Management of Asymptomatic Carotid Stenosis …...Management of Asymptomatic Carotid Stenosis Medical Friedlander v. Wechsler Making an Asymptomatic Patient Better “The physician

Management of Asymptomatic Carotid Stenosis

Medical v. Surgical

Friedlander v. Wechsler

Management of Asymptomatic Carotid Stenosis

Medical

Friedlander v. Wechsler

Making an Asymptomatic Patient Better

“The physician must be able to tell the antecedents, know the present, and foretell the future — must mediate these things, and have two special objects in view with regard to disease, namely, to do good or to do no harm.” Hippocrates: Of the Epidemics

CEA for Symptomatic Stenosis - NASCET

Barnett et al. NEJM 1998

Surgical

Medical

Years

CEA for Asymptomatic Stenosis - ACST

1 2 3 4 50Years

ACST Lancet 2004

Asymptomatic Stenosis RCTs:CEA v. Medical Therapy

Years Pts F/UStr-Dth/Yr

MedStr-Dth/Yr

Surg ARR / Yr

VACS 1983-1987 444 4 yrs 2.4%* 1.2%* 1.2%*

ACAS 1987-1993 1659 5 yrs 2.2% 1% 1.2%

ACST 1993-2003 3120 5 yrs 2.4% 1.3 1.1%

* ipsilateral nonfatal and fatal stroke

Hobson et al. NEJM 1993; ACAS JAMA 1995; ACST Lancet 2004

Stent v. CEA Randomized Trials

Study Year Pts Stenosis Endpoint CEA Stent

SAPPHIRE 2004 334 Sx >50% and Asx >80%

MACE 30d + Ips str 1yr 9.8% 4.8%

EVA-3S 2006 527 Sx 60-99% Str/Dth 30 d 3.9% 9.6%

SPACE 2006 1183 Sx 70-99% Ips Str/Dth 30 d 6.3% 6.8%

ICSS 2010 1713 Sx 50-99% Str/Dth/MI 120 d 5.2% 8.5%

CREST Study Design Prospective, multicenter, randomized, controlled trial

with blinded endpoint adjudication

Comparing CEA and CAS in conventional risk patients with > 50% symptomatic or > 70% asymptomatic stenosis (> 70% by US or CTA)

108 US and 9 Canadian sites

Primary endpoint: Periprocedural stroke, MI, death and any ipsilateral stroke up to 4 years

Surgeons and interventionalists carefully screened by expert committee

CREST Results

CAS CEA HR 95% CI P Value

Primary Endpoint < 4 yrs* 7.2% 6.8% 1.11 0.81-1.51 0.51

Periprocedural Stroke 4.1% 2.3% 1.79 1.14-2.82 0.01

Periprocedural MI 1.1% 2.3% 0.50 0.26-0.94 0.03

Major Stroke 0.9% 0.6% 1.35 0.54-3.36 0.52

Ipsilateral Stroke up to 4 yrs 2.0% 2.4% 0.94 0.50-1.76 0.85

* Any periprocedural stroke, MI, death plus ipsilateral stroke thereafter

Brott et al. NEJM 2010

CREST Results:Symptomatic v. Asymptomatic

CAS CEA HR 95% CI P Value

Primary Endpoint < 4 yrs*

Symptomatic 8.6% 8.4% 1.08 0.74-1.59 0.69

Asymptomatic 5.6% 4.9% 1.17 0.69-1.98 0.56

Periprocedural Stroke/Death

Symptomatic 6.0% 3.2% 1.89 1.11-3.21 0.02

Asymptomatic 2.5% 1.4% 1.88 0.79-4.42 0.15

Periprocedural Stroke

Symptomatic 5.5% 3.2% 1.74 1.02-2.98 0.04

Asymptomatic 2.5% 1.4% 1.88 0.79-4.42 0.15

Periprocedural MI

Symptomatic 1.0% 2.3% 0.45 0.18-1.11 0.08

Asymptomatic 1.2% 2.2% 0.55 0.22-1.38 0.20

* Any periprocedural stroke, MI, death plus ipsilateral stroke thereafter

Brott et al. NEJM 2010

CREST CEA v. Stent by Age

0

1

2

3

4

40 50 60 70 80 90

Haza

rd R

atio

Age (Years)

Pinteraction = 0.020

CEA Superior

CAS Superior

Primary outcome – 4 year

Improved Outcomes with Medical Therapy

Old Results New Results

Asymptomatic stenosisACAS - 1995 2.2% stroke / yrACST - 2004: 2.2% stroke / yr

Goessens - 2007: 0.8% stroke / yrAbbott - 2005: 1% stroke / yr

Intracranial stenosisHistorical controls before 2005: 10.7% stroke and death in first 30 days

SAMMPRIS - 20115.8% stroke and death at 30 days with intensive medical therapy

DesmoteplaseDIAS I – 200522% favorable outcome

DIAS II – 200946% favorable outcome

Intracerebral hemorrhagerFVIIa phase IIb - 2005Poor outcome (mRS 5,6) 45%

FAST – 2008Poor outcome (mRS 5,6) 24%

IV tPA > 3 hrsATLANTIS – 1999mRS < 1 40%

ECASS III – 2008mRS < 1 45%

Should we revascularize any patients with asymptomatic stenosis?

