Chapter 7 – Reperfusion of the Ischaemic Brain by Endovascular Thrombectomy and Thrombolysis




Abstract




Endovascular thrombectomy (EVT) with highly effective reperfusion devices is beneficial for: 1) relatively broadly selected acute ischaemic stroke patients with anterior circulation large vessel occlusions (LVOs) who have failed or are ineligible for intravenous fibrinolysis, up to 7 h after onset; and 2) imaging-selected patients with a favorable penumbral profile (small core and substantial salvageable tissue) 6–24h after onset. Among early-presenting patients, benefit is strongly time-dependent; for every 4 m delay in door-to-reperfusion time, 1 of every 100 patients has a worse disability outcome. Based on the trial evidence, EVT is strongly endorsed by guidelines worldwide. Within the first 7h, benefit is evident in patients under and over age 80, and in patients with up to moderate early ischaemic changes on imaging (ASPECTS 6-10). Systems of care should be optimized to deliver likely LVO patients to endovascular-capable stroke centers, and for procedure start (arterial puncture) within 75m, and optimally within 45m, after ED arrival. Large-scale trials are testing: best prehospital recognition and routing protocols: novel device designs to increase reperfusion rates in large and also medium vessel occlusions; bridging neuroprotection and collateral enhancement; potential benefit in patients with large cores; and best concomitant therapies, including sedation mode and post-procedure blood pressure management.





Chapter 7 Reperfusion of the Ischaemic Brain by Endovascular Thrombectomy and Thrombolysis



Meng Lee


Jeffrey L. Saver



Rationale


About 70% of all strokes worldwide are caused by occlusion of a cerebral artery, resulting in focal brain infarction (ischaemic stroke) (Feigin et al., 2017). The obstruction is usually a thrombus that has formed in situ on an atherosclerotic plaque or a thrombus that has embolized from a proximal source such as the extracranial neck vessels, the aortic arch, the heart, or the leg and pelvic veins.


Endovascular treatments aim to rapidly restore blood flow, before all the ischaemic brain in the territory supplied by the artery has become infarcted, by using catheter-delivered strategies to remove or disrupt fresh thrombi or other occlusive material. Endovascular therapies encompass mechanical and pharmacological approaches. Endovascular mechanical thrombectomy uses catheter-delivered devices, including retrievers and aspirators, to capture and extract the target thrombus. Endovascular mechanical angioplasty uses expandable balloons and implanted stents to restore the arterial lumen by pushing thrombus and atherosclerotic plaque against the arterial wall. Endovascular pharmacological thrombolysis (or, more correctly, fibrinolysis) lyses fresh thrombi by using intra-arterial infusions to deliver thrombolytic drugs at high concentration directly to, and within, the target clot.


Endovascular reperfusion is a complementary strategy to intravenous (IV) thrombolysis. As IV delivery yields relatively modest fibrinolytic drug concentration arriving at target thrombi, IV thrombolysis is more effective at digesting the smaller clots that obstruct small- and medium-size vessels, and less effective for large vessel occlusions (LVOs) with sizeable clot burdens (Legrand et al., 2013). In contrast, mechanical thrombectomy devices are highly efficient at recanalizing large proximal occlusions and less effective for small distal occlusions in vessels too small for easy device access.



Evidence



Study Designs and Patients


A total of 17 randomized controlled trials (RCTs) have compared endovascular recanalization therapy added to non-endovascular therapy (supportive care or intravenous fibrinolysis [IVT]) with non-endovascular therapy alone in 3361 highly selected patients (O’Rourke et al., 2010; Wardlaw et al., 2014; Badhiwala, et al., 2015; Bendszus et al., 2016; Rodrigues et al., 2016; Muir et al., 2017). The great preponderance of patients underwent vessel imaging to confirm presence of a target LVO prior to enrolment, including 2355 patients (12 trials) qualifying by computed tomography or magnetic resonance angiography (CTA or MRA, 12 trials) and 350 patients (4 trials) qualifying by catheter angiography. Another 656 patients (1 trial) were enrolled based on having substantial deficits likely to reflect LVO presence. Patients almost entirely had proximal intracranial occlusions in the anterior circulation, generally in the intracranial internal carotid artery or the M1 segment of the middle cerebral artery (MCA), and less often in the M2 MCA. Posterior circulation and more distal anterior circulation occlusions were rarely enrolled.


