	Full perfusion with filling of all distal branches, contrast material clears as rapid as unaffected branches.

The patients were randomized in a 2:1 ratio to receive intra-arterial (IA) prourokinase or placebo infusion within 6 h from symptoms onset. Both groups also received IV heparin infusion. Forty patients were randomized (26 received prourokinase and 14 received placebo). Partial or complete recanalization in the prourokinase group was observed in 15 of 26 patients (57.7 %) compared with 2 of 14 patients (14.3 %) in the placebo group (p = 0.017). Symptomatic hemorrhagic transformation occurred in 15.4 % and 5.1 % of the prourokinase and the placebo groups, respectively (p = 0.61). The authors observed higher absolute rates of excellent neurological outcome in the IA cohort (modified Rankin Scale score of 0–1: 30.8 % vs. 21.4 %; Barthel Index score of 9–10: 42.3 % vs. 35.7 %; NIHSS score of 0–1: 19.2 % vs. 7.1 %), but these difference did not reach statistical significance [17].

These encouraging results led to the PROACT II trial, which was published in 1999 [18]. In PROACT II, patients with angiographically proven MCA occlusion were randomized to receive IA Prourokinase plus IV heparin (n = 120) or IV heparin alone (n = 60) within 6 h from stroke symptoms onset in a 2:1 ratio. The primary outcome was slight or no disability at 90 days as defined by modified Rankin Scale (mRS) of 2 or less. The total recanalization rate was 66 % in the Prourokinase group and 18 % in the control group. The rate of good neurologic outcome (90 days mRS 0–2) was 40 % for the Prourokinase group vs. 25 % for the placebo group. This was the first clinical trial that demonstrated a benefit of IAT in AIS. However, Prourokinase failed to get FDA approval in the USA and is therefore not available.

Another IAT study with MCA occlusion was done in Japan, and published in 2007 [19]. The Middle Cerebral Artery Embolism Local Fibrinolytic Intervention Trial (MELT) was halted prematurely in 2005 due to the approval of IV-rtPA in Japan, and further enrollment into a control arm (not receiving IV-rtPA) was considered unethical [19]. In the MELT trial, a total of 114 patients were randomized to receive IA Urokinase versus placebo. Although more patients in treatment group met the primary end point of a mRS 2 or less, the difference did not reach statistical significance (49.1 % vs 38.6 %, p = 0.345). However, excellent clinical outcome (mRS of 0 or 1), which was a preplanned secondary outcome, was statistically more frequently seen in the Urokinase group than in the control group (42.1 % vs 22.8 %, p = 0.045).

For posterior circulation AIS, a small randomized study of 16 patients within 24 h of stroke symptom onset was reported [14]. Eight patients were randomized into each arm, with higher stroke severity at baseline in the Urokinase arm. A good functional clinical outcome was observed in four of eight patients who received intra-arterial Urokinase compared with one of eight patients in the control patients [14].

A meta-analysis of chemical IA thrombolysis [20], showed overall favorable outcome with IA therapy over controls, as shown in Fig. 4.4.

Fig. 4.4

Meta-analysis of intra-arterial chemical thrombolysis clinical studies. (a) Good outcome (mRS 0–2) and (b) Excellent outcome (mRS 0–1). Reproduced from Wolters Kluwer Health, Stroke, Efficacy of Intra-Arterial Fibrinolysis for Acute Ischemic Stroke: Meta-Analysis of Randomized Controlled Trials, Meng Lee, Keun-Sik Hong, Jeffrey L. Saver, May 1, 2010, Volume 41, Issue 5

Combined IV and IA Therapy

Intravenous thrombolytic therapy has certain advantages over IA therapy; it is more widely accessible, since it can be administered rapidly in the emergency room, and potentially in a stroke mobile unit ambulance, or via Telestroke across the country. Therefore, the combined (bridging) approach takes advantage of the rapidity by which IV-rtPA can be administered, and the high recanalization efficacy of the IAT. The “bridging” approach is a method by which the patient receives systemic thrombolysis at the field (in a mobile stroke unit), an outside hospital (“drip and ship” to tertiary stroke center), or locally in the receiving hospital; then is transferred immediately to the angiography suite for possible additional local IA therapy. If symptoms resolve, or intervening imaging such CT angiography shows no large vessel occlusion, or angiogram shows no occlusion, then IA therapy is aborted.

