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 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.

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

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).

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%, P_interaction = 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).

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).