Carotid Stenting: (An) American Perspective. Kenneth Rosenfield, M.D. Section Head Vascular Medicine and Intervention MGH Boston, MA

Transcription

1 Carotid Stenting: (An) American Perspective Kenneth Rosenfield, M.D. Section Head Vascular Medicine and Intervention MGH Boston, MA

2 Kenneth Rosenfield, MD Conflicts of Interest Scientific Advisory Board Abbott Vascular Complete Conference Management Equity Medical Simulation Corporation Primacea Research or Fellowship Support Abbott Vascular Cordis Lutonix/Bard Atrium IDEV Board Member VIVA Physicians

3 Kenneth Rosenfield, MD Additional Disclosure I am a Carotid Stentor, and do not perform CEA take that at face value

4 Carotid Therapies Consensus after 16 years of CAS WHAT CONSENSUS??? There seems to be very little of it across stakeholders! So how have we gotten to this (unfortunate) place?

5 Challenges in comparing carotid strategies: moving targets Medical Rx evolving - better drugs and increased understanding of pathophysiology CAS Difficult improving to integrate - better devices, new data increased with existing experience, & better case selection information (and biases) to come up with CEA also improving - evolving techniques best management for our patients! Other Challenges Event rates low - large number of patients required to detect difference (or equivalence) noise from other causes of stroke Physicians/patients - pre-conceived notions about best Rx; reluctance to accept change

6 THERAPY FOR CAROTID ARTERY STENOSIS Stenting or CEA (or Medical Therapy)? What is the role of each??? Remains a HOT topic

7 American Perspectives on CAS Stakeholders Physicians Vascular Surgeon Cardiologist Neurologist Radiologist Neurosurgeon Internist Other Parties Industry FDA CMS Payors Patients Ken Rosenfield

8 Carotid Artery Disease The problem with this field Stakeholder interests extend beyond those of the patient Economics Politics Control Tradition Many unfortunately only see in the data what they want to see, and use that to support their preconceived biases (or self-interest) No one is immune vasc surgeons, cardiologists, neurologists, interventionalists, payors, industry, and all other stakeholders

9 Carotid Artery Disease Data Jungle Evidence base derived from flawed trials, registries, and databases with inconsistent methodologies: Comparisons made between patients who are fundamentally different (apples to oranges) Operators with highly variable competency differential skill level and procedural experience between those doing CAS vs. CEA Inconsistent neurologic assessment for stroke Utilization of equipment that is outdated for CAS Preponderance of Medicare age patients (commercial payors won t allow investigational Rx)

10 NATIONAL INPATIENT SAMPLE DATA Different populations and no validated risk adjustment CAS patients were, by definition, high risk Most CEA patients were conventional risk Variable experience in stent operators vs. experienced CEA surgeons No independent neuro assessment for CEA, but ~100% for CAS Inappropriate and invalid comparison J Vasc Surg 2007;46:1112-8

11 SVS CAS/CEA Registry Different populations and no validated risk adjustment CAS patients were, by definition, high risk Most CEA patients were conventional risk Variable experience in stent operators vs. experienced CEA surgeons No independent neuro assessment for CEA, but ~100% for CAS Inappropriate and invalid comparison J 11 Vasc Surg Dec, 2008

12 Variability in CEA results: What happens when the operator measures his/her own outcome? stroke and/or death from CEA in 51 studies ( ) risk of CVA or death according to study methods/authorship: Study characteristic #studies %stroke/death multiple surgeon authors single surgeon author independent neurologist assessor retrospective prospective Rothwell and Warlow, Stroke, 1996;27:

13 Comparing CAS and CEA Characteristics of patients referred for CAS differ markedly from those referred for CEA. Because of extreme clinical disparities between these patients, generalizable comparative effectiveness analyses of observational data will be difficult.

14 30 day death and stroke (%) RCT s The data jungle continues EVA-3S fundamentally flawed design the role of operator training and experience CEA CAS 9,6 5 3,9 0 Primary Endpoint

15 EVA 3S Are-You-Kidding-Me? Trial - Metzger Extremely inexperienced operators Minimum of 5 CAS in your CAREER (c/w minimum of 25 CEA/ year)! Tutored randomization! 5% emergency CEA! 1.7 randomizing centers! EPD not mandated, often not used early No predilatation >80% cases!! No core lab,?cec Unheard of stroke rates for CAS

16 ICSS another RCT of Symptomatic Standard Risk Outcomes CAS (853) CEA (857) HR P value Death, stroke, MI 8.5% 5.2% Any stroke 7.7% 4.1% Any stroke or death 8.5% 4.7% Disabling stroke or death 4.0% 3.2% All-cause death 2.3% 0.8%

17 ICSS: Operator Training and Experience Are-You-Kidding-Me 2 Trial?

18 Ken Rosenfield, MD my first NASCAR race

19 30 day death and stroke (%) SPACE (Sxatic Standard Risk Patients) terminated early because of finances Conclusion did not meet non-inferiority for CAS 20 73% of CAS done w/o EPD!! 15 CEA CAS High % w/ no predilatation ,34 6,84 High % w/ single bolus heparin CAS enrollment dominated by IR 0 Primary Endpoint Notable that CAS was equal at termination!

