New Trials in Progress: ACT 1. Jon Matsumura, MD Cannes, France June 28, 2008

Transcription

1 New Trials in Progress: ACT 1 Jon Matsumura, MD Cannes, France June 28, 2008

2 Faculty Disclosure I disclose the following financial relationships: Consultant, CAS training director, and/or research grants from Abbott, Abraxis, Bard, Cook, Cordis, ev3, Gore, Lumen, and Medtronic. Carotid stent/ep systems are not approved for standard risk for CEA patients and it is an investigational use

3 Agenda Evidence for CEA for asymptomatic patients VA trial, ACAS, ACST CAS randomized trials with 338 asymptomatic subjects Cavatas, Kentucky, Sapphire ACT 1 trial design and lead in data

4 VA Asymptomatic Trial 444 men with 50 99% stenosis 11 VA hospitals; operative risk 2.4% stroke and 1.9% death, angio stroke risk 0.4% Blinded evaluation of endpoints Ipsilateral events/stroke/death at 4 years: Surgical arm 8.0%/4.7%/33.1% Medical arm 20.6%/9.4%/33.5% NEJM

5 Asymptomatic Carotid Atherosclerosis Study 1662 patients with 60 99% NASCET stenosis 39 centers with < 3% stroke rate Independent evaluation of endpoints Stroke or death risk at 5 years: Surgical arm 5.1% Medical arm 11.0% Not adequately powered to detect differences in Gender? Fatal/disabling stroke risk reduction? Selected surgeons

6 ACAS: Ipsilateral Stroke JAMA 1.0 Surgical 5.1% Event-Free Medical 11.3% Year of Study

7 MRC ACST Asymptomatic Carotid Surgery Trial 3120 Asymptomatic patients > 60% stenosis by ultrasound Exclusion Criteria Prior ipsilateral CEA, Poor surgical risk, Major lifethreatening condition Patients received appropriate medical care (antiplatelet therapy, antihypertensive treatment, and in recent years lipid lowering therapy) Risk of Stroke or Death within 30 days of CEA 3.1% 5 year Stroke Risk Immediate CEA 6.4% Deferred CEA 11.8% Benefit in age to 74 yo and stroke severity Stratified by stenosis, lesser degrees with more benefit Gender? Collaborating physicians, most were neurologists

8 Asymptomatic Carotid Surgery Trial ACST benefit of intervention with Med Rx over Med Rx alone Lancet 2004;363 Time (years)

9 ACST Lancet 2004;363 Use of medical treatments

10 CAS Randomized Clinical Trials of Asymptomatic Patients

11 CAVATAS Carotid and Vertebral Artery Transluminal Angioplasty Study Lancet 2001

12 CAVATAS Carotid and Vertebral Artery Transluminal Angioplasty Study Lancet 2001

13 Kentucky Single center Symptomatic arm n=104 Asymptomatic arm n=85 No complications in the CEA or endovascular arm. Brooks et al JACC 2001;38:

14 Study is not powered for subgroup analyses Symptomatic/Asymptomatic: Randomization stratified by +/ symptoms Subgroup analyses pre specified Subgroup sample sizes SAPPHIRE STUDY Subgroup Analyses Symptomatic Patients: 96 Asymptomatic Patients: 237 FDA Panel, NEJM

15 SAPPHIRE Asymptomatic: 30 Day MAE (ITT) 25 CEA (n=120) Stent (n=117) 20 % P=0.46 P=0.22 9,2 P=0.54 6,7 6,0 P=0.62 5,1 3,3 2,6 1,7 0,8 Death Stroke MI MAE

16 SAPPHIRE Asymptomatic: 360 Day MAE (ITT) 25 CEA (n=120) Stent (n=117) 20 19,2 P=0.07 % ,8 P=0.15 P=1.00 7,5 7,7 8,3 P= ,3 5 5,1 2,6 0 Death Stroke MI MAE

17 CRITICAL CONCEPT: Risk Factors for CAS Advanced age Recent symptoms < 2 weeks Poor access arch and iliofemoral Tortuosity unable to use EPD Severe calcification Free floating thrombus String sign Experience level of interventionalist

18 ACT 1 Study Design Prospective, randomized, non inferiority, multi center trial 3:1 randomization ratio of CAS to CEA Lead in enrollment of up to 200 subjects Maximum of 1858 pivotal subjects (>530 randomized) Prescribed contemporary medical therapy guidelines for all patients Subjects followed at 1, 6, 12 months post procedure and annually for 5 years

19 Key Inclusion Criteria Subject > 18 and < 80 years of age. Subject asymptomatic no stroke or TIA (hemispheric or ocular) within the 180 days prior to the procedure neurologist must confirm status Carotid stenosis 70% and 99% by carotid duplex (accredited lab) or angiography (visual estimate)

20 Key Exclusion Criteria Clinical Bilateral significant carotid stenosis (contralateral stenosis > 60% by duplex or angiography) High risk surgical candidate Known cardiac sources of emboli

