“Update on SAMMPRIS Trial -Angioplasty / Stenting vs. Medical

Therapy for Symptomatic Intracranial Arterial Stenosis”

“Update on SAMMPRIS Trial -Angioplasty / Stenting vs. Medical

Therapy for Symptomatic Intracranial Arterial Stenosis”

Marc I. Chimowitz, MBChBProfessor of Neurology

Associate Dean for Faculty DevelopmentMedical University of South Carolina

Charleston, SC

DisclosuresDisclosures

Dr. Chimowitz is the recipient of research funding from the Dr. Chimowitz is the recipient of research funding from the NIH / NINDS for a K24 award, the WASID trial, the NIH multi-NIH / NINDS for a K24 award, the WASID trial, the NIH multi-center intracranial stenting registry, and the randomized trial of center intracranial stenting registry, and the randomized trial of stenting vs. medical therapy (SAMMPRIS trial) which is stenting vs. medical therapy (SAMMPRIS trial) which is ongoingongoing

Bayer and Bristol-Myers Squibb supplied aspirin, warfarin, and Bayer and Bristol-Myers Squibb supplied aspirin, warfarin, and placebos for WASID trial but no other supportplacebos for WASID trial but no other support

Boston Scientific is providing Wingspan stent system for Boston Scientific is providing Wingspan stent system for SAMMPRIS trial and support for 3SAMMPRIS trial and support for 3rdrd party monitoring of the trial party monitoring of the trial but no other financial support of SAMMPRISbut no other financial support of SAMMPRIS

AstraZeneca providing Crestor (rosuvastatin) for SAMMPRISAstraZeneca providing Crestor (rosuvastatin) for SAMMPRIS

90% stenosis

Copyright © 2000 American Academy of Neurology

Volume 55(4)             22 August 2000             p 465

Best treatment for intracranial arterial stenosis?:

50 years of uncertainty

Benesch, Curtis G. MD, MPH; Chimowitz, Marc I. MB, ChB; for the WASID Investigators

Major Hemorrhages and Death in WASIDMajor Hemorrhages and Death in WASID

AspirinAspirin

Events / 100 Events / 100 pt.yrspt.yrs

WarfarinWarfarin

Events/100 Events/100 pt.yrspt.yrs

p-p-valuevalue

Major Hem.Major Hem. 1.81.8 4.44.4 0.010.01

DeathDeath 2.42.4 5.25.2 0.020.02

Primary EndpointPrimary EndpointStrokeStroke and Vascular Deathand Vascular Death

AspirinAspirin WarfarinWarfarin

# of Patients# of Patients 280280 289289

# Patients with Event# Patients with Event 62 ( 22%)62 ( 22%) 63 (22%)63 (22%)

1yr / 2yr rates1yr / 2yr rates 15 / 21 15 / 21 17 / 2217 / 22

Log-Rank p - valueLog-Rank p - value 0.830.83

Hazard Ratio (95% CI)Hazard Ratio (95% CI) 1.04 (0.73 – 1.48)1.04 (0.73 – 1.48)

Primary EndpointPrimary Endpoint

Stroke and Vascular DeathStroke and Vascular Death

0

0.1

0.2

0.3

0.4

0 1 2 3 4 5

Years after Enrollment

Aspirin

Warfarin

Pro

bab

ilit

y o

f S

tro

ke /

Vas

cula

r D

eath

p = 0.82

WASID: Ischemic Stroke In WASID: Ischemic Stroke In Territory of Symptomatic ArteryTerritory of Symptomatic Artery

AspirinAspirin WarfarinWarfarin

# of Patients# of Patients 280280 289289

# Patients with Event# Patients with Event 42 (15%)42 (15%) 35 (12%)35 (12%)

1yr / 2yr rates1yr / 2yr rates 12 / 15 12 / 15 11 / 1311 / 13

Log-Rank p – valueLog-Rank p – value 0.310.31

Hazard Ratio (95% CI)Hazard Ratio (95% CI) 1.26 (0.81 – 1.97)1.26 (0.81 – 1.97)

What has been the Impact of WASID on Clinical Practice?

