1. Treatment of Asymptomatic Carotid Stenosis
Emily Pilger M.D.
Neurology Journal Club
October 28, 2008

2. Case Presentation Stroke Consult
76 year old woman on the vascular surgery service
History of hypertension and diabetes, no known prior stroke
Admitted for scheduled fem-pop bypass
Team got routine Carotid Dopplers, which showed 80-89% stenosis on the left
Stroke Consult for “neuro input” into management of her carotid stenosis

3. PICO Patient Population
In elderly women with asymptomatic carotid stenosis (≥70%)
Intervention
Is medical management
Comparison
Or CEA
Outcomes
More effective in decreasing future risk of stroke or TIA due to the carotid stenosis, taking into account the risk from the CEA itself

4. Carotid Atherosclerosis
Most frequently in the common carotid bifucation and proximal internal carotid artery. Carotid siphon (portion in the cavernous sinus) is also vulnerable.
Risk Factors: male gender, older age, smoking, hypertension, diabetes, hypercholesterolemia
May be responsible for up to 20-30% of ischemic stroke
Annual stroke rate for asymptomatic patients with hemodynamically significant carotid stensois ranges from 2-5% (13% per year for symptomatic patients)
Atherosclerotic lesions often form at branching points of arteries, regions of distrubed blood flow.
Those risk factors for carotid disease are also risk factors for stroke
Symptomatic carotid disease: stroke or TIA within the vascular distribution of the artery. May be caused by artery-to-artery emboli or low cerebral blood flow due to stenosis. Emboli from the carotid bifurcation may consist of platelet aggregates that form on irregular or ulcerated surfaces or plaque debris liberated by turbulent flow and intraplaque hemorrhage.
Clinical manifestations of carotid artery occlusion: contralateral weakness or sensory loss, expressive aphasia, and amaurosis fugax (transient partial or complete loss of vision in the ipsilateral eye, due to embolus to ophthalmic artery).

5. Diagnosis of Carotid Stenosis
Sensitivity*
Specificity*
Carotid Duplex Ultrasound
81-98%
82-89%
MRA (contrast enhanced)
93-94%
81-93%
CTA
77%
95%
Cerebral Angiography~
Ultrasound: Detects focal increases in blood flow velocity indicative of high grade carotid stenosis.
Advantage: noninvasive, safe, relatively inexpensive % sensitive, 82-89% specific in detecting a significant stenosis of the internal carotid artery, obtains information about plaque composition
Disadvantage: May miss hairline residual lumens, tends to overestimate degree of stenosis, less precise in determining stenoses of <50% compared with stenosis of higher degrees, possibly 50-69% (rarely impacts clinical utility, most patients not considered for CEA unless stenosis > or = 70%), only cervical portion of ICA evaluated (but transcranial Doppler can provide information on downstream vessels), operator dependent
MRA: 3D time of flight and contrast enhanced MRA. Sensitivity 88% and specificity 84% for 70-99% stenosis; if contrast enhanced sensitivity 93-94% and specificity 81-93% for 70-99% stenosis. Contrast enhanced MRA tends to overestimate degree of stenosis.
CTA: Sensitivity 77%, specificity 95% for diagnosis of 70-99% stenosis. Requires contrast bolus, so impaired renal function is relative contraindication
Cerebral Angiography: Gold standard. Development of intraarterial digital subtraction angiography reduces dose of contrast, uses smaller catheters, and shortens the length of procedure – although there is lower spatial resolution, DSA has largely replaced conventional angiography.
Advantage: Evaluates entire carotid artery system, showing info of tandem atherosclerotic disease, plaque morphology, and collateral circulation.
Disadvantage: Invasive, high cost, risk of morbidity and mortality (4% risk of all neurologic complications, 1% risk of serious neuro complication or death)
The absence of a bruit does not preclude the possibility of a hemodynamically significant lesion, so bruits are neither sensitive nor specific for carotid occlusive disease.
*For detecting 70-99% stenosis
~Cerebral Angiography is gold standard

