Chapter 6 – Reperfusion of Ischaemic Brain by Intravenous Thrombolysis




Abstract




Intravenous thrombolytic therapy (IV) with recombinant tissue-plasminogen activator (alteplase; 0.9 mg/kg over 1h) is beneficial for acute ischaemic stroke patients with potentially disabling neurological deficits, and without contraindications, when started =4.5h of onset. Benefit is time-dependent: among 1000 patients, IVT =3h lessen long-term disability in 178 patients, between 3-4.5h in 66. IVT under 4.5h is associated with an increase in symptomatic haemorrhage, but not an increase in death or severe disability. Based on trial evidence, IVT =3h is strongly endorsed, and between 3-4.5 hours moderately endorsed, by guidelines on 5 continents. Benefit is evident in patients under and over age 80, and in patients with up to moderate, but not extensive (more than 100 cc), early ischaemic changes on initial CT or MRI. IVT is also beneficial for patients =4.5h after onset with substantial salvageable tissue on penumbral CT or MR imaging. Systems of care should be optimized to start IVT =60m, and optimally =30m, after ED arrival. Large-scale trials are needed to further enhance IVT, testing: faster treatment start in mobile stroke units (mobile CT ambulances): fibrinolytic agent and concomitant lytic-enhancing combinations; bridging neuroprotection and collateral enhancement; and the optimal way to combine intravenous thrombolytic therapy and endovascular mechanical thrombectomy.





Chapter 6 Reperfusion of Ischaemic Brain by Intravenous Thrombolysis



Jeffrey L. Saver


Joanna Wardlaw



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, and the leg and pelvic veins.


When a thrombus forms or lodges in an artery, plasminogen, a precursor of plasmin, binds to the fibrin strands encasing the platelets and red blood cells in the clot. Endogenous tissue plasminogen activator (tPA), which is naturally made by endothelial cells, cleaves local plasminogen, thereby releasing active plasmin. The plasmin, in turn, breaks down cross-linked fibrin into soluble fibrin degradation products, lysing the clot. Frequently, however, such spontaneous lysis of the thrombus and recanalization of the artery do not occur until after the ischaemic brain has become fully infarcted.


Exogenous thrombolysis (or, more correctly, fibrinolysis) aims to rapidly restore blood flow by lysing fresh thrombi (in situ or embolic) which underpin many, but not all, ischaemic strokes, before all the ischaemic brain in the territory supplied by the artery has become infarcted. However, although some emboli consist of fresh thrombus, which is highly lysable by fibrinolysis, others are older, organized thrombi, which are less responsive, and others are non-lysable substances such as calcium, bacteria, tumour, and prosthetic material. Hence, not all ischaemic stroke is likely to respond to reperfusion by thrombolysis.



Evidence



Study Designs and Patients


A total of 29 randomized controlled trials (RCTs) comparing intravenous (IV) fibrinolytic treatment with non-fibrinolytic management within the first hours after onset of ischaemic stroke, in 10,903 patients, were reported between 1995 and 2019 (Wardlaw et al., 2014; von Kummer et al., 2016; Lorenzano and Toni, 2017; Khatri et al., 2018; Ma et al., 2019). All patients underwent computed tomography (CT) or magnetic resonance imaging (MRI) brain scan before randomization to exclude non-stroke disorders and haemorrhagic stroke, including 2994 patients (15 trials) treated identifiably within 3 hours and 6221 patients (10 trials) treated identifiably between 3 and 6 hours of stroke onset.


The RCT data with supportive care control arms were acquired over a broad, 25-year period, during which supportive medical management was evolving, including increasing delivery of supportive medical care on dedicated stroke units. More than one-quarter of the patients, and the preponderance of patients over 80 years of age, come from the later Third International Stroke Trial (IST-3). While several trials were fully double-blind, others used open label treatment with outcome assessment by blinded observers. The great preponderance of studies (28 trials, 10,589 patients) enrolled only or predominantly patients with disabling deficits at presentation; a single trial (313 patients) evaluated only patients with non-disabling deficits at presentation.


In addition to trials with non-lysis control arms, 20 RCTs, enrolling 6873 patients, have compared different IV fibrinolytic agents or doses against one another (Pancioli et al., 2008, 2013; Wardlaw et al., 2013; Saqqur et al., 2014; Mori et al., 2015, Anderson et al., 2016; Huang et al., 2016; Logallo et al., 2017; Campbell and E-IT Investigators, 2018), and 9 trials, enrolling 2269 patients, have compared therapies to enhance thrombolysis, including adding antithrombotics or ultrasound to IV fibrinolytics versus IV fibrinolytics alone (Pancioli et al., 2008, 2013; Saqqur et al., 2014; Wardlaw et al., 2014; Alexandrov et al., 2016; Anderson et al., 2016; Huang et al., 2016; Nacu et al., 2017).


Complementing broad study-level meta-analyses, an individual patient-level data systematic analysis, permitting more detailed adjustment for prognostic variables, has analysed 9 trials of IV tPA versus non-lytic controls, enrolling 6756 patients (Emberson et al., 2014; Lees et al., 2016).



Interventions


In trials with non-lysis control arms, the thrombolytic agents tested were urokinase (UK), streptokinase (SK), recombinant tissue plasminogen activator (rt-PA), and desmoteplase. About three-quarters of the patients come from the 18 RCTs testing IV rt-PA.


In trials comparing different doses, IV rt-PA was the most studied agent, investigated in 6 trials. Agents tested in trials comparing one fibrinolyic agent against another included UK, tissue-cultured UK, rt-PA, and tenecteplase. Agents tested in RCTs evaluating fibrinolytic-enhancing concomitant therapies included aspirin, the glycoprotein IIb/IIIa agent eptifibatide, the direct thrombin inhibitor argotroban, and external ultrasound with or without ultrasound-responsive lipid microspheres.