The endovascular therapies tested in these trials evolved over time, from moderately effective reperfusion techniques, including intra-arterial fibrinolysis, and coil retriever and combined aspiration–maceration devices (1994–2012: 7 trials, 1486 patients) to highly effective reperfusion techniques, including stent retriever and large-bore aspiration devices (2010 forward: 10 trials, 1875 patients) (Saver, 2013).


Standard care therapy, administered to participants in both endovascular and non-endovascular study arms, included IVF for all enrolled patients in 6 trials (1480 patients); IVF for all IVF-eligible and supportive care for IVF ineligible patients in 6 trials (1527 patients); supportive care with enrolment of only internationally IVF-ineligible patients in 4 trials (240 patients); and supportive care with enrolment of only nation-specific IVF-ineligible patients in 1 trial (114 patients).


In addition to trials with non-endovascular control arms, 5 randomized controlled trials, enrolling 1140 patients, have compared different endovascular mechanical thrombectomy devices against one another (Nogueira et al., 2012; Saver et al., 2012; Lapergue et al., 2017; Mocco et al., 2018; Nogueira et al., 2018); and 3 trials, enrolling 443 patients, have compared endovascular reperfusion therapies alone against IV reperfusion strategies alone (Ducrocq et al., 2005; Ciccone et al., 2010, 2013).


Complementing broad study-level meta-analyses, an individual patient-level data systematic analysis, permitting more detailed adjustment for prognostic variables, has analysed the first 5 trials of highly effective mechanical reperfusion devices versus non-endovascular controls, enrolling 1287 patients (Goyal et al., 2016; Saver et al., 2016).



Interventions


In randomized trials of intra-arterial administration of fibrinolytics, agents tested were urokinase, pro-urokinase, recombinant tissue plasminogen activator (rt-PA), and rt-PA with enhancement by ultrasound emitted from the catheter tip. In randomized trials of early generation mechanical thrombectomy, devices tested coil retrievers to physically enclose and remove the entire target thrombus and combined aspiration–maceration devices to break up and aspirate the thrombus without capturing it whole. In randomized trials of later generation mechanical thrombectomy, devices tested were (1) stent retrievers to physically enclose, trap, and retrieve the entire target thrombus; (2) large-bore aspiration catheters to physically suction the entire target thrombus; (3) large-bore aspiration catheters to engage the proximal clot by suction and then retrieve the entire the target thrombus; and (4) simultaneous, combined endovascular mechanical thrombectomy with both retriever and aspiration for clot extraction (EMBRACE technique). The later generation devices, alone and combined, were superior to lytic and early generation mechanical techniques, as confirmed in head-to-head randomized trials (Nogueira et al., 2012; Saver et al., 2012). Accordingly, later generation, highly effective recanalization devices are the mainstay of current clinical practice, and the evidence from trials testing these devices is a special focus of this chapter.



Results for All Endovascular Interventions against Non-Endovascular Controls


Overall, across all trials and all forms of endovascular intervention, random allocation to endovascular reperfusion therapy was associated with increased freedom from disability (modified Rankin score [mRS] 0–1 at 3–6 months, 29.1% vs 17.3%; relative risk [RR] 1.72, 95% confidence interval [CI]: 1.44–2.06; p < 0.00001) and increased functional independence (mRS 0–2 at 3–6 months, 44.8% vs 29.3%; RR 1.58, 95% CI: 1.34–1.86; p < 0.00001) (Figures 7.1 and 7.2). In addition, patients allocated to endovascular therapy had reduced mortality (16.8% vs 19.3%; RR 0.84, 95% CI: 0.73–0.98; p = 0.02), and a non-significantly higher symptomatic haemorrhage rate (5.6% vs 4.1%; RR 1.24, 95% CI: 0.90–1.7; p = 0.19) (Figures 7.3 and 7.4).





Figure 7.1 Disability-free outcome (mRS 0–1) at 3 months – endovascular reperfusion therapy vs controls.





Figure 7.2 Functional independence (mRS 0–2) at 3 months – endovascular reperfusion therapy vs controls.





