CEA

Symptomatic

NASCET (1991) [1]^,[2]

• Prospective, randomized
• 2226 patients who had TIAs or stroke within 4 months of enrollment.
• Looked at symptomatic pts with stenoses 30-99% and whether they have fewer fatal and nonfatal strokes after CEA (1108 patients) than patients treated medically (1118 patients).
• Also stratified to study 2 patient populations: 70-99% stenoses and 30-69% stenoses.

For high-grade lesion population (70-99%)

• 30-day CEA M&M = 5%
• Medical treatment group stroke rate = 24%
• CEA treatment group stroke rate = 7%
• Absolute risk reduction = 17%
• Relative risk reduction = 71% with surgery.
• Mortality rate in medical group = 12%
• Mortality rate in CEA group = 5%
• Relative mortality risk reduction = 58%
• 30-day rate of death or disabling ipsilateral stroke persisting at 90 days = 2.1%. This increased to 6.7% at 8 years.

For lower-grade lesion population (30-69%)

• 30-day M&M = 6.7%
• 5-year ipsilateral stroke rate in CEA group = 15.7%
• 5-year ipsilateral stroke rate in medical group = 22%
• Beneficial effect for stenosis 50-69% but NOT <50%.

VA Symptomatic Trial (1991) [3]

• Prospective, randomized
• 189 patients
• Medial group stroke rate = 19.4% stroke or crescendo TIAs
• CEA group stroke rate = 7.7% stroke or crescendo TIAs
• Study halted earlier than expected because the results of ECST and NASCET came out.

ECST (1991) [4]

• Prospective, randomized
• 2518 patients
• Stratified into 3 groups: (10-29%), (30-69%), and (70-99%)
• Different method of calculating %stenosis than NASCET.
• Significant benefit of CEA in (60-90%).
• 6X reduction in subsequent strokes over 3-year period.

Asymptomatic

CASANOVA (1991) [5]

• Prospective, randomized
• 410 patients
• Concluded CEA gave no benefit to asymptomatic patients.
• But high-risk patients were excluded
• 118 of 206 (57%) of patients randomized to medical treatment were withdrawn as they became “high risk” and were treated surgically. But they were counted as being treated “medically”.
• NO conclusions can be drawn from this study.

VA Asymptomatic Carotid Stenosis Study (1993) [6]

• Prospective, randomized
• 444 pts (too few pts to make a definitive statement about stroke prevention alone).
• 4.7% ipsilateral stroke rate in CEA group
• 8.6% ipsilateral stroke rate in medical group
• This difference is just short of statistical significance.
• No difference in survival rate.
• CEA + ASA more effective than ASA alone in reducing combined incidence of TIAs and stroke in pts with stenosis of >50%.

ACAS (1989) [7]

• Prospective, randomized
• 1622 pts
• Stenoses 60-99% by angio
• Risk of ipsilateral stroke for medical group = 11%
• Risk of ipsilateral stroke for CEA group = 5.1%
• Relative risk reduction of 53%
• Absolute risk reduction of 1% per year.
• CEA mortality = 0.14%
• CEA stroke rate = 1.38%
• 30-day stroke M&M rate = 1.52%

ACST (1994) [8]

• Prospective, randomized
• 3128 pts
• Stenoses >70% by U/S
• Risk of 5-year stroke in medical group = 11%
• Risk of 5-year stroke in CEA group = 3.8%
• Risk of 30-day stroke or death for CEA group = 3.1%
• In pts 75 years or older with stenosis >70%, CEA reduced stroke risk by 50%.

CAS

Prospective, randomized trials comparing CAS to CEA

1. CAVATAS (2001) [9]

1. Randomized, prospective
2. 504 patients, CAS for 251 patients, CEA for 253 patients.
3. In CAS àstents in 26%, balloon angioplasty alone in 74%
4. 30-day rate disabling stroke or death for CEA = 5.9%
5. 30-day rate disabling stroke or death for CAS = 6.4%
6. 30-day rate for any stroke >7 days (not just disabling) or death for CEA = 9.9%
7. 30-day rate for any stroke >7 days (not just disabling) or death for CAS = 10%
8. Cranial neuropathy in 8.7% CEA pts, 0% CAS pts
9. Major groin or neck hematoma in 6.7% CEA pts, 4% CAS pts
10. 1 year after treatment, 70-99% ipsilateral recurrent stenosis more frequent after CAS than CEA (14% vs. 4%).
11. But no difference in rate of ipsilateral stroke due to recurrent stenosis.
12. Bottom line: CAS has similar major risks and effectiveness at stroke prevention over 3 years compared to CEA.