Results for Patients with Disabling Deficits, Only or Predominantly: All Thrombolytic Agents against Non-lysis Controls



Alive and Disability-free at (or near) 3–6 Months

Overall, among patients with only or predominantly disabling deficits treated up to 9 hours after ischaemic stroke, random allocation to thrombolytic therapy was associated with an increase in alive and disability-free outcome (modified Rankin Scale [mRS] 0–1) at (or near) 3–6 months after randomization (35.1% thrombolysis, 28.8% control; risk ratio [RR] 1.21, 95% confidence interval [CI]: 1.14–1.28; P < 0.00001). This represents 63 more disability-free patients per 1000 treated with thrombolysis compared with control (Figure 6.1). There was low heterogeneity of treatment effect across the 4 different agents (I2 = 4.2%, P = 0.37), indicating that the favourable treatment effect was qualitatively similar in all 4 agent subgroups. There was mild heterogeneity of treatment effect among the individual trials (I2 = 19%, P = 0.20) that visual inspection suggested was driven by larger treatment effects in trials with earlier start of thrombolytic therapy.





Figure 6.1 Alive and disability-free outcome (mRS 0–1) at 3–6 months, IV Lytics vs Controls, all trials enrolling patients with disabling deficits, only or predominantly, and treatment start within 9 hours (h) of onset.



Alive and Functionally Independent at (or near) 3–6 Months

Thrombolysis within 9 hours after ischaemic stroke was also associated with an increase in alive and functional independent outcome (mRS 0–2) at (or near) 3–6 months after randomization (47.5% thrombolysis, 43.0% control; RR 1.09, 95% CI: 1.04–1.13; P < 0.0001). This represents 45 more functionally independent patients per 1000 treated with thrombolysis compared with control (Figure 6.2). There was no significant heterogeneity of the treatment effect, either across the 4 different agents (I2 = 0%, P = 0.67) or across individual trials (I2 = 2%, P = 0.44).



Death by 3–6 Months

By (or near) 3–6 months, patients allocated thrombolytic therapy had an increased frequency of death (18.3% thrombolysis, 17.3% control; RR 1.13, 95% CI: 1.02–1.25; P = 0.02), representing an extra 10 deaths per 1000 patients treated with thrombolysis compared with control (Figure 6.3). There was moderate heterogeneity across the 4 agent groups (I2 = 36.0%, P = 0.20) and among individual trials (I2 = 35%, P = 0.04) (see agent comparison section below for more details). Across all 17 trials using IV rt-PA, no excess of mortality was noted (RR 1.07, 95% CI: 0.95–1.20). In the trials using SK, there was an excess of deaths (RR 1.43, 95% CI: 1.10–1.88) (further discussed in the section on different agents below).





Figure 6.2 Alive and functionally independent outcome (mRS 0–2), IV Lytics vs Controls, all trials enrolling patients with disabling deficits, only or predominantly, and treatment start within 9 h of onset.





Figure 6.3 Death from all causes during study follow-up, IV Lytics vs Controls, all trials enrolling patients with disabling deficits, only or predominantly, and treatment start within 9 h of onset.



Early Symptomatic Intracranial Haemorrhage

Thrombolytic therapy was associated with an increase in early symptomatic intracranial haemorrhage, within 7–10 days of treatment (7.2% thrombolysis, 1.9% control; RR 3.79, 95% CI: 3.06–4.70; P < 0.00001), equivalent to an excess of 53 symptomatic intracranial haemorrhages per 1000 patients treated (Figure 6.4). There was moderate heterogeneity between thrombolytic agent classes (I2 = 57.2%, P = 0.07) and individual trials (I2 = 40%, P = 0.02) (further discussed in the section on different agents below).





Figure 6.4 Early (7–10 days) symptomatic intracranial haemorrhage, IV Lytics vs Controls, all trials enrolling patients with disabling deficits, only or predominantly, and treatment start within 9 h of onset.



Degree of Disability at (or near) 3–6 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, analyses of the distribution of outcomes over the entire mRS count all transitions across all 7 degrees of post-stroke disability that the scale assesses, from asymptomatic, through varying degrees of impairment, to death. While systematic analyses of the distribution of disability outcomes have not been performed for all lytic agents, an analysis is available for IV rt-PA (discussed below).



Results for Patients with Non-disabling Deficits: All Thrombolytic Agents against Non-lysis Controls


The single RCT enrolling only patients with non-disabling deficits at presentation (PRISMS) tested IV rt-PA versus control in 313 patients who started treatment within 3 hours (Khatri et al., 2018). The control patients had generally very good outcomes at 3 months, limiting the opportunity for lytic intervention to improve outcome. No differences were noted with IV rt-PA for freedom from disability (mRS 0–1) at 90 days, 78.2% versus 81.5%, RR 0.98 (95% CI: 0.81–1.18, P = 0.81); mortality, 0.6% versus 0.0% (P = 0.50); or symptomatic intracerebral haemorrhage, 1.3% versus 0.0% (P = 0.30).



Results for Patients Treated with Different Thrombolytic Drugs, Doses, or Concomitant Therapies



Results for Patients Treated with Different Thrombolytic Drugs

Different IV thrombolytic agents have been compared against control and against one another. Direct, head-to-head comparisons of agents (rt-PA vs UK; tissue-cultured UK vs conventional UK; tenecteplase vs rt-PA) were undertaken in 8 trials, enrolling 2281 patients (Wardlaw et al., 2013; Huang et al., 2016; Logallo et al., 2017; Campbell and E-IT Investigators, 2018). Overall, no statistically significant difference was shown between different thrombolytic drugs tested. However, among patients with CT- or MR-confirmed large or medium artery target occlusions, tenecteplase, compared with rt-PA, was associated with higher rates of reperfusion and reduced death or disabled outcomes (as detailed below).


