1. Acute Transient Ischemic Attack
Brett Cucchiara, MD
Associate Professor of Neurology
Comprehensive Stroke Center
University of Pennsylvania Medical Center

2. Case
A 65 yo M presents to the ED with 15 minutes of transient expressive aphasia. His symptoms have completely resolved. His PMH is notable for HTN and hyperlipidemia.
His BP is 130/80; neurological exam is normal.
HCT is normal as is basic blood work.
What do you do?

3. What is a “TIA”?
Traditional definition: Transient neurologic dysfunction caused by focal brain or retinal ischemia that resolves completely in less than 24 hours
24 hour time limit is arbitrary and not based on pathophysiology
Widely stated “fact”: most TIAs are < 1 hour (???)
If symptoms last > 1 hour, less than 15% chance of complete resolution within 24 hours (Levy D, Neurology 1988)

4. TIA Stroke Reversible ischemia Infarction Minor stroke DWI+ TIA
Acute neurovascular syndrome
Reversible ischemia
Infarction
Minor stroke
DWI+ TIA
TIA
Reversible ischemic neurologic deficit (RIND)
Stroke
Cerebral infarction with transient signs

5. AHA Endorsed Revised Definition of TIA: A transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction

7. “When the Okies Left Oklahoma and moved to California, they raised the average intelligence in both states.”

8. Will Roger’s Phenomenon: an epidemiological paradox
TIA patients with infarction (MRI DWI lesions) are the ones at highest risk of recurrent stroke
New definition of TIA recategorizes such patients as stroke
Prognosis of TIA – i.e. risk of subsequent stroke – improves substantially by removing DWI+ patients from the disease category of TIA
TIA patients with infarction are now strokes, despite being neurologically back to normal
Prognosis of stroke – i.e. disability and death – improves substantially by adding DWI+ TIA into the disease category of stroke

9. Sensitivity analysis of reduction in 90 day post-stroke disability
Quantifying Impact of Will Roger’s Phenomenon with Redefinition of TIA (Mullen M, Stroke, 2011)
90-day risk of stroke following TIA ↓ to ~1%.
Post-stroke disability ↓ 3.4%
Annual ischemic stroke incidence ↑ from 691,650 to 747,755
Sensitivity analysis of reduction in 90 day post-stroke disability

10. 90 Day Outcome Following TIA Johnston S, JAMA 2000

11. Risk In Other Populations
Cincinnati, n =790 (1)
9.2% stroke at 30 days
13.3% stroke at 90 days
Oxford, n=209 (2)
8.6% stroke at 7 days
12.0% stroke at 30 days
Ontario (first ever TIA), n=167 (3)
6% stroke at 7 days
8% stroke at 30 days
Portugal, n=141 (4)
12.8% stroke at 7 days
21.4% stroke at 1 year
1. Panagos, Acad Emerg Med 2003; 2. Lovett, Stroke 2003; 3. Gladstone, CMAJ 2004; 4. Correia, Stroke 2006

12. BUT… Risk in other populations
Philadelphia, n=117 (1)
1.7% stroke at 48 hours
1.7% stroke at 90 days
Paris, n=629 (2)
0.0% stroke at 48 hours
1.9% stroke at 90 days
Paris, n=201 (3)
2.0% stroke at 48 hours
3.5% stroke at 90 days
Oxford n=160 (4)
0.6% stroke at 48 hours
0.6% stroke at 90 days
1. Cucchiara, Stroke 2006; 2. Lavallee, Lancet Neuro 2007; 3. Calvet, Cerebrovasc Dis 2007; 4. Rothwell, Lancet 2007

13. % risk from day 8 to day 90
Early Risk of Stroke After TIA: Effect of Study Population and Methodology (Giles M, Lancet Neuro 2007)
% risk in first 7 days

14. Clinical risk scores – features of patient and event Brain imaging
So How Do We Tell WHICH Patients Are At Highest Risk? 3 Tools in Your Toolbox
Clinical risk scores – features of patient and event
ABCD2 score
Brain imaging
MRI Diffusion Weighted Imaging (DWI) CT
Vascular imaging

15. Clinical risk scores – features of patient and event Brain imaging
So How Do We Tell WHICH Patients Are At Highest Risk? 3 Tools in Your Toolbox
Clinical risk scores – features of patient and event
ABCD2 score
Brain imaging
MRI Diffusion Weighted Imaging (DWI) CT
Vascular imaging

