Thrombolysis for Acute Ischaemic Stroke

							Thrombolysis for acute
ischaemic stroke – the
   challenges ahead

       Catrin Blank
        June 2011
                Overview
Challenges for thrombolysis in acute stroke
Too late to treat?
Too mild to treat?
Too severe to treat?
Too old to treat?
Better means of delivering treatment?
No known time of onset?
  How many stroke patients per year in UK*
  might avoid being ‘dead or dependent’ with
               each treatment?
               % treated with     Number      Benefit per    Number who
                     this       treated per     1000        avoid death or
                intervention       year        treated       dependency



   Aspirin         80%          104000           13            1350

 Stroke Unit       60%           78000           56            4370

Thrombolysis        2%           2080            63             130

Thrombolysis       30%           31200           47            1470
               *130,000 strokes per year
    Barriers to Thrombolysis
• In Canada/USA 2-3% patients AIS treated
  with thrombolysis
• Up to 20% treated in certain centres (60%
  arrive <3hrs & 1/3 treated)
• UK national figures <0.2% AIS patients
  treated with thrombolysis (National Sentinel
  Audit of Stroke 2006)
• Sheffield 2%
• Glasgow 20% treated
        Patients Not Treated
         in Calgary 1996-99
• N= 2165, 1168 (54%) AIS
• 73% delay to presentation
• 29% patients waiting to see if would
  improve
• 24% uncertain time of onset
• 9% transfer from outlying hospital
• 6% inaccessibility of treating hospital
    Barriers to Thrombolysis
• Too late to treat?
• Service delivery – patient recognition,
  ambulance services, FAST test
• Hospital services – telemedicine?
• 2 Trials: STRokE DOC, Telestroke
           Telemedicine Trials
STRokE DOC (lancet neurol 2008) n= 234
US study: telemedicine with telephone
  decisions. Patients <12 hrs from onset.
Primary outcome: ‘correct decision’ according to
  NINDS criteria
98% telemedicine group v 82% in telephone
  group

Telestroke (Paris), 2006, n=400, stroke onset
  <2 hours, treatment < 3 hours
Telemedicine decision & reomote treatment v
  standard care: patients from remote hospital
  transferred to stroke unit.
Outcome of Patients Not Treated
      in Calgary 1996-99
• 13% too mild
• 18% significant improvement
• Of these 32% remained dependent at
  hospital discharge or died
Are we being too conservative?
Particular deficits less likely to improve?
Aphasia poorly assessed by NIHSS?
            Too mild to treat?

• Expert opinion varies about whether to treat
  – Mild (NIHSS 0-5) / severe (NIHSS > 25)
  – Routine practice varies between centres

  • European approval for iv rtPA excludes mild
    and severe strokes
    Non-randomised data: VISTA
functional outcomes x baseline NIHSS




                       Mishra, N. K. et al. Stroke 2010;41:2612-2617
NINDS subgroups: effect of baseline NIHSS
on likelihood of favourable outcome (mRS)




                          Ingall, T. J. et al. Stroke 2004;35:2418-2424
               Conclusion?
• Very few mild and severe strokes included in
  randomised trials
• Effects in mild and severe strokes UNCLEAR
  – NINDS
  – Non-randomised VISTA database analysis
• European approval for iv rtPA excludes mild
  and severe strokes
• More evidence required
      Third International Stroke Trial.
  A large randomised trial to answer the
question: can a wider variety of patients be
   treated with iv thrombolytic therapy?
     Main features of IST - 3
• Randomised, open, blinded outcomes study of
  i.v. rt-PA vs control,
• Target 3100 patients < 6 h of acute ischaemic
  stroke (n=2902)
• No age or severity exclusion criteria
• Primary outcome: the proportion of patients
  alive and independent at six months
• Randomisation by telephone or internet
• Imaging: CT or MR, perfusion/angio data if
  available.
• Blinded central review of all scans
                    NIHSS
700
600
500
400
300
200
100
 0
      0 to 5   6 to 10   11 to 15 16 to 20 21 to 35
 IST-3 will report its results at
     ESC 2012 in Lisbon
Main results
• Primary outcome all cases 0-6h
Main subgroups
• Effect x time 0- 6h
• Effect x severity:
  ~ 600 with NIHSS < 5 (mild)
  ~ 400 with NIHSS > 24 (severe)
• Effect x age
  ~ 1500 patients aged > 80 years).
        Too old to treat?
• 30% of AIS occur >80 years
• Randomised trials of rTPA largely
  excluded patients >80 years
• Randomised data from NINDS only n=
  42
• European rTPA licence excludes
  patients > 80 years
               Two views
• We already know who to treat: ‘There is
  no need to continue with randomised trials,
  we now can treat at any age, any severity
  and up to 4.5 hours (or even beyond)’
• The evidence is not as clear as some
  experts make out: ‘We need randomised
  evidence on the effects in:
  – people > 80yrs
  – NIHSS <5, NHSS >25’
• Conclusion: We need both clinical
  experience and RCT evidence
 Routine care: the older you are, the less likely
you are to get rt-PA for stroke: Germany (similar
                     in USA)
               10.0
                9.0
                8.0
                7.0
  Percentage