2. SAPPHIRE (2004) [10]

1. Showed benefit of CAS using DEPD
2. 334 patients
3. Precise stent + AngioGuard (Cordis)
4. Asymptomatic patients with stenoses >80%
5. Symptomatic patients with stenoses >50%
6. 30-day stroke and death rate for CEA= 7.3%
7. 30-day stroke and death rate for CAS + DEPD = 4.4%
8. Proved CAS + DEPD was NOT inferior to CEA.
9. 3-year follow up data[11]:
1. Data available for 260 patients
2. Major secondary endpoint at 3 years = composite of death, stroke, or MI within 30 days after procedure or death or ipsilateral stroke between 31 days and 3 years.
3. 24.6% incidence of secondary endpoint in CAS group.
4. 26.9% incidence of secondary endpoint in CEA group.
5. No significant difference seen in long-term outcomes between CAS and CEA.

3. EVA-3S (2006) [12] (trial stopped)

1. Randomized, multicenter, non-inferiority trial
2. 527 pts (target was 872)
3. Trial stopped for safety & futility
4. Symptomatic patients with at least 60% stenosis
5. Primary endpoint: 30-day stroke or death

f. The 30-day incidence of disabling stroke or death was 1.5% after CEA

g. The 30-day incidence of disabling stroke or death was 3.4% after CAS

8. RR 2.5 for CAS versus CEA for any stroke or death
9. RR 2.2 for CAS versus CEA for disabling stroke or death.
10. Bottom line: CAS has significantly higher stroke rate than CEA
11. 4-year follow-up data[13]:
1. Cummulative probability of periprocedural stroke or death and non-procedural ipsilateral stroke after 4 years 11.1% for CAS, 6.2% for CEA.
2. This is largely due to higher periprocedural (within 30 days of procedure) risk of CAS compared to CEA.
3. After periprocedural period, risk of ipsilateral stroke was low and similar in both CAS and CEA
4. CAS is as effective as CEA for middle-term prevention of ipsilateral stroke, but safety needs to be improved.

4. SPACE (2006) [14]

1. Randomized, prospective, non-inferiority trial
2. 1183 patients
3. Symptomatic carotid stenosis, within 180 days of TIA or moderate stroke.
4. 30-day death or ipsilateral stroke rate 6.84% for CAS
5. 30-day death or ipsilateral stroke rate 6.34% for CEA
6. Failed to prove non-inferiority of CAS vs. CEA.
7. 2-year follow-up data[15]:
1. 1214 patients
2. No difference between CAS and CEA in rate of ipsilateral stroke 2 years out.
3. Recurrent stenosis >70% significantly more frequent in CAS vs. CEA (10.7% vs. 4.6%)

Several Registries of CAS patient who were deemed high-risk for CEA.

Definition of “high risk” (as per SAPPHIRE trial):

• CHF (class III or IV) or known severe LV dysfunction (EF<30%)
• Open heart surgery needed within 6 weeks
• Recent MI (>24 hr and <4 wk)
• Unstable angina (class III or IV)
• Severe pulmonary disease
• Contralateral carotid occlusion
• Contralateral laryngeal nerve palsy
• Radiation therapy to neck
• Previous CEA with recurrent stenosis
• High cervical ICA lesions or CCA lesions below the clavicle
• Severe tandem lesions
• Age older than 80 years

1. ARCHeR (ARCHeR 1 = no DEPD, ARCHeR 2 = with DEPD, ARCHeR 3 = Rapid exchange system for CAS + DEPD) (2003) [16]

1. Prospective, non-randomized, multicenter, single-arm trial
2. 513 pts @ 41 sites
3. AccuLink (Guidant)
4. CAS is safe & effective in high-risk patients
5. 30-day stroke or death rate = 3.8%, 2.5%, 2.8% (ARCHeR 1,2,3)

2. SECURITY (2003) [17]

1. Prospective, non-randomized, single-arm trial
2. 305 pts
3. Xact + NeuroShield (Abbott)
4. 30-day Death, stroke, and MI rate = 7.2% (vs. 11-15%)

7. CaRESS (2003) [22]

1. Prospective, randomized
2. Determine if stroke and death rates after CAS + DEPD were comparable to those for CEA in treating all patient with symptomatic (>50%) and asymptomatic (>75%) stenoses.
3. 397 pts
4. Wallstent + GuardWire (ISES)
5. 30-day combined all-cause mortality and stroke rate for both CEA and CAS = 2%
6. 30-day combined all-cause mortality, stroke, and MI rates = 2% for CAS and 3% for CEA.
7. 1-year combined all-cause mortality and stroke rate = 10% for CAS and 13.6% for CEA
8. 1-year combined all-cuase mortality, stroke, and MI rates = 10.9% for CAS and 14.3% for CEA.

