1. Anthony J. Comerota, MD, FACS, FACC
Carotids
Are We There Yet?
Anthony J. Comerota, MD, FACS, FACC
Jobst Vascular Center
Toledo, Ohio USA
Adjunct Professor of Surgery,
University of Michigan

2. Anthony J. Comerota, MD, RVT
DISCLOSURES
Anthony J. Comerota, MD, RVT
Consulting Fees
Aastrom, Cook Medical, Covidien, Bristol-Myers Squibb, sanofi-aventis U.S. LLC, Talecris Biotherapeutics, Inc.
Honoraria
Bristol-Myers Squibb, Covidien, Otsuka, sanofi-aventis U.S. LLC, Servier, ZymoGenetics
Grants/Contracted Research
Aastrom Biosciences, Inc., Abbott Vascular, Baxter Healthcare, Bristol-Myers Squibb, Boehringer Ingelheim, BSN, Colorado Prevention Center, CVRx, ev3, Inc., Lombard Medical, Medtronic CardioVascular, Inc., National Institutes of Health, Pfizer, sanofi-aventis U.S. LLC, Schering-Plough Corp. / Merck & Co., Inc., Talecris Biotherapeutics, Inc.

3. Stroke
Brain Infarction
Can this be avoided?
What are the data?

4. Carotid Artery Disease

5. When should this plaque be removed?
Symptomatic Carotid Lesion
Hemispheric Stroke or TIA
Ulcer
Subintimal
Hemorrhage
When should this plaque be removed?
Luminal
Thrombus
(platelet-rich)

6. Early Carotid Endarterectomy Questions
What is the purpose of CEA?
To prevent a Stroke!
Who is at greatest risk?
Patients with symptomatic lesions, especially stroke!
When is the patient at greatest risk of stroke?
Soon after the first ischemic event!
Do we need to reassess the risk of stroke from asymptomatic carotid disease?
First Slide after Title Slide only (or first slide with title)! Use only once.
For sure!

7. Current preoccupation…
Carotid Artery Disease
Fact
Current preoccupation…
Treat vast number of ASX patients
Assume that…
All 60-99% ASX carotid stenosis identified
All Rx’ed with ≤ 2.3% procedure risk
…Outcome…
Will do little to reduce overall burden of stroke
…97% of strokes will still occur!!
Naylor AR
Eur J Vas Endovas Surg 2008;35:383

8. Risk of Stroke After TIA or Minor Stroke Recurrent Stroke
70% of strokes after
symptomatic disease
occurred within 14 days
80% of those…within 4 days
Strokes clustered soon after TIA/Stroke
Coull A et al
BMJ 2004;328:

9. Soon After The Initial Event!
Early Carotid Endarterectomy
Acute Stroke
When is the patient at higher risk for recurrence?
Soon After The Initial Event!
First Slide after Title Slide only (or first slide with title)! Use only once.

10. Symptomatic Carotid Disease Acute Stroke
Why are there proponents of delayed intervention?
Fear…
Hemorrhagic conversion…
Procedure related stroke…
First Slide after Title Slide only (or first slide with title)! Use only once.
Any Data to Justify this Fear?

11. No increased morbidity from early CEA
Early Carotid Endarterectomy
Acute Stroke
Early vs. Late
Days to CEA Stroke Rate
Whittemore et al 11 0
Rosenthal et al <3 weeks 3%
Sbarigia et al 1.5 days 0%
Alesic et al 4 days 6%
Ballotta et al <30 days 2%
Paty et al 1 week 2.8% *
First Slide after Title Slide only (or first slide with title)! Use only once.
* 3% had symptomatic deterioration but unchanged CT
No increased morbidity from early CEA

12. 228 patients with acute stroke having CEA within 4 weeks
Early Carotid Endarterectomy:21 Year Review
Acute Stroke
228 patients with acute stroke having CEA within 4 weeks
Results
Interval (weeks)
0-1*
Op stroke 2.8% 3.4% 3.4% 2.6%
First Slide after Title Slide only (or first slide with title)! Use only once.
71% op strokes due to thrombosed ICA
Only one hemorrhage
Significantly greater NIHSS score
Paty PSK, et al
J Vasc Surg 2004;39:148

13. Early Carotid Endarterectomy Ischemic Stroke: Prospective Study
96 patients having very early CEA after completed stroke
Protocol:
NIHSS ≤22
Brain infarct <2/3 MCA territory
Carotid stenosis
Mean time to CEA 1.5 days
50% within 24 hrs
98% within 1 week
60% had CT time of CEA
First Slide after Title Slide only (or first slide with title)! Use only once.
Sbargia E et al
Eur J Vasc Endovasc Surg 2006;32:22

