Do we need more Carotid Trials after Crest to convince CMS Mark Wholey M.D.UPMC Shadyside Hospt..

Mark H. Wholey, MD Consulting Fees Abbott Vascular Medrad, Inc. Cordis Corporation Covidien AccessClosure, Inc. Ownership Interest (Stocks, Stock Options or Ownership Interest)

Board Membership CarMell Therapeutics NIT

New Carotid Trials are Dead in the Water If not dead then seriously questioned Mark Wholey M.D. UPMC Shadyside,,Vascular Surgery

Do we need more trials since we have: Experience with 45,000 patients 33 US Registries 8 Randomized CAS Clinical Trials 15 years of Experience with CAS . 4O years of Experience with CEA .15 Years without reimbursement

MAE in high risk carotid stent IDE trials: 2002-2009 (n>4000) 11 device approval trials: all approved …and rapidly improving outcomes MAE in high risk carotid stent IDE trials: 2002-2009 (n>4000)

Remarkable data for latest devices: all-comers N>1000 patients Lumen/Invatec Fibernet (2008) 30 day MAE: 3.0% WL Gore Flow Reversal System (2008) 30 day MAE: 2.9% Abbott Vascular Gen V Emboshield (2008) 30 day MAE: 1.8% Invatec ARMOUR (2009) 30 day MAE: 2.7% (More experienced operators and better patient selection

CAS is technology dependent and continual improvement in stent design and embolic protection will occur.

Major Strokes less than 1% in both arms Cranial nerve palsy 4% CEA .3% CAS

CREST CEA CAS Myocardial infarction 2.3% 1.1% Strokes 2.3% 4.1 % Major Strokes <1% <1% Cranial Nerve Palsy 4% .3%

The rate of stroke and death in the surgical group was the lowest ever reported in a large stroke prevention trial. It was also the lowest in any RCT with CAS.

NIH News 2-16-10 One of the largest stroke prevention trials ever (2502 patients). Efficacy and safety of the two procedures largely the same with equal benefits.

T. Brott, P.I. for CREST “Crest results show we have two safe and effective methods to treat carotid artery disease, tried and true CEA and the new kid on the block CAS.”

Too Long String Sign Mobile Clot Too Tortuous The carotid trials; Stenting patients who should not have been enrolled Dangerous Common Carotid Too Long String Sign Mobile Clot Too Tortuous

PROBLEMS of the aortic arch Complexities of the aortic arc are responsible for almost all technical failures More Trouble Ideal Trouble

Everybody makes mistakes

Eva-3s trial Prospective, randomized trial 257 CEA 247 CSA 20 academic and 10 non-academic centers in France Symptomatic >60% stenosis Stroke, death (6 months) CEA 6.1% CSA 11.7% OR 2.0 Trial stopped for both safety issues and futility NEJM 2006;355:1660-71

Space trial 1200 Symptomatic Pts randomized to CEA vs CAS Primary endpoint: stroke, death at 30-days: 6.84% CAS VS. 6.34% CEA (p=0.09) Failed to prove Non-inferiority of CAS RESTENOSIS Most cases occurred within first 6 Mos. 28 Cases CAS vs. 12 CEA Lancet 2006;368:1239-1247

International Carotid Stent Study (ICSS) Largely UK effort Randomized 1710 symptomatic patients to either CEA or CAS 3 year primary endpoint: fatal or disabling stroke in any territory Interim analysis published in Lancet 120 day death, stroke, or MI CEA operators: >50 operations/>10 per year CAS operators: >50 stent procedures (anywhere), 10 lifetime CAS cases---fellow-level experience Inexperienced operators had to complete 20 randomized cases satisfactorily to be released

ICSS: further observations Very low rate of MI in both groups suggests that they weren’t routinely assessed (unclear from Methods) Embolic protection not mandated and choose whatever stent you want Major stroke was ~2% in each group, double what is seen in US (One operator ,enrolled 11 pts and 5 disabling strokes) Poorly trained operators getting poor results

We Need More Carotid Trials before We Decide CEA vs. Stenting in symptomatic octogenarians CEA vs. Stenting in asymptomatic octogenarians CEA vs. Stenting in symptomatic low risk patients CEA vs. Stenting in asymptomatic low risk patients CEA vs. Stenting in patients with prior CVA CEA vs. Stenting in African Americans Stenting vs. optimal medical therapy in asymptomatic high risk patients CEA vs. Medical management in transatlantic vs. transpacific Tacit vs Pacit Stenting with Bivalurudin vs. Heparin Stenting with femoral access vs. radial access Stenting with 300 mg loading dose of Clopidrogel vs. 600 mg Stenting with 24 observation in the hospital vs. same day discharge Stenting in smaller community hospital vs. tertiary care center Stenting with your left hand vs. your right hand This Nonsense is Over

THE CAROTID TRIALS WHEN IS ENOUGH, ENOUGH?

No one is willing fund additional Carotid Trials? Volatile U.S. equity markets Eurozone sovereign debt with Ireland, Greece,Spain and Portugal almost bankrupt Japan bear market for 20 years.

