TPA Trials Flashcards
NINDS-I
NEJM, 1995
Evaluated TPA patients at only 24 hours.
No difference found.
NINDS-II.
NEJM. 1995
.9 mg per kg. within 3 hours.
Part 1: No benefit of TPA within 24 hours for either resolution of deficits or 4-point improvement in NIHSS.
Part 2: At three months improvement on all for scales: Barthel index. Glasgow outcomes. NIHSS. Modified Rankin.
ECASS II
Lancet. 1998
The prior ECASS trial has tried 1.1 mg/kg dose of alteplase compared to 0.9 mg/kg dose in NINDS trial. While there was no difference in the efficacy, the mortality rate and the incidence of ICH were found to be higher in alteplase group with ECASS. Hence, the current trial i.e, ECASS II is designed to assess the safety and efficacy at 0.9 mg/kg (to match that of NINDs-tPA trial. Administration time six hours.
Patients: 800 adult stroke patients (aged 18-80) with a clinical diagnosis of moderate to severe hemispheric ischemic stroke within 6 hours of symptoms onset. Patients were excluded if they had brain swelling in more than 33% of the MCA territory on CT. Intervention: t-PA (0.9mg/kg) Comparison: placebo Primary outcome: Proportion of patients with a favourable outcome (a score of 0-1 on the modified Rankin scale). (This trial was started post-NINDS, and had a pre-specified 0-3 hour subgroup.)
Results
There was no difference in the primary outcome. 40% of patients had a favourable outcome with t-Pa as compared to 37% with placebo. There was no change in mortality (11% in both groups). There was an increase in major intracerebral hemorrhage (11.8% vs 3.1%). In the 0-3 hour group, there was no benefit for the primary outcome (34% with t-Pa vs 29% with placebo, p=0.28). In the 0-3 hour group, mortality was higher with t-PA (14% vs 8%). One secondary outcome, percentage of patients with mRs 0-2 did favor tPa.
TAKE HOME MESSAGE:
While alteplase did show benefit in neurological outcome measures in the specified population, it was not statistically significant. Further 2.5 fold increase in intracranial hemorrhages was noted.
Nevertheless, IV tPA was deemed efficacious in the context of favorable results from other trials.
ECASS III
Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke”. The New England Journal of Medicine. 2008.
Intravenous alteplase improved neurologic outcomes within 4.5 hours of stroke onset among patients with acute ischemic stroke. Beyond the conventional 3-hour time window established in the NINDS trial (1995), Despite an increased incidence of intracranial hemorrhage, there was no mortality benefit.
More people in the treatment group ended up with a favourable modified Rankin score (0-1): 52.4% with t-Pa vs 45.2% with placebo.
There was not a statistically significant difference in the Glasgow outcome scale or the Barthel index between the two groups, and the global outcome (encompassing all of the above) was also not statistically significant, but was close.
Mortality was unchanged: 7.7% with t-Pa and 8.4% with placebo.
Symptomatic hemorrhage was higher. According to their definition 2.4% vs 0.2%, p=0.008. According to the NINDS definition, 7.9% vs 3.5%.
ATLANTIS-B
JAMA 1999
TPA vs Placebo.
3-5 hrs p LKW. (They stopped enrolling <3 hrs p NINDS-2 came out).
No difference in % with NIH=1 at 90 days.
Significant increase in symptomatic ICH.
ATLANTIS-A
Stroke. 2000
TPA vs Placebo
0-6 hrs.
Outcomes:
decrease in NIH of 4 or more at 24 hrs and 30 days.
Infarct size at 30 days.
24 hrs: TPA better NIH: 21% of placebo have an improvement of 4 or more on the NIHSS as compared to 40% with t-Pa
30 days: no-TPA better: 75% of the placebo group and only 60% of the t-PA groups improving my 4 or more points
Mortality was much higher with t-Pa (25% vs 7%, p<0.01)
Symptomatic intracranial hemorrhage was higher (11% vs 0%).