16. The ABCD2 Score Johnston SC, Lancet 2007
Age:
> 60 years 1 point
Blood pressure:
SBP>140 mmHg and/or DBP>90 mmHg 1 point
Clinical features:
Unilateral weakness 2 points
Speech disturbance without weakness 1 point
Other symptoms points
Duration of symptoms:
> 60 minutes 2 points
10-59 minutes 1 point
< 10 minutes 0 points
Diabetes:
Yes point
The ABCD2 Score Johnston SC, Lancet 2007

17. ABCD2 Score and Risk of Stroke After TIA Johnston SC, Lancet 2007
Patients (%)
% risk at 2 days
0-3
1628 (34%)
1.0%
4-5
2169 (45%)
4.1%
6-7
1012 (21%)
8.1%

18. Problems with the ABCD2 score
Things may not be as clear as they seem…

19. Problems with the ABCD2 score:
ABCD2 score predicts disabling stroke after TIA, less reliable at predicting any stroke (Asimos An, Ann Emerg Med 2010; Chandratheva, Stroke 2010)
Largest independent validation study to date (Perry JJ, CMAJ 2011):
2056 patients in 8 Canadian EDs – “real world” practice
ABCD2 score > 5 had sensitivity for stroke only ~30%
C-statistic 0.56
Studies evaluating risk scores have occurred on a background of standard treatment – they are not “natural history” studies
Inter-rater reliability > surprisingly poor! (Ishida, JSCVD 2015)
Individual patients may have unique risk factors indicating high short-term stroke risk not captured in the clinical risk scores

20. Clinical risk scores – features of patient and event Brain imaging
So How Do We Tell WHICH Patients Are At Highest Risk? 3 Tools in Your Toolbox
Clinical risk scores – features of patient and event
ABCD2 score
Brain imaging
MRI Diffusion Weighted Imaging (DWI) CT
Vascular imaging

21. Brain imaging: MRI Diffusion Weighted Imaging (DWI)
MRI DWI+ lesion = acute infarction (rare exceptions)
Can appear within minutes of ischemic event
Generally normalize by about 1-2 weeks post event
~1/3 of TIA patients are DWI+ (Redgrave, Stroke 2007)

22. An MRI DWI+ lesion means your patient has DEFINITIVELY had a cerebrovascular event
No matter what the risk factors or lack thereof
No matter what the clinical features of the event
No matter how crazy the patient seems

23. Another way of looking at the problem

26. Stroke risk at 7 days: Interaction of MRI DWI and ABCD2 score Giles M, Neurology 2011
positive
negative
0-3
4/ 223
(1.8%)
1/ 1023
(0.1%)
4-5
35/ 469
(7.5%)
7/ 1031
(0.7%)
6-7
24/ 192
(12.5%)
1/ 268
(0.4%)

27. Brain imaging: Head CT Giles M, Neurology 2011
CT unable to reliably distinguish between new and old infarction
But, presence of any infarction indicates higher risk of future stroke in TIA patients (OR 6 adjusted for ABCD2 score)
Negative CT does NOT have same NPV as MR
ABCD2
score CT
positive
negative
0-3
3/ 76
(3.9%)
3/ 343
(0.9%)
4-5
22/ 170
(12.9%)
15/ 506
(3.0%)
6-7
17/ 81
(21.0%)
14/ 192
(7.3%)

28. Clinical risk scores – features of patient and event Brain imaging
So How Do We Tell WHICH Patients Are At Highest Risk? 3 Tools in Your Toolbox
Clinical risk scores – features of patient and event
ABCD2 score
Brain imaging
MRI Diffusion Weighted Imaging (DWI) CT
Vascular imaging

29. Urgent vascular imaging easily obtained with CT angiography

30. Vascular Imaging: Large Vessel Stenosis = Increased Stroke Risk Purroy F, Stroke 2007
388 TIA patients
90 day stroke rate = 9%
Large vessel stenosis was independent predictor of subsequent stroke
ABCD2 score (dichotomized at ≥ 5) not an independent predictor of stroke

31. Vascular Imaging: Large Vessel Stenosis = Increased Stroke Risk
2654 TIA patients at multiple centers (Merwick, Lancet Neurol 2011)
Stroke risk post-TIA substantially ↑ with carotid stenosis ≥ 50%, even after adjustment for ABCD2 score and MR DWI
At 7 days, OR 3.3 (95% CI: , p 0.05)
At 90 days, OR 3.3 (95% CI: , p=0.006)
510 TIA/minor stroke patients at single center (Coutts, Stroke 2012)
CT/CT angiography protocol in ED for all patients
Large vessel occlusion/stenosis >50% associated with stroke progression/recurrence
Intracranial – OR 5.1 (95% CI )
Extracranial – OR 2.4 (95% CI )

