0 0 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 CAROTID STENTING Clinical Trial Overview SRIRAM S. IYER Lenox Hill Hospital, New York Clinical Trial Overview SRIRAM S. IYER Lenox Hill Hospital, New York

1 1 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 Disclaimer and Conflicts With the exception of the Guidant Accunet/Acculink for High Surgical risk patients, Carotid Stenting with or without cerebral protection is an investigational procedure. Consultant for Abbott With the exception of the Guidant Accunet/Acculink for High Surgical risk patients, Carotid Stenting with or without cerebral protection is an investigational procedure. Consultant for Abbott

2 2 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 Subsets for Carotid Intervention Symptomatic or Asymptomatic?  Criteria for Defining Symptomatic  Hemispheric Symptoms  Amaurosis Fugax  6-9 Months from Index Event High or Usual Surgical Risk?  FDA-Trial Defined Criteria  Anatomical v/s Comorbidities  Potential For Abuse  High Risk for Surgery ≠ High Intervention Risk  Do not forget medical alternative! Symptomatic or Asymptomatic?  Criteria for Defining Symptomatic  Hemispheric Symptoms  Amaurosis Fugax  6-9 Months from Index Event High or Usual Surgical Risk?  FDA-Trial Defined Criteria  Anatomical v/s Comorbidities  Potential For Abuse  High Risk for Surgery ≠ High Intervention Risk  Do not forget medical alternative!

3 3 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 Subsets for Carotid Intervention Symptomatic Patients Usual Surgical Risk

4 4 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 CREST (Now Includes Asymptomatic!) Carotid Revascularization Endarterectomy Stent Trial vs.

5 5 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 Multi Center Data: CREST LEAD In N=749 Symptomatic (>50%) n=232 (31%) Asymptomatic (>70%) n=517 (69%) Peri procedural stroke and death Entire Cohort: 33/749 (4.4%) < 80 years old: 21/650 (3.2%) >80 years old: 12/99 (12%) N=749 Symptomatic (>50%) n=232 (31%) Asymptomatic (>70%) n=517 (69%) Peri procedural stroke and death Entire Cohort: 33/749 (4.4%) < 80 years old: 21/650 (3.2%) >80 years old: 12/99 (12%) Hobson RW et al J Vasc Surg 2004 Dec; 40(6):

6 6 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 Primary Safety End-Points (30 Days): ≥80y 6/03-1/05N=42(43) Death0 Major Stroke0(0%) Retinal Infarction1(2.3%) Minor Stroke0 (0%) Death/Stroke/MI*1/43(2.3%) CREST Lead in: 12/99 =12%

7 7 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 Subsets for Carotid Intervention High Surgical Risk

8 8 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 High Surgical Risk Groups Group 1 (Anatomic) High Lesions, Low lesions, prior CEA, Contra Occlusion, prio neck radiation, cervical immobility etc Group 2 (Co Morbidities) Cardiopulmonary (specific criteria), need for surgery etc Group 1 (Anatomic) High Lesions, Low lesions, prior CEA, Contra Occlusion, prio neck radiation, cervical immobility etc Group 2 (Co Morbidities) Cardiopulmonary (specific criteria), need for surgery etc

9 9 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 High Surgical Risk Groups CEA Risks: Contralateral Occlusion: 14% Prior CEA: 5-10% High Lesions, Prior Radiation, Tstomy ? Combined Coronary and Carotid Disease, Diminished LV Function, Anesth risks …. CEA Risks: Contralateral Occlusion: 14% Prior CEA: 5-10% High Lesions, Prior Radiation, Tstomy ? Combined Coronary and Carotid Disease, Diminished LV Function, Anesth risks ….

10 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 High Surgical Risk Carotid Stent Trials SAPPHIRE (Randomized Arm) ARCHER (FDA Approved) SECURITY BEACH MAVERICK SAPPHIRE (Randomized Arm) ARCHER (FDA Approved) SECURITY BEACH MAVERICK

11 Lenox Hill Heart and Vascular Institute of New York SCAI Day Composite Endpoint in Carotid Stenting Trials Patients (%) 5.8% ARCHeR 2 (ACC 2003) SAPPHIRE (AHA 2002) SECuRITY (TCT 2003) BEACH 7.8%7.8% 7.2%

12 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 SAPPHIRE: High Surgical Risk Randomized Data (n=307: 156/151) Surgical Refusal: Stent Registry (n=409) Symptomatic (> 50% Stenosis ) Asymptomatic (> 80% Stenosis ) Randomized Data (n=307: 156/151) Surgical Refusal: Stent Registry (n=409) Symptomatic (> 50% Stenosis ) Asymptomatic (> 80% Stenosis )