Figure 7.4 Early (7–10 days) symptomatic intracranial haemorrhage – endovascular reperfusion therapy vs controls.





Figure 7.3 Death from all causes during study follow-up – endovascular reperfusion therapy vs controls.



Results for Patients Treated with Different Endovascular Recanalization Therapies


In the trials of endovascular recanalization therapy against non-endovascular controls, there was evidence that different endovascular treatment approaches differed in their effect upon freedom from disability (mRS 0–1) (heterogeneity p = 0.005), functional independence (mRS 0–2) (heterogeneity p = 0.0001), and mortality (heterogeneity p = 0.02), though not symptomatic haemorrhage. For both functional outcomes and for all-cause mortality, the highly effective mechanical thrombectomy reperfusion interventions had the greatest benefit, with lesser benefits with intra-arterial fibrinolysis, and no benefit with moderately effective mechanical thrombectomy reperfusion techniques.


These findings were confirmed in two randomized trials that directly compared stent retrievers, a highly effective endovascular mechanical thrombectomy technique, against coil retrievers, an earlier, moderately effective recanalization technique. Study-level meta-analysis of these two trials indicates that highly effective reperfusion therapies, compared with moderately effective therapies, are associated with increased achievement of substantial reperfusion (original thrombolysis in cerebral infarction [oTICI] scale 2b or 3 – Hi-Eff devices 68.3%, Mod-Eff devices 39.2%; RR 1.70, 95% CI: 1.35–2.15; p < 0.0001). This improved reperfusion was associated with more disability-free outcomes at 3 months (Hi-Eff devices 26.4%, Mod-Eff devices 16.3%; RR 1.61, 95% CI: 1.01–2.58), more functional independence at 3 months (Hi-Eff devices 38.6%, Mod-Eff devices 23.9%; RR 1.56, 95% CI: 1.09–2.24), without alterations in death or symptomatic intracranial haemorrhage.


Three randomized trials have compared different highly effective devices against one another, including stent retrievers versus aspiration devices (Lapergue et al., 2017; Mocco et al., 2018), and combined stent retrievers and aspiration devices versus aspiration devices alone (Nogueira et al., 2018). The different techniques performed roughly comparably in achieving substantial reperfusion and disability-free and independent functional outcomes, with low mortality and symptomatic haemorrhage rates.



Results for Highly Effective Endovascular Interventions against Non-Endovascular Controls, among Broadly Selected Patients Early after Onset


A total of 9 trials enrolling 1849 patients tested highly effective endovascular interventions against non-endovascular controls among relatively broadly selected patients presenting early after stroke onset. Permitted time windows, target occlusion locations, and degree of early ischaemic changes on presenting imaging varied across the trials, but the great preponderance of enrolled patients were within 6 hours of last known well, had intracranial internal carotid artery (ICA) or M1 segment MCA occlusions, and modest ischaemic changes on brain imaging (Alberta Stroke Program Early CT Score [ASPECTS] scale 7–10).



Freedom from Disability at 3 Months

Among these generally early-presenting acute ischaemic stroke (AIS) – LVO patients participating in trials predominantly testing highly effective reperfusion devices, random allocation to endovascular intervention was associated with an increase in disability-free outcome (mRS, 0–1) at 3 months after randomization (29.0% thrombolysis, 16.3% control; RR 1.72, 95% CI: 1.44–2.06; p < 0.00001). This represents 127 more disability-free patients per 1000 treated with endovascular reperfusion compared with control (see Figure 7.1). There was no heterogeneity across individual trials (heterogeneity p = 0.49), indicating consistency in evidence of treatment benefit.



Functional Independence at 3 Months

Endovascular therapy predominantly with highly effective mechanical devices was also associated with an increase in functional independence (mRS 0–2) at 3 months after randomization (47.2% endovascular therapy, 30.1% control; RR 1.58, 95% CI: 1.34–1.86; p < 0.00001). This represents 171 more functionally independent patients per 1000 treated with endovascular reperfusion compared with control (see Figure 7.2). Indications of benefit were consistent across studies, without evidence of variability (heterogeneity p = 0.51).



