MANAGEMENT OF ASYMPTOMATIC CAROTID STENOSIS Thomas C. Hammond M.D., FAAN UCNS certified in Neuroimaging Marcus Neuroscience Institute, Boca Raton, Florida STROKE TRIVIA: Which one of these men will die from a stroke? Winston Churchill, Franklin D. Roosevelt, and Joseph Stalin at Yalta Conference in February 1945 N Engl J Med 1995 ; 332 : 1038
WORLD LEADERS FROM YALTA CONFERENCE Winston Churchill died 1/24/1965 age 90yo Cause of death: Stroke 15 days prior Joseph Stalin died 3/5/1953 age 74yo Cause of death: Stroke TYPES OF STROKE Subarachnoid
Albers GW, et al. Chest. 2004;126:483S512S. STROKE CLASSIFICATION LARGE VESSEL ATHEROSCLEROTIC DISEASE C. Miller Fisher in the 1950s described the role of carotid plaque in TIA and stroke. Until then 55% of
strokes were attributed to vasospasm. First CEA performed in 1953, by Dr. Michael DeBakey SYMPTOMATIC CAROTID STENOSIS THE NASCET TRIAL Published in the NEJM August,1991, North American Stroke and Carotid Endarterectomy Trial, started in 1987 Lead investigator H.J.M. Barnett (ran the 1st study that proved aspirin prevents stroke, and the failed extra cranial intracranial bypass trial)
Rationale: in 1985 107,000 carotid endarterectomies in U.S. with uncertain benefit from the procedure 662 patient with symptomatic high grade carotid stenosis enrolled to receive CEA or optimal medical therapy Medical therapy: aspirin 1300 mg daily (lower if side effects) and as indicated antihypertensive, anti-lipid, and anti-diabetic therapy (no strict targets for medical therapy) Early termination of trial in patients with stenosis greater than 70% due to evidence of treatment efficacy in the CEA group. The stroke risk in first 24 months was 26% for medical and 9% for surgical therapy (NNT was 6 to prevent 1 stroke) Benefit was higher for higher grade of stenosis. LESSONS FROM NASCET TRIAL
Definition of symptomatic vs asymptomatic carotid stenosis Symptomatic Carotid stenosis defined as : 1.) A hemispheric transient neurologic deficit (an episode of distinct focal neurologic dysfunction). Or a non-disabling stroke with unilateral motor, or sensory disturbance, or aphasia. Must be in territory of the carotid stenosis. 2.) Transient monocular blindness persisting for less than 24 hours in the appropriate carotid territory 3.) Vertebral/basilar TIA symptoms were excluded 4.) Symptoms have occurred in the past 120 days (some studies have extended this to 180 days). Symptoms must have occurred in the past 4 6 months to be considered as symptomatic carotid stenosis
to 5.) Symptoms occurring beyond 6 months ago do not count as Symptomatic, those patients re-enter the asymptomatic carotid stenosis pool. We have no evidence base to prove similar benefit for CEA or CAS in this group LESSONS FROM NASCET TRIAL November, 1998 follow-up review on the moderate stenosis (50-69%) group NEJM
Benefit from CEA was less robust with less severe stenosis. Observational period extended to 5 years to demonstrate benefit. After 5 years 22.2 % stroke rate in medical group vs 15.7% in surgical group (NNT 15 to prevent 1 stroke over 5 years) Subgroup analysis indicates gender differences with negligible benefit in women in this moderate stenosis group (NNT 67 or higher). Women have lower 5 year stroke risk than men (15% compared with 25%) and higher surgical risk Lipid lowering drugs were given in 16% of medical and 13% of the surgical patients, optimum medical therapy was suboptimal by current standards Less than 50% stenosis showed no benefit from CEA. CEA timing: should be > 2 days and < 2 weeks after symptom occurred for best results Current Guideline recommendations: CEA be considered in men and medical Rx in
women with symptomatic stenosis 50-69% Note: patients > 80yo were excluded, Moderate to severe strokes were excluded, Surgeons in NASCET were top performers (surgical risk of stroke or death 2%) SYMPTOMATIC CAROTID ARTERY STENOSIS Carotid stenting (CAS) now available as alternative to CEA, multiple studies, meta-analysis shows that CAS is associated with increasing procedural stroke risk in a linear fashion with patient age. CAS is superior in <70 yo, CEA in >70yo patients International Stroke conference in Ft Lauderdale 2001, Dr. H. J. Barnett presented study on CEA in elderly > 80 yo with symptomatic stenosis, NNT is 3 patients to
prevent 1 stroke (very effective in this group) Optimal medical therapy in all major CEA trials was suboptimal by current standards. Now medical management includes aggressive lipid lowering with intensive statin use, aggressive BP management with a high percentage of patients meeting BP goals of systolic BP <140, and more aggressive diabetic management, as well as lifestyle modifications with exercise and dietary regimens. The symptomatic intra-cranial stenosis trials, WASID and SAMMPRIS showed a marked reduction in stroke in the medical arm when aggressive medical management was applied. The importance of aggressive medical management is even more significant in patients with asymptomatic carotid stenosis