13 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 Sapphire: Surgical Experience Median Annual CEAs : 30 (15-100) MeanComplication Rates: Stroke:1.0% Death:1.0% MI:1.0%

14 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 Sapphire: Interventional Experience Median Carotid Stents : 64 (20-700) MeanComplication Rates: Stroke:2.0% Death:0.0% MI:0.0% TIA: 2.0%

15 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 Sapphire Randomized Patients: 30Day events Stent (n=156) CEA (n=151) Death0.6%2.0% Stroke3.8%5.3% MI2.6%7.3% Death/Stroke4.5%6.6% Death/Stroke/ MI 5.8%12.6%

16 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 Randomized Symptomatic Patients: 30Day events Stent (n=48) CEA (n=39) Death0%5.1% Stroke2.1%7.7% MI2.1%5.1% Death/Stroke2.1%10.3% Death/Stroke/ MI 4.2%15.4%

17 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 Registry Patients: 30Day events Stent (n=408) 95% CI Death2.5% Stroke5.6% MI1.7% Death/Stroke6.9% Death/Stroke/MI7.8%5.2,10.5

18 Lenox Hill Heart and Vascular Institute of New York SCAI Year Data Randomized Patients (Per Protocol) Stent CEA P= % 11.9%

19 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 * All Stroke to 30 days and ipsilateral stroke from Days SAPPHIRE STUDY Cumulative % of Stroke* to 720 Days Randomized Patients - Kaplan Meier Analysis Time after Initial Procedure (days) Cumulative Percentage of Stroke 4.9% Stent 5.8% CEA 6.4% Stent 6.8% CEA * All Stroke to 30 days and ipsilateral stroke from Days

20 Lenox Hill Heart and Vascular Institute of New York SCAI SAPPHIRE STUDY Cumulative % of MAE to 720 Days Randomized Patients – Kaplan Meier Analysis 12.2% 20.1% Time after Initial Procedure (days) Cumulative Percentage of MAE 20.1% 12.2% 26.4% 19.6%

21 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 SAPPHIRE STUDY Cumulative % of TLR to 720 Days Randomized Patients - Kaplan Meier Analysis Time After Initial Procedure (days) Cumulative Percentage of TLR 4.3% CEA 0.6% Stent 1.4% Stent 6.1% CEA

22 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 SAPPHIRE STUDY Restenosis Rates and TLR at 360 Days In-Vessel Restenosis by U/SStent (n=167) CEA (n=167) P-value >50% Diameter Stenosis*19.7% (24/122) 31.3% (30/96) 0.06 >70% Diameter Stenosis0.8% (1/122)5.2% (5/96)0.09 >80% Diameter Stenosis0.8% (1/122)4.2% (4/96)0.17 TLR – Clinically driven (to 360 days) TLR – Clinically driven (to 720 days) 0.6% (1/167) 1.4% (2/167) 4.3% (6/167) 6.1%(10/ * Protocol Definition

23 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 ARCHER: Enrollment and Device Overview ARCHeR 1ARCHeR 2ARCHeR 3 Stent ACCULINK Stent Delivery System ACCULINK (OTW)RX ACCULINK Embolic Protection Device NoneACCUNET (OTW) RX ACCUNET Patients 158 (+ 51 lead-ins) 278 (+ 25 lead- ins) 145

24 Lenox Hill Heart and Vascular Institute of New York SCAI Day Endpoint Event Rates *Non-hierarchical **Hierarchical ARCHeR 1 N = 158 ARCHeR 2 N = 278 ARCHeR 3 N = 145 Death* Stroke related Non-stroke related 2.5% 0.6% 1.9% 2.2% 0.7% 1.4% 0.0% 1.4% Stroke* Major Minor 4.4% 1.9% 2.5% 5.8% 1.4% 4.3% 6.2% 1.4% 4.8% MI* Q-wave Non-Q wave 2.5% 1.3% 2.9% 1.1% 1.8% 0.7% 0.0% 0.7% Death/Stroke/MI** 7.6%8.6%8.3% Major + Fatal strokes 1.9%1.4%

25 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 Asymptomatic High Surgical Risk Patients Incidentally diagnosed – “asymptomatic bruit” Pt with asymptomatic bruit in need of an unrelated surgical procedure (typically CABG) Incidentally diagnosed – “asymptomatic bruit” Pt with asymptomatic bruit in need of an unrelated surgical procedure (typically CABG)

26 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 Subsets for Carotid Intervention Asymptomatic Patients

27 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 ASYMPTOMATIC PATIENTS Large proportion of patients seen in a cardiology practice: “Asymptomatic Bruit” % stenosis needed for treatment Let neurologist decide symptom status Stroke Risk for conservative treatment is typically small Benefit of treatment is stroke reduction Rigorously audit treatment results Large proportion of patients seen in a cardiology practice: “Asymptomatic Bruit” % stenosis needed for treatment Let neurologist decide symptom status Stroke Risk for conservative treatment is typically small Benefit of treatment is stroke reduction Rigorously audit treatment results CAUTION!!