Death by 3 Months

By 3 months, patients allocated to endovascular therapy predominantly with highly effective devices had a non-significant trend toward lower mortality (14.5% endovascular therapy, 17.6% control; RR 0.83, 95% CI: 0.66–1.05; p = 0.13), representing a potential 31 fewer deaths per 1000 patients treated with endovascular therapy compared with control (see Figure 7.3). Signals of benefit were consistent across studies (heterogeneity p = 0.34).



Early Symptomatic Intracranial Haemorrhage

Endovascular therapy predominantly with highly effective devices was not associated with alteration in rates of early symptomatic intracranial haemorrhage within 7–10 days of treatment (4.2% endovascular therapy, 4.0% control; RR 1.10, 95% CI: 0.70–1.73; p < 0.68) (see Figure 7.4). Effect findings were consistent across trials (heterogeneity p = 0.68).



Other Complications

Endovascular therapy with highly effective thrombectomy devices is associated with additional, less-common complications, including, most notably, infarcts in new territories and femoral artery access site haematoma or pseudoaneurysm. These were not uniformly recorded in all the major randomized trials, but information on their frequency is available from subsets of the trials. An infarct in a new territory most commonly arises when control is lost over a thrombus or a fragment of a thrombus being retrieved from the cerebral circulation, and the released thrombus embolizes to a new territory. For example, a clot grasped and withdrawn from the M1 MCA may escape device control during passage through the ICA siphon and embolize to the anterior cerebral artery, causing ischaemia and infarction in the previously uninvolved anterior cerebral artery. Across 2 of the trials, infarcts in a new territory occurred in 5.4% (18/336) of endovascular versus 0.3% (1/370) of medical patients, RR 19.8, 95% CI: 2.7–147.7; p = 0.004 (Berkhemer et al., 2015; Jovin et al., 2015). A haematoma or pseudoaneurysm at the femoral arterial access site is a potential complication of all endovascular procedures. With endovascular thrombectomy, across 2 of the trials, femoral artery haematoma or pseudoaneurysm occurred in 5.6% (15/268) of endovascular versus 0% (0/253) of medical patients, RR 29.3, 95% CI: 1.8–486.7; p = 0.02 (Goyal et al., 2015; Jovin et al., 2015).



Degree of Disability at 3 Months

Analyses of dichotomized outcomes consider only a single health state transition that treatment may affect. For example, the outcome of being alive and disability-free counts only transitions across the border between mRS level 2 and mRS level 1, while the outcome of being alive and independent counts only transitions between mRS level 3 and mRS level 2. In contrast, analyses of ordinal outcomes consider simultaneously multiple valuable health state transitions that treatment may affect (Saver, 2011; Bath et al., 2012). For example, analysis of the distribution of outcomes over the entire mRS counts all transitions across all seven degrees of post-stroke disability the scale assesses, from asymptomatic, through varying degrees of impairment, to death.


An analysis has been conducted of the effect of highly effective reperfusion devices on the distribution of patient outcomes across all 7 levels of disability assessed by the mRS using participant-level data from the first 5 completed trials, enrolling 1287 patients (Goyal et al., 2016) (Figure 7.5). In these trials, allocation to endovascular thrombectomy resulted in increased proportions of patients at all disability ranks, including more patients who are asymptomatic (mRS 0), disability-free (mRS 0–1), functionally independent (mRS 0–2), ambulatory (mRS 0–3), not needing continuous care (mRS 0–4), and alive (mRS 0–5). Overall, treatment with highly effective endovascular thrombectomy versus control increased the odds of a better (less disabled) outcome state, adjusted common odds ratio (cOR) 2.49 (95% CI: 1.76–3.53). Using the automated algorithmic min–max joint outcome table method, for every 1000 patients treated with endovascular thrombectomy, a net of 423 patients will have a lower level of disability as a result of treatment (Tokunboh et al., 2018).





Figure 7.5 Level of disability at 3–6 months, endovascular thrombectomy with highly effective devices versus control, pooled trial analysis, based on data in Goyal et al. (2016).