Industry will not fund these trials? . Absent re-imbursement Rejection by CMS – in spite of results Regulatory and FDA approval issues have been a constant battle. Why sould they ; CAS has been a loser

P.T. Barnum said “There’s a sucker born every minute.” Further investing in carotid trials is a suckers game

1. A Billionaire that wants to become a Millionaire So who will invest in CAROTID TRIALS without reimbursement ? Some sucker or someone stupid enough to do it. 1. A Billionaire that wants to become a Millionaire 2.Maybe Bernie Madoff 3.With Eurozone debt Greece, Ireland, Spain ,Portugal can’t buy each other lunch let alone a 1million dollar trial. They are bankrupt.

CAS and CEA trials have become an Economic Nightmare

We have spent over 300 million dollars on carotid trials in the USA CREST was a 100 million dollar trial There is no way we can afford, in the current economic environment, another carotid trial

Further carotid trials would be a waste of time and tax payers money The public would not allow it

will any of these leaders support another 100 million dollar trial

Conclusion We have enough evidence to support either CAS or CEA but we do not need more trials to duplicate data we already have. You make your own decision. We don’t care. And we don’t need a trial to know this asymptomatic patient needs carotid repair and not BMM. 60% and 70% lesions don’t need any trial.!!!

This was the take home message from CMS This was the take home message from CMS .Let’s hope Crest will change this attitude .

Do we need more trials since we have: Experience with 45,000 patients 33 US Registries 8 Randomized CAS Clinical Trials 15 years of Experience with CAS . 4O years of Experience with CEA .15 Years without reimbursement

The government has bigger things on its mind

This is a smart Doctor; Don’t be a sucker.

No one is willing to fund additional Carotid Trials? Deteriorating unemployment Volatile U.S. equity markets Eurozone sovereign debt with Ireland, Greece,Spain and Portugal almost bankrupt Japan bear market for 20 years.

What Sucker will fund these trials? Industry will not. Why would they? Absent re-imbursement Rejection by CMS – in spite of results Regulatory and FDA approval issues have been a constant battle.

We have enough of evidence to support either CAS or CEA, but we do not need more trials to duplicate data that already exists.

MAE in high risk carotid stent IDE trials: 2002-2009 (n>4000) 11 device approval trials: all approved …and rapidly improving outcomes MAE in high risk carotid stent IDE trials: 2002-2009 (n>4000)

POSTMARKET SURVEILLANCE REGISTRIES Name (Source) CAPTURE (Catheter Cardiovasc Interv. 2007;69:341-348; Ann Surg 2007;246:551-558) CAPTRURE 2 (Stroke. 2010;4:757-764) CASES (Catheter Cardiovasc Interv. 2007;70:316-323; J Am Coll Cardiol. 2010;56:49-57) CHOICE (http://www.strokecenter.org/ trials/TrailDetail.aspx?tid=1033) aNonhierarchial Name (Source) CREATE PAS (ev3 Inc.) CRISTALLO (J Endovasc Ther. 2008; 15:186-192) EXACT (http://wwwstrokecenter.org/trials /TrialDetail.aspx?tid=774; Presented at the i2 Summit 2007: Emboshield and Xact Post Approval Cartoid Stent Trial) SAPPHIRE WW (Catheter Cardiovasc Interv. 2009;73:129-136) SONOMA (http://clinicaltrials.gov/ct2/show/NCT00478673) aNonhierarchial Name (Source) ARCHER (J Vasc Sug. 2006;44:258-268) ARMOUR (Invatec) BEACH (j Am Coll Cardiol. 2008;51:427-434; Boston Scientific Corporation) CABERNET (Boston Scientific Corporation) CREATE (ev3 Inc; J Am Coll Cardiol. 2006;47:2384-2389) CREATE SpideRX Arm (Published online in J Interv Cardiol. July 8, 2010) EMPIRE (Published online in Catheter Cardiovasc Interv. Sept. 7, 2010) EPIC Pivotal Trial (Lumen Biomedical) aNonhierarchial POSTMARKET SURVEILLANCE REGISTRIES

We Need More Carotid Trials before We Decide CEA vs. Stenting in symptomatic octogenarians CEA vs. Stenting in asymptomatic octogenarians CEA vs. Stenting in symptomatic low risk patients CEA vs. Stenting in asymptomatic low risk patients CEA vs. Stenting in patients with prior CVA CEA vs. Stenting in African Americans Stenting vs. optimal medical therapy in asymptomatic high risk patients CEA vs. Medical management in transatlantic vs. transpacific Tacit vs Pacit Stenting with Bivalurudin vs. Heparin Stenting with femoral access vs. radial access Stenting with 300 mg loading dose of Clopidrogel vs. 600 mg Stenting with 24 observation in the hospital vs. same day discharge Stenting in smaller community hospital vs. tertiary care center Stenting with your left hand vs. your right hand This Nonsense is Over

Will this be the last US Cartoid Trial? The Crest Trial Will this be the last US Cartoid Trial?