32. Echocardiography in TIA
740 patients with TIA and no known cardiac source of embolism( CSE)
603 (81%) underwent echo
Potential CSE identified in 60 (10%)
Yield of echo 29% in patients with both CAD and acute infarction on MRI, 14% with one of these, and 5% with neither (p<0.0001)
A CSE identified by echocardiography prompted initiation of anticoagulation in 2.5% subjects
Wilson, Stroke 2014 (abstract)

33. The Curve Ball Bal, Stroke 2012
Pooled data from CATCH and VISION (2 TIA/minor stroke studies from Calgary), n=333
Low risk of recurrent clinical stroke in patients with “cryptogenic” TIA or minor stroke
1.2% at 90 days
BUT – High rate of recurrent clinically silent radiographic stroke
14.5% at 90 days had new brain lesions on follow up MRI

34. Treating TIA To Prevent Stroke

35. Treating TIA Acute therapies should:
Optimize potentially compromised cerebral perfusion
Prevent progressive thrombosis
Stabilize potentially active embolic sources
Restore vessel patency if significant stenosis or occlusion present in select cases
Long-term strategies to prevent recurrent vascular events are identical to those used in patients with stroke

36. Perfusion Imaging in TIA
1/3 of TIA patients had evidence of a perfusion abnormality when scanned < 12 hours from symptom onset

37. Hospital Admission for TIA
Minimize on-going cerebral ischemia or risk of recurrent ischemia with supportive care and antithrombotic therapy
Expedite evaluation and treatment of specific mechanisms – CEA for carotid stenosis, anticoagulation for atrial fibrillation
Observation for further events, with potential expedited thrombolysis
TIA patients who have a subsequent stroke can and should be treated with IV tPA; risk of sx ICH similar to stroke patients in general (McKinney J, JSCVD 2011)
Avoid the lawyers

38. Hospital Admission for TIA: AHA Guidelines (Easton JD, Stroke 2010)
Reasonable to hospitalize patients with TIA who present within 72 hours of symptom onset and have one of the following:
a) an ABCD2 score of 3 or greater
b) an ABCD2 score of 0-2 but the diagnostic evaluation cannot be completed within 48 hours as an outpatient
c) an ABCD2 score of 0-2 and other evidence suggesting that the symptoms were caused by focal ischemia
Note: this is an eminence-based, not evidence-based guideline!

39. Acute therapy: Anticoagulation
Rationale:
Minimize thrombus propagation and distal embolization
Effective in acute coronary syndromes
Risk of hemorrhage in TIA may be lower than in stroke given lack of significant structural brain injury (in general)

40. Heparinism: Not Dead Yet?

41. Trials of heparin in TIA
Putman and Adams, Arch Neurol 1985
Small pilot trial of dose adjusted IV heparin – no control group
74 patients
7% stroke
12% bleeding complications
Biller et al, Stroke 1989
Randomized trial of aspirin vs. IV heparin
55 patients
Stroke in 1/27 patients given heparin, 4/28 given aspirin
No bleeding complications
Study too small for any meaningful statistical analysis
Keith DS, Mayo Clin Proc 1987
Retrospective study of heparin in patients with recent (< 30 days) TIA.
No significant difference in risk of stroke between 102 patients treated with heparin and 187 patients who did not receive heparin

42. Heparin in TIA: The Bottom Line
Studies have largely evaluated unselected stroke patients
Benefit would likely only be seen in patients with particular mechanisms such as large vessel stenosis
Is the risk of ICH really lower in TIA?
More data needed… ?

43. Acute Therapy: Antiplatelet Agents
Two large studies (IST, CAST) have shown benefit of aspirin in acute ischemic stroke, and extrapolation to TIA seems reasonable
Combination therapy with aspirin + clopidogrel?

45. FASTER Study Design (Kennedy J, Lancet Neuro 2007)
Minor stroke or high-risk TIA < 24 hours

46. FASTER: Results 392 patients enrolled
Aspirin plus clopidogrel vs. aspirin alone
3.7% absolute reduction in total stroke (10.8% vs. 7.1%, p=0.19)
3% absolute increase in symptomatic extra- or intracranial hemorrhage (p=0.03)
½ of bleeding events severe (ICH 1% clopidogrel vs. 0% ASA)
Statin vs. placebo
3.3% excess of stroke with simvastatin (p=0.25)

47. Minor stroke (NIHSS ≤ 3) or high-risk TIA < 24 hours
CHANCE: Study design
Minor stroke (NIHSS ≤ 3) or high-risk TIA < 24 hours