20 Operator Experience in RCT s Trial EVA-3S Operator Experience Poor (12 lifetime CAS or 35 supra-aortics with 5 CAS) SPACE Adequate for era (but not comparable to CEA) ICSS Poor (50 stents anywhere, 10 lifetime CAS or supervised) CREST Adequate for era (but not comparable to CEA) Source: William A. Gray MD, Presented at Oxford University, England 20

21 Fully credentialed to perform periph. PTA 30 angiograms (15 as primary operator) 25 carotid stents (13 as primary operator) JACC, JVS, CCI January, 2005 JVM Feb, 2005

22 Physician Experience Dictates Outcomes Data from CAPTURE 2 72 Source: JACC Interv 2011 ;Gray et al: 22

23 RCT of CEA vs. CAS: Adequate comparisons? Why did the leadership of EVA-3S, SPACE, and ICSS propose such limited requirements for endovascular experience and how were such protocols accepted by ethics committees? The reasons might have been the absence of procedural insight or concerns about funding or slow enrollment. Regardless, no surgeon would have ever allowed a peer with total lifetime experience of just ten CEA procedures to participate in a randomised trial. Importantly, the endovascular requirements in the mentioned trials do not comply with current minimum recommendations. Lancet Neurology, February 26, 2010

24 Mortality % CEA Mortality 2,50 113,300 Medicare Patients ( ) 30-Day Follow Up 2,00 1,50 1,00 0,50 0,00 1. Wennberg, et al., Variation in Carotid Endarterectomy Mortality in the Medicare Population. JAMA, 279: , 1998

25 Carotid Endarterectomy (CEA) Established gold standard for revascularization Caveats: Procedures were done by experienced operators at experienced centers, MANY years after CEA introduced Major studies excluded high surgical risk pts Results worse for inexperienced operators OR high risk patients

26 NASCET and ACAS Exclusions Age>79 Prior ipsilateral CEA Unstable coronary syndrome MI in previous 6 months Cardiac valvular or rhythm abnormality likely to cause embolic cerebrovascular symptoms Contralateral occlusion A more severe lesion cranial to the surgical lesion Contralateral CEA within previous 4 months Uncontrolled hypertension or diabetes Organ failure likely to cause death within 5 years Total occlusion Major surgical procedure in previous 30 days Prior severe CVA Progressing neurologic syndrome

27 Risk of stroke/death in high surgical risk CEA Age >75 years: 7%-10% Congestive heart failure: 8%-9% Co-existent CAD requiring bypass surgery: 8%-10% Contralateral carotid occlusion: ACAS: 2% increase over medical therapy NASCET: 14% Prior CEA and recurrent stenosis Mayo Clinic and Cleveland Clinic: 8%-10% Renal insufficiency: Cr >1.5 mg%: 8% Cr >2.9 mg%: 43% Wong JH et al. Stroke May 1997; 28(5), Daily PO et al. J Thor Cardiovasc Surg; June 1996:111(6), Goldstein LB et al. Stroke April 1998:29(4),

28 Outcomes in high surgical risk patients There are still no randomized CEA trials (vs. Medical therapy) in high surgical risk patients to guide recommendations for therapy

29 SAPPHIRE RCT: 1-Year Outcome Sx and Asx high surgical risk Cumulative Percentage of MAE Endarterectomy 20.1% Stent p= % Time after Initial Procedure (days)

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

31 High Surgical Risk Patients in CAS IDE Trials MAE: (n>4000) William A. Gray MD, Presented at Oxford University, England 32

32 PROTECT Trial High surgical risk pts Contemporary outcomes w/newer EPD 220 enrolled 11/2006 to 1/2008 Mean age 72.5 years, 30% octogenarian 13% symptomatic Results: 30 Day DSMI 2.3%, 95% CI [0.74,5.22] DS 1.8%, 95% CI [0.50,4.59] MI 0.5%, 95% CI [0.01,2.51] 102 with Obsolete EP 30 day DSMI 5.9% Freedom from 30d DSMI/ 3y ispi stroke = 95.4% Matsumura et al, JVS 2012

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

34 CAS will only get better Potential reduction in HITS and silent but worrisome MRI defects seen in ICSS Extends capability of CAS