Indirect comparisons of outcomes in 11 RCTs of different thrombolytic agents (urokinase, SK, rt-PA, and desmoteplase) versus control also found no significant between-agent difference in the effect of the thrombolytic drugs on death or disability (mRS 2–6) or death or dependence (mRS 3–6) (Wardlaw et al., 2014). In indirect comparisons, for death by 3–6 months there was moderate heterogeneity across the 4 agent groups (I2 = 37.5%, P = 0.19) and among individual trials (I2 = 37%, P = 0.03) (see Figure 6.3). Visual inspection suggested the heterogeneity arose from an increased mortality rate with active treatment in SK trials. The other 3 agents had formally neutral effect on mortality, while in the trials using SK there was an excess of deaths (RR 1.43, 95% CI: 1.10–1.88). Similarly, SK produced the greatest increase in symptomatic intracerebral haemorrhage (see Figure 6.4). Although potentially related to intrinsic properties of SK, these disparate safety effects may well instead be related to the higher relative dosages employed and the more frequent use of concomitant antiplatelet and anticoagulant therapy in the SK trials.



Recombinant Tissue Plasminogen Activator

Recombinant tissue plasminogen activator is a recombinant protein corresponding to a natural plasminogen activator found on human endothelial cells. It has high fibrin specificity, and free rt-PA in the serum has a short, 4-minute half-life, though bound rt-PA is active substantially longer.


Intravenous rt-PA has been compared with non-lytic controls in 18 trials (n = 8347 patients) enrolling acute ischaemic stroke patients treated up to 9 hours, including 17 trials (8034 patients) enrolling only or predominantly patients with disabling deficits at presentation, and a single trial (313 patients) enrolling only patients with non-disabling deficits at presentation. Among patients presenting only or predominantly with disabling deficits, treatment with IV rt-PA was associated with increased alive and disability-free (mRS 0–1) outcome, RR 1.21 (95% CI: 1.14–1.29, P < 0.00001), increased alive and independent (mRS 0–2) outcome, RR 1.10 (95% CI: 1.05–1.15, P < 0.0001), no alteration in deaths, RR 1.07 (95% CI: 0.95–1.20), and an increase in symptomatic intracerebral haemorrhages, RR 3.93 (95% CI: 3.06–5.05, P < 0.00001). This represents, per 1000 patients treated with rt-PA compared with control, 64 more patients alive and disability-free at long-term follow-up, 45 more patients alive and independent at long-term follow-up, no significant change in death, and 54 more patients with early symptomatic haemorrhage. There was mild heterogeneity across individual trials for alive and disability-free (I2 = 27%, P = 0.14), death (I2 = 35%, P = 0.08), and symptomatic haemorrhage (I2 = 36%, P = 0.07), which visual inspection suggested was driven by larger benefits and fewer harms in trials with earlier start of thrombolytic therapy.


An analysis has been conducted of the effect of rt-PA on the distribution of patient outcomes across all 7 levels of disability assessed by the mRS, incorporating individual participant-level data on 6756 patients from 9 randomized trials (Lees et al., 2016) (Figure 6.5). In these trials, allocation to IV tPA resulted in increased nominal proportions of patients at long-term follow-up who were asymptomatic (mRS 0), alive and disability-free (mRS 0–1), alive and independent (mRS 0–2), and alive and ambulatory (mRS 0–3), with no change in the proportions of patients who were alive and not requiring continuous care (mRS 0–4) or alive (mRS 0–5) (Figure 6.5). Overall, treatment with IV rt-PA yielded a lower final degree of disability compared with control (Mann–Whitney test, P < 0.004). Using the automated algorithmic min–max joint outcome table method (Saver et al., 2009), the treatment group outcomes indicate that, for every 1000 patients treated with IV tPA, a net of 121 patients will have a lower level of long-term disability as a result.





Figure 6.5 Level of disability at 3–6 months, IV rt-PA versus Control, pooled trial analysis.


Outcome distribution is based on a pooled analysis of 6756 patients (3391 rt-PA, 3365 control), adjusted for age, presenting deficit severity, and onset to treatment time.


Desmoteplase

Recombinant desmodus salivary plasminogen activator a-1 (desmoteplase) is a recombinant protein corresponding to a natural plasminogen activator from the vampire bat (Desmodus rotundus). It is theoretically attractive because of its high fibrin specificity, nonactivation by 13-amyloid, long terminal half-life, and absence of neurotoxicity compared with rt-PA (Liberatore et al., 2003; Reddrop et al., 2005). Desmoteplase has been evaluated compared with non-fibrinolytic controls in 6 trials enrolling 1108 patients, predominantly later than 3 hours after onset, with imaging findings suggesting still-salvageable tissue based on relatively small infarct cores accompanied by larger regions of hypoperfusion or evidence of large or medium artery occlusion. Over the full 7-level mRS, a non-significant favourable trend was noted toward reduced level of disability with desmoteplase therapy (3 trials, common odds ratio [cOR] 1.19, 95% CI: 0.92–1.53; P = 0.18). Dichotomous endpoints did not show major differences for outcomes of alive and disability-free (mRS 0–1), RR 1.06 (95% CI: 0.84–1.33), alive and independent (mRS 0–2), RR 1.07 (95% CI: 0.93–1.23), or mortality, RR 1.13 (95% CI: 0.76–1.68) (see Figures 6.1, 6.2, 6.3). A non-significant trend towards increased symptomatic intracranial haemorrhage was present, RR 3.76 (95% CI: 3.03–4.66; P = 0.11) (see Figure 6.4).



