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Guidelines for Managing Carotid Stenosis
- 1. Guidelines in the Management of Carotid Stenosis Professor Alun H Davies Academic Section of Vascular Surgery, Imperial College, Charing Cross & St Mary’s Hospital, London
- 2. Stroke • Each year 120,000 people suffer 1st stroke • Within 1 year 33% dead • 3rd most common cause of death (UK) Symptoms due to: - Critical Stenosis - Occlusion - Unstable plaque
- 3. Aetiology of Stroke • Ischaemic (80%) - 75% Carotid territory - 50% thrombo-embolism of ICA or MCA - 25% small vessel disease - 15% cardiac embolus, - 10% other: Takayasu’s arteritis, FMD - 15% Vertebrobasillar features - 10% unknown • Haemorrhagic (20%) Under-perform by 2-3 fold CEA/CAS
- 4. Natural history of severe symptomatic and asymptomatic carotid artery stenosis 50 60 70 80 90 100 Golledge J, Greenhalgh RM, Davies AH. Stroke 2000 6 12 18 Time (months) Freedom from ipsilateral stroke (%) ACAS (60-99%) ECST symptomless vessel (70-99%) ECST (80-99%) NASCET (70-99%)
- 5. Life-table analysis of stroke related to presentation 0 10 20 30 40 50 60 70 80 90 100 0 6 12 18 24 30 36 Amaurosis TIA Transient stroke Established stroke Progressive stroke Crescendo TIA Avoidance of stroke (%) Time (months) Golledge J, Cuming R, Beattie DK, Davies AH, Greenhalgh RM JVS 1996
- 6. Life-table analysis of survival related to presenting symptom 0 10 20 30 40 50 60 70 80 90 100 0 6 12 18 24 30 36 Amaurosis TIA Transient stroke Established stroke Progressive stroke Crescendo TIA Survival (%) Time (months) Golledge J, Cuming R, Beattie DK, Davies AH, Greenhalgh RM JVS 1996
- 7. Stroke Risk: NASCET and ECST • 13.1% major ipsilateral stroke at 2 years • 13%/yr for ANY ipsilateral stroke • ECST - 16.2% for ANY ipsilateral stroke at 3 years • Most strokes occur within first year of signal event • Risk is directly proportional to degree of stenosis Stroke, 1999
- 8. 30 Day stoke and death rates following carotid surgery at Charing Cross (CX) and Leicester Royal Infirmary (L) 0 1 2 3 4 5 Pre 1996 1996-2000 C X C X L L Number 460 494 291 500 823 % 2001-8
- 10. Number of stokes saved at 5 years Per 1000 CEAs in 50-99% stenosis Naylor
- 11. Benefit of Urgent Treatment Naylor 2007
- 12. Natural history - stroke rate in asymptomatic carotid artery stenosis Patients with <75% stenosis - annual stroke rate 1.3% Patients with >75% stenosis - annual stroke rate 3.3% Chambers BR, Norris JW Stroke 1991
- 13. Asymptomatic Disease • Stroke risk with asymptomatic stenosis (NASCET) > 60% is 9.9% at 5 yrs < 60% risk stroke 5.4% at 5 yrs • ACST : DEGREE OF STENOSIS 60%-80% = 9.5% risk stroke at 5 yrs 80%-99% = 9.6% risk stroke at 5 yrs • NO INCREASE IN STROKE WITH INCREASE IN STENOSIS • THEREFORE There is NO high risk subgroup of asymptomatic patients based on degree of stenosis
- 14. Asymptomatic stenosis 0 1 2 3 4 5 6 7 8 9 VA ACAS ACE ACST Trial % risk of stroke % medical risk % surgical risk 2004
- 15. ACST
- 17. Single center studies 1990- 1999 Studies Number of arteries PTA 13 714 Endarterectomy 20 6970 Stent used in 44% of patients with cerebral protection in 11% Technical failure in 37 Cases (7%) Golledge J, Mitchell A, Greenhalgh RM, Davies AH Stroke 2000
- 18. 30 Day Stroke or Death Rate 0 1 2 3 4 5 6 7 8 9 Angioplasty Endarterectomy Any stroke or death Disabling stroke or death % Golledge J, Mitchell A, Greenhalgh RM, Davies AH Stroke 2000
- 19. Odds ratio for outcome Any stroke Disabling or fatal stroke TIA Death Any stroke or death Disabling stroke or death 1 2 3 4 5 6 70 Relative odds 2.22 2.09 4.02 0.68 Surgery Angioplasty Golledge J, Mitchell A, Greenhalgh RM, Davies AH Stroke 2000
- 20. CAVATAS CAVATAS trial compared carotid endarterectomy with carotid angioplasty. The rate of any stroke lasting more than 7 days, or death were 9.9% and 10% respectively. CAVATAS investigators Lancet June 2001
- 22. EVAS -3 • RCT • N=527 Stoke/Death Rates • 30 day CEA 1.5 % vs CAS 3.4% RR 2.2 • 6/12 CEA 6.1% vs CAS 11.7% p<0.02 • 4 yrs CEA 6.2% vs CAS 11.1% RR 1.97 p<0.03 Mas et al, 2006 ,2008
