Established ischemic stroke:
the role of lytics and surgery
Michelle-Lee Jones
September 1, 2010
OUTLINE
• Case presentation and discussion
• IV r-tPA – evidence for its use
• IA r-TPA in conjunction with IV r-tPA and/or
mechanical clot retrieval - a real work in
progress
• Decompressive surgery (craniectomy) for
“malignant infarctions”
• Summary points
• Question period
Case presentation to whet the
intellectual appetite
• Called urgently to the ER to see a 66-year- old
right-handed male (an author), for a “CODE
STROKE”
• PMHx is significant for CHF (LVEF ≈ 25-30%),
HTN, bladder cancer with surgical resection in
2007
• Meds: ASA 80mg QD, Carvediol, Lipitor,
Furosemide, Ramipril, Empracet, NTG spray
PRN
• NKDA, ex-smoker
Case presentation
• HPI:
– While standing and watching TV at home,
sudden collapse witnessed by wife
– On the floor, found to have right sided
weakness and inability to speak
– Wife looked at clock (18:12) and called 911
– Subsequently he was able to grunt/mumble
and then say ‘yes’ to every question
– No other neurologic symptoms observed
Case presentation
• On exam circa 18:40:
– BP 146/72, HR 68, sat 99%, afebrile, blood glucose
5.5 mmol/L
– MS: Alert, says “yes” or “yup” to all questions, not
consistently following first order commands
– Cranial nerves:
• P 3  2 bil; Left gaze preference, does not cross
the midline;  blink to threat - right eye
• Right facial droop sparing forehead
• Soft palate symmetrically; no tongue deviation
Case presentation
– Motor:
• Bulk: normal
• Tone: flaccid R. arm
> R. leg
• Power: spontaneous
movement noted on
the left, 0/5 in the
right UE and LE
– Sensory:  withdrawal
right hemibody, right
hemispace neglect
– Coordination & gait not
assessed
3+
3+
3+
3+
2+
2+
2+
3+
2+
2+
Case presentation
• Labwork:
– INR 1.06, PTT 29.7
– Lytes normal, glucose 5.7 creatinine 106,
urea 6
– WBC 7, Hgb 144, plts 121
• So, what exactly is going on here and
what are you going to do about it?
Case presentation
Initial CT head
without contrast
Case presentation
CTA head
Case presentation
CTA head
Case presentation
• IV r-tPA full dose (0.9 mg/kg) given 1 hr 44 min
into the window
• No significant change in the physical exam
noted at 1 hr and 2hrs post r-tPA administration
• Mechanical thrombectomy attempted at 3.5 – 4
hours into window, but a tortuous left ICA
precluded thrombus retrieval
• WOULD YOU HAVE DONE THINGS
DIFFERENTLY?
Much ado about IV r-tPA
The evidence for IV r-tPA
The evidence for IV r-tPA
•Randomized, double-blind trial that investigated the short and longer term
effects of rt-PA (0.9 mg/kg) administration vs. placebo within 3 hours
•Part 1: n = 291, changes in neurological status (NIHSS) at 24h
Part 2: n = 333, global neurological outcome (4 measures) at 3
months
•Each group was subdivided into OTT (0-90 m, 91-180 m, 0-180 m)
•The proportion of patients with favourable outcome was determined and
defined as:
1. Resolution of symptoms or NIHSS score improvement by ≥ 4,
particularly in the first 24h
2. Barthel Index 95 or 100, NIHSS or mRS ≤ 1, GOS 1 for the ITT
analysis at 3 months
* Secondary measures included the incidence of intracerebral
haemorrhage (symptomatic and asymptomatic) and mortality
The evidence for IV r-tPA
•
Baseline characteristics of the patients were essentially similar w.r.t
age, gender, median NIHSS score (14-15), stroke subtype, BP, etc.