28 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 Asymptomatic:Indication for Treatment ACAS: 60% By general consensus, most physicians will not treat asymptomatic patients unless stenosis is >80% ACAS: 60% By general consensus, most physicians will not treat asymptomatic patients unless stenosis is >80%

29 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 Is there a difference in the stroke risk “ Asymptomatic Bruit” v/s Pt with an asymptomatic stenosis in need of an unrelated surgical procedure (typically CABG) or the patient with a contralateral occlusion “ Asymptomatic Bruit” v/s Pt with an asymptomatic stenosis in need of an unrelated surgical procedure (typically CABG) or the patient with a contralateral occlusion

30 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 Asymptomatic: Is the >80% requirement Valid for a patient with contralateral occlusion? How about a patient who needs surgery (CABG) especially with bilateral stenosis? Valid for a patient with contralateral occlusion? How about a patient who needs surgery (CABG) especially with bilateral stenosis?

31 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 L.H. 76BF. 10/08/02 Are we ready for a carotid stent trial involving Asymptomatic Patients?

32 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 Asymptomatic Patients: Usual Surgical Risk ACT 1 Trial (Abbott) 3:1 Randomization (Stent:CEA) Trial Has Started Enrollment (1750)

33 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 Case 1: 70 year Male Asymptomatic Right Carotid 100% Left Carotid 70% and supplies R ACA and MCA via patent Ant Co A Indication for Intervention? 70 year Male Asymptomatic Right Carotid 100% Left Carotid 70% and supplies R ACA and MCA via patent Ant Co A Indication for Intervention?

34 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 Case 2: 70 year Male Asymptomatic Right Carotid 100% Left Carotid 70% and supplies R ACA and MCA via patent Ant Co A Needs CABG Indication for Intervention? 70 year Male Asymptomatic Right Carotid 100% Left Carotid 70% and supplies R ACA and MCA via patent Ant Co A Needs CABG Indication for Intervention?

35 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 Primary Safety End-Points (30 Days): Asymptomatic 6/03-3/05N=167 Death0 Major Stroke1 (1.0%) Retinal Infarction1 (0.5%) Minor Stroke*3 (1.5%) Death/Stroke/MI5/167(3.0%) * All 3 minor strokes recovered completely by 30 days

36 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 CAS with and without Filters: TCD and Clinical Outcome Group 1 (n=161): prior to EPD era Group 2 (n=151): Filters Group 3 (n=197): no EPD Non randomized Clinical End Points: Cerebral Isch events and Death TCD End Points: Microemboli (Isolated and showers), macroemboli and distal thrombus Group 1 (n=161): prior to EPD era Group 2 (n=151): Filters Group 3 (n=197): no EPD Non randomized Clinical End Points: Cerebral Isch events and Death TCD End Points: Microemboli (Isolated and showers), macroemboli and distal thrombus Jon Albert Vos et al Radiology 2005; 234:

37 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 CAS with and without Filters: TCD and Clinical Outcome Microemboli more in EPD group Macroemboli more in non protected Thrombus distal to the stent seen in the Filter group (5%) Microemboli more in EPD group Macroemboli more in non protected Thrombus distal to the stent seen in the Filter group (5%) Outcome GP 1 (n=161) GP 2 (n=151) GP 3 (n=197) Death Major Stroke or Death Any Stroke or death

38 Lenox Hill Heart and Vascular Institute of New York SCAI arteries Without EP n = 809 With EP n = 588 P value Minor Stroke 33 (4.1%) 7 (1.2%) <0.001 Major Stroke 8 (1.0%) 2 (0.3%) ns Fatal Stroke 4 (0.5%) 2 (0.3%) ns All Strokes 45 (5.6%) 11 (1.9%) <0.001 All Death 9 (1.1%) 5 (0.9%) ns Non Stroke Death 5 (0.6%) 3 (0.5%) ns Death + Stroke 50 (6.2%) 14 (2.4%) < Day Outcomes Results: 30 Day Outcomes