                6.0
                5.0
                4.0
                3.0
                2.0
                1.0
                0.0
                      25–34 35–44 45–54 55–64 65–74 75–84 85+      all
                                     Age                          ages
                                               Förch. Stroke 2009;40:1900-2
Thrombolysis in the very elderly –
     data from SITS-ISTR
• SITS – ISTR international registry (Safe
  Implementation of Treatment in Stroke-
  International Stroke Thrombolysis Registry
• Part of rTPA licencing criteria in EU
• Assess efficacy and safety of thrombolysis in
  ‘real world’
• Centres enrol & collect demographic &
  outcome data volitionally
Thrombolysis in the very elderly-
     is it safe? Effective?
• BMJ 2010
• Comparison of rTPA -treated patients in
  registry with historical control patients derived
  from VISTA (Virtual International Stroke Trials
  Archive)
• Primary outcome: 90 day mRS in rTPA
  treated patients versus historical controls,
  ordinal scale & dichotimised mRS
• < 80 years with controls & patients > 80 years
  with controls
• Look at data set 10 year cohorts 20-30 80-90
  etc
                      Results
• ~29 000 patients in SITS-ISTR (~2 230 > 80 years)
• ~6 100 controls in VISTA database (~1230 > 80
  years)
• Overall benefit of rTPA in all patients, with distribution
  of all the scores on the mRS better (ie lower mRS) in
  rTPA treated patients cf controls (OR 1.6)
• Benefit of rTPA in patients > 80 years similar
  to < 80 year group OR of better distribution of mRS
  1.4 in > 80s v 1.6 in < 80s or dichotomised mRS 2.1 v
  1.9 for avoiding death & dependency
• Distribution of scores on mRS better for all cohorts
  from 40-90 (small numbers <30 & >90 years)
• Similar rate of SICH in < 80 years & > 80 years 1.9%
  v 2.5% (NIHSS change >4 points)
           Too old to treat?
• Non-randomised data suggests risks &
  benefits of rTPA similar in patients aged 80-
  90 years compared with patients < 80 years
• Insufficient data in patients > 90 years
• Randomised data: 2 on-going trials TESPI &
  IST3
• TESPI Italian, 2008, >80 years, 0-3 hrs,
  n=600
                                  Age
         1000

         800
Number




         600

         400

         200

           0
                 18-50   51-60   61-70         71-80   81-90   91-100
                                         Age
                Already over 1200 patients aged >
                        80 years in study!
    Conclusion: iv thrombolysis
• There is no reliable randomised trial
  evidence about optimum stroke severity or
  age limit for iv treatment
• Uncertainty about
  – Age: how old is ‘too old’ ?
  – Severity: too mild ? / too severe?
• Current trials (IST-3 & TESPI) will help
  resolve these uncertainties
       Pooled analysis of 7 rt-PA trials (n= 3670)
Time to treatment and odds of ‘good outcome’ (mRS 0-1)




                                       Lees et al Lancet 2010
What factors affect outcome after
                       tPA?
• Vessel occlusion – early spontaneous recanalisation
  occurs in 29% vessels (CI 25%-32%)
• Recanalisation predicts outcome
• After IV rTPA, TCD showed 32% MCA & branches
  completely recanalised (partial 21%)
• No recanalisation associated with mRS 3-6 in 90%
  (CI 74-94%), complete recanalisation associated with
  mRS 3-6 in 14% (3-51%)
• Analysis of 1905 patients with hyperdense MCA
  showed persistent occlusion associated with mRS 3-6
  in 81% cf 58% patients in whom hyperdense MCA
  resolved.
• Achieving recanalisation much more important
  predictor of outcome than time of treatment
        Further advances
• Identify patients in whom IV rTPA
  unlikely to be of benefit: large clots,
  internal carotid occlusions, proximal
  MCA occlusions distal to ICA stenosis
• Consider IA approach to these high risk
  patients
          What is available?
• intra-arterial thrombolysis
• thrombolysis combined with mechanical
  thrombectomy

