Thrombolysis in acute ischemic stroke

Introduction
Administration of IV tPA within 4.5 hours of onset to all eligible patients arriving at the hospital within 3.5 hours of onset for all ischemic stroke patients is a Neurocritical Care Society Clinical Performance Measure.

Pathophysiology
One problem that may limit the effect of thrombolytics is that acute ischemic stroke thrombi seem to have an outer shell of densely compacted thrombus components (fibrin, von Willebrand factor, platelets), that makes it less susceptible to thrombolysis.

Timing
IV tPA is of most benefit within 4.5 hours (or even 5 hours) to achieve mRS 0-1.

Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP, October 2018)
This trial randomized patients with wake-up stroke of unknown time of onset to IV alteplase or placebo, provided they had a DWI lesion on MRI with no associated FLAIR change. They planned to enroll 800 patients but due to cessation of funding stopped enrollment after 503 patients. The primary outcome (mRS 0-1) occurred in 53.3% of the alteplase patients and 41.8% of placebo patients (aOR 1.61, 95% CI 1.09-2.36). Shift of the mRS was also significant (aOR 1.62, 95% CI 1.17-2.23). There was a trend towards more death within 90 days in the alteplase group, but this was not statistically significant (4.1% vs 1.2%, aOR 3.38, 95% CI 0.92-12.52). Symptomatic intracranial hemorrhage was more common in the alteplase group.

Extending the Time for Thrombolysis in Emergency Neurological Deficits (EXTEND, May 2019)
This trial randomized patients within 4.5-9 hours after stroke onset or awakening from stroke with penumbra-core mismatch (ratio of > 1.2, an absolute difference in volume > 10 mL, and an ischemic core volume of < 70 mL) to IV alteplase or placebo. The trial planned to enroll 310 patients but terminated early after 225 patients, ostensibly for loss of equipoise after the publication of WAKE-UP. Suspiciously, the trial protocol was amended, and the planned analysis of the primary outcome was altered only several months prior to publication. In unadjusted analysis, there was no difference in the primary outcome (mRS 0-1 at 90 days) between teh two groups (RR 1.2, 95% CI 0.82-1.76). However, when adjusted for age and baseline NIHSS there were more patients in the alteplase group compared with placebo that achieved mRS 0-1 at 90 days (35.4% vs 29.5%, risk ratio 1.44, 95% CI 1.01-2.06). There were more patients in the alteplase group with major neurological improvement (improvement of NIHSS by 8 points or to 0 or 1) within 24 hours (unadjusted risk ratio 2.43, 95% CI 1.27-4.67; adjusted risk ratio 2.76, 95% CI 1.45-5.26). There was a nearly significant increase in symptomatic intracranial hemorrhage in the alteplase group (6.2% vs 0.9%, risk ratio 7.22, 95% CI 0.97-53.54). Ordinal analysis of mRS showed no clear difference between the two groups. This was a flawed study, with statistical analyses that were flawed, raising major red flags.

European Cooperative Acute Stroke Study 4 (ECASS-4, July 2019)
This trial randomized patients within 4.5-9h after symptom onset who had DWI-PWI mismatch on MRI to IV alteplase vs placebo. They planned to enroll 264 patients but only enrolled 119 due to poor recruitment. There was no clear benefit of thrombolysis, but the study was underpowered.

Tsivgoulis et al. Meta-analysis (2020)
This study included WAKE-UP, EXTEND, ECASS-4, and a small trial that only enrolled 12 patients. The meta-analysis showed significant benefit of alteplase in both unadjusted and adjusted analyses. For mRS 0-1 at 3 months, unadjusted OR was 1.48 (95% CI 1.12-1.96). For mRS 0-2 at 3 months, unadjusted OR was 1.42 (95% CI 1.07-1.90). For symptomatic intracranial hemorrhage, unadjusted OR was 5.28 (95% CI 1.35-20.68). There was a trend toward higher mortality in the alteplase group (OR 1.75, 95% CI 0.93-3.29). For every 1,000 patients treated with alteplase instead of placebo, 95 more would achieve mRS 0-1, 20 more would have symptomatic intracranial hemorrhage, and 31 more might die.

