Reevaluation of the 80% Carotid Stenosis in Asymptomatic Patients in 2011 Kenneth Rosenfield, MD, FACC, FAHA Section Head, Vascular Medicine and Intervention Massachusetts General Hospital Boston, Massachusetts, U.S.A.

Kenneth Rosenfield, MD Conflicts of Interest Consultant Abbott Vascular Complete Conference Management Harvard Clinical Research Institute Lumen Micell Vortex VuMedi Equity Icon CardioMEMs Contego Medical Simulation Corporation Primacea Research or Fellowship Support Abbott Vascular Atrium Bard Baxter IDEV Invatec-Medtronic Lutonix Board Member VIVA Physicians www.vivapvd.com

The asymptomatic lesion - 2011 1) Your 78 year old mother has an asx 80% stenosis of the Lt Carotid artery by DUS.  She is otherwise in good health.  You would: a) Intensify medical therapy, adding statins, ASA, etc. b) do (a) plus CEA (assume experienced surgeon) c) do (a) plus CAS  (assume experienced stenter) d) allow her to choose either a, b, or c, based on her own preference Responses: c if good anatomy, stent it b. d but depends on anatomy; could also follow on meds and if worsening duplex then d

Question What if her stenosis was 70%?

Question What if she was 86 y.o.? …more likely to Rx conservatively? …more likely to stent than CEA? ...or the other way around?

Carotid Artery Disease Patient subsets Symptomatic High-risk Asymptomatic High-risk Symptomatic Standard-risk Asymptomatic Standard-risk

Treatment of Asx Carotid Disease… It’s clear this is a “moving target” Medical therapy is improving. Carotid stenting results have improved, due to technologic advances, experience of operators, and better case selection But so is CEA improving…  Difficult to integrate new data with old to come up with best management for our patients!

Carotid Artery Disease The problem with this field Many stakeholders with interests that extend beyond those of the patient Each stakeholder too easily falls into the trap of seeing only what they want to see, to enhance and support their preconceived bias.

NATIONAL INPATIENT SAMPLE DATA J Vasc Surg 2007;46:1112-8 9

Carotid Revascularization for Asx Pts Legitimate questions in the current era Should any asx patient undergo revasc AT ALL??? Medical therapy much improved now What degree of stenosis is appropriate to revasc??? Higher grade -->hemodynamic compromise Lower grade --> plaque rupture By which modality, CEA or CAS??? “Conventional” vs. “high-risk” for CEA

Reevaluation of the 80% stenosis Question #1 Is it appropriate to revascularize any asymptomatic patient in the current era?

THE WALL STREET JOURNAL MARCH 3, 2009 Drug Therapy Gains Favor to Avert Stroke By THOMAS M. BURTON A major study nearing completion is expected to help resolve a longstanding debate over whether surgery or the insertion of a flexible stent is the better way to prevent stroke for people with blocked arteries in the neck. But the study doesn't aim to answer another pressing question: How many patients may be better off avoiding those risky procedures altogether? An influential group of doctors say there is growing evidence that certain drugs could be of benefit greater than or equal to surgery or stents in preventing stroke -- with much reduced risk. These drugs include statins -- commonly associated with treating high cholesterol -- as well as blood-pressure medications and anticlotting drugs such as aspirin. The problem, these doctors say, is that unless a single study is done in which patients are randomly assigned to one of the three therapies, it's impossible to judge what is the best option for most patients. "I've commonly had people come in for a second opinion after surgery or a stent was recommended," says Frank J. Veith, a vascular surgeon at New York University Medical Center. "After I explain the risks from procedures and the possible benefits, almost all of them opt for statins." At issue are strokes caused when clots or fatty plaque in the carotid arteries begin to impede blood flow to the brain. A glob of this debris can dislodge, float up into the brain and block any of several small arteries there. Brain-tissue death can begin quickly, leaving patients with a range of outcomes from mild impairment to paralysis or death. Doctors say carotid-artery blockage plays a role in as many as half the 780,000 strokes that occur in the U.S. each year. Other factors that cut oxygen flow to the brain account How many patients may be better off avoiding those risky procedures altogether? An influential group of doctors say there is growing evidence that certain drugs could be of benefit greater than or equal to surgery or stents in preventing stroke -- with much reduced risk. At the International Stroke Conference in San Diego last week, researchers presented stroke-specific data from the recent heart-disease prevention trial known as Jupiter, which involved 17,802 patients. Patients taking Crestor…had a 48% decrease in risk of stroke

SPARCL: High Dose Atorvastatin vs Placebo In Patients with Prior CVA/TIA Stroke or TIA N Engl J Med 2006;355:549-559 13