•
Primary Outcomes – statistical difference in outcome only at 3 months
The evidence for IV r-tPA
•
Outcomes at 3 months – tPA pts were at least 30% more likely to
have a favourable outcome as compared to those treated with
placebo (absolute increase of 11% - 13%)
The evidence for IV r-tPA
•
Increased rates of symptomatic haemorrhage* (6 – 7%) occurred in
the tPA group but the rate of asymptomatic haemorrhage was similar
between the 2 groups
* Not seen previously on
CT and suspicion of
haemorrhage or any  in
neuro status
The evidence for IV r-tPA
•
There was no statistically significant difference in the occurrence of
new ischemic strokes between the 2 groups (part 1  8% for tPA, 7%
for placebo; part 2  4 % for both groups)
•
Importantly, there was no statistically significant difference in mortality
between the 2 groups ( 17% for tPA group and 21% for placebo
group)
• It was therefore concluded that the administration of
tPA within 3 h conferred moderate benefit w.r.t to the
neurological outcome at 3 months despite an
increased risk of symptomatic haemorrhage
The evidence for IV r-tPA
Enter the pooled analysis:
The evidence for IV r-tPA
• Analysis of common results from 6 randomised
controls trials involving tPA administration for acute
stroke, n = 2775, baseline NIHSS  11
• The trials: NINDS part 1 and 2, ECASS, ECASS II,
ATLANTIS part A and B
• TPA window effectively extended to 6 hours
• They correlated the likelihood of a favourable 3
month outcome with the OTT (stroke onset to Rx
time)
• Secondary outcome  intracranial haemorrhage
incidence
The evidence for IV r-tPA
• Probability of a favourable outcome is inversely proportional
to the OTT
The evidence for IV r-tPA
• Substantial parenchymal haemorrhage occurred on 5.9%
tPA pts vs. 1.1% in placebo (no statistical link with OTT
or baseline NIHSS score, but increased risk with greater
age)
• The adjusted hazard ratio for death was not significantly
increased within the 0 – 270 min window
• Given the odds ratio for a favourable outcome was 1.4
for those treated within 180 – 270 min, there may be
potential benefit with the extension of the tPA window
beyond 3 h
• The declining benefit with time was attributed to the
“progressive disappearance of the ischaemic penumbra”
The evidence for IV r-tPA
The sooner the better but…ECASS III
The evidence for IV r-tPA
•
•
•
•
•
Randomised double blind trial to assess the
effectiveness and safety of tPA (alteplase)
administered 3 – 4.5 h after the onset of stroke
symptoms
821 patients were enrolled, 403  placebo and
418  tPA (0.9 mg alteplase /kg, max 90 mg);
following various exclusions  375 tPA pts and
355 placebo patients
Median time for administration was 3h 59 m
10% 3-3.5 h; 46.8% (3.5-4 h); 39.2% (4-4.5h)
An ITT analysis was employed; worst score
assigned if missing data and patient still alive
ECASS III
Notably, there were
statistically significant
differences between
placebo and tPA groups
w.r.t the baseline NIHSS
score and the history of
stroke
The evidence for IV r-tPA
• Major outcome measures:
1. 90-day disability via mRS (≤ 1  favourable and
2-6  unfavourable)
2. 90-day global outcome (mRS, BI, NIHSS,GOS)
3. Mortality at 90 days
4. ICH, symptomatic ICH (extravascular blood in
the brain or in the cranium associated with
clinical deterioration  ≥ 4 points in the NIHSS,
or that led to death and that was identified as the
predominant cause of neurologic deterioration),
and symptomatic edema
The evidence for IV r-tPA
•Favourable outcome at 90 days (MRS ≤ 1): 52.4% tPA group vs.