- 23. SPACE Trial • n=1200 • CAS n=605 or CEA n=595 • 30 days CAS 6.84% vs CEA 6.34% SPACE failed to prove non-inferiority of CAS compared to CEA. Results do not justify the widespread use in the short term of CAS for treatment of carotid- artery stenosis. Reingleb et al 2006 The incidence of recurrent carotid stenosis at 2 years, as defined by ultrasound, is significantly higher after carotid artery stenting. Older patients do worse with CAS. Eckstein et al 2008
- 24. Carotid endarterectomy was performed with lower stroke and death rates than carotid artery stenting in the USA in 2003 and 2004 • During the calendar years 2003 and 2004, an estimated 259,080 carotid revascularization procedures were performed in the United States. CAS had a higher rate of in-hospital postoperative stroke (2.1% vs 0.88%, P < . 0001) and higher postoperative mortality (1.3% vs 0.39%) than CEA. • For symptomatic patients (8%), the rates for postoperative stroke (4.2% vs 1.1%, P < .0001) and mortality (7.5% vs 1.0%, P < .0001) were significantly higher after CAS McPhee et al, 2007
- 25. Clinical results of carotid artery stenting compared with carotid endarterectomy • Ten trials encompassing 3580 patients were analyzed. Patients who underwent CAS had a higher risk of 30-day stroke/death relative to patients who underwent CEA (risk ratio [RR], 1.30; 95% CI, 1.01-1.67). • Subgroup analysis of trials enrolling only symptomatic patients showed higher risk of 30-day stroke/death (RR, 1.63; 95% CI, 1.18-2.25), but trials enrolling both symptomatic and asymptomatic patients showed no significant differences (RR, 0.89; 95% CI, 0.59-1.35). Brahmandam et al 2008
- 26. Risk-adjusted 30-day outcomes of carotid stenting and endarterectomy: results from the SVS Vascular Registry. • When CAS and CEA were compared in the treatment of atherosclerotic disease only, the difference in outcomes between the two procedures was more pronounced, with death/stroke/MI 6.42% after CAS vs 2.62% following CEA, P < .0001. • Following best possible risk adjustment of these unmatched groups, symptomatic and asymptomatic CAS patients had significantly higher 30-day postprocedure incidence of death/stroke/MI when compared with CEA patients. Sidway et al 2009
- 27. Further on Going Trials • Various RCTs on CEA vs PTA + Stent CAVATAS II ACST II TACIT SPACE II Equipoise!
- 28. Timing of Angioplasty Many suggest wait 6 weeks Assuming similar stroke rate CEA still prevents 170 more strokes per 1000 interventions
- 29. Better out than in !
- 31. 30 Day Stroke Rate 0 1 2 3 4 5 6 7 8 Angioplasty Endarterectomy Any stroke Disabling/ fatal stroke TIA Death % Golledge J, Mitchell A, Greenhalgh RM, Davies AH Stroke 2000
- 32. 2009
- 33. CREST Study Design • RCT of CAS vs CEA • 1:1 randomisation, stratified by centre and symptomatic status • Lead-in credentialing for CAS – N=20 CAS – 427 applicants, 224 (52%) approved to randomise • Primary end-point – composite: – Any stroke, MI (including biochemical) or death within 30 days – Ipsilateral stroke to 4 years • Target recruitment 2,500 • Industry sponsored
- 36. NEJM 2010;363(1):11-23 CREST at 4 Years
- 37. CREST • symptomatic (n=1,321) or asymptomatic (n=1,181) • At 30 days, the rate of stroke was significantly higher with stenting, at 4.1% vs. 2.3% with surgery. • Myocardial infarction was higher with carotid endarterectomy, at 2.3% vs. 1.1% with stenting. • when death and stroke are considered alone, there are almost twice as many events with carotid stenting/angioplasty as there are with carotid endarterectomy. “I do not believe the results of CREST should alter the conclusion that endarterectomy remains the treatment of choice for symptomatic patients” Moore 2010, PI CREST
- 38. CREST Limitations • Composite endpoint • Biochemical MI • Underpowered to show difference in death and major ipsilateral stroke • Heterogeneity of symptomatic and asymptomatic patients • Not all patients on statins • More lipid lowering in CEA • More anti-platelets in CAS • Advances in BMT, CEA stent and embolic protection since CREST commenced in 2000 • Can CREST CAS results be reproduced in wider practice? • Left to interpretation based on personal bias?
- 39. Identify at risk asymptomatic patients • NNT • Degree of stenosis • Plaque type
- 41. Is asymptomatic carotid endarterectomy a good use of resources?
