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![Page 1: Treating Asymptomatic Patients: Truth and Illusion William A. Gray MD Associate Professor of Medicine Columbia University New York.](https://reader036.fdocuments.in/reader036/viewer/2022062404/551ae84c5503465e7d8b4ae9/html5/thumbnails/1.jpg)
Treating Asymptomatic Patients: Truth and Illusion
William A. Gray MDAssociate Professor of Medicine
Columbia University New York
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Can patients with carotid stenosis be identified as at risk for stroke?
• Classically risk is assigned by:– Clinical syndrome
• Recently symptomatic >> asymptomatic
– Stenosis severity• Regardless of symptom status, risk increases with stenosis
grade
• Attempts to further stratify risk in the asymptomatic population have included:– Plaque characterization --Intracranial signaling– Cerebrovascular reserve --Clinical comorbidities
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Plaque characterization:In search of the “loaded gun”
Fat-suppressed T1 Fat-suppressed T2
Intra-plaque hemorrhage
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Perspectives on plaque characterization and stroke event prediction
• In asymptomatic carotid stenosis, per annum rates of stroke events either with natural history (~2%-4%) or post-CEA or CAS (1.0%-1.5%) low PROSPECT coronary analogue
• Any advanced plaque imaging modality with meaningful clinical utility would require a: High positive predictive value for a given marker(s) within a
clinical relevant time window
• There are currently no clinical population-based predictive data to drive decision-making based on advanced plaque characterization in asymptomatic patients
years
PROSPECT
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Conclusions regarding risk stratification of patients with asymptomatic carotid stenosis
• Additional stroke risk may predicted by: Stenosis severity Asymptomatic emboli Stenosis progression Co-morbidities: Cerebrovascular reserve -Renal insufficiency Plaque characteristics -Contralateral symptoms
• However randomized control studies to date have selected patients based on stenosis severity and symptom status, and have excluded co-morbidities. Other potential predictors of increased risk have not been
systematically studied
Most importantly, the concept of the “low risk” patient has not clearly been defined, nor identified
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What is the preferred therapy for stroke prevention for asymptomatic patients?
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The best available evidence supports revascularization as a principal treatment option
in asymptomatic patients
• Two RCTs show superiority of revascularization over medical therapy for asymptomatic patients
• Systematic review and population based studies purporting to show improvements in best medical therapy over time has significant flaws
• Claims that medical therapy has greatly reduced stroke rates can therefore only be viewed as hypothesis-generating at best, and do not supplant Tier 1 evidence showing clear patient benefits from revascularization
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Carotid endarterectomy versus medical management:Perioperative stroke or death or subsequent ipsilateral stroke
Three Positive Randomized Trials Favoring CEA
Perhaps medical therapy has improvedenough to negate that benefit
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CEA outcomes are improving
0
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ACAS 95 ACST 04 No NE VascGrp 08
NSQIP 09 CREST 10
CEA Stroke/death (%)
Current risk with CEA is half what it was in ACST Trial.
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Medical Treatment for Asymptomatic Carotid StenosisIs the current annual risk really less than 1%?
Marquardt et al. Stroke 2010
Clinical Trials
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Medical Treatment for Asymptomatic Carotid StenosisIs the current annual risk really less than 1%?
Study Reference Patients PSV DetailsSMART Goessens
Stroke 2007221 with >50% stenosis 150cm/sec Only 96 pts had
PSV >210, 7% had carotid repair
Oxford Vascular Study
MarquardtStroke 2010
101 with >50% stenosis(Only 32 with >70%)
150cm/sec Vascular death in 7.7%
ASED AbbottStroke 2005
202 with >50% stenosis 150cm/sec TCD
Patients with minimal disease generally have minimal risk of stroke
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3
Asymptomatic Internal Carotid Artery Stenosis Defined by Ultrasound and the Risk of Subsequent Stroke in the Elderly: The Cardiovascular Health Study. Longstreth et al Stroke. 29(11):2371-2376, November 1998.