3. CAPTURE (2007) [18]

1. Non-randomized, post-approval trial to uncover unanticipated or rare events.
2. 3500 patients
3. Acculink/Accunet (Guidant)
4. 30-day death, stroke, or MI = 6.3%

4. CREATE (2006) [19]

1. Single-group assignment, safety-efficacy study
2. Protégé stent and SpiderFX filter (ev3)
3. 419 patients
4. 1-year follow-up
5. High-risk patients
6. Stroke, MI, procedure-related contralateral CVA or death within 30 years = 6.2%

5. BEACH (2008) [20]

1. Prospective, non-randomized, single-arm trial
2. 747 pts
3. 4-year follow-up
4. Wallstent + EPI FilterWire (Boston Scientific)
5. Total composite endpoint = 5.8%
6. Symptomatic and asymptomatic patients
7. 1-year composite endpoint = 8.9%
8. CAS with Wallstent + FilterWire is non-inferior to CEA at 1 year in high-risk surgery patients.

6. CABernET (2008) [21]

1. Non-randomized, open-label, intention to treat.
2. NexStent (EndoTex) and Filterwire (Boston Scientific)
3. 488 patients
4. 1 year follow-up
5. High-risk, asymptomatic or symptomatic patients with stenosis >60% by angio (for asymptomatic) or >50% by angio (for symptomatic).
6. 30-day major adverse event rate = 3.8%
7. 96.9% NexStent placement success rate, 99.1% FilterWire placement success rate.

Ongoing & Future Trials (reviewed in Ricotta JJ 2^nd, Malgor RD. Perspect Vasc Surg Endovasc Ther. 2008 Sep; 20(3): 299-308.)

CREST[23]

1. Randomized, prospective, blinded.
2. Inclusion criteria like NASCET
3. 2522 patients enrolled.
4. Asymptomatic patients with >60% stenoses by angio, >70% by U/S, or 80% by CTA or MRA.
5. Symptomatic patients (TIA, amaurosis fugax, or non-disabling stroke within 180 days) with >50% stenosis by angio, >70% by U/S, or >70% by CTA or MRA.
6. CAS associated with 13% stroke and death rate in patients >80 years.
7. Has finished enrolling patients. Analysis pending. Follow-up to last 4 years.

2. ICSS (International Carotid Stenting Study), aka CAVATAS-2

1. Randomized, prospective
2. 1700 patients to be enrolled.
3. To compare risks & benefits of primary carotid stenting vs. CEA for patients at high risk for stroke.
4. Symptomatic patients with stenosis >70%
5. 5-year follow-up

3. ACT 1

1. Randomized, prospective
2. CAS vs. CEA
3. 1858 patients to be enrolled.
4. For asymptomatic carotid stenosis
5. Standard-risk patients.

4. TACIT

1. Randomized, prospective
2. 3500 patients to be enrolled.
3. 3 treatment arms: Medical treatment alone, CEA, CAS.
4. For asymptomatic carotid stenosis >60%
5. Standard-risk patients. High-risk patients excluded.

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[1] North American Symptomatic Carotid Endarterectomy Trial Collaborators: Beneficial effect of carotid endarterectomhy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 325-445, 1991.

[2] Barnett JH, Taylor DW, Eliasziw M, Fox AJ, Ferguson GG, Haynes RB, Rankin RN, Clagett GP, Hachinski VC, Sackett DL, Thorpe KE, Meldrum HE, Spence JD: Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med 1998 Nov 12; 339(2): 1415-25.

[3]Mayberg MR, Wilson SE, Yatsu F, et al, for the Veterans Affairs Cooperative Studies Program 309 Trialist Group: Carotid endarterectomy and prevention of cerebral ischemia in symptomatic carotid stenosis. JAMA 266: 3289, 1991.

[4] European Carotid Surgery Trialists’ Collaboratic Group: Medical Research Council European Carotid Surgery Trial: Interim results for symptomatic patients with severe (70-99%) or with mild (0-29%) carotid stenosis. Lancet 337: 1235, 1991.