6. Symptomatic Carotid Stenosis (not what we’re talking about)
NASCET Trial
Enrolled 659 patients with hemispheric or retinal TIA or nondisabling stroke within 120 days before entry, and had 70-99% stenosis in the ipsilateral carotid artery
For patients with 70-99% symptomatic carotid stenosis, average cumulative ipsilateral stroke risk at 2 years was 26% for patients treated medically and 9% for those treated medically + CEA
This correlates with a 65% relative risk reduction at 2 years favoring surgery
For patients with 50-69% symptomatic carotid stenosis, 29% relative risk reduction at 5 years favoring surgery
CEA most beneficial if performed within 2 weeks of symptom onset. More benefit in patients >75 years and men>women.
NASCET (North American Symptomatic Carotid Endarterectomy Trial)
-All patients in NASCET were given antiplatelet therapy
-For a major or fatal ipsilateral stroke, the corresponding estimates were 13.1% (medical) and 2.5% (medical +CEA).

7. VA Trial Multicenter randomized control trial 11 VA medical centers
Enrollment: April 1, 1983-September 30, 1987
Primary Objective: Compare incidence of TIA, transient monocular blindness, and stroke, in patients with asymptomatic carotid stenosis (≥50%) randomly assigned to:
Surgical Group: CEA with optimal medical management including antiplatelet therapy (ASA 650 bid)
Medical Group: Optimal medical management and antiplatelet therapy alone
Patients randomly assigned to CEA underwent the operation within 10 days of randomization
All the patients received an initial dose of ASA 650 mg bid, which was reduced to 325 mg daily for patients who could not tolerate the larger dose during subsequent clinical follow up
Once a neurologic outcome (TIA, stroke) occurred, a crossover from medical to surgical treatment was permitted.
Hobson, R.W., et.al. Efficacy of carotid endarterectomy for asymptomatic carotid stenosis. New England Journal of Medicine (4):

8. VA Trial Inclusion Criteria Adult male patient
Positive noninvasive testing for substantial stenosis (≥50%), confirmed arteriographically
Exclusion Criteria
Previous cerebral infarction, previous CEA with restenosis, previous extracranial-to-intracranial bypass
High surgical risk due to associated medical illness
Long-term anticoagulant therapy, intolerance of aspirin or long-term aspirin therapy at high dose
Life expectancy under 5 years
Surgically inaccessible lesion
Noncompliance, refusal to participate in the protocol
Noninvasive testing: ocular pneumoplethysmography and optional duplex ultrasonography
Patients who met all the medical criteria of the study were required to undergo selective carotid arteriography before randomization.

9. VA Trial Enrolled 444 patients → 211 surgical/233 medical
30 day operative mortality: 1.9% (3 deaths from MI, 1 from MI→stroke)
There were 5 nonfatal post-operative strokes (2.4% incidence) and 3 nonfatal strokes as a result of arteriography (0.4% incidence)
No significant differences in clinical characteristics of patients in surgical vs. medical group. 32% had a history of ischemic events due to contralateral stenoses, 80% of which were reported as TIA/the remainder as strokes with minimal residual neurologic deficits.
The referral of all patient to centers capable of low rates of surgical complications is essential in a plan that includes CEA with optimal medical management.
In contrast, during the first 30 days after the assignment of patients to the medical group, there was one death due to suicide (0.4%) and 2 neurologic events (0.9%) (1 permanent stroke and one TIA).
The table includes ipsilateral neurologic events. There were 65 ipsilateral neurologic events (TIA, transient monocular blindness, stroke): 12 (8%) in the surgical group and 48 (20.6%) in the medical group. The absolute reduction in risk was 12.6% and the relative risk 0.38.
Incidence of Neurologic End Points for Ipsilateral Events Only

10. VA Trial
Kaplan-Meier Curves for Event-free Rates of First Ipsilateral Stroke and TIA Including Transient Monocular Blindness
Kaplan-Meier Curves for Event-free Rates of Stroke and Death in the Surgical and Medical Groups
Figure 1. Presents the date from the table on the previous slide
Figure 2. The study patients were elderly veterans, many of whom had substantial coronary or cerebral vascular disease. There were no significant differences between groups in the incidence of stroke and death (from all causes including stroke, MI, cardiac causes, other, unknown).