45.2% placebo group (absolute benefit 7.2%, OR 1.34); 1.42 for
post hoc ITT anaysis
•Favourable outcome at 90 days (Global outcome): OR 1.28
The evidence for IV r-tPA
•Increased risk of ICH in the tPA group, and the risk of
symptomatic haemorrhagic was estimated at 2.4% vs. 0.2 % in
placebo
•The rates of mortality and symptomatic oedema were not
statistically different between the 2 groups
The evidence for IV r-tPA
•CAVEATS from ECASS III:
•Modest clinical benefit at 90 d acquired with the
administration of tPA between 3 and 4.5 h
•The above finding pertains to strokes on the milder end
of the spectrum  NIHSS median scores 10.7, 11.6
•The incidence of symptomatic haemorrhage was
increased relative to placebo, but still relatively low
(2.4%)
•There was no significant difference in mortality
between the two groups, in spite of the haemorrhage
incidence
•Bottomline: Although there may some benefit beyond
3h (and under 4.5 h), it is essential to treat as early as
possible
Intra-arterial thrombolyis in
acute stroke
IA r-tPA  the trials
• The second Prolyse in Acute Cerebral Thromboembolism
(PROACT II) demonstrated the clinical benefit and safety of
intra-arterial thrombolysis in patients with acute ischemic
stroke of 6-hour duration due to MCA occlusion
• Notably, noncontrast CT did not correlate with baseline stroke
severity and did not predict outcome in patients with stroke
due to MCA occlusion
• Rather, “lack of infarct growth rather than final infarct volume
• appears to be the best CT indicator of response to
• thrombolytic therapy.” Outcome was also influenced by clot
location & the presence of a collateral supply (Stroke 2002;
33:1557-1567)
IA r-tPA  the trials
PROACT II
IA r-tPA  the trials
• IA r-tPA and mechanical thrombectomy  the
MERCI series:
• MERCI Safety and Efficacy of Mechanical Embolectomy
in Acute Ischemic Stroke
– N = 141 trials 1 and 2 (number in which device was deployed) but 151
used in intention to treat analysis
– Enrolled patients underwent the mechanical embolectomy with the
MERCI retrieval System ( MERCI  mechanical embolus removal in
cerebral ischemia) with follow-up assessments at 24 hours, 30 days
and 90 days
– Arterial recanalization was evaluated using the TIMI (thrombolysis in
myocardial infarction) grading system
– Successful recanalization was defined as TIMI II or III
IA r-tPA  the trials
• Results:
– Recanalization (TIMI 2 & 3) of treatable vessels in 48%
(p<0.0001, as compared to the 18% spontaneous rate reported
in ProAct 2)
– Postprocedure TIMI scores of treatable vessels were TIMI 2 and
3 (24%), TIMI 1 (18%), and TIMI 0 (33%)
– Interestingly, the MCA had the lowest rate of recanalization (45%
vs. 53% and 50% for the ICA and posterior circulation
respectively)
– Good neurological outcomes (MRS) were more frequent at 90
days in patients with successful recanalization compared with
patients with unsuccessful recanalization (46% vs 10%, p <
0.0001), and mortality was decreased (32% vs 54%, p = 0.01).
Similar trend was noted at 30 days
IA r-tPA  the trials
Note that:
• Adjuvant therapy was used in 51 instances after deployment of the
device (e.g. IA tPA, angioplasty)
• Clinically significant procedural complications occurred in 7%
patients
• Symptomatic ICH noted in 7.8% of patients (NIHSS ≥ 4 associated
with blood on CT, any ICH with no further NIHSS & patient died, any
SAH)
• In 3%, the devices fractured and likely caused the death of 2
patients
• Overall mortality for the trial was 44%
IA r-tPA  the trials
• MultiMERCI Trial (Stroke 2008;39;1205-1212)
– International, multicenter, prospective, single arm trial (2004 –
2006; N = 164)
– Overall aim:
• To determine the safety and efficacy of the latest Merci Retriever
(model L5) with respect to perfusion restoration during acute
ischemic stroke in patients with a large vessel intracranial occlusion
• In contrast to MERCI 1, IV rt-PA patients with persistent large
vessel occlusion were included and adjunctive IA rt-PA following
failed mechanical thrombectomy was allowed
– Inclusion Criteria: As with MERCI 1, except that patients treated
with IV rt-PA with persistent occlusion on angio were included
(29.3%). Target vessels were the same as in MERCI I