U.S. Stroke Neurologists

(n=170)

Preferred Rx MCA or Siphon

Warfarin

Antiplatelet**

Combination

Pre / Post

43% / 7%

44% / 86%

12% / 3%

Preferred Rx Vert. or Basilar

Warfarin

Antiplatelet**

Combination

Pre / Post

50% / 15%

37% / 74%

12% / 6%** aspirin used most

commonly

Impact of Risk Factor Management On Outcome in Patients with Intracranial

Stenosis

Achievement of Target LevelsAchievement of Target Levels(Baseline to Year 2, n=229)(Baseline to Year 2, n=229)

Risk FactorRisk Factor BaselineBaseline Year 2Year 2

SBP < 140 mm HgSBP < 140 mm Hg 55%55% 53%53%

MAP < 107 mm HgMAP < 107 mm Hg 84%84% 82%82%

Cholesterol < 200 mg/dlCholesterol < 200 mg/dl 55%55% 79% ***79% ***

LDL < 100 mg/dlLDL < 100 mg/dl 29%29% 56% ***56% ***

LDL < 70 mg/dlLDL < 70 mg/dl 9%9% 10% 10%

HDL HDL ≥ 40 mg/dl≥ 40 mg/dl 64%64% 63% 63%

Ratio < 4.4Ratio < 4.4 47%47% 66% ***66% ***

Triglyceride < 200 mg/dlTriglyceride < 200 mg/dl 79%79% 76%76%

Hgb A1C Hgb A1C ≤ 7% ****≤ 7% **** 32%32% 52% *52% *

Not SmokingNot Smoking 80%80% 84% *84% *

Alcohol useAlcohol use 45%45% 37% *37% *

*p<0.05, ** p<0.01, *** p<0.001, **** Diabetic patients only

Risk Factors Associated with Risk Factors Associated with Ischemic Stroke in WASID Ischemic Stroke in WASID

Risk FactorRisk Factor

(RF)(RF)

Event Rate Event Rate

+ RF + RF

Event RateEvent Rate

- RF- RF

Hazard Rate, Hazard Rate,

P-valueP-value

SBP SBP >> 140 140 23%23% 15%15% 1.6 (1.1-2.4)1.6 (1.1-2.4)

P=0.012P=0.012

MAP MAP >> 107 107 38%38% 15%15% 2.8 (1.9, 4.3)2.8 (1.9, 4.3)

P<0.0001P<0.0001

Cumulative Incidence of Ischemic Stroke in the Cumulative Incidence of Ischemic Stroke in the Territory of the Stenotic Artery According to Mean Territory of the Stenotic Artery According to Mean

Systolic Blood Pressure (SBP)Systolic Blood Pressure (SBP)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 1 2 3 4 5

Follow-up (yrs)

<120

120-139

140-159

160+

`

Turan et al. Circulation 2007 P<0.0065

Risk Factors Associated with Risk Factors Associated with Ischemic Stroke in WASIDIschemic Stroke in WASID

Risk FactorRisk Factor

(RF)(RF)

Event Rate Event Rate

+ RF + RF

Event RateEvent Rate

- RF- RF

Hazard Rate, Hazard Rate,

P-valueP-value

Cholesterol Cholesterol >> 200200

23%23% 12%12% 2.1 (1.4-3.1)2.1 (1.4-3.1)

P=0.0006P=0.0006

LDL LDL >> 100 100 19%19% 12%12% 1.7 (1.04-2.9)1.7 (1.04-2.9)

P=0.033P=0.033

LDL LDL >> 70 70 17%17% 7%7% 2.3 (0.6-9.4), 2.3 (0.6-9.4), p= 0.23p= 0.23

HDL < 40HDL < 40 19%19% 15%15% 1.3 (0.8-2.0)1.3 (0.8-2.0)

P=0.23P=0.23

Triglyceride Triglyceride >> 200200

20%20% 15%15% 1.4 (0.9-2.2)1.4 (0.9-2.2)

P=0.15P=0.15

WASID Risk Factor Data SummaryWASID Risk Factor Data Summary

Poorly controlled hypertension and elevated LDL Poorly controlled hypertension and elevated LDL associated with significantly higher rates of major associated with significantly higher rates of major vascular eventsvascular events

Implications: Implications:

1. Aggressive management of these risk factors in 1. Aggressive management of these risk factors in particular should be part of treatmentparticular should be part of treatment

2. Don’t maintain higher B.P. in patients with 2. Don’t maintain higher B.P. in patients with intracranial stenosis during follow-up “to avoid intracranial stenosis during follow-up “to avoid hypoperfusion”hypoperfusion”

January 31, 2006

Baseline Factors-Multivariate Baseline Factors-Multivariate AnalysisAnalysis

CharacteristicCharacteristic Hazard Ratio Hazard Ratio (95% CI)(95% CI) p–valuep–value

% Stenosis (≥70% vs <70%)% Stenosis (≥70% vs <70%) 2.34 (1.46 – 2.34 (1.46 – 3.75)3.75)

0.00040.0004

Qualifying Event to Qualifying Event to Enrollment Enrollment (≤17 days vs >17 days)(≤17 days vs >17 days)

1.71 (1.06 – 1.71 (1.06 – 2.76)2.76)

0.030.03

NIH Stroke Scale (> 1 vs ≤ 1)NIH Stroke Scale (> 1 vs ≤ 1) 2.17 (1.27 – 2.17 (1.27 – 3.72)3.72)

0.0050.005

Gender (Female vs Male)Gender (Female vs Male) 1.61 (1.00 – 1.61 (1.00 – 2.58)2.58)

0.050.05

Severity of Stenosis and Risk of StrokeSeverity of Stenosis and Risk of Stroke

WASID Stroke in the Territory1 year rate

>70% stenosis = 18%Vs.

< 70% stenosis = 7-8%

Combining 70-99% Stenosis and Time from Qualifying Event to Enrollment

1 year1 year 2 year2 year

30 30 daysdays

22.9 % 22.9 %

(95% CI 15.4 – 30.4%) (95% CI 15.4 – 30.4%)

25% 25%

(95% CI 17.2% - (95% CI 17.2% - 32.9%)32.9%)

> 30 days> 30 days

9% 9%

(95% CI 2.1 – 16.0%) (95% CI 2.1 – 16.0%)

9% 9%

(95% CI 2.1 – 16.0%) (95% CI 2.1 – 16.0%)

Should antithrombotic “failure” be required before Should antithrombotic “failure” be required before considering more aggressive therapy such as considering more aggressive therapy such as

stenting? stenting?

Stroke or Vascular Death Stroke or Vascular Death over mean f/u of 1.8 yrsover mean f/u of 1.8 yrs

On antithrombotic at Q.E. On antithrombotic at Q.E. in WASIDin WASID

21% 21%

No antithrombotic at Q.E in No antithrombotic at Q.E in WASIDWASID

23%23%

Turan et al. Stroke 2009

Practice of waiting for antithrombotic “failure” before considering more

aggressive Rx may not be prudent

Is There a Role for Angioplasty or Stenting?

Endovascular TherapyEndovascular Therapy

Angioplasty aloneAngioplasty alone

Angioplasty and StentingAngioplasty and Stenting

– Balloon Expandable StentsBalloon Expandable Stents

– Self-expanding StentSelf-expanding Stent

AngioplastyAngioplasty

No prospective studiesNo prospective studies

No multi-center Phase I trials No multi-center Phase I trials

Single center case series, sometimes combinedSingle center case series, sometimes combined

No endpoint evaluation by neurologistsNo endpoint evaluation by neurologists

High technical success (~ 95%), relatively High technical success (~ 95%), relatively atraumatic, safe BUT:atraumatic, safe BUT:

elastic recoil (> 50% residual stenosis post PTA) elastic recoil (> 50% residual stenosis post PTA) in ~ 50%, dissection in ~20%, stroke or death in ~ 50%, dissection in ~20%, stroke or death within 30 days: 4-40%, re-stenosis in 24-40% within 30 days: 4-40%, re-stenosis in 24-40%