11. VA Trial
Conclusions
CEA combined with optimal medical management can reduce the incidence of ipsilateral neurologic events in high-risk male patients with arteriographically confirmed asymptomatic carotid stenosis
Incidence of ipsilateral neurologic outcome events was reduced from 20.6% in medical group to 8.0% in the surgical group (p<0.001), relative risk 0.38
Although the incidence of ipsilateral stroke alone was lower in the surgical group, the combined incidence of stroke and death (post-op and all causes) showed no benefit from operation
In the presence of high mortality from other causes, it may be difficult to identify the contribution of less frequent events, such as stroke.
The incidence of ipsilateral stroke alone was 4.7% in the surgical group and 9.4% in the medical group.
Not all patients should be considered candidates for CEA-despite their higher risk of TIA and stroke, most of them will die as a result of coronary atherosclerosis.
“For example, to detect a reduction of 50% in the stroke rate in the surgical group as compared with the medical group would require more than 3000 patients – beyond the scope of any contemporary clinical trial in patients with asymptomtic carotid stenosis.” -> but this is the ACST trial
Including TIA in the analysis of neurologic outcomes is justified by their importance as indicators or predictors of stroke.
“We did not find a significant influence of CEA on the combined incidence of stroke and death, but because of the size of our sample, a modest effect could not be excluded.”

12. ACAS Prospective, multicenter, randomized trial
39 clinical sites in US and Canada
December 1987-December 1993
Primary Objective: Will CEA added to aggressive reduction of modifiable risk factors and administration of aspirin reduce the 5-year risk of ipsilateral cerebral infarction in individuals with asymptomatic hemodynamically significant carotid artery stenosis (≥60%)?
ACAS-Asymptomatic Carotid Atherosclerosis Study
Secondary Objectives: Determine the surgical success in lesion removal and the incidence of recurrent carotid stenosis, the rate of progression or regression of carotid atherosclerosis in the medically treated comparison group, and the incidence of all other vascular events such as TIA, MI, and death related to vascular disease during follow-up.
Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid stenosis. JAMA (18):

13. ACAS Inclusion Criteria Age 40-79 years
Compatible history and findings on physical and neurological examinations
Performance of required laboratory and electrocardiographic examinations no earlier than 3 months before randomization
Patient accessibility and willingness to be followed for 5 years
Valid informed consent
Exclusion Criteria
Cerebrovascular events in the distribution of the study carotid artery or in that of the vertebrobasilar arterial system
Symptoms referable to the contralateral cerebral hemisphere within the previous 45 days
Contraindication to aspirin therapy
A disorder that could seriously complicate surgery
A condition that could prevent continuing participation or was likely to produce disability or death within 5 years
ACAS definition of hemodynamically significant carotid stenosis required that at least 1 of 3 criteria was met: arteriography within the previous 60 days indicating stenosis of at least 60% reduction in diameter, Doppler examination within the preceding 60 days showing a frequency or velocity greater than the instrument specific cut point with 95% PPV, or Doppler examination showing a frequency or velocity greater than the instrument specific 90% PPV cut point confirmed by ocular pneumoplethysmographic (OPG-Gee) examination perfomred within the previous 60 days.
A patient could enter the study with unilateral or bilateral asymptomatic hemodynamically significant stenosis, but only one artery was the study artery (the one with the greatest stenosis, or the left one if identical stenosis).

14. ACAS
Medical Treatment: ASA 325 daily, risk factor modification for stroke
Surgical Treatment: Medical Treatment + CEA
All patients undergoing CEA on the basis of Doppler were required to have arteriogram prior to surgery (showing stenosis of ≥60%).
End Points:
Initially: ipsilateral TIA, stroke, or any perioperative TIA, stroke, or death
As of March 1993: restricted to stroke and perioperative complications or death
Risk factor modification included discussion of diastolic and systolic hypertension, diabetes mellitus, abnormal lipid levels, excessive consumption of EtOH, and tobacco use.
Surgical group: Scheduled to undergo CEA within 2 weeks of randomization. Asymptomatic cerebral infarction demonstarted by CT was not an exclusion for surgery. (536 baseline CTs were classified as having cerebral infarction).
The primary end point was changed as the VA trial had demonstrated that CEA is preferable to medical management for preventing TIA in asymptomatic carotid stenosis, but hadn’t resolved the issue of whether CEA prevents unheralded cerebral infarction.
The study was stopped after the eighth test (eighth pre-selected interval), when the critical value was 2.38 corresponding to a nominal significance level of