Tenecteplase

Tenecteplase is a genetically engineered variant of the rt-PA molecule, with three mutations introduced to yield increased plasma half-life, resistance to plasminogen-activator inhibitor 1, and fibrinolytic potency against platelet-rich thrombi. Compared with rt-PA, tenectaplase has greater fibrin specificity and can be delivered as a single bolus IV injection, rather than continuous infusion. Five randomized trials, enrolling a total of 1593 acute ischaemic stroke patients, have compared tenecteplase at varying doses with rt-PA. The largest trial, NOR-TEST, compared tenecteplase at a dose of 0.4 mg/kg to rt-PA in 1107 acute ischaemic stroke patients within 4.5 hours of symptom onset (Hughes, 2017). No difference was noted in outcomes of alive and disability-free (mRS 0–1) at 3 months (tenecteplase 64.5%, alteplase 62.6%, OR 1.08, 95% CI: 0.84–1.38) or in symptomatic intracerebral haemorrhage (2.7% vs 2.4%, OR 1.16, 95% CI: 0.51–2.68). However, enrolled patients had quite mild deficits at entry (median National Institutes of Health Stroke Scale [NIHSS] score 4.0), placing a ceiling on attainable improvements and also indicating that many patients likely had small vessel occlusions with minimal target clot volumes, likely to respond well to any lytic agent. Patients in whom CT or MR angiography confirms the presence of a large or medium vessel occlusion (LVO or MVO) prior to therapy start may be more likely to exhibit differential responses to different lytic agents. Three trials have enrolled 271 such patients, allocated to a lower tenecteplase dose of 0.25 mg/kg (138 patients) compared with standard-dose rt-PA (133 patients) (Bivard et al., 2017; Campbell and E-IT Investigators, 2018). In fixed effects combined analysis, tenecteplase was associated with increased revascularization, (34.8% vs 17.3%, OR 2.55, 95% CI: 1.44–4.51); reduced death and disability (51.6% vs 63.2%, OR 0.62, 95% CI: 0.38–1.00); reduced death and dependency (38.5% vs 54.7%, OR 0.51, 95% CI 0.32–0.83); reduced mortality (11.0% vs 17.4%, OR 0.58, 95% CI: 0.29–1.17); and unchanged low symptomatic haemorrhage rate (0.7% vs 1.5%, OR 0.48, 95% CI: 0.04–5.34).



Results for Patients Treated with Different Thrombolytic Doses

Different doses (of rt-PA, UK, desmoteplase, or tenecteplase) were compared in 15 trials (n = 4775 patients), including one large trial enrolling 3310 patients that compared a standard 0.9 mg/kg dose of rt-PA with a lower 0.6 mg/kg dose (Wardlaw et al., 2013; Anderson et al., 2016). Since all trials testing SK used the same dose, it was not possible to compare doses for SK. A higher dose of thrombolytic therapy, compared with a lower dose of the same agent, was associated with higher rates of symptomatic intracerebral haemorrhage (2.9% vs 1.6%, OR 1.78, 95% CI: 1.19–2.66; P = 0.006) and death by end of follow-up (10.0% vs 8.2%, OR 1.25, 95% CI: 1.02–1.53; P = 0.03), but no difference in rates of combined death or dependency (mRS 3–6) (58.6% vs 58.6%, OR 1.00, 95% CI: 0.88–1.14; P = 1.00). These analyses confirm that higher doses of thrombolytic agents lead to higher rates of bleeding and increased fatal outcome.


The ENCHANTED trial, comparing standard-dose (0.9 mg/kg) to low-dose (0.6 mg/kg) rt-PA, suggests that, within the range of effective doses, higher doses may have a bidirectional effect, increasing good outcomes (presumably by increasing reperfusion rates) but also increasing poor outcomes (through increased major intracerebral haemorrhage). With standard dose compared with low dose, rates of alive and disability-free outcome at 3 months were non-significantly increased, 48.9% versus 46.8% (OR 1.09, 95% CI: 0.95–1.25), but rates of death were also non-significantly increased, 10.3% versus 8.5% (OR 1.25, 95% CI: 0.99–1.58).



Results for Patients Treated with Different Concomitant Therapies


Antithrombotic Therapy Started at Same Time as Thrombolysis

Concomitant antithrombotic drugs given at the same time, or soon after, IVT potentially can improve recanalization and deter re-occlusion, but also can increase bleeding complications. Randomized trials have evaluated antiplatelet (aspirin, eptifibatide) and anticoagulant (argatroban) agents as concomitant therapies with fibrinolysis.


Aspirin added to IVT has been evaluated in two randomized trials. In the MAST-I trial, under a 2 × 2 factorial design, patients were randomized within 6 hours of onset to SK plus aspirin, SK alone, aspirin alone, or neither. Among 156 SK plus aspirin patients versus 157 SK alone patients, no benefit was noted in functional independence (mRS 0–2) at 6 months (37% vs 38%). Conversely, harm was observed in death by 6 months (44% vs 28%, RR 1.56, 95% CI: 1.14–2.12; P = 0.005), likely related to an increase in haemorrhagic transformation (not able to be fully assessed due to patient deaths before re-imaging) (Ciccone et al., 2000). In the ARTIS trial, 640 patients were randomized to added IV aspirin 300 mg within 90 minutes of start of standard-dose rt-PA or rt-PA alone. Aspirin did not change the frequency of alive and independent outcome (54.0% with ASA+IV rt-PA vs 57.2% with IV tPA alone, OR 0.91, 95% CI: 0.66–1.26; P = 0.58) or death (11.2% vs 9.7%, OR 1.17, 95% CI: 0.71–1.95; P = 0.54), but did increase the frequency of symptomatic intracranial haemorrhage (4.3% vs 1.6%, OR 2.86, 95% CI: 1.02–8.05; P = 0.04) (Zinkstok et al., 2012). These findings support the avoidance of routine aspirin therapy for the first 24 hours after fibrinolytic treatment.


Eptifibatide, a platelet glycoprotein 2b/3a inhibitor antiplatelet agent, was studied as a concomitant therapy to IV rt-PA in 3 trials, 2 randomized and 1 with historic controls, assigning 197 patients to combined therapy and 50 to IV rt-PA alone (Pancioli et al., 2008, 2013; Adeoye et al., 2015). The studies compared escalating doses of eptifibatide (75 µg/kg bolus or 135 µg/kg bolus, followed by 0.75 µg/kg infusion for 2 h) combined with escalating doses of IV rt-PA (0.3, 0.45, 0.6, and 0.9 mg/kg) versus standard-dose IV rt-PA (0.9 mg/kg). The regimen judged most promising to proceed to future larger trials was eptifibatide at the higher bolus dose added to standard-dose IV rt-PA (at a median 37 min after start of IV rt-PA), which had an acceptable symptomatic intracerebral haemorrhage (SICH) rate compared with historic IV rt-PA only controls (3.7% vs 10.0%, OR 0.35, 95% CI: 0.38–3.13).