    •   Merci retriever
    •   Phenox clot retriever
    •   Penumbra aspiration system
    •   Stent assisted clot retrieval
             IA Therapy
• PROACT II n=180 only randomised study IA
  thrombolysis (pro-urokinase)
• 3-6 hrs from stroke onset
• 40 % treated patients v 25% controls
  achieved mRS 0-2 at 90 days (p=0.04)
• Recanalisation in 66% v 18%
• SICH 10% v 2 % controls, mortality not
  affected (25 & 27% respectively)
• Pro-urokinase not licenced
• Potential to prolong the time window to
  treatment
           Merci Retriever
• the first device for intra-cranial clot
  removal.

• consists of a corkscrew shaped, flexible
  nitinol wire that traverses the clot,
  snares it and which can then be
  removed by traction
Merci Retriever
                Merci Trial
• Industry sponsored non-randomised trial
• < 8 hours from onset
• All patients ineligible to receive IV rTPA
• n =151
• Recanalisation in 46% (cf 18% historical
  controls)
• SICH 7.1%
• Option for patients ineligible to receive IV
  rTPA/ > 4.5 hours
 Penumbra aspiration system
• combines a microcatheter with a separator
  and allows for continuous aspiration
• basically a ‘hoover’ generating a suction force
  of -700mm Hg.
• has the potential of opening a vessel without
  the use of thrombolytics
• can be used in distal branches (M2/A2 size)
               Penumbra clot aspiration system

                                Matched 041
                                Separator™
Reperfusion
Catheter 041



                               Matched 032
                               Separator
Reperfusion
Catheter 032


                              Matched 026
                              Separator
Reperfusion
Catheter 026


  1274B
Penumbra Pivotal StrokeTrial
• Phase 1 study
• n=125
• < 8 hours, NIHSS >8 & complete occlusion of
  large intracranial vessel
• Primary endpoints revascularisation & safety
• Reperfusion rates of 81% & complication
  3.2%
• Improvement over MERCI device
• Non-randomised data
stent deployment to allow blood flow,
 deployment of lytics & clot retrieval
  Combined approach – ongoing
        randomised trial
• IMS III, Phase 3 open-label, international
  randomised trial
• n= 900, onset < 3 hours
• IV rTPA v IV/IA rTPA
• IV/IA get 0.6mg/kg dose IV followed by angio.
  If clot still present will get either IA rTPA, or
  rTPA & U/S or clot retrieval
• Primary outcome will be mRS 0-2 at 90 days
             IA approach
• Potentially treats patients with contra-
  indications to IV thrombolysis
• Extends the time window
• May be best approach for patients with
  proximal large vessel occlusion
     What to do if time of onset
            uncertain?
• 41M previously fit
• Last seen well 10 pm
• Woke at 7am & spoke to wife from bed
• Wife heard crash in bathroom at 07.05.
• Came downstairs 07.10 right hemiparesis &
  aphasia
• Arrived RHH 10.15
• NIHSS 16, R hemiparesis & aphasia
• BP & BM satisfactory
              And now?
• 76 M Type II diabetes, renal dialysis
• Last seen well 10pm
• In bed when son left house at 0700
• Found on kitchen floor by daughter
  0730 mute & plegic
• Arrived 08-45
• NIHSS 25, L TACS
    Can we select patients who may
     benefit beyond 4.5 hr window?
•   Not all brain tissue infarcts at same rate
•   Extend study, Australian, n= 400, IV rTPA
•   stroke onset 3-9 hours or waker-upers
•   NIHSS 4-26
•   Mismatch on MRI
•   MR dwi/pwi show large area of reduced brain
    blood flow (perfusion) ie tissue at risk, small
    area of infarcted (irreversibly damaged tissue
    (mismatch)
            Other Studies
• DIAS-4 n =320
• International double-blinded randomised
  study investigating use of Desmoteplase
• 3-9 hours after stroke onset
• MRI/CTA must demostrate proximal large
  vessel occlusion & exclude extensive early
  infarction
• STH will be recruiting soon
                Summary
• Thrombolysis is an exciting & rapidly
  developing field
• Need to focus on maximising the number of
  patients eligible for treatment
• Service re-organisation
• Commitment to enrolement of patients in
  ongoing clinical trials: to extend time window
  (Extend, DIAS-4), determine if safe to offer
  thrombolysis to elderly (TESPI) & those with
  less severe stroke (?PRISM)