Curr Opin Neurol 2007;20:58-64 14

Optimal Medical Therapy Trials forming basis for “new paradigm” of therapeutic nihilism about revasc all have issues: pt cohorts- prior CVA patients endpoint of “all-cause stroke”, not carotid stroke That said, there is NO DOUBT, OMT is better now BUT… CEA and CAS results have improved as well Benefits of new OMT may be additive to revasc No Level I evidence to support a strategy of Med Rx only (w/o revasc) for those at risk for stroke from carotid stenosis It is inappropriate (and unscientific) to simply assume that OMT alone is better now than revasc plus OMT…one cannot simply discard the level I evidence accrued in prior trials

The other problem with Med Therapy MARCH 3, 2009 Drug Therapy Gains Favor to Avert Stroke By THOMAS M. BURTON A major study nearing completion is expected to help resolve a longstanding debate over whether surgery or the insertion of a flexible stent is the better way to prevent stroke for people with blocked arteries in the neck. But the study doesn't aim to answer another pressing question: How many patients may be better off avoiding those risky procedures altogether? An influential group of doctors say there is growing evidence that certain drugs could be of benefit greater than or equal to surgery or stents in preventing stroke -- with much reduced risk. These drugs include statins -- commonly associated with treating high cholesterol -- as well as blood-pressure medications and anticlotting drugs such as aspirin. The problem, these doctors say, is that unless a single study is done in which patients are randomly assigned to one of the three therapies, it's impossible to judge what is the best option for most patients. "I've commonly had people come in for a second opinion after surgery or a stent was recommended," says Frank J. Veith, a vascular surgeon at New York University Medical Center. "After I explain the risks from procedures and the possible benefits, almost all of them opt for statins." At issue are strokes caused when clots or fatty plaque in the carotid arteries begin to impede blood flow to the brain. A glob of this debris can dislodge, float up into the brain and block any of several small arteries there. Brain-tissue death can begin quickly, leaving patients with a range of outcomes from mild impairment to paralysis or death. Doctors say carotid-artery blockage plays a role in as many as half the 780,000 strokes that occur in the U.S. each year. Other factors that cut oxygen flow to the brain account "I'm a big believer in medical therapy," says Michael R. Jaff, a Harvard professor and medical director of the Massachusetts General Hospital's vascular center. However, he said: "It is well-known that many patients who require drug therapy either don't get it, don't get treated to goal [to achieve target numbers for cholesterol and blood pressure] or are not compliant with their meds."

Stroke Prevention by Revascularization What is the evidence… RCT: CEA beats medical Rx* in standard surgical risk patients CAS equals CEA in high surgical risk patients

ACST - Early vs. Deferred Carotid Endarterectomy in Asymptomatic Patients with ICA Stenosis Any Stroke or Perioperative Death Time (years)  Benefit of Med Rx with Revascularization over Med Rx alone ACST Investigators. Lancet 2004;363:1491-1502

-AHA/ASA Guideline; Stroke, Feb06 CEA vs. Med Rx for Stroke Prevention Recommendation based on Asx RCT’s (Level I) CEA, on top of contemporary medical therapy, is beneficial in selected (“e.g. conventional risk”) patients, ages 40-75 years, who are expected to live for >5 years, if: Stenosis 60-99% and physician/hospital stroke/death rate < 3% -AHA/ASA Guideline; Stroke, Feb06

Optimal Medical Therapy alone vs Revasc Trials forming basis for “new paradigm” of therapeutic nihilism about revasc all have issues: pt cohorts- prior CVA patients endpoint of “all-cause stroke”, not carotid stroke No Level I evidence to support a strategy of Med Rx only (w/o revasc) for those at risk for stroke from carotid stenosis It is inappropriate (and unscientific) to simply assume that OMT alone is better now than revasc plus OMT…one cannot simply discard the level I evidence accrued in prior trials

Reevaluation of the 80% stenosis Question #2 Which mode of revascularization should I offer? Is CAS equal to CEA now?

Therapy for for stroke prevention: RCT’s: CAS vs. CEA completed* SAPPHIRE * ongoing Symptomatic High-risk Asymptomatic High-risk KENTUCKY * Symptomatic Standard-risk Asymptomatic Standard-risk EVA3s, SPACE 1 * ACT 1, SPACE 2 CREST *

SAPPHIRE 3-Year Outcomes Freedom from MAE N Engl J Med 2008;358:1572-9

SAPPHIRE Asymptomatic: 360-Day MAE (ITT) % P=1.00 P=0.08

Real world outcomes for asx high risk patients: AHA guidelines met or exceeded by >500 operators (never demonstrated by CEA) N=4282 2.9 1.1 0.8 0.6 1.8 1 2 3 4 5 6 7 8 Death/Stroke Death/Major Stroke Death Stroke Minor (1.8%) Stroke Major (0.6%) (%) Subjects EXACT/CAPTURE 2 (combined): 30-day major adverse events asymptomatic patients <80 years 3% AHA guideline Gray et al., Circ Cardiovasc Intervent 2009; March 6 26