Argatroban, a direct thrombin inhibitor anticoagulant, was studied in a pilot, dose-escalation randomized trial comparing low- and high-dose argatroban added to standard-dose IV rt-PA to IV rt-PA alone (Barreto et al., 2012). Argatroban was given as a 100 µg/kg bolus (median 60 min after IV rt-PA), followed by a 48-hour infusion adjusted to achieve a partial thromboplastin time of 1.75 × baseline in the low-dose group and 2.25 × baseline in the high-dose group. Among the 61 patients in the two argatroban plus rt-PA arms, compared with the 29 patients in the rt-PA alone arm, argatroban added to rt-PA was associated with non-significantly higher rates of alive and disability-free (mRS 0–1) outcome (31% vs 21%, R 1.57, 95% CI: 0.7–3.3; P = 0.24) but also higher SICH (4.9% vs 0%, P = 0.55).



Previous Antithrombotic Therapy at Time of Start of Thrombolysis

Different manners of reporting preclude formal meta-analysis of patients taking antiplatelet therapy at baseline prior to onset of ischaemic stroke and enrolment in a randomized trial of IV fibrinolysis (Wardlaw et al., 2014). However, salient information is available from individual trials. In the two NINDS-tPA Study trials, the ECASS 3 trial and the IST-3 trial, a total of 2037 of 4466 (56.6%) enrolled patients were taking antiplatelet therapy prior to stroke onset, predominantly aspirin. In each trial, pretreatment antiplatelet therapy did not modify the effect of alteplase upon rates of alive and independent outcome (NINDS t-PA Stroke Trial Study Group, 1997; Bluhmki et al., 2009; Lindley et al., 2015). While pretreatment antiplatelet therapy did not increase the risk of ICH in the 3 early window trials, NINDS-tPA Part 1, NINDS-tPA Part 2, and ECASS 3, it was associated with increased SICH in the 6-hour window IST-3 trial (interaction P-value = 0.02). In IST-3, among patients without pretreatment antiplatelet therapy, SICH occurred in 4.6% treated with rt-PA versus 1.4% of patients treated without IV rt-PA (OR 3.46, 95% CI: 1.35–8.86). Among patients with pretreatment antiplatelet therapy, SICH occurred in 9.0% treated with rt-PA versus 0.8% of patients treated without IV rt-PA (OR 13.26, 95% CI: 4.38–40.14). In the ECASS 3 trial, pretreatment antiplatelet therapy did not modify the risk of death at end of follow-up.


These findings from individual trials are supported by a meta-analysis of 7 confounder-adjusted observational studies, analysing 58,059 patients treated with IV rt-PA, among whom 47.6% had prior antiplatelet therapy. Prior antiplatelet therapy was associated with increased SICH (OR 1.21, 95% CI: 1.02–1.44), but no change in favourable functional outcome (OR 1.09, 95% CI: 0.96–1.24) or death at end of follow-up (OR 1.02, 95% CI: 0.98–1.07) (Luo et al., 2016). Accordingly, both trial and observational data indicate that, although patients with prior antiplatelet therapy have a potentiated risk of SICH associated with IV rt-PA within 4.5 hours of onset, they nonetheless experience the same long-term benefit upon favourable functional outcomes and the same neutral effect upon death at the end of follow-up from fibrinolysis as do antiplatelet-naïve patients.


Patients with prior anticoagulant therapy in therapeutic range at time of stroke onset were generally excluded from clinical trials testing IV thrombolysis (IVT), due to concern regarding elevated bleeding risk. Observational series have compared IVT among patients not taking warfarin and patients taking warfarin but with subtherapeutically achieved anticoagulation, generally international normalized ratio below 1.7. In unadjusted analysis of 11 studies analysing 79,357 patients, patients receiving prior subtherapeutic warfarin therapy (present in 5%), compared with no prior warfarin therapy, had increased frequency of SICH (5.7% vs 4.3%, OR 1.33, 95% CI: 1.16–1.53; P < 0.0001) (Diener et al., 2013; Seiffge et al., 2015; Xian et al., 2017a). But patients taking oral anticoagulants differ in several other features from non-anticoagulated patients. In each of the three largest studies, collectively enrolling 74,769 IV fibrinolysis patients, the increased risk of SICH among patients with subtherapeutic anticoagulation disappeared when adjustment was made for other prognostic features (Xian et al., 2012; Seiffge et al., 2015; Xian et al., 2017a).


No trials have addressed risk of IV rt-PA among patients who were taking non-vitamin-K oral anticoagulants (NOACs) prior to stroke onset. In two observational series, 666 of 50,083 IV fibrinolysis patients were on unreversed NOACs prior to therapy, and NOACs were associated with increased SICH in unadjusted analysis (5.9% vs 4.1%, OR 1.47, 95% CI: 1.06–2.04; P = 0.02) (Seiffge et al., 2015; Xian et al., 2017a). However, in each study, the increased risk of SICH among patients with NOACs disappeared when adjustment was made for other prognostic features. For the direct thrombin inhibitor NOAC, dabigatran, several small series and case reports have described reversing anticoagulant effect with the humanized monoclonal antibody idarucizumab, followed by administration of IV rt-PA. Among 40 patients treated with rt-PA following idarucizumab, symptomatic haemorrhagic transformation occurred in 1 (2.5%) and the great preponderance of patients had a favourable clinical course (Kermer et al., 2017; Pikija et al., 2017).