5 year risk of strokeAn inflection pointat a PSV >250
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NASCET: Inzitari et al. NEJM 2000;342:1693
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The support for medical therapywithout revascularization for severe asymptomatic
carotid stenosis rests on retrospective analyses
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Significant methodological flaws with Abbott review
• Mainly based on observational data (8 of 11 studies)• Most of the asymptomatic patients in the included studies would
not be candidates for revascularization– Sixty percent (60%) of patients in the systematic review did not meet
current AHA guidelines for revascularization
• The heterogeneity of the populations across studies makes it inappropriate to include in a single analysis– Earlier studies had a higher minimum stenoses than later studies– Studies used different imaging modalities– Some studies excluded patients with any prior CV events – Some studies included patients with prior revascularizations
• Medical management was variable across studies– Not clearly adjudicated across studies – Other causes of stroke were not controlled for, such as atrial fibrillation
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Studies included in Abbott analysis are incomplete
Largest randomized trial in asymptomatic carotid disease is omitted (ACST, 1500 medically treated patients)
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Poor documentation of medical therapies, heterogeneity in populations
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Critical appraisal of Abbott analysis
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Ipsi
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eReported Ipsi. Stroke RateEarly studies drive
reported trend
Trend sensitive to effects of early studywith more complex patients
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Ipsi
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45%
50%
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80%
% S
teno
sis
Reported Ipsi. Stroke Rate
% Stenosis
The Change in Minimum Stenosis Thresholds in Studies Over Time Mirrors the Reported Decline
In Stroke Rates
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Ipsi
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Early study drives reported trend
Largest REACH study (n=3,164) not included and is contradictory
Largest and most recent REACH study (N = 3164) published after the systematic review
contradicts the review findings Aichner FT, et al. Eur J Neurol 2009; 16:902-908.
REACH3164
ACST1560
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Weighted Regression without REACH
Weighted Regression with REACH
If the systematic review’s analysis had adjusted for minimum % stenosis, or had included more recent
studies (REACH and ACST) the trend in stroke rates would have been in the opposite direction (p = 0.55)
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“CBAS should not currently undergo widespread practice, which should await results of
randomized trials.”“These and other consensus conclusions will
help physicians in all specialties deal with CBAS in a rational way rather than by being guided by
unsubstantiated claims.”
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“ Everything has been said before, but since nobody listens we have to keep going back and beginning all over again.. ”
Andre Gide, Le Traite du Narcisse 1891
Stampfer MJ et al. Prev Med. 1991 Jan;20(1):47-63.Hulley S et al. JAMA 1998;280(7):605-613
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Randomized trial data in asymptomatic patientsACST trial
• Asymptomatic patients with standard surgical risk
• Randomized trial CEA vs. non-directed medical care
• 5 year follow-up published 2004, 10 year in 2010
• Primary endpoint: Any stroke or peri-operative death
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Rate and implication of cross-over in ACST
Results are reported based on ITT analysis
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ACST 10 year outcomes:Significant and sustained benefit from revascularization
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ACST outcomes:CEA results in contralateral stroke reduction
2.2%0.7%
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ACST outcomes: More than ½ of deferred strokes are disabling
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ACST outcomes:Deferred surgery has twice the complication rates
Immediate CEA
DeferredCEA
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Significant medication penetration in ACST
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ACST:Population with lipid-lowering Rx
demonstrate continued benefit with CEA Not on lipid-lowering therapy at entry On lipid-lowering therapy at entry
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Best Medical Therapy in carotid artery disease:
what’s missing• Knowledge as to the correct “cocktail” of medication class,
specific to carotid-related targets– What is “Best Medical Therapy”?
• What BP med? What target BP? • Which lipid med? What target lipid levels? For LDL? For HDL?• How do we improve smoking cessation rates?
• Measures and assurances of compliance and side effect issues– NHANES reports <25% patients achieve BP goal
• Randomized data showing equivalence or superiority to revascularization in asymptomatic severe carotid stenosis
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What role does CAS play in the asymptomatic patient?
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CAS in the asymptomatic patient
• There are no randomized outcome data for CAS vs. medical therapy in the asymptomatic (or symptomatic) patient
• CAS has been compared only to the established standard of care, CEA
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In a combination of symptomatic and asymptomatic patients, there are no differences in outcome for CAS and CEA
CREST
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Periprocedural outcomes in CREST:No difference between CAS and CEA for Asx
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q23eq
Comparison HR
HR Confiden
ce Interval
Log Rank
P-value
MI vs. Control 2.81[1.53 - 5.17] 0.0005
Minor Stroke vs. Control 0.52
[0.13 – 2.09] 0.34
MI vs. Minor Stroke 5.18[1.15 – 23.4] 0.02
Long-term mortality is predicted by MINo association with minor stroke but strong
association with MI
Gray et al. Circulation. In press
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CASN = 1,131
CEAN = 1,176 p-value
Procedure related cranial nerve injury 0.0% 5.3%
(62/1176) <0.0001
Unresolved at one month 0.0% 3.6%
(42/1176) <0.0001
Unresolved at six months 0.0% 2.1%
(25/1176) <0.0001
CREST:Fate of CEA cranial nerve injury
Gray et al. Circulation 2012
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Per Protocol CASN = 1,131
CEAN = 1,176 p-value
Access Site Complication Requiring Treatment 1.1% 3.7% 0.0001
Events may occur more than once in the same patient.Other includes pain requiring IV analgesics (5), incision complication (3), pseudoaneurysm (2), occlusion (1)
5 5
02 1
20
57
0
11
2
17
0
5
10
15
20
25
Hematoma Bleeding Infection Occlusion Other
Coun
t
CASCEA
Patients requiring re-operation
Gray et al. Circulation 2012
CREST:Access complications greater with CEA
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N=4282
2.91.1 0.8 0.6
1.8
012345678
Death/Stroke Death/Major Stroke Death Stroke Minor (1.8%)Stroke Major (0.6%)
(%) S
ubje
cts
EXACT/CAPTURE 2 (combined): 30-day major adverse events asymptomatic patients <80 years
Hierarchical- Includes only the most serious event for each patient and includes only each patient first occurrence of each event.