Results for Highly Effective Endovascular Interventions against Non-Endovascular Controls, among Imaging-Selected Patients Late after Onset

In acute cerebral ischaemia, when an artery is abruptly occluded, collateral vessels provide compensating blood flow to the supplied region. The robustness of the collateral supply varies widely from individual to individual, depending on variations in circle of Willis anatomy, stenoses and occlusions in the alternative channels themselves, the site of the new occlusion, and systemic blood pressure. Shortly after the inciting vascular occlusion, a small brain region within the supplied field may experience complete loss of blood flow, causing cellular death within 1 to a few minutes. But a much larger, surrounding zone will experience moderate reductions in blood flow that the brain cells can tolerate for tens of minutes to several hours. As time from onset lengthens, the zone of the completed, irreversible infarction – the core – expands and the rim of threatened but still salvageable tissue – the penumbra – shrinks.


CT and MRI techniques indexing core and penumbra volume permit identification of the subset of patients with well-defined onset times who are ‘slow progressors’ and still harbour rescuable tissue in later time windows (Wheeler et al., 2015). They also enable assessment of tissue status in patients with uncertain onset times, due to stroke onset some time during sleep or awake onset in an unaccompanied patient, with aphasia or confusion precluding patient report or observation of onset time. With CT, perfusion CT imaging identifies as core regions with extreme reduction in blood flow or blood volume, and as penumbra regions with moderate blood flow reduction (perfusion–core mismatch). With MRI, diffusion MR sequences identify as core regions with substantial diffusion abnormality, indicating advanced bioenergetic compromise, and perfusion MRI sequences identify as penumbra regions with moderate-to-severe blood flow reduction not yet showing diffusion abnormality (perfusion–diffusion mismatch). Alternative, less precise but more readily obtained, approaches to identifying patients with penumbra estimate the volume of perfusion reduction using the presence of LVO (vessel–core mismatch), the extent of collateral vessels (collateral–core mismatch), or the severity of neurological deficits (clinical–core mismatch).


Using imaging evidence of persisting salvageable tissue to select a subset of late-presenting patients has been tested in 2 trials comparing highly effective endovascular reperfusion devices with non-endovascular treatment. Across both trials, random allocation to endovascular reperfusion therapy was associated with increased freedom from disability (mRS 0–1 at 3–6 months, 31.2% vs 11.1%; RR 2.76, 95% CI: 1.75–4.35; p < 0.0001) and increased functional independence (mRS 0–2 at 3–6 months, 46.7% vs 14.8%; RR 3.12, 95% CI: 2.15–4.53: p < 0.00001) (see Figures 7.1 and 7.2). In addition, patients allocated to endovascular therapy had no alteration in mortality (16.6% vs 21.7%; RR 0.76, 95% CI: 0.41–1.40; p = 0.38), or symptomatic haemorrhage rate (6.3% vs 3.7%; RR 1.63, 95% CI: 0.65–4.06; p = 0.29) (see Figures 7.3 and 7.4).



Results for Different Treatment Times, Treatment Settings, and Types of Patients, among Broadly Selected Patients Early after Onset


A pooled, individual-level patient data meta-analysis was undertaken to explore for heterogeneity of treatment effect according to time from onset to treatment start, age, and presenting deficit severity (Goyal et al., 2016). The analysis included 1287 patients from 5 randomized trials of highly effective endovascular reperfusion devices. Among the 634 patients allocated to the endovascular arm, 558 (88.0%) actually underwent endovascular intervention; the most common reasons for not pursuing intervention were clinical improvement, clot resolution, and inability to access the target vessel. Among patients undergoing an endovascular intervention, a stent retriever device was employed in 532 (95.3%).



Effect of Onset to Treatment Time and Door-to-Treatment Time

Among the 1287 patients, 194 (15.1%) were treated within between 0.5 and 2 hours of onset, 657 (51.0%) between 2 and 4 hours, 352 (27.4%) between 4 and 6 hours, and 79 (6.1%) between 6 and 12 hours.



Alive and Functionally Independent at the End of Patient Follow-up

Earlier treatment was associated with greater benefit in increasing functional independence (mRS 0–2) at 3 months. With time from onset (last known well) to arterial puncture of 2 hours, allocation to endovascular reperfusion therapy was associated with more frequent alive and independent outcome (52.0% endovascular therapy, 27.0%, control; RR 1.93, intercept of full population ordinal model) (Figure 7.6). This represents 250 more alive and functionally independent patients per 1000 treated with endovascular reperfusion compared with control. In contrast, with time from onset (last known well) to arterial puncture of 5 hours, allocation to endovascular reperfusion therapy increased alive and independent outcome to a lesser degree (43.8% endovascular therapy, 27.0% control; RR 1.62). This represents 168 more alive and non-disabled patients per 1000 treated with endovascular therapy compared with control.





