SAMMPRIS Trial Update.ppt

“ Update on SAMMPRIS Trial - Angioplasty / Stenting vs. Medical Therapy for Symptomatic Intracranial Arterial Stenosis ” Marc I. Chimowitz, MBChB Professor of Neurology Associate Dean for Faculty Development Medical University of South Carolina Charleston, SC

Disclosures
Dr. Chimowitz is the recipient of research funding from the NIH / NINDS for a K24 award, the WASID trial, the NIH multi-center intracranial stenting registry, and the randomized trial of stenting vs. medical therapy (SAMMPRIS trial) which is ongoing
Bayer and Bristol-Myers Squibb supplied aspirin, warfarin, and placebos for WASID trial but no other support
Boston Scientific is providing Wingspan stent system for SAMMPRIS trial and support for 3 rd party monitoring of the trial but no other financial support of SAMMPRIS
AstraZeneca 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 WASID Aspirin Events / 100 pt.yrs Warfarin Events/100 pt.yrs p-value Major Hem. 1.8 4.4 0.01 Death 2.4 5.2 0.02

Primary Endpoint Stroke and Vascular Death Aspirin Warfarin # of Patients 280 289 # Patients with Event 62 ( 22%) 63 (22%) 1yr / 2yr rates 15 / 21 17 / 22 Log-Rank p - value 0.83 Hazard Ratio (95% CI) 1.04 (0.73 – 1.48)

Primary Endpoint Stroke and Vascular Death Probability of Stroke / Vascular Death p = 0.82

WASID: Ischemic Stroke In Territory of Symptomatic Artery Aspirin Warfarin # of Patients 280 289 # Patients with Event 42 (15%) 35 (12%) 1yr / 2yr rates 12 / 15 11 / 13 Log-Rank p – value 0.31 Hazard Ratio (95% CI) 1.26 (0.81 – 1.97)

What has been the Impact of WASID on Clinical Practice? ** aspirin used most commonly 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%

Impact of Risk Factor Management On Outcome in Patients with Intracranial Stenosis

Achievement of Target Levels (Baseline to Year 2, n=229) *p<0.05, ** p<0.01, *** p<0.001, **** Diabetic patients only Risk Factor Baseline Year 2 SBP < 140 mm Hg 55% 53% MAP < 107 mm Hg 84% 82% Cholesterol < 200 mg/dl 55% 79% *** LDL < 100 mg/dl 29% 56% *** LDL < 70 mg/dl 9% 10% HDL ≥ 40 mg/dl 64% 63% Ratio < 4.4 47% 66% *** Triglyceride < 200 mg/dl 79% 76% Hgb A1C ≤ 7% **** 32% 52% * Not Smoking 80% 84% * Alcohol use 45% 37% *

Risk Factors Associated with Ischemic Stroke in WASID Risk Factor (RF) Event Rate + RF Event Rate - RF Hazard Rate, P-value SBP > 140 23% 15% 1.6 (1.1-2.4) P=0.012 MAP > 107 38% 15% 2.8 (1.9, 4.3) P<0.0001

Cumulative Incidence of Ischemic Stroke in the Territory of the Stenotic Artery According to Mean Systolic Blood Pressure (SBP) Turan et al. Circulation 2007 P<0.0065

Risk Factors Associated with Ischemic Stroke in WASID Risk Factor (RF) Event Rate + RF Event Rate - RF Hazard Rate, P-value Cholesterol > 200 23% 12% 2.1 (1.4-3.1) P=0.0006 LDL > 100 19% 12% 1.7 (1.04-2.9) P=0.033 LDL > 70 17% 7% 2.3 (0.6-9.4), p= 0.23 HDL < 40 19% 15% 1.3 (0.8-2.0) P=0.23 Triglyceride > 200 20% 15% 1.4 (0.9-2.2) P=0.15

WASID Risk Factor Data Summary
Poorly controlled hypertension and elevated LDL associated with significantly higher rates of major vascular events
Implications:
1. Aggressive management of these risk factors in particular should be part of treatment
2. Don’t maintain higher B.P. in patients with intracranial stenosis during follow-up “to avoid hypoperfusion”

January 31, 2006

Baseline Factors-Multivariate Analysis Characteristic Hazard Ratio (95% CI) p–value % Stenosis (≥70% vs <70%) 2.34 (1.46 – 3.75) 0.0004 Qualifying Event to Enrollment (≤17 days vs >17 days) 1.71 (1.06 – 2.76) 0.03 NIH Stroke Scale (> 1 vs ≤ 1) 2.17 (1.27 – 3.72) 0.005 Gender (Female vs Male) 1.61 (1.00 – 2.58) 0.05