14. 96 patients having very early CEA after completed stroke
Early Carotid Endarterectomy
Ischemic Stroke: Prospective Study
96 patients having very early CEA after completed stroke
Results
30-day morbidity/mortality 7.3%
2 deaths: Heart Failure Aspiration
Worsening neuro status 3.1%
No new infarcts on CT scan
No intracranial hemorrhage
First Slide after Title Slide only (or first slide with title)! Use only once.
Sbargia E et al
Eur J Vasc Endovasc Surg 2006;32:22

15. YES! Symptomatic Carotid Disease Consistent Observations
Delaying therapy expose patient to unnecessary risk!
No increased risk of early CEA…
Stroke
Intracranial hemorrhage
First Slide after Title Slide only (or first slide with title)! Use only once.
However…
…has risk of delayed CEA or benefit of early CEA been quantified?
YES!

16. Strokes Prevented at 5 Years
Carotid Endarterectomy Trialists Collaboration
Symptomatic Patients: NASCET & ECST
Stenosis N
CEA Risk
5 Year Risk
Surg Med
RRR
NNT
Strokes Prevented at 5 Years
(1000 CEA’s)
<30%
1746
18.4%
15.7% -
None
30-49%
1429
6.7%
22.4%
25.5%
10% 38 26
50-69%
1549
8.4%
20.0%
27.8%
28% 13 78
70-99%
1095
6.2%
17.1%
32.7%
48% 6
156
String
262
5.4%
22.3% 0%
Lancet 2004
Stroke 2004

17. Pooled data from NASCET and ECST
CEA for Symptomatic Carotid Stenosis
Timing of Procedure
Pooled data from NASCET and ECST
5,893 patients
33,000 patient years of follow-up
Benefit of CEA
Males P =0.003
Age ≥75 P =0.03
<2 weeks from event P =0.009
First Slide after Title Slide only (or first slide with title)! Use only once.
Rothewell PM et al
Lancet 2004;363:915

18. Strokes prevented at 5 years/1000CEAs Symptomatic Carotid Disease
ARR of Ipsilat Ischemic Stroke at 5yrs by CEA
Stratified by Time to Randomization
Strokes prevented at 5 years/1000CEAs
Symptomatic Carotid Disease
All 50-99% Stenosis
Time to Randomization
ARR
NNT
CVA/1000*
< 2 Weeks
18.5 5
185
2 - 4 Weeks
9.8 10 98
Weeks
5.5 18 55
> 12 Weeks
0.8
125 8
Waiting ≥ 4 weeks
reduces benefit by 70%
Naylor AR
Eur J Vas Endovas Surg 2008;35:383

19. Strokes prevented at 5 years/1000CEAs Symptomatic Carotid Disease
ARR of Ipsilat Ischemic Stroke at 5yrs by CEA
Stratified by Time to Randomization
Strokes prevented at 5 years/1000CEAs
Symptomatic Carotid Disease
All 70-99% Stenosis
Time to Randomization
ARR
NNT
CVA/1000*
< 2 Weeks
23.0 4
230
2 - 4 Weeks
15.9 6
159
Weeks
7.9 13 79
> 12 Weeks
7.4 14 74
Waiting ≥ 4 weeks
reduces benefit by 66%
Naylor AR
Eur J Vas Endovas Surg 2008;35:383

20. CEA for Symptomatic Carotid Stenosis Timing of Procedure
Pooled data from NASCET and ECST
Number of patients requiring CEA to prevent one stroke in 5 years
Subgroup NNT
CEA < 2 weeks 5
Age ≥
Males 9
Age <
Women 36
CEA at 6 weeks 62
CEA ≥12 weeks 125
No signal that hemorrhage occurred…
…only benefit to early CEA!
First Slide after Title Slide only (or first slide with title)! Use only once.
Rothewell PM et al
Lancet 2004;363:915

21. Symptomatic Carotid Disease
61 yo. man with nondisabling stroke and carotid stenosis (NASCET patient)
How long would you wish to wait after a stroke to have this lesion removed?

22. Symptomatic carotid artery disease should be treated as a
Symptomatic Carotid Disease
Symptomatic carotid artery disease should be treated as a
Vascular Emergency!

23. Non Disabling Stroke/TIA Carotid Endarterectomy (within 48 hours)
Symptomatic Carotid Disease
Non Disabling Stroke/TIA
Carotid Duplex
CT/MRI Brain
≥50% Carotid Stenosis …and… ≤67% MCA Territory Infarct
URGENT CEA PROTOCOL
• ASA 81mg • Clopidogrel 600mg
• Atorvastatin 80mg • Glucose ≤ 120
• BP ≤ 135/85
Carotid Endarterectomy (within 48 hours)

24. Asymptomatic Carotid Disease
Optimal Treatment
Question: Is risk of stroke from asymptomatic carotid disease changing?