Concomitant Transcranial Doppler Ultrasound

In model systems, ultrasound has direct mechanical thrombolytic capacity at low frequencies (8–10 kilohertz [kHz]), enhances enzymatic fibrinolysis at high frequencies (including the 2-megahertz [MHz] frequency of diagnostic transcranial Doppler ultrasound), and may further augment pharmacological fibrinolysis when co-administered with ultrasound contrast gaseous microspheres, which oscillate and burst under the ultrasound beam (Saqqur et al., 2014). Low-frequency ultrasound added to IV rt-PA has been tested in only one small trial (26 patients); after it found high rates of haemorrhagic transformation, further development was not pursued (Daffertshofer et al., 2005). In contrast, high-frequency ultrasound, with or without microspheres, added to IV rt-PA has been compared with IV rt-PA alone in 5 randomized trials enrolling 1046 patients (Saqqur et al., 2014; Alexandrov et al., 2016; Nacu et al., 2017). In 3 proof of target activity trials, enrolling a total of 197 patients with confirmed target large vessel occlusions, sonothrombolysis was associated with increased early complete recanalization (42.9% vs 18.5%, OR 3.31, 95% CI: 1.72–6.36) and reduced death or disability (50.0% vs 75.8%, OR 0.38, 95% CI: 0.20–0.70). However, in 2 pivotal, pragmatic trials, enrolling ischaemic stroke patients and stroke mimics without a confirmed target vessel occlusion, benefit was not seen. Combining all 5 trials, among 1046 patients, sonothrombolysis, compared with IV tPA alone, was associated with no alteration in death or disability (61.9% vs 65.9%, OR 0.88, 95% CI: 0.67–1.14), death or dependency (47.7% vs 52.0%, OR 0.86, 95% CI: 0.67–1.10), mortality (15.8% vs 15.1%, OR 1.05, 95% CI: 0.75–1.49), or symptomatic haemorrhage (3.4% vs 2.5%, OR 1.37, 95% CI: 0.66–2.83).


In contrast to these studies of high-frequency ultrasound combined with IV rt-PA, one small trial (26 patients) evaluated low-frequency ultrasound added to IV rt-PA and found high rates of haemorrhagic transformation, and has not undergone further development (Daffertshofer et al., 2005).



Concomitant Neuroprotection

Neuroprotective (NP) agents block the molecular elaboration of injury in hypoxic environments, enabling brain tissue to tolerate ischaemia for longer periods. As NP drugs are often safe in haemorrhagic as well as ischaemic stroke, they could be given early after onset to stabilize threatened tissues, allowing more salvageable brain to be present at the time of later reperfusion by IVT (Fisher and Saver, 2015). Initial trials testing NP agents added to IVT began the NP agents in hospital, but only after thrombolysis had been started. For example, in two early randomized trials of NP agents added to IV fibrinolysis, the NP drugs (lubeluzole and clomethiazole) were started only well after the start of IV rt-PA, 45 minutes later in one trial and more than 140 minutes later in the other (Grotta, 2001; Lyden et al., 2001). However, more recent trials have tested NP agent start by paramedics in the field, before hospital arrival and fibrinolysis initiation. In 3 trials of different prehospital NP agents (remote ischaemic preconditioning, glyceryl trinitrate, and magnesium), 43% (188/433), 24% (10/41), and 27% (452/1700) of enrolled patients subsequently received IV rt-PA after hospital arrival (Ankolekar et al., 2013; Hougaard et al., 2014; Sanossian, 2017). In the FAST-MAG trial testing magnesium sulfate, prehospital study drug start preceded IV rt-PA start by a median of 95 minutes (Sanossian, 2017). These studies demonstrate that delivery of bridging neuroprotection in the ambulance prior to reperfusion therapy is a feasible strategy.



Concomitant Mechanical Clot Disruption

As IV delivery yields relatively modest fibrinolytic drug concentration arriving at target thrombi, it is more effective at digesting the smaller clots that obstruct small- and medium-size vessels, and less effective for LVOs with sizeable clot burdens (Legrand et al., 2013). In contrast, mechanical thrombectomy devices are highly efficient at recanalizing large proximal occlusions that have been unresponsive to IV fibrinolysis, and less effective for small distal occlusions in vessels too small for easy device access. In a pooled meta-analysis of individual patient-level data from the first 5 trials of modern endovascular reperfusion (ERT) devices, ERT added to IV rt-PA compared with IV rt-PA alone increased alive and independent (mRS 0–2) outcome at 3 months (46.4% vs 27.0%, RR 1.67, 95% CI: 1.37–2.05; P < 0.00001) and improved disability levels over the entire mRS (common OR 2.45, 95% CI: 1.68–3.57), and was associated with a non-significant reduction in death by 3 months (13.7% vs 18.4%, RR 0.75, 95% CI: 0.50–1.12) (Goyal et al., 2016).


In these completed randomized trials, all IVT-eligible patients were treated with IVT, and, among IVT-eligible patients, ERT plus IVT was found superior to IVT alone. However, an important additional consideration is whether, among IVT-eligible patients, ERT alone is better or worse than IVT plus ERT. IVT before ERT might improve outcomes, compared with ERT alone, by producing reperfusion before ERT, pre-conditioning clots to yield better recanalization with ERT, and providing lysis of distal thrombi after ERT. But IVT before ERT may also worsen outcomes by slowing start of ERT and promoting intracranial haemorrhage (Fischer et al., 2017). Randomized trials have not yet compared ERT alone versus IVT plus ERT. Conversely, one pilot trial compared different agents for IVT, tenecteplase versus standard rt-PA, as bridging therapy to ERT, and found that tenecteplase yielded higher rates of early reperfusion with IVT alone, making ERT unnecessary (22% vs 10%, adjusted OR 2.6, 95% CI: 1.1–5.9) (Campbell et al., 2018).



Results for Different Treatment Times, Treatment Settings, and Types of Patients


A meta-analysis of pooled individual patient-level data was undertaken to explore for heterogeneity of treatment effect according to time from onset to treatment start, age, and presenting deficit severity (Emberson et al., 2014; Lees et al., 2016; Whiteley et al., 2016). The analysis included 6756 patients from 9 randomized trials of IV rt-PA, among whom 1549 (23%) were treated within 3 hours of onset, 2768 (41%) between 3 and 4.5 hours, 2196 (33%) between 4.5 and 6 hours, and 198 (3%) beyond 6 hours.



