Treatment of Ischaemic and haemorrhagic stroke Flashcards
What are used for Intravenous thrombolysis: standard IV thrombolysis: evidence?
- NINDS trial 1995
- Cochrane review
- ECASS-3
- IST-3
What is NINDS-2 trial?
randomized, double-blind trial of intravenous recombinant tissue plasminogen activator (t-PA) for ischemic stroke after recent pilot studies suggested that t-PA was beneficial when treatment was begun within three hours of the onset of stroke
What did part 1 of NINDS trial assess?
Changes in neurologic deficit 24 hours after the onset of stroke as a measure of the activity of t-PA
What did part 2, pivotal study of NINDS trial use?
Four outcome measures representing different aspects of recovery from stroke to assess whether treatment with tPA resulted in sustained clinical benefit at 3 months
What was part 1 of NINDS trial designed to test?
Whether t-PA had clinical activity
Specifically, whether a greater proportion of patients treated with t-PA as compared with those given placebo had early improvement
How was early improvement defined as by NIHSS?
Complete resolution of neurologic deficit or an improvement from base line in score by 4 or more points 24 hour after the onset of stroke
How was each group in part 1 of NINDS trials assessed according to?
Time from onset of stroke to the beginning of the treatment 1. 0 to 90 minutes 2. 91 to 180 minutes 3. 0 to 180 minutes after onset of stroke
What was the primary hypothesis for part 2 of NINDS trial?
There would be a consistent and persuasive difference between t-PA and placebo groups in terms of proportion of patients who recovered with minimal or no deficit three months after treatment
When did the study find a benefit of intravenous t-PA therapy for patients with ischemic stroke?
When treatment was initiated within 3 hours of the onset of symptoms
What werepatients that were treated with t-PA likely have?
at least 30% more likely to have minimal or no disability at three months as measured by the outcome scales
This benefit was not associated with any increase in mortality
an improvement in clinical outcome at three months was found in patients
treated with intravenous t-PA within three hours of the onset of acute ischemic stroke.
What are Grotto bars?
Distribution of modified Rankin scores by OTT interval
- 0 = no symptoms at all
- 1 = no significant disability, despite symptoms, able to perform all usual duties and activities.
- 2 = slight disability; unable to perform all previous activities but able to look after own affairs without assistance
- 3 = moderate disability, require some help but able to walk without assistance
- 4= moderately severe disability, unable to walk without assitance and ubale to attend to own bodily needs
- 5.severe disability = bedridden, incontinent, constant nursing care and attention
- 6= dead
What is the difference between placebo and tPA group?
About 13%
13% absolute risk reduction
What is most of the interest in stroke trial between?
0-2 on the scale e.g. heavy stroke
What happems if tPA is completely neutral?
the OTTs ( a statistical measure) ratio will be 1
What happens if anything below OTT line?
The treatment is harmful
What happens if anything is above OTT line?
The treatment is beneficial
What does the Cochrane review bring together?
Information on controlled studies (mostly randomised controlled trials) in a standard format
Cochrane Review 2003
- 18 trials (16 iv, 2ia) - 5727 patients
- 4 agents: rtPA (50%), SK, UK, rpUK
- Fewer patients dead or dependent
- More deaths in the first 7-10 days
- rtPA possibly less hazard and more benefit
Where does many of the important treatment that is given in medicine go through?
Very standardised and very dull process of evaluation where they take all of the data
What did Cochrane Review 2003 analyse?
Data with different agents
They were looking at the principles of giving thrombolytic agents
What did Cochrane Review 2003 demonstrate?
Benefits in the meta-analysis
Demonstrated that most benefit will be within the first 3 hours and the patients were treated with tPA
What is ECASS-I?
First large randomized, multi-centre, double-blind, placebo-controlled trial of thrombolysis for stroke
What was ECASS-3: 3-4 ½ hours designed to evaluate?
Efficacy of IV tPA within 6 hours of symptom onset when compared to placebo in patients presenting with acute hemispheric ischemic stroke with moderate to severe neurologic deficit
ECASS-3: 3-4 ½ hours
European trial with different countries and they repeated the NINDS trial with the same inclusion and exclusion criteria and same kind of population
ECASS-3: 3-4 ½ hours
They looked at time window of 3-4 ½ hours instead of 0-3 hours
What is the absolute reduction risk for ECASS-3: 3-4 ½ hours?
7%
the benefit was clearly very statistically significant
What did the IST-3 sought to determine?