25. Asymptomatic Carotid Artery Disease Principles of Care!
Caveat #1 Any procedure offered to patients should reduce the risk of a stroke…
… compared to best medical care.
Caveat #2 If procedure related-stroke/death is not less than best medical care… … procedure should not be performed.
Are these reasonable?

26. Treated an average of 17 years ago
ACAS: Asymptomatic Atherosclerosis
Procedure Related Stroke/Death and Stroke to 5 Years
Randomized
42 Days
5 Years
Treated an average of 17 years ago
CEA
2.3%
5.1%
MED Rx
0.4%
11.0%
JAMA 1995; 273:1421

27. 5 Year Risk of Cerebral Events RRR: Approx 30-50% for stroke endpoints
Asymptomatic Carotid Stenosis
Randomized Trials
5 Year Risk of Cerebral Events
ACAS
ACST
BMT
CEA
ARR
Ipsilat Stroke
11.0%
5.1%
5.9%
4.4%
1.1%
Any Stroke
17.5%
12.4%
11.8%
6.4%
5.4%
Major Stroke
9.1%
2.7%
6.1%
3.5%
2.6%
RRR: Approx 30-50% for stroke endpoints
Naylor A R et al
EJVES (epub 4/09)

28. 1000 CEA’s with procedural risk - 2.3%
Asymptomatic Carotid Disease
Patient Implications
1000 CEA’s with procedural risk - 2.3%
…will prevent 59 ipsilateral strokes in 5 years (according to medical risk years ago)
ACAS
JAMA 1995; 273:1421

29. Asymptomatic Carotid Disease
Observation
If it were possible to identify and operate on all asymptomatic % stenoses…
…with a procedural risk of 2.3%
…fewer than 5% of all strokes would be prevented
Naylor A R
Surgeon 2007; 5:23
Hankey G J
Med J Aust 1995; 163:197

30. Asymptomatic Carotid Disease
Randomized Trials
ACAS & ACST
Relationship of carotid stenosis to stroke
None
Benefit to women
None* *unless operative stoke/death were excluded
JAMA 1995
Lancet 2004

31. Randomized Trials: Asymptomatic Disease Risk of Stroke: Medical Care
No definition of “best medical care”
No defined pharmacotherapy
No treatment targets Therefore … this was not “best” medical Rx … … and probably not good medical Rx!

32. Asymptomatic Carotid Disease Risk of Stroke and Medical Rx
Has the risk of stroke and death from atherosclerotic carotid artery disease decreased in the past years?
…If yes, we cannot accept historical medical controls for comparators to today’s procedures.
Therefore…the current controversy regarding management of asymptomatic carotid disease

33. 135,701 Carotid Revascularizations
Carotid Procedures in the USA
2005
135,701 Carotid Revascularizations
90% CEA 92% Asymptomatic
10% CAS 8% Symptomatic
McPhee J T et al
J Vasc Surg 2005; 48:1442

34. Extrapolating ACAS to 2005 (Same Medical Risk)
Carotid Endarterectomy in the USA
Extrapolating ACAS to 2005 (Same Medical Risk)
122,986 Procedures (2.3% Procedural Risk)
7,256 Strokes Prevented at 5 Years …but Conversely
115,730 Unnecessary Procedures
21 billion dollars on unnecessary procedures
$369,685 to prevent any stroke in 5 years
McPhee J T et al
J Vasc Surg 2005; 48:1442

35. Carotid Endarterectomy in the USA
US Multistate CEA Audit
Procedural Risk (Stroke/Death) - 3.8%
“? Real-World Results”
44 ipsilateral strokes prevented per procedures at 5 years
5,411 strokes prevented from 122,986 procedures
$428,510 per stroke prevented
Based on medical Rx 20 years ago
Kresowik T F
J Vasc Surg 2004; 39:372

36. Asymptomatic Carotid Disease
What evidence is there that improvements in medical therapy are reducing the annual stroke risk?