48. CHANCE: Results 5170 patients enrolled ASA + clopidogrel vs. aspirin
3.5% absolute reduction in stroke (11.7% vs. 8.2%, p<0.001)
No difference in severe bleeding (0.2% in both arms) 12
11.7%
8.2% 8
Stroke (%) 4
ASA
ASA + Clop

49. CHANCE: Results

50. Issues with CHANCE Chinese population
Different risk-factor profile
Different stroke mechanisms (intracranial stenosis highly prevalent)
Different background medical therapy (little statin use)
Lack of true aspirin loading dose in many patients?
Post-hoc analysis suggests benefit exclusively in those with intracranial stenosis

51. CHANCE: Intracranial atherosclerosis subgroup analysis
Intracranial athero present
Intracranial athero absent
Liu L, Stroke 2014 (abstract)

52. Ongoing Trials of Antiplatelet Therapy
POINT (Platelet Oriented Inhibition in New TIA) Trial
NINDS funded, RCT of aspirin + clopidogrel vs. aspirin alone
High-risk TIA (ABCD2 score  4) or minor stroke (NIHSS ≤3)
Within 12 hours of symptom onset
Primary endpoint: stroke, MI, vascular death at 90 days
Expected enrollment ~ 5800 patients
SOCRATES
Industry funded, RCT of aspirin alone vs. ticagrelor alone
High-risk TIA or minor stroke
Within 24 hours of symptom onset
Primary endpoint: stroke, MI, death at 90 days
Expected enrollment ~ 10,500 patients
TARDIS (Triple Antiplatelets for Reducing Dependency After Ischaemic Stroke)
UK gov funded, RCT of ASA + Clopidogrel + Dipyridamole vs. guideline rx
High-risk TIA or stroke
Within 48 hours of symptom onset
Primary endpoint: Functional disability at 3 months
Expected enrollment ~ 4100 patients

53. Acute therapy: carotid revascularization (Rothwell, Lancet 2004)
Clear evidence of long-term benefit for carotid endarterectomy in patients with 70-99% stenosis who have stroke or TIA referable to the stenosis
Reduced but still significant benefit in patients with 50-69% stenosis if CEA done early
Bottom line: if >50% stenosis don’t let the patient leave the hospital without CEA/CAS!

54. So… Who should we be most worried about? What should we do with them?
Those with weakness, speech difficulty, longer duration
Those with MRI DWI lesions or CT evidence of infarction
Those with large vessel stenosis
What should we do with them?
Hospital admission
Same things we do with stroke patients
? Double antiplatelet therapy
CEA with > 50% ICA stenosis
When should we do it?
ASAP

55. Probably depends on pre-test probability!
CATCH Study: Accuracy of CT/CTA and DWI for Predicting Recurrent Stroke Coutts, Stroke 2012
Sensitivity
Specificity
PPV
NPV
CT/CTA +
67%
68%
14%
96%
MR DWI+
75%
43% 9%
Probably depends on pre-test probability!
Is this high enough?

56. Ischemic stroke (NIHSS ≤ 20) within 24 hours
EARLY: Study design
Ischemic stroke (NIHSS ≤ 20) within 24 hours

57. EARLY: Results 543 patients enrolled ASA + ER-DP vs. aspirin
4% absolute reduction in non-fatal stroke (10% vs. 6%, p=0.15)
No difference in major bleeding (< 1% in both arms)

58. Pooled data from 2654 TIA patients at multiple centers
Vascular Imaging: Carotid Stenosis = Increased Stroke Risk Merwick, Lancet Neurol 2011
Pooled data from 2654 TIA patients at multiple centers
Early stroke risk post-TIA substantially ↑ with carotid stenosis ≥ 50%, even after adjustment for ABCD2 score and MR DWI
At 7 days, OR 3.3 (95% CI: , p 0.05)
At 90 days, OR 3.3 (95% CI: , p=0.006)
This may underestimate the risk of carotid stenosis
Many patients underwent CEA, thus reducing short-term stroke risk (i.e. confounding by intervention)

59. 510 TIA/minor stroke patients at single center in Calgary
Rapid Vascular Imaging Can Identify Patients at Increased Stroke Risk CATCH Study, Coutts, Stroke 2012
510 TIA/minor stroke patients at single center in Calgary
CT/CT angiography protocol
MR DWI also done in most patients
Large vessel occlusion/stenosis >50% associated with stroke progression/recurrence
Intracranial – OR 5.1 (95% CI )
Extracranial – OR 2.4 (95% CI )