ANGIOPLASTY & STENTING FOR EXTRACRANIAL & INTRACRANIAL ATHEROSCLEROTIC DISEASE 2010 UPDATE MICHEL E. MAWAD, M.D. PROFESSOR & CHAIR DEPARTMENT OF RADIOLOGY BAYLOR COLLEGE OF MEDICINE ST. LUKE ’ S EPISCOPAL HOSPITAL TEXAS HEART INSTITUTE HOUSTON, TEXAS

Introduction 80% of strokes are ischemic in nature. Carotid stenosis (CS) accounts for approximately 30% of ischemic strokes Incidence of CS increases with age from approximately 0.5% in the sixth decade to 10% in people >80 years. The most recent American Heart Association guidelines recommend CEA for symptomatic pts with CS ≥ 50% if the perioperative risk of stroke or death is <6%, and for asymptomatic pts with CS ≥ 60% if the perioperative risk of stroke or death is <3%.

BACKGROUND INFORMATION

CEA/CAS Randomized Controlled Trials ICSS CREST

CEA/CAS BACKGROUND INFORMATION

Leicester J Vas Surg. Naylor et al, 1998 First published prospective randomized trial comparing CEA and CAS. Single-center from UK randomized symptomatic CS >70%. All CAS arm received stents, none with distal protection device. Trial stopped at 23 pts randomized (11 CAS, 12 CEA). Only 17/23 received allocated treatment at that time. 10/17 underwent CEA without complication. Remaining 7/11 underwent CAS, 5 suffered strokes. Stroke and death rate for the CAS group in this study was 45% (5 out of 11) compared with 0% for CEA. Although prospective, randomized study, but single-center and small sample to draw any meaningful conclusions.

CAVATAS Lancet First multicenter RCT comparing CEA and CAS. Stenting was rolled late into the trial. 24 centers in Europe, Australia, and Canada enrolled 504 pts. High-risk surgical pts were excluded. Mixed symptomatic and asymptomatic pts. 253/504 randomized to CEA and 251/504 to endovascular tx (65 received stents, 26%). No distal protection device. Results: No statistically significant difference between both arms in the rate of stroke, death or MI within 30 days and 1-year stroke or death rates Encouraging results generated interest in CAS, and inspired more studies to be undertaken.

First multicenter RCT in United States comparing CEA and CAS. Began in 1996, randomized 219 symptomatic pts (CS ≥ 60% within 120 days of sxs). Pts were not stratified according to their operative risk. All CAS arm 112/219 received stents without protection device. 107/219 pts underwent CEA. Results: Stroke and death at 30 days and 1-year follow-up were significantly lower for CEA vs CAS. Therefore, trial was prematurely stopped Concerns were raised about the lack of experience of the endovascular operators. WALLSTENT Stroke. 2001

KENTUCKY Brooks. 2001,2004 Single-center prospective randomized trial published 2001 All pts were symptomatic CS >70%, all CAS arm received stents without distal protection. Total 104 pts, 51/104 CEA and 53/104 CAS. A separate series published 2004 included asymptomatic arm. Total 85 pts, 43/85 CEA and 42/85 CAS. Results: 1 pt died from MI following CEA in sxs group. No other deaths or strokes in either arms treated with either stenting or surgery. 24 months using carotid duplex revealed no differences between 2 groups with regard to re-stenosis or recurrence of symptoms.

SAPPHIRE N Engl J Med 2004, 2008 First RCT comparing CEA with CAS using distal protection. Multicenter, prospective, randomized trial based in United States set out to prove CAS with distal protection was not inferior to CEA in patients at high risk for surgery. 747 pts enrolled , asymptomatic CS ≥ 80% and symptomatic CS ≥ 50%. 334/747 pts placed in the randomized arm, remaining 413 into either a stent or surgical registry. Inclusion criteria (included symptomatic eligibility) and exclusion criteria.