[5] The CASANOVA Study Group: Carotid surgery versus medical therapy for asymptomatic carotid stenosis. Stroke 22: 1229, 1991.

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[8]Halliday AM, Mansfield TD: The Asymptomatic Carotid Surgery Trial (ACST): Rationale and design. Eur J Vasc Surg 8: 703-710, 1994.

[9] Endovascular versus surgical treatment in patients with carotid stenosis in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS): A randomized trial. Lancet 2001 Jun 2; 357: 1729-1737.

[10]Yadav JS, Wholey MH, Kuntz RE, et al: Protected carotid-artery stenting versus endarterectomy in high-risk patients. N Engl J Med 351: 1493-1501, 2004.

[11]Gurm HS, Yadav JS, Fayad P, et al.; SAPPHIRE Investigators: Long-term results of carotid stenting versus endarterectomy in high-risk patients. N Engl J Med. 2008 Apr 10; 358(15): 1572-9.

[12]Mas JL, Chatellier GC, Branchereau A, et al: Endarterectomy versus Stenting in Patients with Symptomatic Severe Carotid Stenosis. N Engl J Med 355: 1660-1671, 2006.

[13]Mas JL, Trinquart L, et al.; EVA-3S investigators: Endarterectomy Versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) trial: results up to 4 years from a randomised, multicentre trial. Lancet Neurol. 2008 Oct; 7(10): 885-92.

[14] The SPACE Collaborative Group: 30-day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: A randomised non-inferiority trial. Lancet 2006 Oct 7; 368: 1239-47.

[15] Eckstein HH, Ringleb P, Allenberg JR, Berger J, Fraedrich G, Hacke W, Hennerici M, Stingele R, Fiehler J, Zeumer H, Jansen O: Results of the Stent-Protected Angioplasty versus Carotid Endarterectomy (SPACE) study to treat symptomatic stenoses at 2 years: a multinational, prospective, randomised trial. Lancet Neurol. 2008 Oct; 7(10): 893-902.

[16]Wholey M: The ARCHeR trial: Prospective clinical trial for carotid stenting in high surgical risk patients – preliminary 30-day results. Paper presented at the American College of Cardiology Annual Meeting, March 6-9, 2003, Chicago.

[17]Whitlow P: A registry study to evaluate the MedNova EmboShield bre-wire filter and MedNova Xact self-expanding carotid stent system in patients at high-risk for carotid endarterectomy (SECuRITY trial). Paper presented at TransCatheter Cardiovascular Therapeutics (TCT) Meeting, September 15-19, 2003, Washington, DC.

[18] Gray WA, Yadav JS, Verta P, et al.; CAPTURE Trial Collaborators: The CAPTURE registry: predictors of outcomes in carotid artery stenting with embolic protetion for high surgical risk patients in the early post-approval setting. Catheter Cardiovasc Interv. 2007 Dec 1; 70(7): 1025-33.

[19]Safian RD, Bresnahan JF, et al.; CREATE Pivotal Trial Investigators: Protected carotid stenting in high-risk patients with severe carotid artery stenosis. J Am Coll Cardiol 2006 Jun 20; 47(12): 2384-9.

[20]Iyers SS, White CJ, Hopkins LN, Katzen BT, Safian R, Wholey MH, Gray WA, Ciocca R, Bachinsky WB, Ansel G, Joye JD, Russell ME; BEACH Investigators: Carotid artery revascularization in high-surgical-risk patient using the Carotid WALLSTENT and FilterWire EX/EZ: 1-year outcomes in the BEACH Pivotal Group. J Am Coll Cardiol 2008 Jan 29; 51(4): 427-34.

[21] Hopkins LN, Myla S, Grube E, Wehman JC, Levy EI, Bersin RM, Joye JD, Allocco DJ, Kelley L, Baim DS: Carotid artery revascularization in high surgical risk patients with the NexStent and the Filterwire EX/EZ: 1-year results in the CABERNET trial. Catheter Cardiovasc Interv. 2008 Jun 1; 71(7): 950-60.

[22] CARESS Steering Committee: Carotid revascularization using endarterectomy or stenting systems (CARESS): phase I clinical trial. J Endovasc Ther. 2003 Dec; 10(6): 1021-30.

[23]Yadav JS, Wholey MH, Kuntz RE, et al: Protected carotid-artery stenting versus endarterectomy in high-risk patients. N Engl J Med 351: 1493-1501, 2004.