3% AHA guideline
CAS achieves AHA guidelines in asymptomatic patientsLarge, prospective, multicenter neurologically-audited/independent
adjudication single arm studies in high-surgical risk patients
Gray et al. Circ Cardiovasc Interv. 2009 Jun;2(3):159-66
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CAPTURE 2: Asymptomatic <80 y.o. patients
N=137230 day stroke/death distribution by site
No stroke or death in 81% (134/166) of sites
Gray et al. JACC Cardiovasc Interv. 2011 Feb;4(2):235-46
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CAS outcome improvement
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2011 Multi-Society Guideline Document
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Revascularization of asymptomatic stenosis
recommendation grade guideline
Selection of asympt pts for car revasc should be guided by an assessment of comorb cond, life expectancy….and …disc of risks+ benefits of the proc w… understanding of patient preferences
I, LoE C AHA 2011
It is reasonable to perform CEA in asymptomatic pts with a >70% ICA stenosis if the risk of periop stroke, MI, and death is low.
IIa, LoE A AHA 2011
In asympt pts w car sten ≥60%, CEA should be considered as long as the stroke/death rate is <3% and patient’s life expectancy > 5y
IIa, LoE A ESC 2011
Prophylactic CAS might be consid in highly selected pts w asympt car sten, its effectiveness comp w med ther is not .. established
IIb, LoE B AHA 2011
In asympt pts …, CAS may be considered as an alternative to CEA in high-volume centres (death/stroke rate <3%)
IIb, LoE B ESC 2011
Should be consideredbenefit >>risk, class IIa
Strongly recommendedbenefit >>>risk, class I
Might/may be consideredbenefit >/=risk, class IIb
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CREST 2
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• To assess if contemporary REVASCULARIZATION, either CAS or CEA, provides an incremental benefit of 1.2% annual risk reduction over contemporary medical therapy
CREST 2: Primary Aim
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• The primary outcome will be the classical composite of stroke or death within 30 days of enrollment or ipsilateral stroke up to 4-years thereafter.
CREST 2: Primary outcome
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• Sample size ~2000 participants at approximately 70 centers.
• Statistical power will be ~ 90% to detect a 4.8% treatment difference (1.2% per year)
CREST 2: Key design elements
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After randomization, the CAS and CEA groups imbedded in
the REVASC and MEDICAL arms will allow randomized-
protected comparisons of CEA-intended and CAS-intended patients to the
MEDICAL patients.
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Managing patients with asymptomatic carotid stenosis: Summary
• Asymptomatic carotid stenosis is a risk factor for stroke
• Surgical revascularization therapy is proven beneficial vs. unmonitored (but probably real world) medical therapy
• CAS outcomes have demonstrated similar outcomes to CEA (CREST), achieved AHA guidelines, and now is Class 2b recommendation in asymptomatic patients (CEA Class 2a)
• The role of medical therapy remains a tantalizing but unproven alternative to revascularization in patients with established severe carotid stenosis. Until such time as this benefit is demonstrated to be superior, the
available randomized controlled data support revascularization in suitable patients
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Final perspectives on CEA, CAS and Best Medical Therapy
• CEA, CAS and medical therapy likely have all had outcome improvements over the past couple of decades
• They have will likely have complementary, not competitive roles in the patient requiring revascularization, and the judicious and selective use of these therapies can result in overall improved patient outcomes:– Fewer strokes, fewer MI’s – Less disability and less CV mortality
• Defining the comparative outcomes between CAS and CEA is still pending the dedicated study that ASCT2 represents
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Patient level (ACST) cost-effectiveness analysis for carotid revascularization
0 1 2 3 4 50
1
2
3
ACST
Contemporaryevent rates
£10, 000 per QALY
£30, 000 per QALY
£20, 000 per QALY
Less cost-effective
More cost-effective
Peri-operative stroke or death / %
An
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te /
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Ankur Thapar: Imperial College, London