ECASS-3 Discussion

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Late Breaking Trials An update.

• Michael D. Hill
• Calgary Stroke Program

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Disclosure Slide

• In the last 5 years
• I have been funded by CIHR, HSF
  Alberta/NWT/Nunavut, CSN, AHFMR, NINDS (NIH)
• I have received speaker fees/honouraria from
  Hoffmann-La Roche Canada Ltd., Sanofi Canada,
  Boehringer-Ingelheim Canada, Novo-Nordisk Canada
• I have been an advisor to NovoNordisk Canada,
  Genentech Ltd, Stem Cell Therapeutics, Vernalis
  Group Ltd., Sanofi Canada, Portola Therapeutics.
• I hold no stock or direct investment in any
  pharmaceutical or device company (except those
  possibly in mutual funds)
• I believe you/we should give the juice (ie.
  tPA) far more often that we do

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Outline - Focus on RCTs

• ECASS-3
• Hemicraniectomy
• Telestroke
• FASTER
• PROFESS
• ONTARGET, TRANSCEND, HYVET

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ECASS-3
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RR Outcome

• . csi 219 182 199 221, exact
• Exposed Unexposed
  Total
• ------------------------------------------------
  ---
• Cases 219 182
  401
• Noncases 199 221
  420
• ------------------------------------------------
  ---
• Total 418 403
  821
• Risk .5239234 .4516129
  .4884287
• Point estimate 95
  Conf. Interval
• -------------------------------
  ---------------
• Risk difference .0723105
  .0040978 .1405233
• Risk ratio 1.160116
  1.007389 1.335997
• Attr. frac. ex. .1380174
  .0073352 .2514956
• Attr. frac. pop .0753761
• --------------------------------
  ---------------
• 1-sided Fisher's
  exact P 0.0226

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RR outcome

• 7.2 Absolute risk benefit
• NNT 14 (13.8)
• Treat 14 patients in the 3-4.5 window and get 7
  excellent functional outcomes at 90d instead of
  6, OR one additional excellent functional outcome
  (mRS 0-1)
• This includes an increased risk of ICH and no
  difference in mortality

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090 min, n311 91180 min, n618 181270
min, n801 270360 min, n1046. Values do
not equal 100 because of rounding.
Time is an effect modifier
The ATLANTIS, ECASS, and NINDS rt-PA Study Group
Investigators. Lancet 2004 363 (9411) 768-774.
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Results Pooled Analysis

• Odds Ratios for Favorable Outcome
• Time Odds Ratio 95 Conf. Interval
• 0-90 2.8 1.8, 4.5
• 91-180 1.5 1.1, 2.1
• 181-270 1.4 1.1, 1.9
• 271-360 1.2 0.9, 1.5

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Adverse Events
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Human Nature?
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SITS-ISTR
Lancet 2008 on-line. N664 patients
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Whats new in 2008?

• 2008
• 8 new trials (n1477, total n7152)
• Drugs 3 rt-PA 2 UK 3 desmoteplase
• Route 2 intra-arterial, 6 intravenous
• Time windows 0-6, 3-4.5, 3-9, 0-24 hrs
• Imaging pre randomisation
• CT 5
• MR 3 (1) DWI/PWI mismatch
• Age over 80 42

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rt-PA 2008- OR and events per 1000 treated
rt-PA Effect per 1000
Symptomatic ICH lt3 hrs
70
60
3-6 hrs
Death by three months lt3 hrs
0
20
3-6 hrs
Dead or Dependent lt3 hours
-110
- 40
3-6 hours
0.1 0.66 0.84 1.0
1.33 3.37 10 OR
better thrombolysis
worse
CDSR 2008
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Death or dependency subgroups
OR (95 CI)
n Trials n patients
Latest time to treatment, all drugs (hours)
3 1 624 4.5
2 1161 6 9
3463 9 3 325
0.62 (0.45, 0.85) 0.85 (0.68, 1.07 0.84 (0.73,
0.96) 0.85 (0.52, 1.39)
Treatment time rt-PA (hours)
0.64 (0.5. 0.8) 0.83 (0.7, 0.9)
0-3 5 930 3-6
6 2766
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Conclusion, Update 2008

• Heterogeneity still confounds interpretation
• ECASS 3 consistent with existing rt-PA
  meta-analysis.
• Potential for benefit to at least six hours
• Limited new knowledge on latest time windows.
• Almost complete lack of data on older patients
  antithrombotic use stroke severity/subtype,
  diabetes
• Outcome following selection on MR mismatch not
  apparently different to CT.
• No material change in main outcomes since 2003.

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Proposed CSS BPR

• 3.5.1 All patients with disabling acute ischemic
  stroke who present to a hospital capable of
  administering thrombolytic therapy within a 4.5
  hour treatment window should be evaluated
  without delay to determine their eligibility for
  treatment with intravenous tissue-plasminogen
  activator (tPA).