39 Lenox Hill Heart and Vascular Institute of New York SCAI arteries Without EP n = 91 With EP n = 129 6/03-1/05n=43 Minor Stroke 7 (7.7%) 2 (1.6%) 0 Major Stroke 6 (6.6%) 1 (0.8%) 1*(2.3%) Fatal Stroke 1 (1.1%) 00 All Strokes 14 (15.4%) 3 (2.3%) 1*(2.3%) All Death 2 (2.2%) 00 Non Stroke Death 1 (1.1%) 00 Death + Stroke 15 (16.5%) 3 (2.3%) 0 30 Day Outcomes Age  80y : 30 Day Outcomes * Retinal Infarction

40 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 Why the inconsistencies…I? The event rate, in general, is small  Statistical comparisons based on small sample sizes are invalid The event rate is related to the case mix  Symptomatic v/s asymptomatic  Tortuous v/s “straight shots”  Restenosis following prior CEA  Hence non randomized comparisons are invalid The event rate, in general, is small  Statistical comparisons based on small sample sizes are invalid The event rate is related to the case mix  Symptomatic v/s asymptomatic  Tortuous v/s “straight shots”  Restenosis following prior CEA  Hence non randomized comparisons are invalid

41 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 Why the inconsistencies….II? All of the steps in carotid stenting cannot be “neuroprotected”  Manipulation of the Arch  Impact of the learning curve Recognize that case selection is the most important predictor of complication  The “best” protection device will fail if the anatomy is unfavourable All of the steps in carotid stenting cannot be “neuroprotected”  Manipulation of the Arch  Impact of the learning curve Recognize that case selection is the most important predictor of complication  The “best” protection device will fail if the anatomy is unfavourable

42 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 Arch Normal:Proximal Tortuosity in CCA May not be possible to “Straighten the Bend” VTK Catheter may not be the ideal choice Proximal “Straightening” changes distal lesion morphology Good Time to quit

43 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 Contraindication/Tortuosity 1.90° origin of ICA 2.Severe Stenosis involving CCA ECA and ICA 3.Additional Stenosis in ICA 4.Carotid Redundancy

44 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 Contraindication Right Angled Take Off of the ICA Severe Stenosis involving the CCA and ICA/ECA 3 loops in the ICA Anatomy will become more unfavorable after placement of the sheath

45 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 Contraindication: Heavily Calcified Lesions

46 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 Why the inconsistencies….III? Do not underestimate importance of technique and technical issues  Amount of manipulation needed  Dwell time of the protection device All Protection devices are not created equal  Adequacy of protection  Tendency to Formation of Fibrin Do not underestimate importance of technique and technical issues  Amount of manipulation needed  Dwell time of the protection device All Protection devices are not created equal  Adequacy of protection  Tendency to Formation of Fibrin

47 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 Multi Center Data (14 sites): CARESS Broad Risk Patient Population with CAS 2:1 Randomization (CEA:CAS) 397 Treated;68% Asymptomatic (>75%) 30 day all cause mortality and stroke Broad Risk Patient Population with CAS 2:1 Randomization (CEA:CAS) 397 Treated;68% Asymptomatic (>75%) 30 day all cause mortality and stroke CARESS Investigators al J EndovascTher 2003 Dec; 10(6): CEA (n=254) CAS (n=143) Death+Stroke2% Death+Stroke +MI3%2%

48 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 L.H. 76BF. 10/08/02 Are we ready for a carotid stent trial involving Asymptomatic Patients?

49 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 L.H. 76BF. 10/08/02 Yes, because we have learnt to recognize the patients who are High risk for carotid stenting! “The 3% Rule”

50 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 The expected procedural related complication cannot exceed 3%! Particularly vulnerable is the elderly asymptomatic patient with a limited life expectancy The expected procedural related complication cannot exceed 3%! Particularly vulnerable is the elderly asymptomatic patient with a limited life expectancy The un-breachable rule in treating Asymptomatic ICAS “The 3% Rule”

51 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 Contraindications Tortuosity  Extended Arch  Marked Tortuosity of ICA  Combination Calcium Filling Defect Tortuosity  Extended Arch  Marked Tortuosity of ICA  Combination Calcium Filling Defect or Or How can you avoid breaching this rule?

52 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 Yes, in 2005 we are ready for an Asymptomatic Trial Careful Patient Selection Judicious use of EPD Carotid Stenting  Symptomatic: 6%  Asymptomatic: 3% Careful Patient Selection Judicious use of EPD Carotid Stenting  Symptomatic: 6%  Asymptomatic: 3%

53 Lenox Hill Heart and Vascular Institute of New York SCAI 2005 C arotid Stenting: Implications of Data Trial Based Experience Based* Symptomatic High Risk Yes Asymptomatic High Risk ?Yes Symptomatic Usual Risk CRESTYes Asymptomatic Usual Risk CREST ACT I Yes