15. ACAS
Randomized 1662 patients→825 surgical/834 medical (3 lost to follow up)
Table 1
The 1659 patient were compared for 189 baseline characteristics, with only 6 tests yielding nominal statistically significant differences at the 0.05 level.
Two-thirds of the patients were men, 95% were white, and 48% were aged years. Approximately 75% had a bruit associated with the study artery, 43% had a contralateral carotid bruit. 25% had a previous hemispheric event contralateral to the study artery, and 70% were asymptomatic in the distribution of both arteries.
Of the 825 surgical patient, 101 did not have ipsilateral arteriography of CEA (45 because of patient refusal despite prior agreement to accept either treatment). Arteriograms found 33 patients to be ineligible, 6 because of intracranial abnormalities and 27 because of less than 60% carotid artery stenosis.
Of the 834 patient randomized to medical treatment, 45 received CEA without a verified ipsilateral TIA or stroke

16. ACAS
Surgical group: During the perioperative period, 2.3% had a stroke or died
Of the 414 patients who underwent arteriography prior to CEA, 5 had a cerebral infarction (1.2% complication rate, up to 2.7% complication rate if all patients received arteriography prior to CEA)
Medical group: During the comparible perioperative period, 0.4% had a stroke or died
Surgical patients: 19 (2.3%) had a stroke or died: 2 had stroke, 1 died prior to hospitalization, 5 had cerebral infarction as a direct result of arteriography, 1 of whom died. There were 10 nonfatal strokes and 1 fatal MI during the 30-day postsurgery period.
It is estimated that if all 724 patients receiving CEA had undergone arteriography as part of ACAS, the overall complication rate would have been 2.7%.
Harrisons: Nearly half of the strokes in the surgical group were caused by preoperative angiograms
It was the judgment of ACAS that the medical group should not undergo arteriography, because of the hazards and costs of the procedure.
Medical group: 2 patients had a cerebral infarction and 1 patient died

17. ACAS
The estimated 5-year risk of ipsilateral stroke and any perioperative stroke or death was 11.0% for the medical group and 5.1% for the surgical group (relative risk reduction of 53%). p value 0.004
The results for secondary end points are in the same direction although not always statistically significant
The study achieved its significance boundary after a median of 2.7 years of follow-up (only 9% completed the 5 years of follow up at term).
Because surgical patients were at greatest risk during the first month after CEA, wheras the risk for medical patients was distributed throughout 5 years, comparisons near term greatly understated the differences expected after 5 years.

18. ACAS
Figure
For the primary endpoint of ipsilateral stroke and any perioperative stroke or death, the survival curves in the figure cross near 10 months and become significantly reduced in the surgical group by 3 years (p 0.004)
Major ipsilateral stroke or any perioperative major stroke or death (p 0.12)
3. For patients with 60-69%, 70-79%, and 80-89% stenosis, there was no statistically significant gradation in redeuction of 5-year risk or primary event (but sample sizes were small).
Ipsilateral TIA or stroke or any periperative TIA or stroke or death (the original primary end point): showed a 57% reduction in 5 year risk for the surgery group (p<0.001)
Any stroke or perioperative death (p 0.09)
Any major stroke or perioperative death (p 0.26)
Any stroke or death: The surgery group had a 20% reduction in events (p 0.08)

19. ACAS
Table 5
Table 5 summarizes results for ipsilateral stroke or any perioperative stroke or death by patient subgroup.
In men, CEA reduced the 5-year event rate by 66%. In women, the event rate was reduced by 17%. Also more women had perioperative complications (3.6% vs. 1.7%)
There is a larger risk reduction due to CEA for younger patients, but the difference is not statistically significant.
There are no significant differences in primary event rates between patient groups with and without symptoms or previous CEA of the contralateral carotid artery.