Balloon-Mounted Coronary StentsBalloon-Mounted Coronary Stents

Small single center studies, all the methodological Small single center studies, all the methodological flaws of angioplasty studiesflaws of angioplasty studiesSingle step procedure with excellent immediate Single step procedure with excellent immediate post-treatment results, BUTpost-treatment results, BUTRigid delivery system that is challenging to deliver Rigid delivery system that is challenging to deliver through tortuous intracranial vasculature through tortuous intracranial vasculature andand high high pressure, non-compliant deploymentpressure, non-compliant deployment >>> more traumatic delivery than TPA alone>>> more traumatic delivery than TPA aloneHigh rates (20-30%) of peri-procedural High rates (20-30%) of peri-procedural complications and restenosis in some series complications and restenosis in some series

Fiorella et al., Fiorella et al., NeurosurgeryNeurosurgery 2007 2007

Balloon-Mounted Intracranial StentsBalloon-Mounted Intracranial Stents

Pharos stentSmall Latin Amercian and European series (n=32, n=21) *; No prospective Phase I trialsOngoing randomized trial

* Fretas et al. Surg Neurol 2007 Kurre et al. Neurorad 2008

Self-Expanding Intracranial StentsSelf-Expanding Intracranial Stents

Hybrid strategy: flexible devices with Hybrid strategy: flexible devices with conservative PTA, stent to avoid recoilconservative PTA, stent to avoid recoil

Phase I clinical trial >>> FDA approval under Phase I clinical trial >>> FDA approval under HDE Nov 2005, Subsequently:HDE Nov 2005, Subsequently:

Two large multicenter registries of Wingspan Two large multicenter registries of Wingspan stent stent

Extensive post-marketing clinical experience Extensive post-marketing clinical experience with Wingspan in USA (> 5000 patients treated)with Wingspan in USA (> 5000 patients treated)

Wingspan European / Asian Multicenter Phase I Trial

• 45 patients with symptomatic intracranial arterial stenosis (50-99%)

• Technical success: 98%

• Stroke or death within 30 days: 4.4% (0.5%-15.2%)

• Ipsilateral stroke or death 1 year: 9.3% (2.6-22.1%)

• Restenosis > 50% at 6 months: 7.5% (1.6%-20.4%)

Intracranial Stenting Registry Results inPatients with 70-99% Stenosis

4-Center Registry4-Center Registry

(n = 158 )(n = 158 )

NIH Wingspan NIH Wingspan registryregistry

(n = 129 )(n = 129 )

Patient Patient CharacteristicsCharacteristics

50-99% stenosis (2/3 50-99% stenosis (2/3 >> 70%) and TIA / 70%) and TIA /

stroke on Rxstroke on Rx

70-99% stenosis and 70-99% stenosis and TIA / stroke on RxTIA / stroke on Rx

Technical SuccessTechnical Success 98.8%98.8% 96.7% (91.8 – 99.1%96.7% (91.8 – 99.1%

Stroke or death rates:Stroke or death rates:

24 hours24 hours

30 days30 days

+ ipsilat stroke at 6 + ipsilat stroke at 6 months months

- -

6.1%6.1%

--

6.2% (3.2 – 12%)6.2% (3.2 – 12%)

9.6% (5.6 – 16.3%)9.6% (5.6 – 16.3%)

14% (8.7 – 22.1%)14% (8.7 – 22.1%)

>> 50% restenosis 50% restenosis 30%30% 25% 25%

Impact of Operator’s Experience

> 10 patients – High Enrolling, < 10 patients – Low Enrolling

Kaplan-Meier curves for the 2 groups were significantly different

(HR Low / High = 2.9, 95% CI 1.1 to 7.8; P =0.022)

Center Primary Endpoint (PE) Rate at 24 hr.

95% CI PE Rate at 30 days

95% CI PE Rate at 6 months

95% CI

High Enrolling

3.2% 1.0% -9.6% 6.8% 3.1% -14.5% 9.5% 4.9% to 18.3%

Low Enrolling

14.3% 6.2% -31.0% 17.2% 8.1% -34.4% 26.9% 13.8% to 48.5%

How Does Wingspan Stack Up How Does Wingspan Stack Up Against Medical Therapy?Against Medical Therapy?