37. Asymptomatic Carotid Disease
Randomized Trials
Best Medical Care
ACAS - No data re: Changing trends in therapy, compliance or medical outcome
ACST - Considerable data on changes in medical Rx during the 10 year trial
ie: Statins… 17% % % %
JAMA 1995
Lancet 2004

38. * = derived from oral presentations of the 10-year ACST data
Asymptomatic Carotid Disease
ACAS and ACST: Medical Care
Temporal changes in the 5-year risk of “any” stroke and “ipsilateral” stroke
Stroke
Trial
Years
Pub Year
‘Any’
‘Ipsilateral’
ACAS
1 - 5
1995
17.5%
11.0%
ACST
2004
11.8%
5.3%*
6 - 10
2009
7.2%
3.6%*
* = derived from oral presentations of the 10-year ACST data
Naylor A R
J.EJVS

39. Carotid Artery Disease Current Best Medical Care Includes:
Platelet inhibition
Statins
Ace inhibitors/ARBS
Control of hypertension
Glucose control
Diet
Exercise
Smoking cessation

40. Effects of Platelet Inhibition
Stroke and TIA
Effects of Platelet Inhibition
22% reduction of stroke/MI/death with platelet inhibition (18 trials) …32% reduction with low-dose ASA
Antiplatelet Trialists Collaboration
BMJ BMJ 2002
DYP/ASA vs. Placebo – 37% RRR of stroke DYP/ASA vs. ASA – 23% RRR of stroke
(p<.001)
(p=.006)
J Neurological Sciences 1996;143:1
Significant reduction of stroke in high risk patients with ASA/clopidogrel vs. ASA
(p=0.02)
CHARISMA Investigators
NEJM 2006;354:

41. Statins and Risk of Stroke Statins vs. Placebo
Patients
No.
F/U
RRR
Diabetics1
2,828
3.9 yrs
46%
High Risk2
20,536
5.0 yrs
25%
Calhoun HM
Lancet 2004; 364: 685
MRC/BHF HPS Investigators,
Lancet 2002; 360:7

42. Risk Reduction with Statin
SPARCL Trial
Risk Reduction with Statin
4731 stroke / TIA patients
Randomized: atorvastatin 80mg vs. placebo
Results at 4.9 years
Endpoint
RRR
P-value
Stroke (any)
Stroke/TIA
Any CV event
Major CV event
16%
35%
26%
23%
.03
<.001
SPARCL Investigators NEJM 2006;355:549

43. Suggesting Improvement in Medical Care
Asymptomatic Carotid Disease
Annual rates of “ipsilateral” and “any” stroke by date
Suggesting Improvement in Medical Care
Naylor A R
J.EJVS

44. Second Manifestation of ARTerial Disease
The SMART Study (2007)
Prospective
2684 consecutive patients
Clinical manifestations of arterial disease, or
Type II diabetes
No history of cerebral ischemia
Carotid duplex
221 (8%) ≥50% carotid stenosis
Follow-up to 5 years (mean 3.6 years)
Evaluated for ischemic events
Bertine M B et al
Stroke 2007; 38:1470

45. H R Adjusted for Age/Gender
The SMART Study
Asymptomatic Carotid Stenosis
Risk of Stroke*
H R Adjusted for Age/Gender
Degree of Stenosis
Ischemic Stroke
All Events %
0.7
1.0 %
0.6
1.4 %
Occlusion
2.6
1.5
* vs. no stenosis
Bertine M B et al
Stroke 2007; 38:1470

46. Asymptomatic Carotid Disease
SMART Study
Annual risk of “ipsilateral” or “any” stroke with % stenosis was <1%
Goessens B M B et al
Stroke 2007; 38:1470

47. Asymptomatic Carotid Disease
Future Trials
Should (must) contain a “best medical therapy” arm, with enough patients to obtain an answer.
…who will fund such trials?

48. Implications for Current Care
Asymptomatic Carotid Disease
Implications for Current Care
Require appropriate medical care…to target!
Need to select patients for CEA:
Biomarkers (hsCRP, MMPs…..)
Plaque composition
TCD - embolic signals
Contralateral symptomatic disease or occlusion

49. Limited Indication for CAS
Carotid Artery Disease
Symptomatic: - Urgent CEA
Asymptomatic: - Aggressive Medical Care
- Selective CEA
Limited Indication for CAS

50. End Slide

51. US Hospital Discharge Database
CEA vs CAS (N=135,701)
US Hospital Discharge Database
Symptomatic (N=10,495)
CEA
CAS
p-value
In-Hosp Mortality
1.4%
4.6%
0.0002
PostOp Stroke
2.5%
4.1%
0.15
LOS (Median)
4 Days
5 Days
<0.0001
Hosp Charges
$29,894
$49,535
<0.001
McPhee J T et al
JVS 2008; 48:1442

52. US Hospital Discharge Database
CEA vs CAS (N=135,701)
US Hospital Discharge Database
Asymptomatic (N=125,216)
CEA
CAS
p-value
In-Hosp Mortality
0.38%
0.57%
0.18
PostOp Stroke
0.88%
1.6%
0.001
LOS (Median)
1 Day
<0.001
Hosp Charges
$16,956
$28,853
McPhee J T et al
JVS 2008; 48:1442