35 CAS and CEA What is the LEVEL I evidence? RCT: CEA beats medical Rx* in standard surgical risk patients (NASCET, ACAS, ACST) CAS equals CEA in high surgical risk patients (SAPPHIRE) NOW: CAS equals CEA* in standard surgical risk patients (CREST) DOES THIS REDUCE THE CONFUSION??? *Level I evidence

36 Primary endpoint 4 years (mean 2.5) Peri-procedural outcomes 7.2 P=0.38 P= HR % CI: HR % CI:

37

38 CREST: Peri-procedural Stroke and MI All All CAS vs. CEA Hazard Ratio 95% CI CAS vs. CEA Hazard Ratio 95% CI P- Value P- Value Stroke 4.1 vs. 2.3% HR = 1.79; 95% CI: MI Stroke vs. vs. 2.3% 2.3% HR = 1.79; 0.50; 95% CI: Cranial Nerve Palsies Major Stroke 0.9 vs. 0.6% HR = 1.35; 95% CI:

39 Neurological Residual Deficit Rates Associated with Minor 6 Months = 0.50% = 0.02% 40

40 CREST Death, Stroke and MI within 30 Days by EPS Usage (PP) Per Protocol All Death, Stroke, and MI 2 Accunet EPS Used N = 1,073 EPS Not Used N = % 20.8% Note: Only includes each subject s first occurrence of the event. 1 By normal approximation. 2 Hierarchical event in first row, all other are non-hierarchical events. 3 ANM: Assumptions Not Met Difference [95% CI] % [-31.8%, 0.8%] Death 2 0.4% 8.3% -8.0% ANM All Stroke 2 3.8% 8.3% -4.5% ANM Major Stroke 0.7% 4.2% -3.4% ANM Minor Stroke 3.1% 4.2% -1.1% ANM MI 2 1.9% 8.3% -6.5% ANM Source: 41

41 Death or Major Stroke for CAS over CREST Enrollment (all pts) 50% Trial Enrollment August

42 CREST - Cranial Nerve Injury Patients with study procedure attempted/received CAS N = 1,131 CEA N = 1,176 p-value Procedure related cranial nerve injury 0.0% 5.3% (62/1176) < Unresolved at one month 0.0% 3.6% (42/1176) < Unresolved at six months 0.0% 2.1% (25/1176) < Source: 43 tee/circulatorysystemdevicespanel/ucm pdf

43 CREST CEA vs. CAS Access Site Cx Patients requiring re-operation Per Protocol Access Site Complication Requiring Treatment CAS N = 1,131 CEA N = 1,176 p-value 1.1% 3.7% Events may occur more than once in the same patient. Other includes pain requiring IV analgesics (5), incision complication (3), pseudoaneurysm (2), occlusion (1) Source: 44

44 Association of Minor Stroke and MI with Long Term Mortality Comparison HR HR Confidence Interval Log Rank P-value MI vs. Control 2.81 [ ] Minor Stroke vs. Control 0.52 [ ] 0.34 MI vs. Minor Stroke 5.18 [ ]

45 Conclusions Primary endpoint shows equivalence lower minor stroke with CEA and lower MI with CAS Significant liabilities of CEA (access cx, CN palsy, etc.) not captured in endpt Overall results of both are spectacular: Event rates lowest of any large RCT

46 ECVD Guidelines Recommendations of 14 Specialties re: revasc modality Symptomatic patients Symptomatic patients Asymptomatic patients 50-69% stenosis 70-99% stenosis 70-99% stenosis CEA Class I LOE: B Class I LOE: A Class IIa LOE: A Stent Class I LOE: B Class I LOE: B Class IIb LOE: B

47 Perspectives Interventionalist (Cardiologist, Radiologist, INR, Interventional Neurologist) Differences between CEA and CAS outcomes no longer lies in the procedure, but rather: Operator selection of the case equipment and technique Level I evidence and guidelines support offering CAS as (covered) option Operators need appropriate training, experience, and judgement Playing field should be level all patients with Carotid disease medical Rx or undergoing revasc should have closer oversight, independent neuro eval

48 American Perspectives on CAS Vascular Surgery +/- Neurosurgery our disease our patients our procedures our referring docs Published own guidelines Multiple manuscripts disparaging CAS Believe CAS has limited role (CEA restenosis)

49 American Perspectives Internal Medicine Specialists- USPSTF i.e. don t even look for carotid disease, because risk to benefit ratio and cost not worth it and potential harm outweighs benefit 50 Ann Intern Med 2007;147:854-9

50 Perspectives Neurology CMS & others Improved medical Rx may make revascularization obsolete Need more data CREST 2

51 Perspectives - Physicians Vascular Surgeons

52 Perspectives -

53 Perspectives - CMS & Payors Non-Coverage Decision (NCD) In place for nearly 20 years CMS has refused to overturn and agree to cover CAS (except for symptomatic high surgical risk patients a small minority), despite multiple successful trial results, positive post-market surveillance trial data, and new level I evidence supporting CAS as alternative to CEA for standard risk patients (CREST) WHAT ARE THEY WAITING FOR? Director of Coverage wants consensus amongst the medical community on terms of coverage does not wish to referee an inter-specialty battle This will not happen easily, given the challenges described heretofore. We need a way out of the Jungle!