- 42. Are stroke rates changing over time? SMART ASED Johnso n ACAS VA CHS ACBS
- 43. To estimate the lifetime cost-effectiveness of early endarterectomy in the UK based on the Asymptomatic Carotid Surgery Trial ACST, Lancet 2010
- 44. Markov transition state model Henrikkson BJS 2005
- 45. Event rates taken from ACST Halliday et al, Lancet 2010
- 46. Costs standardised to 2010 CEA £33451 Disabling stroke Year 1 £29,3122 Disabling stroke Year 2+ £14,8462 Non-disabling stroke Year 1 £4,9382 Non-disabling stroke Year 2 £1,1522 Medical therapy equivalent both arms Costs 1 NHS HRG Tariff 2010-2011 2 NHS HTA 2006
- 47. ? ? Assessing cost-effectiveness Additional cost (£) Additional effect (QALYs)
- 48. Results -0.1 0.1 0.2 -2000 2000 4000 6000 £20, 000 per QALY £30, 000 per QALY Women > 75y Men > 75y Men < 75y Women < 75y BASE CASE CEA more costly CEA more effective Restriction of crossovers Incremental effectiveness / QALYs Incrementalcost/£ Base case ICER = £7584/QALY
- 50. Limitations • Previous US trials with higher stroke rates, shorter follow up and fewer patients excluded • TIA not included as endpoint • Loss of productivity from stroke not included in costs • Informal care not included in costs • Stenting not considered following interim guidance from NICE
- 51. Interpretation • Endarterectomy was likely to be cost-effective in under 75s • Especially so in young women • Late crossovers to endarterectomy did not improve cost- effectiveness • With lower background stroke rates, endarterectomy may soon become borderline cost-effective, even if it becomes safer • Maintaining cost-effectiveness relies on: • Identification of patients with high risk carotid plaque • Maintaining low rates of operative stroke • Prevention of cardiac death for men in their 70s
- 56. X X X ?
- 58. NEJM 2010;363(1):11-23 Effect of Age
- 60. Lancet Neurol 2011;10:530-537 Effect of Gender
- 61. Impact at 1 Year JACC 2011;58:1557-1565
- 62. Impact of Events – SF36 EJM 2010;363(1):11-23
- 63. Time from Symptoms to Surgery Naylor 2007
- 64. A C S T
- 65. Effect of Symptomatic Status Stroke 2011;42:675-680
Editor's Notes
- The natural histories of equally severe symptomatic and asymptomatic carotid artery stenosis are different This data showing freedom from stroke from the medical arm of the NASCET/ACAS and ECST trials demonstrates this. This suggests a dicotomy in plaque behavior
- We perform 1000 asymptomatic CEAs in the UK every year with an annual cost of approximately £3.5 m. Carotid stenosis is common found in 2-7% of the population over 60.
- ACST – European, 10 year follow, most contemporary medical therapy, large dataset
- Survival after stoke used appropriate UK literature
- Using the concept of incremental costs and incremental effects we define the cost-effectiveness plane. We use this to illustrate the relative cost and effect of an intervention compared to some control. If the intervention lies in the south-east quadrant, it is both less expensive and more effective than the control, and so will be preferred. In the north-west quadrant, an intervention is more expensive and less effective, and so the control will be preferred. In the other two quadrants there is a trade-off between cost and effectiveness. The ICER is illustrated by the slope of a line through the origin and the IE/IC point for an intervention. Compare this with the ‘threshold’ cost-effectiveness ratio – assume around £20,000 to £30,000 per QALY for NICE decisions.
- Explain axes To be cost-effective the data point should lie under the line. Probability of base case being cost-effective at a £30 000 cost per QALY was 84%. Sensitivity analysis determined that CEA was unlikely to be cost-effective in those over 75 years of age In ACST young women had the greatest relative risk reduction with CEA due to the lowest intercurrent mortality and CEA was especially beneficial in this group. Restricting crossover mainly towards late CEA in elderly patients did not improve cost-effectiveness as CEA (per protocol). For women over 75 the subgroup was too small to establish effectiveness with any certainty. For women under 75 CEA was especially effective and life expectancy was longest making this especially cost-effective. Base case ICER £7500 k Men under 75 £3500 k Men over 75 ICER £72 k Women under 75 negative ICER Restriction of crossovers £10 149
- Explain axes The more cost-effective an intervention is the higher it is up the page CREST ACES/Spence/Abbott/SMART
- These assumptions are all conservative assumptions and probably make early CEA more cost-effective
- Late crossovers (per protocol) However as we know, carotid stenosis and stroke become more common in patients over 75. The use of an age cutoff may in fact miss many of the patients with carotid stenosis who are at high risk of stroke. An alternative approach would be to look at the risk of stroke.
- Interpretation Periprocedural risk of events seems to be higher in women who have carotid artery stenting than those who have carotid endarterectomy whereas there is little difference in men. Additional data are needed to confirm whether this differential risk should be taken into account in decisions for treatment of carotid disease in women.
- Among patients undergoing carotid revascularization, CAS is associated with better HRQOL during the early recovery period as compared with CEA—particularly with regard to physical limitations and pain—but these differences diminish over time and are not evident after 1 year. Although CAS and CEA are associated with similar overall HRQOL at 1 year, event-specific analyses confirm that stroke has a greater and more sustained impact on HRQOL than MI.
- There were no significant differences between CAS versus CEA by symptomatic status for the primary CREST end point. Periprocedural stroke and death rates were significantly lower for CEA in symptomatic patients.