Effect of Onset to Treatment Time


Alive and Disability-free at the End of Patient Follow-up

Earlier treatment with rt-PA was associated with greater benefit of therapy in increasing the proportion of patients alive and disability-free (mRS 0–1) at the end of follow-up (I2 = 75%, Pinteraction = 0.02) (Figure 6.6) (Emberson et al., 2014). Among patients treated within 3 hours of onset, allocation to rt-PA was associated with more frequent alive and non-disabled outcome (32.9% thrombolysis, 23.1% control; RR 1.42, 95% CI: 1.21–1.68; P = 0.00002) (Figure 6.6). This represents 98 more alive and non-disabled patients per 1000 treated with thrombolysis compared with control. Among patients treated beyond 3 but within 4.5 hours of onset, rt-PA therapy increased alive and disability-free outcome to a lesser degree (35.3% thrombolysis, 30.1% control; RR 1.17, 95% CI: 1.05–1.31; P = 0.003). This represents 52 more alive and non-disabled patients per 1000 treated with thrombolysis compared with control. Among patients treated beyond 4.5 hours of onset, rt-PA was not associated with a statistically significant increase in the proportion of patients alive and disability-free (32.6% thrombolysis, 30.6% control; RR 1.07, 95% CI: 0.95–1.20; P = 0.29).





Figure 6.6 Effect of treatment time, age, and baseline NIHSS score on alive and disability-free (mRS 0–1) outcome at 3–6 months with IV rt-PA vs Control. Forest plot shows findings of individual patient, pooled data analysis, with findings for each subgroup adjusted for the other two.


Data abstracted from Emberson et al. (2014).

Considering time as a continuous variable, the benefit of treatment declined with later onset to treatment time. The increased odds of an alive and non-disabled outcome with rt-PA therapy declined from about 1.86 with treatment at 1 hour to about 1.52 at 3 hours and about 1.28 at 4.5 hours. The point estimate for time at which treatment benefit entirely disappeared was 6.3 hours, and the time at which the lower 95% CI for treatment benefit first crossed neutral was at 5.1 hours (Figure 6.7A). Among 1000 patients, every 15-minute delay in rt-PA start meant approximately 7 fewer patients would achieve an alive and disability-free outcome.





Figure 6.7 Modification of IV rt-PA benefit by onset to treatment time, for (A) freedom from disability (mRS 0–1); (B) level of disability (across all 7 ranks of the mRS).



Degree of Disability at the End of Patient Follow-up

In ordinal analysis, earlier treatment was associated with greater improved outcomes across all 7 disability levels of the mRS (Figure 6.7B) (Lees et al., 2016). Using the automated algorithmic min–max joint outcome table derivation techniques (Saver et al., 2009), among patients treated within 3 hours of onset, allocation to rt-PA was associated with reduced disability levels in approximately 178 of every 1000 patients treated. Among patients treated beyond 3 but within 4.5 hours of onset, rt-PA therapy reduced disability in 66 of every 1000 patients treated.


Considering time as a continuous variable, the benefit of treatment in reducing degree of disability declined with later onset to treatment time (P = 0.04) (Figure 6.7B) (Lees et al., 2016). The increased odds of a less-disabled late outcome with rt-PA therapy declined from about 1.45 with treatment at 1 hour to about 1.28 at 3 hours and about 1.18 at 4.5 hours. The point estimate for time at which treatment benefit entirely disappeared was 6.1 hours and the time at which the lower 95% CI for treatment benefit first crossed neutral was at 4.6 hours. Among 1000 patients in whom treating physicians were confident of benefit, with every 15-minute delay in rt-PA start, approximately 13 patients had a more disabled outcome (Lansberg et al., 2009).



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

Treatment delay was associated with a non-significant increase in the nominal hazard of death by the end of follow-up (P = 0.22) (Emberson et al., 2014). For different time windows, with treatment with rt-PA rather than control, hazard ratios for death were the following: under 3 hours: hazard ratio (HR) 1.00 (95% CI: 0.81–1.24); 3–4.5 hours: HR 1.14 (0.95–1.36); and more than 4.5 hours: 1.22 (0.99–1.50). The excess of SICH was similar in all onset-to-treatment time windows (Wardlaw et al., 2014; Whiteley et al., 2016).



Effect of Age

Randomized trials have shown that older patients compared with younger patients have worse functional outcomes from acute ischaemic stroke regardless of treatment with or without IVT, but benefit to the same relative degree from thrombolytic treatment (Grotta, 2001; Wardlaw et al., 2014). Among 6756 patients enrolled in 9 pooled IV rt-PA trials, 74% were up to age 80 and 26% over age 80 (Emberson et al., 2014). Thrombolytic therapy up to 6 hours after onset increased the rate of alive and disability-free outcome (mRS 0–1) to a similar relative degree in both age groups, though with worse overall outcomes in older patients (up to age 80: 39.4% vs 33.9%, RR 1.16, 95% CI: 1.08–1.25; over age 80: 17.6% vs 13.2%, RR 1.34, 95% CI: 1.07–1.67) (see Figure 6.6). However, the similar relative benefit translates into a higher absolute benefit for older patients, since their absolute risk is higher to start with. Older patients had similar rates of SICH to younger patients regardless of treatment with or without IVT, and experienced the same relative degree of increased SICH from thrombolytic treatment: (up to age 80: 3.5% vs 0.6%, RR 6.29, 95% CI: 3.59–11.03; over age 80: 4.1% vs 0.6%, RR 7.95, 95% CI: 2.79–22.60; subgroup difference P = 0.83) (Whiteley et al., 2016).