54 Perspectives what makes CMS, payors, and public more skeptical Damaging vision of unregulated, uncontrolled, cowboy interventionalists, driven by greed, potentially inflicting harm on patients and inappropriately increasing health care costs

55 Vascular Surgeons not immune need to keep this from happening in both CEA and CAS! Journal of Stroke and Cerebrovascular Diseases, Vol. 18, No. 4 (July-August), 2009: pp

56 Implications of conflicting trial results, stakeholder battles, regulatory stalemate Confusion for patients and clinicians NB: If other technologies presented at this conference were subjected to the same scrutiny as CAS, few would make it to clinical practice. Nor would CEA have made it performed for 40 yrs before scrutinized all the while becoming more perfected

57 The Most Important American Perspective The PATIENT! 50 year old male anesthesiologist 1996 XRT for nasopharyngeal carcinoma 2004 radical neck dissection and addl XRT 2009 normal DUS 2011 new severe RICA stenosis - asx Duplex CTA PSV 314 EDV 141

58 What would you tell this man? Additional Info Lt SCA occlusion; Rt Lt SC steal Lt vocal cord paralysis Aortic Arch Rt ICA Vasc Surg. Opinion You need an Endarterectomy! CAS has much higher incidence of stroke! 59

59 Patient s opinion Are the results similar? If so, I want the choice I want a stent!

60 Role of the patient in decision-making Principles of patient-centered care Encourage shared decision-making with patients Allow patients to choose b/n two therapies that have similar benefit and risk profile Ask the PATIENT what HE/SHE wants!

61 ACT I one way out of the Jungle RCT CEA vs CAS Asymptomatic Standard risk -suitable for both CEA and CAS Prospective, randomized, 2-arm, multicenter trial 3:1 randomization CAS to CEA 1658 pivotal <80 y.o. subjects; up to 400 lead ins Stenosis 70% and 99% by angiography or DUS Optimal medical therapy for all Surgeon & interventionalist criteria strict/verified (IMC/SMC) Independent neuro assessment; rigorous CEC adjudication Balanced trial leadership Vasc Surg, Card/V Med, Neuro

62 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 0.0% All Stroke 1.7% Major Stroke 0.0% Minor Stroke 1.7% MI 0.0% days, N=157 Ipsilateral Stroke 0.0% 63

63 CAS for Stroke Prevention: Which pts? General principles Prior construct - CAS for pt who is high CEA risk New construct- CAS for pt who is acceptable CAS risk (even some octogenarians) Optimal pt - type I arch, no tortuosity, no clot/ca++,etc. Adequate landing zone Still learning who is optimal and who is not Low risk, young patients may be the BEST

64 American Perspective on CAS Summary 1 Widely divergent and strongly held opinions re: role and efficacy of CAS Well-conducted trials show CAS performed by experienced operators utilizing proper technique in appropriately selected pts is an excellent procedure Say no to high-risk CAS cases Prox. protection may extend utility to more patients CAS does NOT replace optimal medical Rx CAS does NOT replace CEA (ALL high-cas risk, low CEA-risk pts best w CEA or med Rx)

65 Therapy for Carotid Stenosis The Future Better definition of patients appropriate for Medical Therapy only CEA only Stenting only gray zone between revasc or no revasc either CEA or CAS, in which case shared decision-making should occur

66 American Perspective on CAS Summary 2 CMS expansion of coverage - requirements More alignment of medical community Coverage with Evidence Development (CED) Mandatory submission of high quality data High standards for operator training/experience Police ourselves to ensure no inappropriate use Accumulate addl rigorous data - indep. neuro eval. Complete ACT 1 Mandate registry participation Need more evidence re: role of revasc. in asxatic

67 American Perspective Ken Rosenfield s Bottom Line >100,000 patients have had CAS Proven to be safe and effective procedure that is comparable to CEA, in experience hands and with proper patient selection Results have improved with time better operators, case selection, equipment, and technique Level I evidence supports CAS as equivalent to CEA FDA approval obtained based on Level I evidence Multispecialty guidelines support CAS as alternative to CEA in standard surgical risk patients Decision regarding therapy should be individualized for each patient. Patients should be entitled to have choice! Time for CMS to approve coverage