SAPPHIRE N Engl J Med /334 underwent CEA and 167/334 underwent CAS. No demographic or baseline medical history differences between groups; (71%) asymptomatic and approximately 20% of pts > 80 yrs. Primary endpoint death, stoke, and MI. 30-day stroke/death/MI rates: CAS (4.8%) vs. CEA (9.8%) (P =.09). At 1 year, CAS (12.2%) suffered a stroke, MI, or death vs. CEA (20.1%) (noninferior analysis: P =.048). In addition to achieving noninferiority, rates of target vessel revascularization and cranial nerve palsy favored stenting.

SAPPHIRE N Engl J Med 2008 Reported 3-year results Data available 260/334 pts (77.8%), 86% CAS group and 70% CEA group. The prespecified major secondary endpoint at 3 yrs: composite of stroke death and MI within 30 days or death or ipsilateral stroke days Not statistically different. Excluding MI within 30 days of the procedure and deaths from nonneurologic causes, the 3-year stroke, death, MI rate was 8.4% for CAS and 9.0% for CEA. Conclusion: Pts with severe CS and increased surgical risk, no significant difference could be shown in long-term outcomes between patients who underwent CAS with embolic protection device and those who underwent CEA.

CaRESS J Endovasc Ther 2003 Multicenter, prospective but nonrandomized trial to prove equivalence between CAS with cerebral protection and CEA quickly followed SAPPHIRE. Enrollment began in Treatment procedure was chosen by treating physician and patient with 2:1 ratio of CEA:CAS. All patient subsets were permitted, symptomatic, asymptomatic, low risk, and high risk. 379 pts enrolled (CEA = 254; CAS = 143), 32% symptomatic. Nonrandomization likely introduced selection bias however, it represents a generalized perspective on carotid revascularization and more closely resembles its “real world” application as dictated by local practice. Baseline demographics were similar except patients with previous surgery more often received CAS.

CaRESS J Endovasc Ther 2003 Results: No statistically significant difference 30-day and 1-year death and stroke rates between CAS and CEA (2.1% vs 3.6% and 10.0% vs 13.6%, respectively). No differences with respect to re-stenosis, residual stenosis, repeat angiography, and need for carotid revascularization. Overall morbidity and mortality approached those of NASCET and ACAS standards and represented the lowest rates among major CAS trials to date. The low stroke and death rates may be attributable to the ability of the treating physician to consider patient- specific factors and choose the most appropriate treatment for each individual patient. A larger phase II CaRESS trial has been planned but not yet initiated.

SPACE Lancet 2006 To establish noninferiority for CAS in symptomatic pts with CS ≥ 50% and with low surgical risk. Multicenter randomized trial throughout Germany, Austria, and Switzerland. Primary endpoints were ipsilateral ischemic stroke or death from randomization to 30 days post procedure. All patients received aspirin preprocedure pts randomized, 595 to CEA and 605 to CAS.

SPACE Lancet 2006 At 30 days, ipsilateral stroke or death was not different, 6.35% for CEA and 6.8% for CAS (P =.09). Distal protection used only in 27%; subgroup analysis showed no difference between pts with cerebral protection and those without. Stroke 2009 The trial was stopped as result of interim analysis demonstrated that 2500 patients would be needed to reach significance and determine noninferiority of CAS given the results up to that point. The SPACE steering committee acknowledged a lack of funds to expand enrollment to 2500 and therefore suspended the trial. In the final analysis, the SPACE trial failed to prove noninferiority of stenting versus endarterectomy as measured by stroke/death rates at 30 days post procedure in symptomatic patients with CS.

SPACE Lancet Neurol patients were randomly assigned (613 CAS and 601 CEA). At 2 years follow-up: Primary and secondary endpoints were similar. Recurrent stenosis (70% ECST) defined by ultrasound was more frequent in CAS group. Only two incidences of recurrent stenosis after carotid artery stenting led to neurological symptoms.

