Is Carotid Stenting an Option for Treatment of Carotid Stenosis? Joint Hospital Surgical Grand Round WH WONG Queen Mary Hospital

Carotid stenosis- pathophysiology Early degenerative plaque formation (cholesterol/ lipids/ inflammatory cells) ⇓ ulceration/ haemorrhage Flow limiting stenosis ⇙⇘ ThrombosisEmbolism Spagnoli LG et al., JAMA 2004

Investigation modalities Carotid duplex ultrasonography diagnostic study of choice for screening very accurate predictability for high grade lesion (70% stenosis) CT/ MRI angiography useful in collaboration with USG for further characterization of lesion producing >50% stenosis Cerebral angiography gold standard for accurate characterization of plaque and collateral circulation

Treatment modalities Risk factors modification Best medical therapy Surgical treatment

Risk factors modification Hypertension OR of 2.11 for every 20mmHg increase in systolic pressure Dyslipidaemia OR of 1.1 for every 10mg/dL in cholesterol Diabetes Smoking OR of 1.08 for every 5 pack-years of smoking Stroke 1990 N Engl J Med 1997 Circulation 2004

Best medical therapy: Antiplatelets Antithrombotic Trialists’ collaboration (BMJ 2002) Aspirin reduces the risk of TIA/ stroke/ death as monotherapy in high-risk patients Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) (Circulation 2005) Combination therapy reduces the incidence of asymptomatic embolization

Surgical treatment Carotid endarterectomy (CEA) ?? Carotid angioplasty and stenting (CAS)

Superiority of CEA: Asymptomatic stenosis Veterans Affairs Cooperative Trial (N Engl J Med 1993) 444 patients, asymptomatic stenosis >50%, Aspirin + CEA vs Aspirin Lower incidence of ipsilateral stroke/ TIA (8.0% vs 20.6%, P< 0.001) No difference in mortality in 30 days and 4 years Asymptomatic Carotid Atherosclerosis Study (ACAS) (JAMA 1995) 1662 patients, asymptomatic stenosis > 60%, Aspirin +CEA vs Aspirin Cerebral infarction decreased in surgery group (5.1% vs 11%) Asymptomatic Carotid Surgery Trial (ACST) (Lancet 2004) 3120 patients, asymptomatic stenosis >60% 5 years risk reduction in stroke/ death in CEA group (6.4% vs 11%)

Superiority of CEA: Symptomatic stenosis North American Symptomatic Carotid Endarterectomy Trial (NASCET) (N Engl J Med 1998) randomised, prospective multicentre trial of 659 patients with symptomatic stenosis >70% lower cumulative risk of any ipsilateral stroke at 2 years (9% vs 26%, P< 0.001) reduction in rate of major/ fatal stroke in 2 years (2.5% vs 13.1%, P< 0.001) European Carotid Surgery Trial (ECST) (Lancet 1998) 2518 patients surgery benefits most to patients with severe stenosis >70%

Superiority of CEA American Heart Association American Stroke Association Grade IA indication for CEA in carotid stenosis >70% regardless of symptom status Grade IIA recommendation for CEA in asymptomatic men aged of years with >60% stenosis Surgery in only symptomatic women Circulation, 2006

Any place for CAS?

Background of CAS First successful carotid angioplasty by Klaus Mathias in 1980 Angioplasty without stent placement: poor results and complications Primary adverse event in carotid atherosclerosis is embolization of plaque material Stenting provides effective means of mechanical “plaque stabilization” Carotid angioplasty with stenting readily replaces lone balloon angioplasty

CAS in symptomatic carotid stenosis Stent-Protected Angioplasty vs Carotid Endarterectomy (SPACE) Trial randomized multi-centre non-inferiority trial 1183 patients with severe symptomatic stenosis (>70%) no significant difference between CAS and CEA in 30-day rate of stroke (6.84% vs 6.34%) 30-day rate of any stroke or death (7.7% vs 6.5%) 1 year rate of any stroke or death (9.6% vs 8.7%) Failed to show non-inferiority of CAS in treatment of severe carotid stenosis SPACE Collaborative Group, Lancet 2006