IA r-tPA  the trials
MultiMERCI Trial (Stroke 2008;39;1205-1212)
Retrieval devices
IA r-tPA  the trials
• MultiMERCI Trial (Stroke 2008;39;1205-1212)
– The L5 retriever was used first for up to 6 passes
– First generation devices (X5,X6) could be used
thereafter as necessary
– If mechanical thrombectomy was unsuccessful, up to
24 mg of IA t-PA was permitted to open the target
vessel or to treat distal emboli (if proximal ones were
successfully removed)
IA r-tPA  the trials
• MultiMERCI Trial (Stroke 2008;39;1205-1212)
– Results:
• Recanalization was demonstrated in 57.3% with mechanical
thrombectomy alone and in 69.5% with adjuvant treatment
(IA rt-PA)
• Clinically significant procedural complications occurred in
5.5% of patients
• 90-day mRS scores ≤ 2 were seen in 36% of all patients and
mortality at 90 days was 34%
• Symptomatic ICH occurred in 9.8%
• Final recanalization in M1 60 to 61%, as compared to
posterior circulation (86-100%), terminal ICA (65-71%) & M2
(91-93%)
IA r-tPA  the trials
MultiMERCI Trial (Stroke
2008;39;1205-1212)
Results
IA r-tPA  the trials
MultiMERCI Trial (Stroke
2008;39;1205-1212)
Results
IA r-tPA  the trials
IA r-tPA  the trials
•RECANALIZE:
•N = 53 pts in IV tPA – endovascular group and N = 107 in
the IV tPA only group
• Phase 1- patients were treated with 0.9 mg/kg alteplase
• Phase 2 - patients were treated initially with combined IV–
IA alteplase (0.6 mg/kg IV and 0.3 mg/kg IA), as described
previously. After IV alteplase was started, and if arterial
occlusion persisted, IA alteplase was administered
• If recanalisation did not occur after IV and IA
alteplase, additional mechanical procedures were
implemented [snare device or angioplasty balloon]
• Mean OTT 163 m for IV tPA and 132 m for IV-IA
IA r-tPA  the trials
CONCLUSIONS:
• Compared with IV alteplase, the combined IV–endovascular approach
produced higher rates of recanalisation in patients with acute ischaemic
stroke with confirmed arterial occlusion
• This finding was not related to the site of the occlusion and was
associated with early neurological improvement and 90-day favourable
outcome
• Recanalisation rates  87% in the IV–endovascular group and 52% in
the IV group (p<0⋅0001); the eff ect on clinical outcome was
significant for early neurological improvement @ 24h (60% vs
39%) but not for functional outcome at 3 months (57% vs 44%)
• Mortality at 90d was 17% in both groups and symptomatic intracranial
haemorrhage was reported in 9% patients in the IV–endovascular group
vs. 11% patients in the IV group
IA r-tPA  the trials
• IMS (Interventional Management of Stroke)
Series
– IMS II:
• Prospective study to examine the efficacy & safety of
combined IV & IA rt-PA, N = 81 (26  IV rt-PA only vs. 55 
IV & IA rt-PA)
• Baseline NIHSS ≥ 10 (median 19), ages 18-80
• IV rt-PA administered at 0.6 mg/kg over 30 mins (max 60
mg), IA rt-PA via EKOS or standard microcatheter up to a
max of 22 mg (total max dose)
• Median time to initiation of IV rt-PA was 142 minutes compare with 108 minutes for placebo and 90 minutes for rtPA-treated subjects in the NINDS rt-PA Stroke Trial
(P<0.0001)
• No angioplasty or stenting allowed
IA r-tPA  the trials
• IMS (Interventional Management of
Stroke) Series
– IMS II (comparison to placebo arm NINDS rtPA Stroke trial)
• 3 month mortality = 16% (21% in NINDS rt-PA
Stroke trial)
• Symptomatic ICH = 9.9% (6.6% in NINDS rt-PA
Stroke trial, but not significantly different)
• 33% favourable outcome at 3 months (mRS 0 or 1)
• Recanalization rate site specific  73% EKOS,
56% std microcatheter
IA r-tPA  the trials
• IMS (Interventional Management of
Stroke) Series
– IMS III is the ongoing Phase III, randomized,
multi-center, open-label clinical trial that will
look at a whether a combined IV/IA approach
to recanalization is superior to standard IV rtPA alone when initiated within 3 hours of
stroke onset
IA r-tPA  the trials
• Stroke rt-PA/mechanical thrombectomy
algorithm being used in Calgary
– < 3 hrs: 80% rt-PA dose given IV, rest IA
– 3 – 4.5 hrs: 80% IV rt-PA + IA rt-PA (max 20g)
+ mechanical recanalization
– > 4.5 h: IA rt-PA & mechanical recanalization
– Exclusion criteria: no IA Rx if pt > 80 years
• To be used here at the MNI?