Figure 7.6 Modification of endovascular thrombectomy benefit by onset to expected arterial puncture. (A) Common odds ratio for reduced level of disability at 3 months; (B) 3-month outcome rates for each of the 7 levels of the mRS. Reproduced from Saver et al. (2016), with permission from the American Medical Association.


Functionally independent outcome declined more steeply with each delay during the interval from Emergency Department (ED) arrival to puncture (door to puncture) than from last known well to puncture (onset to puncture). Each 60-minute delay in onset to puncture was associated with a reduction in likelihood of functionally independent (mRS 0–2) outcome of OR 0.87 (0.78–0.96), while each 60-minute delay in door to puncture was associated with a reduction of OR 0.55 (0.43–0.71). Likely the faster decline in independent outcome with longer door to puncture than onset to puncture intervals was related to (1) a more accurately identifiable start time for the interval (ED arrival vs last known well), and (2) the screening out from some trials of patients with very rapid progression during the onset to door interval, due to entry criteria in requiring absence of substantial infarct extent upon arrival.



Degree of Disability at the End of Patient Follow-up

Considering time as a continuous variable, the benefit of treatment in reducing degree of disability tended to decline with later onset to treatment time (p = 0.07) (see Figure 7.6). The increased odds of a less disabled late outcome with endovascular recanalization therapy nominally declined from about 3.1 with arterial puncture at 2 hours to about 2.3 at 5 hours and about 1.8 at 8 hours. The point estimate for time at which treatment benefit for functional independence entirely disappeared was 12.2 hours, and the time at which the lower 95% CI for treatment benefit first crossed neutral was at 7.3 hours.


Time delay was associated with a steeper decline in odds of reduced final disability level across all 7 mRS ranks during the door to puncture than onset to puncture interval. Each 60-minute delay in onset to puncture was associated with a reduction in likelihood of functionally independent (mRS 0–2) outcome of OR 0.88 (0.81–0.96), while each 60-minute delay in door to puncture was associated with a reduction of OR 0.56 (0.47–0.67).


In the subset of 390 endovascular arm patients in whom substantial perfusion was achieved, there was a steep decline in final level of disability over 6 mRS ranks with longer door to reperfusion time. Among 100 treated patients, with every 15-minute decrease in ED door-to-reperfusion time, an estimated 39 more patients have a less disabled mRS outcome at 3 months (including 25 more achieving functional independence [mRS 0–2]). For every 4-minute acceleration in ED door-to-reperfusion time, 1 of every 100 treated patients has a less disabled outcome.



Death at the End of Patient Follow-up, and Early Major Haemorrhage

Earlier treatment was associated with greater benefit in reducing mortality at 3 months (p < 0.02). With onset to puncture of 2 hours, allocation to endovascular reperfusion therapy was associated with reduced mortality (6.2% endovascular therapy, 17.9% control; RR 0.35, intercept of full population ordinal model) (see Figure 7.6). This represents 117 more alive and functionally independent patients per 1000 treated with endovascular reperfusion compared with control. In contrast, with onset to puncture of 5 hours, allocation to endovascular reperfusion therapy was associated with a mortality reduction of a lesser degree (9.9% endovascular therapy, 17.9% control; RR 0.55). This represents 80 more alive and non-disabled patients per 1000 treated with endovascular therapy compared with control. In contrast, earlier onset to puncture was not associated with differences in symptomatic haemorrhage rate between thrombectomy and control patients (p = 0.40).



Effect of Age

Randomized trials have shown that older patients compared with younger patients have worse functional outcomes from acute ischaemic stroke but benefit to the same relative degree from endovascular therapy over a wide range of ages, from 50 to over 80 years old. A tendency to a lesser degree of benefit was noted, however, for young adults aged 18 to 49, among whom control group patients have good outcomes related to greater capacity for neural repair and recovery. Among 5 pooled trials of highly effective reperfusion devices, enrolling 1287 patients, 12% were aged 18 to 49, 72% were aged 50 to 79, and 15% were 80 years and older.