CAS in symptomatic carotid stenosis Endarterectomy vs Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) Trial randomized multi-centre non-inferiority trial 527 symptomatic patients with severe stenosis (60-90%) 30-day rate of any stroke or death in CAS and CEA: 9.6% vs 3.9% Failed to establish non-inferiority of CAS vs CEA N Engl J Med 2006

CAS in symptomatic carotid stenosis International Carotid Stenting Study (ICSS) randomized controlled trial of 1713 patients recently symptomatic carotid stenosis >50% determine long-term survival free of disabling stroke sufficient follow-up to be complete in day rate of stroke/ MI/ death of CEA and CAS: (5.1% vs 8.5%, hazard ratio 1.73, P=0.004) Clear superiority of CEA over CAS Cerebrovasc Dis 2009

CAS in asymptomatic carotid stenosis Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) Trial randomized multi-centre trial of 334 patients 68% patients asymptomatic with stenosis >80% 32% patients symptomatic with stenosis >50% high risks: > 80 years/ significant heart or pulmonary disease/ contralateral carotid occlusion/ laryngeal nerve palsy/ prior radical neck surgery/ radiotherapy/ post-CEA restenosis 30-day MI/ stroke/ death rate for CAS/ CEA: 4.8% vs 9.8%, P= year MI/ stroke/ death rate for CAS/ CEA: 12.2% vs 20.1%, P=0.048 CAS not inferior to CEA in treatment of high risk group SAPPHIRE Investigators, N Engl J Med 2004

CAS in both asymptomatic and symptomatic carotid stenosis Carotid Revascularization Endarterectomy vs Stent Trial (CREST) prospective randomized multicentre trial of 2502 patients 108 centres in the USA 9 centres in Canada both symptomatic (>50%) and asymptomatic (70%) carotid stenosis exclusion criteria: previous stroke severe enough to confound assessment of end-points atrial fibrillation within 6 months/ necessitates anticoagulation myocardial infarction within 30 days/ unstable angina CREST Investigators, N Engl J Med 2010

During the periprocedure period, the incidence of the primary end- point was similar (5.2% vs 4.5%, hazard ratio for CAS, 1.18; P=0.01) myocardial infarction more in CEA group (1.1% vs 2.3%, P=0.03) stroke more in CAS group (4.1% vs 2.3%, P=0.01) No significant difference from estimated 4-year rates of the primary end-point (7.2% vs 6.8%, hazard ratio for CAS, 1.11; P=0.51) stroke rate in CAS still higher (6.4% vs 4.7%, P=0.03) Findings from CREST

No modification of treatment effect by symptomatic status (P=0.84) gender (P=0.34) Findings from CREST

Interaction between age and treatment effect (P=0.02) vascular tortuosity severe vascular calcification

Findings from CREST

CAS is associated with higher periprocedural risk of stroke, still significantly evident at 4 years CEA is associated with higher periprocedural myocardial infarction and cranial palsies Incidence of primary outcomes in both CAS and CEA is impressively low importance of training, credentialing & auditing of proceduralists Selection for treatment requires attention to age younger patients have better outcomes with CAS older patients have better outcomes with CEA Conclusion from CREST

Take home message Strength of recommendation Grade 1:strong Grade 2:weak Quality of evidence High:well conducted, large consistent RCTs Moderate:inconsistent RCTs, observational studies Low:observational studies, case series

Clinical guideline Low grade stenosis (symptomatic <50%/ asymptomatic <60%) optimal medical treatment (grade 1 recommendation; high quality evidence) Symptomatic moderate to severe stenosis (>50%) CEA + optimal medical treatment (grade 1 recommendation; high quality evidence) Symptomatic moderate to severe stenosis (>50%) & high risk CAS as an potential alternative to CEA (grade 2 recommendation; low quality evidence) Asymptomatic moderate to severe stenosis (>60%) CEA + optimal medical treatment (grade 1 recommendation; high quality evidence) Against CAS except stenosis >80% or high anatomical risk for CEA (grade 1 recommendation; low quality evidence) J Vasc Surg 2008

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