Whether a wide range of patients might benefit up to 6 hours from stroke onset
What is IST-3?
Biggest trial of intravenous thrombolysis
Looked at group of patients who were not eligible for standard thrombolysis - who are younger than 80 years of age and are treated within 4.5hours
IST-3
A study of patients who could not be thrombolysed ‘routinely’ (n=3035)
- Older patients (>80)
- Presenting later ( after 3hr, then after 4.5hr)
What was the results for IST-3?
- Neutral for ‘favourable outcome’
- Sub-group analyses:
- Not much benefit beyond 4.5 hrs
- Support for tPA for older patients <3hr
What takes about 4 and 1/2 hours to develop?
FLAIR signal
What are the wake-up results?
- Those not receiving the acute treatment – 42%
- Favourable outcome: 53%
- It is not about crossing people over that one threshold between disabled and un-disabled, the other patients are benefitting as well
Why are we using a clock to determine who should be treated and who should not be treated?
- Some of the patients who get an occlusion of a large vessel in intracerebral vessels are going to be able to support the threatened area with good collaterals
- The progression to infarction or permanent damage is going to be very slow
- Other people will have no collaterals at all, and they are going to have permanent infarction of the whole area that is being threatened by the occluded vessel within half hour
EXTEND Trial (May 2019)
- 4.5 to 9hr after stroke onset or woke within 9hr of midpoint of sleep
- Perfusion-mismatch (CT or MR perfusion, automated processing ratio > 1.2 penumbra, >10ml, core <70ml)
- 225 of planned 310 patients enrolled
- stopped early (loss of equipoise)
What was the EXTEND Trial results?
- Their primary outcome was 0-1
- Placebo group is 30% and the treated group is 45%
- The benefit is small
- 6% absolute risk reduction
- If you treat patients later, they will do less well
IV tPA now
- Within 4.5 hrs
- Rapid plain CT (+ CTA for LVO)
- Then get on with it - Unknown time of onset
- MRI to age infarct
- CT/MR perfusion to look for mis-match - Known onset beyond 4.5-9hrs
- Small sub-group who may still benefit
What are two more negative trials (2013)?
- Synthesis-Expansion
- 4.5 hr of stroke onset
- Endovascular vs iv tPA - MR-RESCUE
- 8 hr of stroke onset
- CT perfusion or MR perfusion
- No penumbra: completely neutral
- Penumbra: endo patients did a bit worse
What are the new devices?
- Penumbra
2. Solitaire
MR CLEAN 2015
Randomly assigned eligible patients to either intraarterial treatment plus usual care or usual care alone
The primary outcome was the modified Rankin scale score at 90 days;
What was the conclusion of MR CLEAM
In patients with acute ischemic stroke caused by a proximal intracranial occlusion of the anterior circulation, intraarterial treatment administered within 6 hours after stroke onset was effective and safe.
modified rankin 0-2
What was odd about MR CLEAN
A long time window between time tPA was given routinely and time that were randomised to trial
What is the ESCAPE protocol?
- Good pre-morbid state
- Enrollment up to 12hr post-stroke
- CT and CTA
- Small core infarct (ASPECTS 6-10)
- M1 or M2 occlusion
- Moderate-to-good collaterals on CTA
EXTEND-IA 2015
- tPA candidates only (4.hr window)
- M1/M2 occlusions
- Endovascular within 6 hr
- CT perfusion for ‘salvageable tissue’
- small core (<70ml)
- Penumbra (mismatch > 10ml & >20% of core)
SWIFT-PRIME 2015
- small amount of damage on CT
2. Small core
What is REVASCAT?
Population drawn from broader endovascular registry
DAWN clinical criteria
- Small trial
- Interested in patients that present beyond 6 hours
[ Within 6 hours thrombectomy is an established treatment] - Select patients using imaging criteria rather than time window
- 9% given tPA
DAWN criteria
Assess penumbra by looking at the patients
How big is the stroke
How much brain is threatened by the infarction
DEFUSE-3 clinical trial
conducted a multicenter, randomized, open-label trial, with blinded outcome assessment, of thrombectomy in patients 6 to 16 hours after they were last known to be well and who had remaining ischemic brain tissue that was not yet infarcted.
Not given iv tPA > 4.5 hr from onset
DEFUSE-3 radiological criteria
- Terminal ICA or M1 occlusion (CTA or MRA)
- Core <70 ml
- Penumbra > 15ml
- Total ischaemic volume/core vol > 1.8