We don’t know!! We don’t know!! Comparisons to outcome in WASID have been done by Comparisons to outcome in WASID have been done by both Wingspan registry study groups but NOT both Wingspan registry study groups but NOT scientifically valid:scientifically valid:

- not concurrent controls- not concurrent controls- baseline risk factors different- baseline risk factors different- definitions of events different- definitions of events different- no independent evaluation by neurologists- no independent evaluation by neurologists- medical treatments different- medical treatments different- 95% confidence intervals ignored- 95% confidence intervals ignored- not compared with aggressive medical therapy- not compared with aggressive medical therapy

Parachute Use to Prevent Death and Major Trauma Related to Gravitational

Challenge: Systematic Review of Randomized Controlled Trials

Gordon C S Smith, Jill P PellBMJ VOLUME 327 20–27 DECEMBER 2003

AbstractConclusions: We think that everyone might benefit if the most radical protagonists of evidence-based medicine organized and participated in a double blind, randomised, placebo-controlled, crossover trial of the parachute.

Parachutes’ effectiveness has not been proven with

randomised controlled trials.

Hippocrates (460 – 357 B.C.)

“To know is one thing, merely to believe one knows is another. To know is science, but merely to believe one knows is ignorance”

Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial

Stenosis

An Investigator-initiated and Designed NIH / NINDS Funded Trial

SAMMPRIS Trial

SAMMPRIS Study Design

Stenting (Wingspan) + Aggressive Medical Management

vs.

Aggressive Medical Management alone

-

Aggressive Medical ManagementAggressive Medical Management

Identical in both arms: Identical in both arms:

1.1. Aspirin 325 mg / day for entire follow-upAspirin 325 mg / day for entire follow-up2.2. Clopidogrel 75mg per day for 90 daysClopidogrel 75mg per day for 90 days3.3. Aggressive, protocol driven risk factor Aggressive, protocol driven risk factor

management primarily targeting blood management primarily targeting blood pressure < 140 / 90 mm Hg (130 / 80 pressure < 140 / 90 mm Hg (130 / 80 diabetics) and low density cholesterol diabetics) and low density cholesterol < 70 mg / dl< 70 mg / dl

44.. A lifestyle modification programA lifestyle modification program

SAMMPRIS Hypothesis

Compared with aggressive medical therapy alone, intracranial stenting combined with aggressive medical therapy will decrease the risk of the primary endpoint * by 35% over a mean follow-up of two years in high-risk** patients with symptomatic stenosis of a major intracranial artery.

* Any stroke or death within 30 days of enrollment or revascularization during follow-up OR stroke in the territory of the stenotic / stented artery beyond 30 days

** Patients with 70-99% stenosis and TIA or stroke within 30 days prior to enrollment. NOT required to have failed antithrombotic therapy.

Modeled after CREST

Candidate interventionalists submitted procedure note and documentation of outcome from last 20 consecutive intracranial angioplasty and stent cases

Order of preference– Wingspan – Neuroform for atherosclerosis– Coronary stents for atherosclerosis– Angioplasty for atherosclerosis– Neuroform for aneurysm

SAMMPRIS Credentialing: Methods

Post enrollment:

All Adverse events reviewed by stenting safety monitor

All procedure notes not associated with A/E reviewed by Dr. Fiorella or Derdeyn

SAMMPRIS Credentialing

Sample Size and Participating Sites

N = 764 (382 in each arm)

Enrollment began end of November 2008

Currently 49 active sites

www.SAMMPRIS.org – list of sites and

incl / excl. criteria

Top 10 Recruiting SitesTop 10 Recruiting Sites

Site (Neurointerventional PI) n

Oregon (Barnwell) 16

Buffalo (Levy) 13

UT Southwestern (Pride) 10

Methodist Houston (Klucznik) 10

U. Florida (Hoh) 10

Wayne State (Xavier *) 9

U. Alabama (Harrigan) 9

Barrow (McDougall) 9

Medical Coll. Wisconsin (Zaidat *) 8

Cleveland Clinic (Gupta *) 8

SAMMPRIS Executive Committee

Neurointerventional PIs: Colin Derdeyn MD, Dave Fiorella MD PhD

Statistical PI: Mike Lynn MS

Risk Factor Management: Tanya Turan MD

Project Manager: Bethany Lane BSN, RN

NIH Project Manager: Scott Janis PhD

SAMMPRIS SITES