Stroke Prevention by Revascularization What is the evidence… RCT: CEA beats medical Rx* in standard surgical risk patients CAS equals CEA in high surgical risk patients NOW: CAS equals CEA in standard surgical risk patients

Primary endpoint ≤4 years (mean 2.5) Peri-procedural outcomes P=0.38 P=0.51 7.2 6.8 HR 1.11 95% CI: 0.81-1.51 HR 1.18 95% CI: 0.82-1.68

Peri-procedural Stroke and MI   CAS vs. CEA Hazard Ratio 95% CI P-Value All Stroke 4.1 vs. 2.3% HR = 1.79; 95% CI: 1.14-2.82 0.01 MI 1.1 vs. 2.3% HR = 0.50; 95% CI: 0.26-0.94 0.03 Cranial Nerve Palsies CAS vs. CEA Hazard Ratio, 95% CI P-Value 0.3 vs. 4.7% HR = 0.07; 95% CI: 0.02-0.18 <0.0001

CREST: Additional STRIKING Info from Recent FDA Panel Meeting Primary endpoint rate lower with EPD Minor strokes – residual deficits equal b/n CAS and CEA at 6 mos Incidence of death and major stroke in CAS was almost ZERO for last half of trial (for Symptomatics, it WAS zero) Effect of MI on survival – 25% mortality (vs. minor stroke 5% mortality in same time-frame) – MI had essentially same effect as Major stroke

ACT I: Outcomes Lead In Patients Event 30 days, N=180 Death, Stroke and MI 1.7% (3/180) All Stroke and Death 1.7% Major Stroke and Death 0.0% Death All Stroke Major Stroke Minor Stroke MI 31-365 days, N=157 Ipsilateral Stroke Updated Source: 2009 IDE Annual Report ACT I Study Sept 2009. Source: IDE Annual Progress Report ACT I Study Sep 2008 2 minor ipsi strokes within 30 days.

Higher Risk for CAS: Calcification and Ulceration Heavy concentric calcification

ECVD Guidelines 2011 Recommendations re: revasc modality Symptomatic patients Asymptomatic 50-69% stenosis 70-99% stenosis CEA Class I LOE: B LOE: A Class IIa Stent Class IIb

Bottom Line… Number of patients who have had CAS is now in the hundreds of thousands Proven to be safe and effective procedure that is comparable to CEA Results have improved with time…better operators, better case selection, and better equipment Level I evidence to support CAS as equivalent to CEA Time for FDA and CMS to approve coverage Decision regarding therapy should be individualized for each patient; pts deserve choice

What about the patient’s point of view? MARCH 3, 2009 Drug Therapy Gains Favor to Avert Stroke By THOMAS M. BURTON A major study nearing completion is expected to help resolve a longstanding debate over whether surgery or the insertion of a flexible stent is the better way to prevent stroke for people with blocked arteries in the neck. But the study doesn't aim to answer another pressing question: How many patients may be better off avoiding those risky procedures altogether? An influential group of doctors say there is growing evidence that certain drugs could be of benefit greater than or equal to surgery or stents in preventing stroke -- with much reduced risk. These drugs include statins -- commonly associated with treating high cholesterol -- as well as blood-pressure medications and anticlotting drugs such as aspirin. The problem, these doctors say, is that unless a single study is done in which patients are randomly assigned to one of the three therapies, it's impossible to judge what is the best option for most patients. "I've commonly had people come in for a second opinion after surgery or a stent was recommended," says Frank J. Veith, a vascular surgeon at New York University Medical Center. "After I explain the risks from procedures and the possible benefits, almost all of them opt for statins." At issue are strokes caused when clots or fatty plaque in the carotid arteries begin to impede blood flow to the brain. A glob of this debris can dislodge, float up into the brain and block any of several small arteries there. Brain-tissue death can begin quickly, leaving patients with a range of outcomes from mild impairment to paralysis or death. Doctors say carotid-artery blockage plays a role in as many as half the 780,000 strokes that occur in the U.S. each year. Other factors that cut oxygen flow to the brain account Surgery clearly has benefits for some patients, especially when previous symptoms exist. Bill C. McDonough, of Canton, Mass., suffered a ministroke in August. Doctors found the carotid artery on one side of his neck had 99% blockage, and the artery on the other side, 96%. The 59-year-old retired banker checked in to Massachusetts General Hospital and had surgery on one artery and chose to have a stent placed in the other. Mr. McDonough said he is "100% better" now.

Thank you!