SPACE 2006,2008 Interpretation: Symptomatic pts with CS and low surgical risk, SPACE failed to prove noninferiority of CAS for lack of power from 1214 patients recruited. However, there was no statistical difference in the rate of outcome events These results can be interpreted differently: A vascular surgeon may point out that an equal effect between CEA and CAS was not shown with SPACE because equivalence was missed (P0.09, one-sided value for noninferiority). Interventionalists have focused on the fact that there was no statistical difference in the outcome event rates between CEA and CAS (P0.81, ChiSquare test)

EVA-3S N Engl J Med 2006 Similar to the SPACE trial, RCT designed to assess noninferiority of CAS versus CEA in low-risk, symptomatic patients with CS ≥ 60%. Multicenter study conducted in France. Primary endpoint was 30-day stroke or death. The study was stopped after enrollment of 527 pts for reasons of safety and futility. Primary endpoint was 3.9% CEA vs. 9.6% CAS (P =.01). Protection devices was not required initially. Pts treated without protection had 25% rate of stroke or death at 30 days (5/20), prompting protocol changes. CAS operators had unequal experience compared to surgeons performing CEA.

EVA-3S N Engl J Med 2006 Risk was 9.6% higher than other RCTs. The absolute risk increase of stenting was 5.7%, and for every 17 cases treated with CAS rather than CEA, 1 additional stroke or death occurred at 30 days post procedure. The overall incidence of disabling stroke within 30 days was 3.4% for CAS, 1.5% for CEA. A significantly greater proportion of strokes occurred on the same day of the procedure in the stenting group than in the surgical group (P =.05). Conclusion: Patients with symptomatic CS of ≥60%, CAS was inferior to CEA with respect to the incidence of stroke and death at 30 days post procedure??

ICSS/CAVATAS-2 Lancet Feb 25. International Carotid Stenting Study: An interim analysis. CAS vs. CEA in patients with symptomatic carotid stenosis. Patients are low-risk equally suited for CAS or CEA Multicentre, international, randomized controlled trial The primary outcome: 3-year rate of fatal or disabling stroke in any territory, which has not been analyzed yet. The main outcome measure for the interim safety analysis:120- day rate of stroke, death, or procedural MI. Analysis was by intention to treat (ITT).

1713 patients (CAS 855; CEA 858). Disabling stroke or death: CAS 4.0% vs. CEA 3.2% (hazard ratio [HR] 1.28, 95% CI ). Stroke, death, or procedural MI: CAS 8.5% vs. CEA 5.2% (HR 1.69, , p=0.006). Risks of any stroke (CAS 65 vs CEA 35 events; HR 1.92, ) and all-cause death (CAS 19 vs CEA 7 events; HR 2.76, ) ICSS/CAVATAS-2

Procedural MI: CAS 3 all fatal; CEA 4 all non-fatal. Cranial nerve palsy CAS 1; CEA 45. There were fewer hematomas of any severity in the stenting group than in the endarterectomy group (31 vs. 50 events; p=0.0197). Conclusion: Completion of long-term follow-up is needed to establish the efficacy of CEA vs. CAS. Meanwhile, CEA should remain the treatment of choice for patients suitable for surgery. ICSS/CAVATAS-2

Endpoint CAS No. (%) CEA No. (%) Hazard Ratio (95% CI)P Value Disabling stroke or death 34 (4.0)27 (3.2)1.28 (0.77 – 2.11).34 Stroke, death, or procedural MI 72 (8.5)44 (5.2)1.69 (1.16 – 2.45).006 Any stroke 65 (7.7)35 (4.1) 1.92 (1.27 – 2.89).002 All-cause death 19 (2.3)7 (0.8) 2.76 (1.16 – 6.56).017 ICSS: 120-Day Interim Safety Results

ICSS/EVA-3S/SPACE META-ANALYSIS Lancet 2010;376: Endpoint CASCEA Risk Ratio (95% CI) P Any stroke or death to 120 days, No. (%) 153 (8.9)99 (5.8) 1.53 (1.20 – 1.95).0006