SYMPTOMATIC EXTRACRANIAL AND INTRACRANIAL STENOSIS TRIALS Retinal TIA (TMB/amaurosis fugax) vs hemispheric TIA is less ominous. In NASCET medical arm 3year stroke rate following TMB was the rate following a hemispheric TIA. WASID trial (2005): warfarin vs aspirin in severe intracranial disease was terminated early after 18 months due to increased complications of bleeding and MI/sudden death and vascular death in the warfarin group (doubled). The 2 year rate of ischemic stroke was a dismal 19.7% in the aspirin group (1300 mg/day). Indicating this is a very high risk disease SAMMPRIS trial (9/2011): percutaneous transluminal angioplasty and stenting (PTAS)
for intracranial stenosis compared with intensive medical management. Trial terminated due to high 30 day stroke or death rate in the PTAS group. 1 year stroke rate in medical arm was significantly better than projected (due to more aggressive medical therapy) Optimal medical therapy (OMT): intensive statin target LDL<70, BP multidrug regimen target systolic BP<140 (DM patients <130). Dual or mono antiplatelet Rx, lifestyle changes (30% quit smoking, doubled moderate/vigorous exercise, weight reduction) SAMMPRIS used lifestyle modification MANAGEMENT OF ASYMPTOMATIC CAROTID STENOSIS (N0 SYMPTOMS IN THE PAST 6 MONTHS REFERABLE TO THE VASCULAR LESION)
Carotid stenosis does not cause vertigo, lightheadedness, or syncope (these symptoms are not to be considered as symptoms of carotid stenosis) Prevalence of asymptomatic carotid stenosis (>50%) is low in the general population. Prevalence rates for men and women over 80yo = 7.5% and 5% respectively. Ipsilateral stroke rate currently estimated at 0.5 to 1.0 % per year Major trials (VA, ACAS, and ACST) did not use
optimal medical therapy, so benefit from surgical intervention is overestimated. Systematic review of prospective data have shown annual stroke rates in patients with carotid stenosis have dropped significantly since the 1980s and 1990s. Most CEA surgeries in U.S. are for asymptomatic disease Asymptomatic carotid stenosis is a marker for increased MI and vascular death ASYMPTOMATIC CAROTID STENOSIS
TRIALS VA trial (1993): 444 men, included TIA or stroke as a primary endpoint, confusing outcome data. There was a small absolute risk reduction (ARR) of 1% over 4 years, many problems with this trial Asymptomatic Carotid Atherosclerosis Study (ACAS,1995): 1662 patients, any ipsilateral stroke after 5 years: 5% in the CEA group 11 % in the medical group (47% decrease). However, major stroke was not significantly different (3.6% to 6%). Gender differences were evident, ARR in men 8% in women 1.4%. No clear benefit for women. Based on ACAS, CEA for asymptomatic disease increased in the U.S. (more than of the surgeries)
Asymptomatic Carotid Stenosis trial (ACST 2003) European trial, 3120 patients, benefit similar to ACAS, women showed some benefit but much less benefit than men ASYMPTOMATIC CAROTID STENOSIS NATURAL HISTORY Annual risk for stroke for asymptomatic stenosis in ACAS and ACST was 2-3% This high rate would likely make revascularization a reasonable choice However, recent evidence suggests that with optimal medical therapy the natural history of carotid stenosis has significantly improved In 2004, 5yr data from ACST medical arm 11.8% any stroke risk (2.4%/yr), in 2010 follow up data medical arm 7.2% any stroke risk (1.4%/yr);
ipsilateral stroke risk was 3.6% (0.7%/yr) Several meta-analysis evaluations have indicated that with OMT the annual stroke risk for asymptomatic stenosis is <1% Long term study of carotid stenosis progression showed marked improvement with high dose statin therapy over prior standard care There is a need for studies comparing OMT with CAS or CEA in this disease, the CREST 2 trial has an OMT treatment arm as does the SPACE2 trial ASYMPTOMATIC CAROTID STENOSIS WHO IS AT HIGH RISK Clinical Features: male sex, current smoking, history of TIA opposite side
Stenosis severity: in the 60-90% range higher grade stenosis was not a predictor of future events in ACAS or ASCT, collateral flow compensation is important Progression of stenosis was found to be a predictor of stroke, progression of at least one grade (eg from 70% to 80%) doubles the stroke risk. Progressive stenosis is a reason to operate. Plaque characteristics: using CUS echolucent (lipid rich) plaque higher stroke risk than fibrotic/echodense plaque (3% vs 0.6%), plaque ulceration also increases stroke risk. MRI detection of intraplaque hemorrhage also increases stroke risk. CAROTID PLAQUE ECHOLUCENCY: HIGHER RISK FOR STROKE
MRI PLAQUE HEMORRHAGE ASYMPTOMATIC CAROTID STENOSIS WHO IS AT HIGH RISK Silent emboli: progressive stenosis and high risk plaque imaging features identify unstable plaque which is more prone to produce athero-embolic events. Look for silent embolic events on imaging. Silent ipsilateral embolic infarcts on MRI or CT Brain imaging, subcortical and cortical infarcts felt to be more likely embolic. Better seen on MRI FLAIR (DWI only positive acutely). A number of studies have shown an association between ACS and the prevalence of silent cerebral infarcts. In the ACSRS study 821 patients had a baseline CT brain, annual stroke rate was 3.6% when