Note  In Canada, tPA is currently approved by
the Health Canada Food and Drug Administration
Regulations for administration  within 3 hours of
stroke symptom onset, unless special compensation
has been granted to individual practitioners or
institutions, for example within the context of a
clinical research trial.
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Hemicraniectomy Evidence
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• Enrolled lt48h
• Age limit at 60

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Telestroke
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Study Profile
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Outcomes Correct decision with telestroke
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• F ast
• A ssessment of
• S troke and
• T IA to Prevent
• E arly
• R ecurrence

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Eligibility Criteria

• Patients with TIA or minor acute ischaemic stroke
  (NIHSS ? 3)
• Within 24h of symptom onset
• Patients with
• weakness at time of TIA/minor stroke and/or
  language disturbance at time of TIA/minor stroke
  
• and duration of neurological deficit (TIA) ? 5
  minutes
• Age greater than 40

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FASTER Study Design
All patients within 24 hours of qualifying event
All patients on Aspirin
Simvastatin
Placebo
Clopidogrel
Placebo
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Trial Flowchart
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Clopidogrel Flowchart
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Simvastatin Flowchart
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Primary Outcome
Simvastatin Simvastatin
Clopidogrel 9/100 9.0 5/98 5.1 14/198 7.1
Clopidogrel 12/99 12.1 9/95 9.5 21/194 10.8
21/199 10.6 14/193 7.3
Interaction Ratio 1.39 (0.36-5.24) p0.64
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Primary Outcome
Risk Difference (CI95) Risk Ratio (CI95)
Clopidogrel v Placebo -3.8 (-9.4 to 1.9) 0.7 (0.3 to 1.2)
Simvastatin v Placebo 3.3 (-2.3 to 8.9) 1.5 (0.8 to 2.8)
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Conclusions

• Feasibility
• Increased indications and uptake of statins
  hampered patient enrolment
• Safety
• Haemorrhagic Complications of Clopidogrel in
  keeping with MATCH
• Efficacy
• The addition of clopidogrel to aspirin may be
  associated with a reduction of stroke following
  TIA/ minor stroke
• Appears unlikely that there is a significant
  effect of early statin use

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PLAVIX - FASTER 2Study Design
Standard of care
Within 12 hours symptom onset
R
Double-blind treatment up to 21 days

• gt40 yrs
• Weakness/ speech deficit
• TIA/ minor stroke (NIHSS lt3)

Standard of care
Primary Endpoint all stroke
Placebo loading dose
Placebo dose
Day 2 to 21
Within 12 hours
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Age-specific acute vascular event rates in the
general population
Data from Oxfordshire, UK, 2002-05. Lancet
20053661773-83
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PROFESS
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Cerebrovascular Endpoints


p-value


heterogeneity
Stroke
With Stenosis
0.1245
Without Stenosis
Fatal Stroke
With Stenosis
0.9770
Without Stenosis
Non-Fatal Stroke
With Stenosis
0.4245
Without Stenosis
Stroke or TIA
With Stenosis
0.2592
Without Stenosis
0.4
0.7
1.0
1.3
1.6
2.2
Hazard Ratio (95 CI)
Atorvastatin better
Placebo better
Sillesen H, Amarenco P, Hennerici MG, et al.
Stroke
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TRANSCEND

• Patients intolerant of ACEi
• -cough (88)
• -symptomatic hypotension (4.1), angioedema
  (1.3) and other
• -hypertension requiring treatment
• -primary prevention trial

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Exclusions

• CHF, cardiac outflow/AoV obstruction,
  constrictive pericarditis, complex congenital
  heart dx, unexplained syncope, planned or recent
  cardiac surgery, SBP gt 160 mmHg, heart
  transplant, SAH, RAS, creatinine gt 265 umol/L,
  proteinuria, heaptic dysfunction

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Outcomes

• 1. Composite of cardiovascular death, myocardial
  infarction, stroke or hospitalization for heart
  failure
• 2. Composite of cardiovascular death, myocardial
  infarction or stroke (HOPE primary outcome)

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Adverse Events leading to discontinuation of
study treatment
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Effect beyond 6 months?
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Conclusion

• Neutral trial
• -? Effect after 6 months (PH assumption not met
  interaction with time from randomization)
• Patients were generally well treated
• On statins, b-blockers, starting BP was low

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PROFESS study

• Stroke study
• -2x2 factorial design
• -clopidogrel vs. ASAdipyridamole ER
• -telmisartan vs. placebo
• All patients had stroke lt 90d, age gt 55y
• -median time to randomization was 15d
• -lowered the age limit to gt 50y after 25 of
  patients were enrolled
• -extended window for stroke to 120d 2 risk
  factors

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Exclusions

• Hemorrhagic stroke (ICH or SAH)
• Severe disability after the index stroke,
  contraindication to one of the study medications

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Outcomes

1. Any recurrent stroke.
2. Composite of cardiovascular death, MI, stroke,
   hospitalization for CHF, new-onset diabetes
   mellitus

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Adverse events leading to discontinuation of
study drug
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Major outcomes
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Discussion

• Neutral trial
• Direction of effect similar to TRANSCEND,
  ONTARGET
• Lots of drug discontinuation (?headache from
  dipyridamole)
• Increased harm due to hypotension/syncope
• Patients were well treated (cf. HYVET)
• Suspect that pooled analysis or meta-analysis of
  micardis trials may produce an effect

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REVIEW

1. tPA up to 4.5h.
2. Hemicraniectomy for well-selected patients
3. Telestroke works.
4. Lipitor the good.
5. Antiplatelet therapy your choice.
6. ARBs are safe and effective for ACE intolerant
   patients.
7. ARBs show harm when added ACEi.
8. Older patients should be treated aggressively for
   hypertension

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tPA GIVE THE JUICE!