Effect of Presenting Deficit Severity

Randomized trials have shown that patients presenting with more severe, compared with less severe, deficits have worse functional outcomes from acute ischaemic stroke regardless of treatment with or without IVT, but generally benefit to the same relative degree from thrombolytic treatment (Pancioli et al., 2008). Thrombolytic therapy up to 6 hours after onset increased the rate of alive and disability-free outcome (mRS 0–1) to a similar relative degree across 5 levels of presenting deficit severity (NIHSS ranges of 0–4, 5–10, 11–15, 16–21, and ≥22), though with worse overall outcomes in patients with worse initial severity (see Figure 6.6). For example, rates of alive and non-disabled outcome among mild deficit patients (NIHSS score 0–4) were 68.7% versus 58.9% (RR 1.17, 95% CI: 1.04–1.31) and among severe deficit patients (NIHSS score 16–21) rates were 11.6% versus 8.2% (RR 1.42, 95% CI: 1.02–1.97). A non-significant trend towards a greater relative degree of increased SICH from thrombolytic treatment in patients with greater presenting deficits was noted (subgroup difference P = 0.27) (Whiteley et al., 2016). For example, rates of SICH among mild deficit patients (NIHSS score 0–4) were 1.7% versus 0.3%, and among severe deficit patients (NIHSS score 16–21) were 3.9% versus 0.1%.


Among patients with low initial deficit severity scores, it is important to distinguish those patients in whom the deficits, though delimited, are causing a potentially disabling functional loss (e.g. severe pure motor hemiparesis) and those patients in whom the deficits are non-disabling (e.g. pure hemisensory loss). Patients with non-disabling deficits, as assessed by treating physicians, were generally not enrolled in early trials of IV fibrinolysis. However, observational series noted that some patients in whom thrombolysis was withheld because their deficits were so mild subsequently had stroke progression in the next hours and days, with poor final outcome. Accordingly, a randomized trial, PRISMS, was undertaken, enrolling only patients ineligible for standard therapy, as their deficits were non-disabling, evaluating whether up-front IV rt-PA would avert subsequent stroke progression and improve final outcome. PRISMS enrolled 313 patients and found no improvement in disability-free (mRS 0–1) outcome at 3 months (78.2% vs 81.5.5%, RR 0.98, 95% CI: 0.81–1.18), with a low rate of stringently defined symptomatic haemorrhage (1.3% vs 0.0%) (Khatri et al., 2018). Accordingly, current data suggest that, among patients with low NIHSS deficits, only the subset in whom the deficits are disabling benefit from IV rt-PA therapy.



Imaging Findings on Noncontrast CT

The extent of likely irreversible infarct injury on initial noncontrast CT, evident as loss of grey–white matter distinction or presence of definite hypodensity (hypoattenuation), has been evaluated for potential influence upon response to fibrinolytic therapy. Among patients with no, small, and moderate early infarct signs on CT, randomized trials have shown that participants with more, compared with less, extensive early infarct changes have worse functional outcomes from acute ischaemic stroke regardless of treatment with or without IVT, but generally benefit to the same relative degree from thrombolytic treatment (Emberson et al., 2014), similar to the effect seen for stroke severity. The extent of early ischaemic injury changes on initial noncontrast brain CT scans has been most often quantified using the Alberta Stroke Program Early CT Score (ASPECTS). Among 4 trials enrolling 4413 patients testing IV rt-PA, 74% had mild early infarct changes (ASPECTS 8–10) and 26% had moderate early infarct changes (ASPECTS 0–7, but predominantly 5–7) (Wardlaw et al., 2014). Thrombolytic therapy increased alive and disability-free (mRS 0–1) outcome to a similar relative degree in both small and moderate infarct change patients (subgroup difference I2 = 0%, P = 0.62), though patients with less-extensive infarcts had better outcomes in both treatment groups: no or small infarct signs, mRS 0–1: 43.6% versus 39.3%, RR 1.11, 95% CI: 1.02–1.20; moderate infarct signs, 22.7% versus 19.1%, RR 1.18, 95% CI: 0.94–1.48 (Figure 6.8).





Figure 6.8 Effect of extent of established infarct extent (based on ASPECTS score) on alive and disability-free outcome (mRS 0–1) at 3–6 months with IV rt-PA vs Control.


While patients with no, mild, and moderate infarct signs have been well-studied, patients were generally not enrolled in initial RCTs if they had very large, evident infarcts on initial CT, such as occupying more than one-third of the territory of the middle cerebral artery, exceeding 100 mL in volume, or having an ASPECTS score of 0–4. In the early trials, these patients were presumed to have limited potential to benefit from reperfusion, given their large, apparently established, infarct, and to be at elevated risk of haemorrhagic transformation. Patients with extensive early infarct signs are very uncommon within the first 3 hours of stroke onset, but proportionally increase as time from onset increases thereafter. The later IST-3 trial, undertaken to map more fully the range of therapy benefit, did include patients with very large infarcts. However, the sample size of this subgroup did not afford sufficient power to reliably determine whether very large baseline infarct size modified the effects of IV rt-PA on efficacy and safety outcomes. Among 250 patients with very large infarcts, allocation to IV rt-PA versus control yielded rates of functional independence (Oxford Handicap Scale 0–2) at 6 months of 9.4% versus 8.0% (adjusted OR 1.41, 95% CI: 0.36–5.54), and of symptomatic intracranial haemorrhage of 10.9% versus 3.6% (adjusted OR 3.24, 95% CI: 0.72–14.60) (IST-3 Collaborative Group, 2015). Accordingly, more randomized data in patients with very large infarct are needed before definitive recommendations can be given.


Additional findings evident on baseline noncontrast CT affect patient prognosis but not degree of benefit from fibrinolysis. Among the 3017 patients in the IST-3 trial, poorer functional outcome was associated not only with early ischaemic changes, but also with presence of a hyperattenuated artery sign (a marker of LVO) and the degree of pre-stroke leukoaraiosis and brain atrophy (markers of lower resilience); and SICH was associated not only with extent of early ischaemic changes but also with presence of old infarct and of a hyperattenuated artery sign. But none of these imaging findings, individually or in combination, modified the relative effect of rt-PA on functional independence or SICH (IST-3 Collaborative Group, 2015).

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Mar 22, 2021 | Posted by in NEUROLOGY | Comments Off on Chapter 6 – Reperfusion of Ischaemic Brain by Intravenous Thrombolysis
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