ICSS/EVA-3S/SPACE META-ANALYSIS Lancet 2010;376: Flow diagram of patients in trials included in the meta-analysis

Lancet 2010;376: Meta-Analysis Outcomes by Age : Median Age CASCEARisk Ratio (95% CI) P for trend ITT Analysis <70 years50 (5.8)48 (5.7)1.00 (0.68 – 1.47) ≥70 years103 (12.0)51 (5.9)2.04 (1.48 – 2.82).0014 PP Analysis <70 years43 (5.1)37 (4.5)1.11 (0.73 – 1.71) ≥70 years87 (10.5)36 (4.4)2.41 (1.65 – 3.51).0013

CREST Carotid Revascularization Endarterectomy versus Stenting Trial Prospective randomized CEA vs. CS as prevention of stroke in sxs & asxs patients Composite primary endpoint of any periprocedural stroke/MI/death OR ipsilateral stroke on f/u n = centers North America (CEA 1240, CS 1262)

Primary endpoint (CAS 7.2% vs. CEA 6.8%) nss Individual risks: 30 d. any stroke rate (CAS 4.1% vs. CEA 2.3%) ss Though Major strokes < 1% both groups nss Periprocedural MI (CAS 1.1% VS. CEA 2.3%) ss Ipsilateral mean f/u (2.5y): (CAS 2.0% vs. CEA 2.4%) nss Cranial nerve palsy: (CAS 0.3% vs. CEA 4.8%) ss CREST Results

Age effect: > 69yr better outcome with CEA < 69yr better outcome with CAS Gender effect: No difference Symptoms effect: No difference Sxs: 53% within 180 d. > 70% u/s; > 50% DSA Asxs: 47% 60% DSA CREST Results

EndpointCASCEA Hazard Ratio (95% CI) P Value Primary endpoint (0.81 – 1.51).51 Primary endpoint: periprocedural components: Periprocedural stroke and MI (0.82 – 1.68).38 Any periprocedural stroke (1.14 – 2.82).01 Periprocedural major stroke (0.54 – 3.36).52 Periprocedural MI (0.26 – 0.94).03 Cranial nerve palsies (0.02 – 0.18).0001 Ipsilateral stroke after periprocedural period mean 2.5yrs (0.50 – 1.76).85 CREST: Primary, Secondary, and Safety Endpoints

CAS/CEA - WHERE DE WE STAND? EVA 3S Conclusion: Patients with symptomatic CS of ≥60%, CAS was inferior to CEA with respect to the incidence of stroke and death at 30 days post procedure?? ICSS Conclusion: CEA should remain the treatment of choice for patients suitable for surgery. CREST Conclusion: 30 d. any stroke rate (CAS 4.1% vs. CEA 2.3%) ss Major strokes < 1% both groups nss Periprocedural MI (CAS 1.1% VS. CEA 2.3%) ss

Lancet 2010;376: Median Age CASCEARisk Ratio (95% CI) P for trend ITT Analysis <70 years50 (5.8)48 (5.7)1.00 (0.68 – 1.47) ≥70 years103 (12.0)51 (5.9)2.04 (1.48 – 2.82).0014 PP Analysis <70 years43 (5.1)37 (4.5)1.11 (0.73 – 1.71) ≥70 years87 (10.5)36 (4.4)2.41 (1.65 – 3.51).0013 ICSS/EVA-3S/SPACE META-ANALYSIS CREST Results Age effect: > 69yr better outcome with CEA < 69yr better outcome with CAS

Type III Aortic Arch &/ or severe disease has its own set of embolic potential! Avoid : Excessive catheter Manipulation! Especially: Secondary Curve Catheters!

Beware of Calcium!!

RECENT CVA UNCONTROLLED HYPERTENSION CHRONIC SEVERE STENOSIS UNDERLYING FRAGILE HYALINIZED INTRACRANIAL ARTERIES EXCESSIVE ANTICOAGULATION EXCESSIVE RESPONSE TO ANTIPLATELET THERAPY HEMORRHAGIC COMPLICATIONS