silent strokes were evident at baseline compared with 1% in those with no silent strokes. Many patients have hypertension, diabetes, and hyperlipidemia which leads to small vessel lipohyalinosis and occlusion of small vessels. Not all of the small infarcts are due to carotid plaque embolization TRANSCRANIAL DOPPLER (TCD) ASYMPTOMATIC CAROTID STENOSIS, HIGH RISK Silent emboli: progressive stenosis and high risk plaque imaging features identify unstable plaque which is more prone to produce athero-embolic events. Look for silent embolic using Transcranial Doppler (TCD) for emboli
detection. Asymptomatic Carotid Emboli Study (ACES) from Lancet, 2010; 482 patients with ACS underwent 6 monthly TCDs. The annual risk of ipsilateral stroke was 3.62% with micro-embolic signals, 0.7% in those without micro- emboli. A meta-analysis of six studies with TCD (1,144 patients) showed higher risk of ipsilateral stroke in those with microemboli (HR 6.6%). Most patients in these trials with micro-emboli were still stroke free at 3 years so specificity for stand alone use is lacking. A negative TCD for micro-emboli is associated with an extremely low risk for subsequent stroke.
ASYMPTOMATIC CAROTID STENOSIS, HIGH RISK Assess Cerebrovascular reserve; look for collateral flow Absence of a complete Circle of Willis, absent posterior communicating arteries (isolated anterior and posterior circulation), or absent of anterior communicating artery. Intra cranial stenosis on either side Contralateral extra cranial stenosis Vertebrobasilar stenosis All of the above may decrease cerebral perfusion pressure and increase likelihood of a carotid arterial embolus causing a stroke TCD assessment of MCA flow velocities (can assess cerebral blood flow
reserve with hyperventilation, inhaled CO2, or acetazolamide) Get MRA brain (non-contrast)to evaluate intracranial circulation ASYMPTOMATIC CAROTID STENOSIS WOMEN Women under represented in most trials of CEA and CAS ACAS and ACST trials both showed benefit for men not clearly beneficial for women (none in ACAS , minimal benefit in ACST) Women had higher peri-operative events than men in those trials(not so in the more recent CREST trial) It appears that women with asymptomatic carotid stenosis derive less benefit from revascularization. Current trials such as CREST 2, and SPACE 2 will be focusing more on this gender difference. Surgical or interventional mortality/morbidity must be low and < 3%
(need experienced surgeons and interventionalists) or benefit is lost. In women the vessels are smaller and often more tortuous so intervention is more treacherous. ASYMPTOMATIC CAROTID STENOSIS IN THE ELDERLY CEA is Controversial in the Elderly patient since the benefit statistically takes 5 years to manifest in both ACAS and ACST trials. ACAS trial did not enroll patients over 75 yo ACST trial did not demonstrate a benefit for those over 75 yo (not a prespecified endpoint) Given longer life expectancy, age cannot be an absolute contraindication Based on the CREST data CAS is not advisable in the Elderly with worse outcomes than CEA in patients over 70 yo.
Poorer outcomes with CAS likely due to increased tortuosity of vessels and increased calcified plaque disease with aging. However, the more recent CAS studies are showing improving outcomes with better distal embolization protection. ROADSTER trial is doing CAS via cut down and direct carotid access to minimize the micro-emboli from the aortic arch catheter navigation ASYMPTOMATIC CAROTID STENOSIS SUMMARY Medical and Surgical or Interventional arms of therapy for this condition are evolving and high
improving and stroke risk is declining. Asymptomatic disease does not carry the risk for stroke that symptomatic disease carries Uncertainty remains as to the best treatment and it must be individualized for each patient We await the results from CREST 2 and SPACE 2 which have OMT compared with CEA or CAS (those trial will finish in 3-5 years) Serial CUS are needed, and CEA or CAS should be offered to patients with stenosis >70% who show Progression of stenosis All patients should be on OMT AHA/ASA Guidelines (2014): every one gets OMT, It is reasonable to consider
performing CEA for stenosis >70%, if the peri-operative risk of stroke/death/MI is <3%., peri-operative and post-operative aspirin use recommended. More data needed but TCD emboli detection and MRI showing intraplaque hemorrhage can be helpful in choosing the higher risk patients, look at collateral flow and cerebral reserve. Elderly (>80yo)and life expectancy < 5 years, OMT is most reasonable; if intervention deemed reasonable then CEA appears safer than CAS in this group
IV preparation effective in 50% to restore SR in PAF. Trials were started on oral agent but currently no further development. Restoration of sinus. Efficacy vs side effects. Benefit compared with placebo. Withdrawal due to adverse events. Safety first.
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