21 Key Exclusion Criteria Anatomical/angiographic Tortuosity and/or occlusive disease that might preclude the safe introduction of a guiding catheter/sheath, cerebral protection device, or stent. Severe tortuosity defined as 2 or more >90 degree bend points within 3cm of the target stenosis. If ICA branches from the CCA as a 90 degree angle, this is considered one o bend Aortic arch anatomy unacceptable for carotid stent placement Presence of carotid artery dissection, aneurysm, pseudoaneurysm, arteritis or fibromuscular dysplasia (FMD) in target vessel Occlusion or string sign of carotid artery Excessive calcification at lesion

22 Primary Endpoint Composite Any stroke*, myocardial infarction and death during 30 day post procedural period Ipsilateral stroke* between 31 and 365 days post procedure *Independent neurologic assessment

23 Secondary Endpoints Acute device success Procedural success Prespecified composite c morbidity index: cranial nerve injury bleeding, vascular and/or wound complications requiring treatment access artery, renal, airway and general anesthesia complications Freedom from ipsilateral stroke and mortality at 2, 3, 4 and 5 years Freedom from clinically indicated target lesion revascularization (TLR)

24 Current Study Support Co Principal Investigators Executive Committee Duplex Ultrasound Core Laboratory ECG Core Laboratory Angiographic Core Lab Data Coordinating Center (EDC) Clinical Events Committee Chair Jon Matsumura Kenneth Rosenfield Gary Ansel (SMC Chair), Seemant Chatavurdi, Tom Riles (IMC Chair), Larry Wechsler Michael R. Jaff Vascular Ultrasound Core Laboratory Peter Zimetbaum Harvard Clinical Research Institute Alexandra Lansky Cardiovascular Research Foundation MedNet Solutions Don Cutlip Harvard Clinical Research Institute

25 Asymptomatic Carotid Trial (ACT) Prospective, multi-center, 3:1 randomize (CAS:CEA) Asymptomatic subjects: single de novo lesion within the ICA with or without involvement of the common carotid artery standard risk for CEA & CAS stenosis 70% and 99% by angiography or duplex ultrasound Randomized patients 1,858 Subjects ~ 50 US Sites Roll-in patients N=200 CAS N=1,244 CEA N=414 Clinical & Neuro follow-up Duplex Ultrasound 30d 6mo 12mo 2yr 3yr 4yr 5yr Primary endpoint: Non inferior to CEA using 30 day MAE and ipsi stroke between day rate (4.5%) with equivalence limit of 3.0%; 80% power; =0.05 Platelet inhibition: Clopidogrel 75mg daily min 1 mo., ASA daily indefinitely

26 ACT 1: Patient Demographics Lead in Patients Characteristic N=118 Mean Age 68 % Male 59% Diabetes Mellitus 34% Hypertension requiring medication 81% Hypercholesterolemia requiring medication 84% CAD 59% Cardiac Arrhythmia 14% MI 25% Current Smoker 31% Current Contralateral Disease 47% Previous Coronary Stenting or Angioplasty 34% Renal Insufficiency 9% Previous CABG 25% PAD 33%

27 Core Labs Angio Lesion Morphology Characteristic Pre Procedure (n=118) Post Procedure (n=118) Diameter Stenosis 72.0% 25.7% (mean) Lesion Length 19.9mm NA Calcification None or mild Moderate Severe 73.8% 15.5% 10.7% NA Ulcerated 18.3% NA Thrombus 0.0% 0.0% 30 Day Duplex Proximal ICA Patent 1 49% 50 79% 80 99% Occluded Target Lesion Stenosis 1 49% 50 79% 80 99% Occluded 30 day (n=111) 97.3% (108/111) 2.7% (3/111) 0.0% 0.0% 0.0% 2.7% (3/111) 2.7% 0.0% 0.0% 0.0%

28 S 20mm x 8mm S 20mm x 9mm S 30mm x 10mm S 30mm x 7mm S 30mm x 8mm S 30mm x 9mm T 30mm x 10-8mm T 30mm x 8-6mm T 30mm x 9-7mm T 40mm x 10-8mm T 40mm x 8-6mm T 40mm x 9-7mm Stent Usage S - straight T - tapered 3 patients received 2 stents S 20mm x 7mm # devices used

29 ACT 1: Lead In Patients Event 30 days, N=118 Death, Stroke and MI* 1.7% 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=77 Ipsilateral Stroke 0.0% *Hierarchical Includes only the most serious event for each patient and includes only each patient s first occurrence of each event

30 Summary Randomized trials help define the best therapy for patients ACT 1 will focus on evaluating CAS in the majority of patients with carotid stenosis having operative treatment: Asymptomatic patients excludes high risk for CEA protocol defined excludes high risk for CAS protocol defined surgeon and interventionalist criteria are strict and verified standardized protocol: routinely uses embolic protection central corelabs, independent audit