20. ACAS
Conclusions
Men with a good life expectancy who have asymptomatic carotid artery stenosis (≥60%) are protected from stroke by CEA. The results for women are less certain.
Following CEA, the relative stroke risk reduction for men and women combined is 53%, with an absolute 5-year risk reduction from 11% to 5.1%.
The results are in the same direction (but not statistically significant) for all subgroups considered
The 5-year reduction in stroke risk may have been less in women because of the higher perioperative complication rate in women.
The VA trial differed from the ACAS in that only men were studied and all patients had an arteriogram. Like the VA trial, the ACAS showed an advantage for CEA in preventing TIAs, cerebral infarctions, and death in men. In addition, the ACAS showed an advantage in reducing the risk of ipsilateral stroke alone.

21. ACST
Multicenter randomized trial (per Lancet: Multicentre randomised trial)
126 hospitals in 30 countries
April 1993-July 2003
Primary Objective: Assess the net long-term effects of CEA on overall stroke risk and on fatal or disabling stroke among patients with substantial carotid artery narrowing, but with no relevant neurological symptoms in the previous 6 months
Compared immediate CEA vs. deferral of any CEA until a definite indication was thought to have arisen in patients with substantial carotid artery narrowing (≥60%)
ACST-Asymptomatic Carotid Surgery Trial
VA and ACAS trial showed significant reductions in the incidence of TIA or non-disabling stroke, but not of fatal or disabling stroke (what the ACST sets out to test)
Non-disabling stroke: after 6 months associated with modified Rankin score of 0-2 (at most only slight disability from the index stroke)
Disabling stroke: at 6 months had a score of 3-5 (at least moderate disability from the index stroke, with the need for some help in daily affairs)
Fatal stroke: caused the death of the patient either directly or by some non-neurological complication (PE, PNA)
Perioperative events: all strokes and deaths that occurred within 30 days of CEA
Immediate CEA: procedure was to be carried out routinely as soon as possible, using surgeon’s normal operative techniques.
Deferral of CEA: patient was not to be operated on unless they subsequently had carotid territory symptoms or unless some other definite indication for surgery was thought to have arisen
-Patients in both groups were to receive appropriate medical care, which generally included antiplatelet therapy, antihypertensive treatment, and, increasingly in recent years, lipid-lowering therapy.
The use of antiplatelets, antihypertensives, and lipid-lowering treatment was similar in both treatment groups, so the trial is one of surgery against a background of fairly intensive medical management for most patients.
MRC Asymptomatic Carotid Surgery Trial (ACST) Collaborative Group. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomised controlled trial. Lancet (9420):

22. ACST Inclusion Criteria
Unilateral or bilateral carotid artery stenosis that was considered to be severe (≥60% on ultrasound)
This stenosis had not caused any stroke, transient cerebral ischemia, or other relevant neurological symptoms in the past 6 months
Both doctor and patient were substantially uncertain whether to choose immediate CEA, or deferral of any CEA until a more definite need for it was thought to have arisen
The patient had no known circumstance or condition likely to preclude long-term follow-up
Exclusion Criteria
Previous ipsilateral CEA
Expectation of poor surgical risk (i.e. recent acute MI)
Some probable cardiac source of emboli
Any major life-threatening condition other than carotid stenosis
The degree of carotid artery stenosis recorded at randomisation was based on carotid duplex ultrasound (angiography was not an ACST requirement).

23. ACST 3120 patients→1560 immediate CEA/1560 deferral of CEA
Risk per CEA of perioperative stroke or death: Immediate-2.8%, Deferral 4.5%, Overall 3.1%
There were no significant difference between the initial characteristics of the two groups.
For those allocated Immediate CEA: Half had ipsilateral surgery by 1 month after randomization, 88% by 1 year, 91% by 5 years (main reason for not undergoing surgery was patient changed their mind)
Deferral CEA: About 4% per year underwent ipsilateral surgery
The differences in risk of perioperative stroke or death between immediate and deferral are not significantly different.