Advanced age
A meta-analysis of randomized trials showed that patients over age 80 still benefit from thrombolysis to achieve mRS 0-1 (OR 1.56, 95% CI 1.17-2.08), and may benefit even more than those under age 80 (OR 1.25, 95% CI 1.10-1.42).

Disability (preexisting)
In an analysis of 52,741 stroke patients in Germany, 15,317 patients were treated with IV thrombolysis. Approximately 1/4th of patients had some degree of prestroke disability. IV thrombolysis was associated with favorable outcomes (mRS 0-1 or return to baseline mRS) in all pre-existing mRS categories except for mRS 5, a group that was limited by small size and in whom mRS may not adequately assess treatment as a favorable outcome would essentially be survival. Therefore there is no grounds to withhold thrombolytic treatment in patients solely because of preexisting disability.

Dual antiplatelet therapy prior to treatment
A meta-analysis of nine studies including 66,675 patients showed no significant difference in patients treated with IV thrombolysis who were on DAPT previously compared with those who were not for all outcomes studied, including symptomatic and asymptomatic intracranial hemorrhage, 3-month mortality, 3-month favorable functional outcome, and 3-month independence. Therefore it appears to be safe.

Low NIH stroke scale
Multiple studies show that ~30% of patients who are "too good to treat" are left with mRS 2-6 after untreated stroke. A meta-analysis of randomized trials of alteplase showed continued benefit of IV tPA in patients with minor stroke (NIHSS 0-4) to achieve good outcome of mRS 0-1 (OR 1.48, 95% CI 1.07-2.06). A randomized trial (The Potential of rtPA for Ischemic Strokes with Mild Symptoms, PRISMS) was published in 2018, in which 313 patients with NIHSS 0-5 were randomized to IV tPA or aspirin, and no benefit of IV tPA was seen. Due to poor recruitment it was very underpowered (313 patients of originally planned 948), however, so conclusions were limited. A recent study of 121 patients who underwent MRI prior to thrombolysis for minor stroke showed a very low rate of symptomatic ICH (<1%), and favorable 90 day outcomes with 74% of patients achieving mRS 0-1. However, this is retrospective data, and therefore conclusions are limited.

Tenecteplase
The Tenecteplase versus Alteplase before Endovascular Therapy for Ischemic Stroke (EXTEND-IA TNK, 2018) trial randomized 202 patients with LVO to either tenecteplase (0.25 mg/kg) or alteplase (0.5 mg/kg) within 4.5 hours of stroke onset, followed by thrombectomy. The patients given tenecteplase had a higher rate of >50% reperfusion, and showed better 90-day functional outcomes as measured by median mRS compared with alteplase (common OR 1.7, 95% CI 1.0-2.8), with similar rates of symptomatic intracerebral hemorrhage. A larger dose of tenecteplase (0.40 mg/kg) did not confer any benefit over the 0.25 mg/kg dose prior to planned thrombectomy in the EXTEND-IA TNK Part 2 trial.

Angioedema
Orolingual swelling has occurred in response to IV tPA. Treatment is with IV antihistamines and glucocorticoids, as well as advanced airway management if necessary.

Symptomatic intracerebral hemorrhage
The percentage of patients who develop sICH within 36 hours of IV tPA or mechanical thrombectomy is a Neurocritical Care Society Clinical Performance Measure.

Epidemiology
In one study of 1,135 patients given IV tPA for cerebral ischemia, 24 patients (2.5%) had remote ICH. These were asymptomatic in two-thirds of patients.

Pathophysiology
In one study of 41 remote ICH, 17 of them (41%) occurred in locations where a lesion was already present. Six occurred in the location of a prior cerebral microbleed, 6 in old and 1 in recent infarct, and 4 in areas of white matter hyperintensity.

Risk factors

 * Presence of only lobar cerebral microbleeds (aOR 4.56, 95% CI 1.60-13.01)
 * More (≥ 5)cerebral microbleeds (aOR 5.56, 95% CI 1.48-20.93)
 * Older age (aOR 1.07 per 1 year increase, 95% CI 1.03-1.12)


 * Higher SBP (aOR 1.02 for 1 mmHg increase, 95% CI 1.0003-1.05)

Prognosis
These patients may have worsened outcomes at 3 months according to a small study, although it was not statistically significant.