Surgical options for large malignant MCA territory infarcts
SUMMARY
• Early IV tPA administration is ideal, but note that
there is still modest benefit within the 3 – 4.5 h
window
• IA tPA and endovascular techniques improve
recanalization rates but the ultimate long term
benefit is not clear
• Early decompressive hemicraniectomy (≤ 48 h)
is recommended in pts <60 years with malignant
hemispheric infarction
Selected References
• The National Institute of Neurological Disorders and Stroke rt-PA
Stroke Study Group. Tissue plasminogen activator for acute
ischemic stroke. N Engl J Med 1995; 333:1581-7
• Hacke W, Donnan G, Fieschi C, et al. Association of outcome with
early stroke treatment: pooled analysis of ATLANTIS, ECASS, and
NINDS rt-PA stroke trials. Lancet 2004;363:768-74
• W Hacke, M Kaste, E Bluhmki et al. and the ECASS Investigators,
Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic
stroke, N Engl J Med 359 (2008), pp. 1317–1329
• Implementation and outcome of thrombolysis with alteplase 3–4·5 h
after an acute stroke: an updated analysis from SITS-ISTRThe
Lancet Neurology, Volume 9, Issue 9, Pages 866-874 Niaz. Ahmed,
Nils. Wahlgren, Martin. Grond, Michael. Hennerici, Kennedy R.
Lees, Robert. Mikulik, Mark. Parsons, Risto O. Roine, Danilo. Toni,
Peter. Ringleb, et al.
Selected References
• Furlan AJ, Higashida R, Wechsler L, Gent M, Rowley H, Kase C,
Pessin M, Ahuja A, Callahan F, Clark WM, et al. Intra-arterial
prourokinase for acute ischemic stroke: the PROACT II Study: a
randomized controlled trial. JAMA. 1999;282:2003–2011.
• A. Schulz et. al., Computed Tomographic Findings in Patients
Undergoing Intra-arterial Thrombolysis for Acute Ischemic Stroke
due to Middle Cerebral Artery Occlusion: Results From the PROACT
II Trial * Editorial Comment: Results From the PROACT II Trial
Stroke 2002;33;1557-1565
• Smith, W.S. et. al. Mechanical Thrombectomy for Acute
Ischemic Stroke: Final Results of the MultiMERCI Trial Stroke
2008;39;1205-1212
Selected References
• Smith, W.S et. al. Safety of Mechanical Thrombectomy and
Intravenous Tissue Plasminogen Activator in Acute Ischemic
Stroke. Results of the Multi Mechanical Embolus Removal in
Cerebral Ischemia (MERCI) Trial, Part I AJNR Am J Neuroradiol
27:1177– 82 Jun-Jul 2006
• Smith, W.S. et. al. Safety and Efficacy of Mechanical
Embolectomy in Acute Ischemic Stroke:Results of the MERCI
Trial Stroke 2005;36;1432-1438
• The IMS Study Investigators. Stroke: The Interventional
Management of Stroke Study Combined Intravenous and IntraArterial Recanalization for Acute Ischemic Stroke 2004;35;904911
Selected References
•
•
•
•
J. Hofmeijer, L. Kappelle, A. Algra, G. Amelink, J. van Gijn, H. van der
Worp, Surgical decompression for space-occupying cerebral infarction (the
Hemicraniectomy After Middle Cerebral Artery infarction with Lifethreatening Edema Trial [HAMLET]): a multicentre, open, randomised trial
The Lancet Neurology, Volume 8, Issue 4, Pages 326-333
Treadwell SD, Thanvi B., Malignant middle cerebral artery (MCA)
infarction: pathophysiology, diagnosis and management. Postgrad Med
J. 2010 Apr;86(1014):235-42
H. Huttner, S. Schwab, Malignant middle cerebral artery infarction: clinical
characteristics, treatment strategies, and future perspectives
The Lancet Neurology, Volume 8, Issue 10, Pages 949-958Neurologist.
2009 Jul;15(4):178-84.
Subramaniam S, Hill MD., Decompressive hemicraniectomy for
malignant middle cerebral artery infarction: an update. Neurologist.
2009 Jul;15(4):178-84.