Endovascular thrombectomy among broadly selected patients early after onset tended to reduce final level of disability (over 6 levels of the mRS) to a lesser degree among patients aged 18 to 49 (common odds ratio 1.36) than among patients aged 50 to 80 and above (cORs ranging from 2.41–3.68, heterogeneity p = 0.07). Over the broad range from age 50 to 80 and above, the relative benefit was similar in degree in different age groups but with worse overall outcomes in older patients. For example, for ages 60 to 69, functional independence (mRS 0–2) was 51.9% with endovascular therapy, 27.9% with control, OR 1.78 (95% CI: 1.25–2.55); while for age 80 and above, functional independence was 29.8% with endovascular therapy, 13.9% with control (OR 2.09, 95% CI: 1.03–4.25). Considering mortality, endovascular thrombectomy was associated with reduced death among the oldest old (aged ≥80: OR 0.60, 95% CI: 0.36–0.99) but not younger individuals (aged 18–79: OR 0.95, 95% CI: 0.69–1.37).



Effect of Presenting Deficit Severity

Randomized trials have shown that severe, compared with moderate, presenting neurological deficits are a prognostic, but not a treatment benefit-modifying, patient feature. Across a broad range of presenting deficit severity, patients with more severe deficits benefit to the same relative degree from highly effective endovascular thrombectomy, without evidence of heterogeneity (heterogeneity p = 0.45), but absolute rates of good outcome are lower when initial deficits are greater. The odds of a better level of disability across the entire mRS were improved by endovascular thrombectomy to a similar relative degree across 4 levels of presenting deficit severity (National Institutes of Health Stroke Scale [NIHSS] ranges of ≤10, 11–15, 16–20, and ≥21) (heterogeneity p = 0.45) (Figure 7.7). For example, rates of functional independence among moderate deficit patients (NIHSS 11–15) were 58.1% versus 27.1% (OR 1.70, 95% CI: 1.19–2.43), and among severe deficit patients (NIHSS ≥21) were 23.0% versus 13.8% (OR 1.80, 95% CI: 1.09–2.96).





Figure 7.7 Common odds ratio for more favourable 3-month disability level in patient subgroups of differing presenting deficit severity and differing extent of infarct signs on first imaging. Figure based on data from Goyal et al. (2016).


Patients with mild initial presenting deficits have not been enrolled in substantial numbers in trials of highly effective endovascular thrombectomy. Among the first five trials, three formally excluded patients with NIHSS scores of less than 6 or less than 8, and the remainder enrolled very few patients in this range. However, observational series have noted that patients with initially mild deficits associated with LVOs have a substantial rate of subsequent stroke progression and poor outcome (Rajajee et al., 2006). Randomized trials in these patients are needed.



Effect of Imaging Findings on Noncontrast CT

Randomized trials have suggested that endovascular thrombectomy benefits both patients with mild and patients with moderate early infarct changes on initial brain imaging to the same relative degree, but may benefit patients with extensive early infarct changes less or not at all. The extent of early ischaemic injury changes on initial brain CT and MRI scans has been most often quantified using the Alberta Stroke Program Early CT Score (ASPECTS). Among 5 trials enrolling 1278 patients testing highly effective mechanical thrombectomy, 53% had mild early infarct changes (ASPECTS 9–10), 37% moderate (ASPECTS 6–8), and 9% severe early infarct changes (ASPECTS 0–5, but predominantly 4–5). The odds of a better level of disability across the entire mRS were improved by endovascular thrombectomy to a similar relative degree at each of these 3 levels of presenting deficit severity (heterogeneity p = 0.49) (see Figure 7.7), though patients with less extensive infarcts had better outcomes in both treatment arms: no or small infarct signs (ASPECTS 9–10), 49.7% versus 30.2%, OR 0.84, 95% CI: 0.73–0.96; moderate infarct signs (ASPECTS 6–8), 44.4% vs 23.3%, OR 0.81 (0.61–1.08); extensive infarct signs (ASPECTS 0–5), 23.3% versus 13.3% (see Figure 7.7).

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Mar 22, 2021 | Posted by in NEUROLOGY | Comments Off on Chapter 7 – Reperfusion of the Ischaemic Brain by Endovascular Thrombectomy and Thrombolysis
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