The combined IV/IA treatment strategy was initially tested in a small open-label prospective study of 45 patients [21]. A total of 12 patients received IV-rtPA plus IA-rtPA (IV/IA) with either MCA (9) or internal carotid artery (ICA, 3) occlusions versus 33 patients who received IV-rtPA only [21]. In the IV/IA group: good outcome was seen in 67 % and 83 % at 1 month and 12 months, respectively versus 21 % and 33 % in the control groups at 1 month and 10 months, respectively [21]. The randomized combined IV/IA Emergency Management of Stroke (EMS) Bridging Trial was published in 1999 [22]. Seventeen AIS patients were randomized to IV/IA group and 18 patients into the placebo/IA group within 3 h of symptoms onset. There was no difference in the clinical outcome or symptomatic intra-cerebral hemorrhage (sICH) between the two groups. However, there was a better recanalization rate in IV/IA group compared to the placebo/IA group (68 % versus 10 %, respectively; p = 0.03). This pilot study suggested that combined IV/IA treatment was feasible, safe, and provided good recanalization rates.

The initial Interventional Management of Stroke Study (IMS) [23] was an open-label, single arm study in which patients with moderate to severe stroke who had received IV-rtPA were treated with up to an additional 22 mg of IA-rtPA. Patients in IMS were compared to historical controls from the NINDS IV rt-PA trials who received active treatment (IV-rtPA only comparators) or placebo (no treatment comparators). When compared to patients from the placebo arm of the NINDS IV-rtPA trials, the 3-month mortality was lower but not statistically different (IMS versus Placebo of NINDs trial). The rate of sICH was similar between the IMS patients and the NINDS IV-rtPA treatment group (6.3 % vs 6.6 %, respectively). However, IMS patients had significantly better functional outcome at 3 months than the placebo NINDS group.

The IMS II Study [24] was a phase two trial, with a similar design single arm study; except that patients were treated with only two thirds of the IV-rtPA dose (0.6 mg/kg) within 3 h of symptoms onset, and then received up to an additional 22 mg of IA-rtPA. The results mirrored those of the first IMS Study. In the IMS II study, 81 AIS patients were treated with IV/IA via standard or ultrasound tip microcatheter technique within 3 h of symptoms onset. The 3-month mortality in IMS II was 16 % as compared with the mortality of placebo (24 %) and rtPA-treated patients (21 %) in the NINDS IV Trial. The rate of sICH in IMS II patients (9.9 %) was not significantly different than that for IV-rtPA treated group in the NINDS Trial (6.6 %). IMS II patients had significantly better outcomes at 3 months than NINDS placebo-treated patients for all end points (ORs ≥2.7) and better outcomes than NINDS IV-rtPA-treated patients as measured by the Barthel Index and Global Test Statistic [24].

The IMS phase three (IMS III) trial [25] randomized patients with moderate to severe AIS within 3 h from symptoms onset to receive IV-rtPA with an additional mechanical endovascular therapy (based on the interventionalist choice) or IV-rtPA alone in a 2:1 ratio. The trial started in 2005 using the first-generation AIS mechanical thrombectomy MERCI devices (see below), and was halted early because of futility analysis after 656 patients had been randomized [25]. The primary end point of the proportion of subjects with good outcome (mRS 0–2) was not different between the groups (40.8 % for IV/IA group and 38.7 % for IV-rtPA group). The incidence of sICH was similar in both groups (6.2 % and 5.9 %, respectively) [25]. It was unfortunate that the trial was halted (in April 2012) as soon as new-generation AIS thrombectomy devices (Stent retrievers) were approved by the FDA on March 2012 (theses new devices may have contributed to the positive results of MR CLEAN clinical trial [9], please see below).

Mechanical Thrombectomy Devices

The AIS therapy aim is to improve outcome and reduce mortality by rapidly revascularizing large cerebral artery occlusion, thereby limiting the extent of ischemic brain tissue, has been the main force propelling the development of quicker and more reliable thrombectomy devices. The impetus for the iterative development of various mechanical thrombectomy devices originates primarily from these needs, along with the suboptimal use of IVrtPA in clinical practice, as well as less than optimal rate of complete recanalization, and the technical complexity of using the first-generation mechanical thrombectomy devices (see below).

MERCI Retrievers

The first Mechanical Embolus Removal for Cerebral Ischemia (MERCI) device was conceived in 1995. The MERCI Retrievers (MR) are corkscrew-shaped mini devices attached to micro-wire, that are designed to remove blood clots from large cerebral vessels. They had various diameter and length sizes and housed in constrained format in a small cerebral microcatheter. Once deployed and unsheathed from the microcatheter, the MR becomes coiled in shape to engage and retrieve the clot (Fig. 4.5).

Fig. 4.5

Evolution of the MERCI device. The first-generation X-Series with a tapered design and no filaments. The L-Series with added filaments to provide increased surface area for clot engagement. The V-Series with coil linear configuration and filaments for optimal clot retention

Animal studies began with the device in 1996, and subsequently in humans with a series of MERCI trials, which led to its FDA approval in 2004. The MERCI retriever was the first FDA approved intra-arterial mechanical thrombectomy device for use in humans (Fig. 4.6, MERCI case example).