ACST – Medical Therapy

Halliday et al. Lancet 2010

20

60

80

40

100

Stroke Risk in Medically Treated PatientsACAS and ACST

Trial Yrs Followup Yr Published Any Stroke (%) Ipsil Stroke (%)

ACAS 1-5 1995 17.5 (3.5%) 11.0 (2.2%)

ACST 1-5 2004 11.8 (2.4%) 5.3 (1.1%)

ACST 6-10 2009 7.2 (1.4%) 3.6 (0.7%)

ACAS. JAMA 1995; Haliday et al. Lancet 2004; Halliday et al Lancet 2010

Oxford Vascular StudyStroke Risk with > 50% Carotid Stenosis

Event Number % / yr

Ipsilateral minor stroke 1 0.34%

Ipsilateral major stroke 0 0%

TIA 5 1.78%

• Population based study of 1153 pts with stroke or TIA recruited between 2002 – 2009• All pts treated with intensive medical therapy – AP, statins, BP reduction, lifestyle changes• 101 (8.8%) with > 50% asymptomatic stenosis• Mean followup 3 years

Marquardt et al. Stroke 2010

Subgroup Stroke Risk in ACAS and ACST

No benefit of CEA in females No benefit in patients > 75 yrs

(ACST) No relationship between

severity of stenosis and stroke risk

No increased risk with contralateral occlusion

A.R. Naylor. Nat Rev. Cardiol 2012

CREST 2

Randomized trial of IMT + carotid revascularization v. IMT alone

Asymptomatic, conventional risk patients with > 60% stenosis by angio or > 70% by US

2 parallel trials: CEA + IMT v. IMT and CAS +IMT v. IMT

IMT similar to SAMMPRIS NIH funded

(n = 1,240 in each trial)

S = ScreenedR = Randomized

Intensive Medical Therapy: Antiplatelets

Patients in both trials will take 325 mg ASA daily

CAS patients will also take clopidogrel at least 30 days and per protocol

Preoperative ASA + statin load

(CEA) Dual antiplatelets +

statin load (CAS)

Risk Factor Goal Measurement

Primary Risk Factors

LDL < 70 mg/dL Local lab

Systolic BP < 140 mm Hg Measured each visit

Secondary Risk Factors

Non-HDL < 100 mg/dL Local lab

HgA1c < 7.0% Local lab

Smoking Cessation Self

Weight management BMI <25 kg/mm2 or 10% Weight at each visit

Exercise > 30 min 3 X per week Self

Intensive Medical Therapy

Lifestyle management and cardiovascular disease risk reduction program.

Incorporates SAMMPRIS targets and national guidelines.

Provides individualized risk factor counseling telephone sessions at regular intervals: twice a month for 12 weeks. monthly thereafter.

Case Managers at INTERVENT call center, Savannah, GA.

INTERVENT – Lifestyle Coaching

Design Patients Stenosis Endpoint Results

ACT 1 CEA v. CAS 1454 Asx 70-99%MACE 30 days + Ips str 1 yr

CAS noninferior to

CEA

ACST 2 CEA v. CAS 3600 (1915) Asx 60-99%MACE 30 days + Ips str 5 yrs

3424/3600

SPACE 2CEA or CAS v.

BMT3272 (500) Asx 70-99%

Str/Dth 30 days + Ips str 5

yrsHalted

ECST 2

CEA+OMT v. OMT

CAS+OMT v. OMT

2000Non high risk Sx or Asx 50-

99%

Str/Dth 30 days + any

stroke 5 yrsOngoing

CEA / CAS RCTs

CAS CEA p

ACT I – Primary Endpoint(Str, MI, Dth 30d, ipsil str 1yr) 3.8% 3.4% 0.011

CREST – Primary Endpoint (Str, MI, Dth 30d, ipsil str 4yrs) 5.6% 4.9% 0.562

ACT I – 30 d Stroke, MI, Death 3.3% 2.6% 0.60

CREST – 30 d Stroke, MI, Death 3.5% 3.6% 0.96

ACT I – 30 d Stroke, Death 2.9% 1.7% 0.33

CREST – 30 d Stroke, Death 2.5% 1.4% 0.15

Are Procedures Getting Better?ACT I (2016) v. CREST Asymptomatic (2010)

1 1-sided non-inferiority test2 2-sided superiority test

CREST – 1181 Asx pts: 594 CAS, 587 CEAACT I – 1453 Asx pts: 1089 CAS, 364 CEA

Rosenfield et al. NEJM 2016; Brott et al NEJM 2010

Are there “High Risk” Asymptomatic Lesions?

Stenosis severity Progression Silent infarcts Clinical features Ultrasound Plaque morphology MRI CT

Spence et al. Arch Neurol 2010; Saba et al. Lancet Neurol 2019; Naylor. Nat Rev. Cardiol 2012

MRI

CT

Summary Benefit of CEA for

asymptomatic carotid stenosis in prior RCTs marginal

Stenting and CEA equally effective or ineffective

Medical therapy has changed since RCTs and recent reports suggest lower stroke rates with medical therapy

CREST 2 addressing question of benefit of revascularization v. medical therapy in asymptomatic stenosis with modern medical management