Severity of Stenosis and Risk of Stroke WASID Stroke in the Territory 1 year rate > 70% stenosis = 18% Vs. < 70% stenosis = 7-8%

Combining 70-99% Stenosis and Time from Qualifying Event to Enrollment 1 year 2 year  30 days 22.9 % (95% CI 15.4 – 30.4%) 25% (95% CI 17.2% - 32.9%) > 30 days 9% (95% CI 2.1 – 16.0%) 9% (95% CI 2.1 – 16.0%)

Should antithrombotic “failure” be required before considering more aggressive therapy such as stenting? Turan et al. Stroke 2009 Practice of waiting for antithrombotic “failure” before considering more aggressive Rx may not be prudent Stroke or Vascular Death over mean f/u of 1.8 yrs On antithrombotic at Q.E. in WASID 21% No antithrombotic at Q.E in WASID 23%

Is There a Role for Angioplasty or Stenting?

Endovascular Therapy
Angioplasty alone
Angioplasty and Stenting
Balloon Expandable Stents
Self-expanding Stent

Angioplasty
No prospective studies
No multi-center Phase I trials
Single center case series, sometimes combined
No endpoint evaluation by neurologists
High technical success (~ 95%), relatively atraumatic, safe BUT:
elastic recoil (> 50% residual stenosis post PTA) in ~ 50%, dissection in ~20%, stroke or death within 30 days: 4-40%, re-stenosis in 24-40%

Balloon-Mounted Coronary Stents
Small single center studies, all the methodological flaws of angioplasty studies
Single step procedure with excellent immediate post-treatment results, BUT
Rigid delivery system that is challenging to deliver through tortuous intracranial vasculature and high pressure, non-compliant deployment
>>> more traumatic delivery than TPA alone
High rates (20-30%) of peri-procedural complications and restenosis in some series
Fiorella et al., Neurosurgery 2007

Balloon-Mounted Intracranial Stents
Pharos stent
Small Latin Amercian and European series (n=32, n=21) *;
No prospective Phase I trials
Ongoing randomized trial
* Fretas et al. Surg Neurol 2007
Kurre et al. Neurorad 2008

Self-Expanding Intracranial Stents
Hybrid strategy: flexible devices with conservative PTA, stent to avoid recoil
Phase I clinical trial >>> FDA approval under HDE Nov 2005, Subsequently:
Two large multicenter registries of Wingspan stent
Extensive post-marketing clinical experience with Wingspan in USA (> 5000 patients treated)

Intracranial Stenting Registry Results in Patients with 70-99% Stenosis 4-Center Registry (n = 158 ) NIH Wingspan registry (n = 129 ) Patient Characteristics 50-99% stenosis (2/3 > 70%) and TIA / stroke on Rx 70-99% stenosis and TIA / stroke on Rx Technical Success 98.8% 96.7% (91.8 – 99.1% Stroke or death rates: 24 hours 30 days + ipsilat stroke at 6 months - 6.1% - 6.2% (3.2 – 12%) 9.6% (5.6 – 16.3%) 14% (8.7 – 22.1%) > 50% restenosis 30% 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 Against Medical Therapy?
We don’t know!!
Comparisons to outcome in WASID have been done by both Wingspan registry study groups but NOT scientifically valid:
- not concurrent controls
- baseline risk factors different
- definitions of events different
- no independent evaluation by neurologists
- medical treatments different
- 95% confidence intervals ignored
- 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 Pell BMJ VOLUME 327 20–27 DECEMBER 2003 Abstract Conclusions: 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”

SAMMPRIS Trial S tenting and A ggressive M edical M anagement for P reventing R ecurrent stroke in I ntracranial S tenosis An Investigator-initiated and Designed NIH / NINDS Funded Trial

SAMMPRIS Study Design Stenting (Wingspan) + Aggressive Medical Management vs. Aggressive Medical Management alone -

Aggressive Medical Management
Identical in both arms:
Aspirin 325 mg / day for entire follow-up
Clopidogrel 75mg per day for 90 days
Aggressive, protocol driven risk factor management primarily targeting blood pressure < 140 / 90 mm Hg (130 / 80 diabetics) and low density cholesterol
< 70 mg / dl
4 . A 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 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

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SAMMPRIS Trial Update.ppt

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