Fig. 4.6

A case example of successful use of the MERCI device in right MCA occlusion

In the MERCI and Multi MERCI trials [11, 12], the device was tested in patients with moderate to severe strokes (NIHSS ≥ 8) up to 8 h from symptom onset in a prospective, nonrandomized, single arm, multicenter trial. The results demonstrated a successful TIMI scale of 2 or higher recanalization rate of 48 % and 57.3 %, respectively. These rates were significantly higher than the 18 % rate in the placebo group of PROACT II study [18]. The risk of sICH was similar to historical controls in the PROACT II trial [18]. Good functional outcome was defined as an mRS ≤ 2, which was found more frequently in patients with recanalization versus not. These results emphasized the importance of reestablishing blood flow to ischemic brain tissue to improve outcome. However, the rate of complete recanalization or meaningful recanalization was still limited with the MERCI device; and the time to reperfusion (groin puncture time to successful recanalization) was relatively long. Moreover, the introduction of stent retriever and more efficient suctioning devices may have ultimately led to very limited use in current practice.

Suction Thrombectomy

In 2008, the Penumbra system, a form of suction thrombectomy, was FDA approved and launched for commercial use as a new class of neuro-thrombectomy devices. Suction thrombectomy is performed with a catheter tracked into the face of the clot under X-ray fluoroscopy guidance, then attached to negative suctioning machine (vacuum) to aspirate the occlusive intra-vascular clot in AIS. The first-generation Penumbra system utilizes a special micro-wire called a separator that helps break a larger clot into pieces by a back and forth motion under aspiration (Fig. 4.7).

Fig. 4.7

First-generation penumbra system, consisting of both a thromboaspiration suction device and a separator

Newer-generation Penumbra systems included more trackable and larger bore distal catheter (MAX and ACE systems).

The device was tested with success in a prospective, multicenter, single-arm study called the Penumbra Pivotal Stroke Trial [13]. In this trial, 125 patients were enrolled with an NIHSS ≥ 8 within 8 h of symptom onset. Patients who presented within 3 h could be enrolled if they were excluded from IV-rtPA treatment for any reason. Of the treated vessels, 81.6 % were successfully recanalized based on TIMI scale (≥2). The rate of sICH was 11.2 %, which was comparable to MERCI 9.8 % and IA PROACT II group of 10 %. Despite the high rate of successful revascularization, a relatively low rate of good outcome (defined as 90-day mRS of 0–2) was reported at 25 %. However, the first post-market experience of the Penumbra system (POST study) showed better functional clinical outcome (41 % of 157 patients enrolled) than the original pivotal FDA study [26]. This is comparable with the good outcome rates of 40 % in the PROACT II trial, and slightly higher than the 36 % achieved with Multi-MERCI trial. The sICH rate of 6.4 % was more favorable than those reported in their pivotal study.

Perhaps to explain differences in neurological outcome with relatively similar recanalization rates, the Stroke Treatment and Revascularization Therapy (START) trial was designed to determine if there was a correlation between pretreatment infarct volume and functional outcome at 90 days [19]. Included in this study was Penumbra’s newer-generation device; Max catheter, which was designed to be easier to navigate the cerebral circulation, and to provide a better aspiration than the older-generation Penumbra devices. A total of 77 patients were enrolled with an average NIHSS of 19 (range of 14–24). The imaging methods used to select patients for the study were at each center’s discretion and included non-contrast CT, CT angiography, CT perfusion, and MRI diffusion imaging. The overall results of the study showed a good neurological outcome (mRS 0–2 at 90 days) of 48.1 % (37/77). The Alberta Stroke Program Early CT score (ASPECTS) score was used to evaluate core infarcts. The highest percentage of good neurological outcome 64.3 % was seen in the small core infarcts or an ASPECT score of 8–10 patients (Fig. 4.8 is AIS case example treated with Penumbra).

Fig. 4.8

Acute ischemic stroke secondary to a thrombus occluding the left internal carotid artery terminus (T-Occlusion) treated acutely with the Penumbra Aspiration System. Angiogram in AP and Lateral Pre (left hand pictures) and post (right hand pictures) Penumbra Aspiration System therapy with complete recanalization

With technical advances, a new approach has been to directly aspirate the cerebral clot with new-generation large bore distal access catheter without breaking it up, thus decreasing the chance of distal and new territory embolization, and potentially reducing procedure time [27–29]. Direct aspiration techniques (example of names used for this technique: FAST, MAT, ADAPT) has been used with different brands of large bore distal catheters (LBDC). When the LBDCs are advanced and placed at the proximal surface of the clot, a negative manual hand pressure (or automatic negative pressure pump machine) is applied by a 20 or 50 ml syringe for approximately 20 s. If no flow through the system is seen, the distal tip of the LBDC is assumed to have engaged the clot and the catheter is slowly withdrawn.

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