At 90 days, the median modified Rankin score was 2 in the placebo group and 5 in the t-Pa group
ATLANTIS (0-3)
Acute NonInterventional Therapy in Acute Stroke. STROKE. 2002.
Patients that present within three hours of acute ischemic stroke symptom onset, does alteplase compared to placebo allow more patients to achieve complete recovery?
Following an acute ischemic stroke, treatment with alteplase within three hours of symptom onset appears beneficial but still comes with some risk of hemorrhage and death.
Despite a significant increase in the rate of symptomatic intracranial hemorrhage, tPA-treated patients were more likely to have a very favorable outcome (score of ≤1) on the National Institutes of Health Stroke Scale at 90 days (P=0.01).
WAKE-UP trial
NEJM. 2018.
Mostly Wake-Ups. 90%
>4.5 hr after LKW; <4.5 hr from recognition.
TPA vs Placebo.
Patients who had a DWI/FLAIR mismatch.
MRs 0-1 @ 90 days:
53% of treated. 42% of untreated.
EPITHET
Stroke. 2010
Does TPA benefit stroke at 3 - 6 hrs if significant mismatch by coregistration of perfusion and diffusion MRI maps.
Mild benefit in reducing infarct growth on f/u imaging.
EPITHET was a phase 2 randomised trial of alteplase 3–6 h after stroke onset using perfusion-diffusion MRI, in which 70 patients were treated within the 4·5–6 h time window.
ECASS-4: ExTEND
International Journal of Stroke
2016
4.5 - 9 hr window.
TPA vs Placebo if significant mismatch on MRI: (infarct core volume <100 ml, perfusion lesion: infarct core mismatch ratio >1.2 and perfusion lesion minimum volume of 20 ml).
No significant evidence, but subtle indication towards patients treated with rt-PA in a prolonged time window reaching an excellent clinical outcome if a DWI-FLAIR-mismatch is present on initial stroke MR-imaging.
Alteplase improves excellent functional outcomes (mRS 0-1) at 3 months when administered 4.5-9h or after wake-up stroke <9h from midpoint of sleep in patients with perfusion mismatch (adjusted odd ratio 1.86 95% CI 1.15-2.99 p=0.011)
• Alteplase archived higher rate of good functional outcome, reperfusion, recanalization compared to placebo
• Consistent effect in age, time, Large vessel strata
• sICH increased but did not negate the net benefit in ordinal analysis
• Mortality not significantly different
• Both benefit and risk similar to 0-4.5h alteplase
• Benefit predominantly seen in the patients with automated perfusion mismatch
• Now it is time to extend the thrombolysis time window to 9 hours and for patients with wake up stroke
EXTEND
(NEJM. 2019)
TPA vs placebo in patients presenting between 4.5 and 9 hours.
mRS @ 90 days. 0-1.
Marginal benefit.
35% TPA. 29.5% placebo.
Halted after WAKE_UP results.
Some clinicians feel the benefit seen in EXTEND is sufficient to alter the treatment paradigm, whereas others feel the absolute benefit is modest and that this therapy is not ready for routine application.
treatment can be considered in appropriately selected late-presenting patients with NIHSS scores <10 and in those lacking a large-vessel occlusion.
Association Between Thrombolytic Door-to-Needle Time and 1-Year Mortality and Readmission in Patients With Acute Ischemic Stroke.
JAMA. 2020
TPA.
DTN under vs over 45 mins.
shorter door-to-needle times were associated with lower all-cause mortality and lower all-cause readmission at 1 year
The effect was modest. <5% points.
ENCHANTED
NEJM. 2016
TPA.
No real difference between Low dose (0.6 mg/kg) and standard dose (0.9 mg/kg).
No difference in patients dead or disabled.
No difference in patients alive and independent.
Slightly higher ICH in high-dose group.