24. ACST
Figure 3: The main 5-year results for all strokes (including perioperative events) and for non-perioperative strokes, subdivided by the severity of storke.
3A: Any type of stroke or perioperative death: see early hazards of being allocated immediate surgery and subsequent benefits of successful surgery. Most surgical hazards occur within the first few months, after which over the next 5 years the annual stroke rate is much lower among those allocated immediate CEA. At 2 years, the lines cross, and at 5 years the absolute difference between them is highly significant. There is a highly significant net reduction in the 5-year risk of stroke or perioperative death in those allocated immediate surgery. (6.4% vs. 11.8%)
3B: Fatal or disabling stroke or perioperative death: about half the strokes involved death or disability, so the absolute risks and benefits are only about half as big as in figure 3A. The difference is still significant.
3C: Any type of non-perioperative stroke
3D: Fatal or disabling non-perioperative stroke: Half the non-perioperative strokes were disabling or fatal, so the absolute reduction in the 5-year risk of fatal disabling stroke was only half as great as in figure 3C
3E: non-perioperative carotid territory ischemic stroke
3F: fatal or disabling non-perioperative carotid territory ischemic stroke
(note: the non-perioperative carotid strokes reflect the beneficial effect of allocation to immediate CEA)

25. ACST Non-perioperative carotid stroke in 6 subgroups
4A: Men: 95 total non-perioperative carotid territory strokes (18 immediate vs. 77 deferred, p<0.0001)
4B: Women: 40 total non-perioperative carotid territory strokes (12 vs. 28, p 0.02)-so the results aren’t as definite
4C: Age <65 years: 6 vs. 33 carotid strokes
4D: Age years: 12 vs. 54 carotid strokes
-Note: The results are uncertain for those older than 74 (12 vs. 18, CI -1.9 to 8.4)
4E: Carotid diameter <80%: 2.1% vs. 9.5%
4F: Carotid diameter 80-99%: 3.2% vs. 9.6%
-Thus, the 5-year probability of a carotid stroke appeared to be about as great for those with about 70% stenosis compared to those with 80% or 90% stenosis

26. ACST
Conclusions
Among patients < 75 years of age with severe carotid stenosis (≥60%) on ultrasound but no relevant neurological symptoms, CEA approximately halved the net 5-year risk of stroke. (immediate CEA 6.4%, deferred CEA 11.8%)
The reduction in carotid stroke was separately significant for men and women, for those aged <65 and years, and for those with <80% and 80-99% carotid stenosis.
Although the overall ACAS results were less clear, particularly for fatal or disabling stroke, this probably relates to the smaller numbers of patients in ACAS and the somewhat shorter duration of follow-up.
Although the main reduction was in the risk of ipsilateral carotid stroke, contralateral carotid stroke was also highly significantly reduced, presumably through mechanisms involving collateral arterial flow within the brain (via the circle of Willis).
Those with about 70% stenosis appear to benefit about as much as those with 80-90% stenosis.

27. Summary
CEA in asymptomatic women remains particulary controversial

28. Biostatistics Tip of the Day
Intention to Treat Analysis
Based on initial treatment intent, not on the treatment eventually administered (everyone who enters the treatment is considered part of the trial, even if they drop out)
Done to avoid the effects of crossover and drop-out

29. References
Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid artery stenosis. JAMA , 273(8):
Fauci, A.S., et.al. Harrison’s Principles of Internal Medicine, 17th ed. New York: McGraw-Hill Medical, 2008.
Hobson, R.W., et.al. Efficacy of carotid endarterectomy for asymptomatic carotid stenosis. New England Journal of Medicine , 328(4):
MRC Asymptomatic Carotid Surgery Trial (ACST) Collaborative Group. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomised controlled trial , 363(9420):
Tierney, L. M., et.al. Current Medical Diagnosis and Treatment, 44th ed. New York: Lange Medical Books/McGraw-Hill, 2005.
Author. Evaluation of carotid stenosis?. UpToDate. Date.
Author. Carotid endarterectomy in symptomatic patients? UpToDate. Date

30. Thank You! Andrew Tarulli (Faculty Mentor)
Felicia Chu (Organizing Journal Club)
Neurology Residents

31. ANY QUESTIONS?