03/30/2016 DISCLOSURES TO OPERATE OR NOT THAT IS THE QUESTION CAROTID INTERVENTION IS INDICATED FOR ASYMPTOMATIC CAROTID OCCLUSIVE DISEASE

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1 CAROTID INTERVENTION IS INDICATED FOR ASYMPTOMATIC CAROTID OCCLUSIVE DISEASE Elizabeth L. Detschelt, M.D. Allegheny Health Network Vascular and Endovascular Symposium April 2, 2016 DISCLOSURES I have no financial disclosures. TO OPERATE OR NOT THAT IS THE QUESTION What is the modern benefit of performing carotid endarterectomy for patients with high grade asymptomatic disease? 1

2 THE CRUX OF THE ISSUE Data from ACAS, NASCET and the VA Study were collected nearly 25 years ago. Things have changed Statins Clopidogrel Modern maximal medical therapy has reduced risk of stroke from asymptomatic carotid stenosis to rates equivalent to that obtained from CEA (Abbott et al 2009). Lifetime risk of stroke in a 65-year-old male has decreased from 19.5% in the 1970s to 14.5% today THE REAL ISSUE HISTORICAL PERSPECTIVE OF RCTS VA Study ACAS ACST Year Inclusion criteria Asymptomatic > 50% stenosis Asymptomatic > 60% stenosis Asymptomatic (mainly) > 60% stenosis Comparison CEA + aspirin vs. medical treatment alone CEA + aspirin vs. Aspirin CEA + medical tx vs. medical and risk factor modification tx alone (or until CEA necessary) 80 % on Statins in later years of trial Results Ipsi neuro events 8% for CEA, 20.6% for medical tx, BUT no difference in all strokes and deaths between two groups 5 year risk of ipsi stroke and perioperative stroke or death was 5.1% for CEA, 11% for medical tx 5 year risk of stroke or death was 6.4% for CEA vs 11.8% for medical tx The winner CEA CEA CEA 2

3 IN A NEW ERA, WHAT IS THE BENEFIT? What is the impact of modern maximal medical therapy? Does this impact stroke risk reduction in ACAS? What are the costs of medical treatment vs CAS/CEA? MODERN MAXIMAL MEDICAL THERAPY MAXIMAL MEDICAL THERAPY Smoking cessation Anti-hypertensives Diabetes control Anti-platelets Statins 3

4 MAXIMAL MEDICAL THERAPY Statins 1987 lovastatin (Atorvastatin, Fluvastatin, Pravastatin, Rosuvastatin, simvastatin, Pitavastatin) $29 billion in global sales in 2012 Plavix 1998 clopidogrel $9 billion in global sales in 2010 IMPACT OF THESE DRUGS: STATIN CLOPIDOGREL Cholesterol Treatment Trialists Collaboration Reducing LDL by 1 mmol/l decreases the incidence of major vascular events (nonfatal myocardial infarction, coronary death, any stroke, or coronary revascularization procedure) by ~1/5 Further reductions in LDL cholesterol with more intensive statin regimens yielded further reductions in risk CAPRIE Trial - reduction of cardiovascular events in patients with recent stroke, MI, or peripheral artery disease Expanded indications to include ACS, NSTEMI, STEMI, coronary stent BUT CAPRIE Trial No difference in clopidogrel vs aspirin in > 6000 with recent ischemic stroke Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance trial clopidogrel plus aspirin = aspirin alone in preventing vascular events in patients with a prior stroke, TIA, or other cardiovascular disease or in patients with high risk for cardiovascular disease. 4

5 AND STATINS FOR STROKE PREVENTION: DISAPPOINTMENT AND HOPE The number of strokes prevented per 1000 patients treated for 5 years in patients with CHD is 9 for statins, compared with 17.3 for antiplatelet agents. Statins do not prevent recurrent stroke in patients with prior stroke Statins may increase the risk of hemorrhagic stroke Amarenco & Tonkin Circulation. 2004;109:III-44 III-49. META-ANALYSIS OF 9 MAJOR LONG-TERM STATIN TRIALS PATIENTS WITH KNOWN CHD OR CONSIDERED AT INCREASED RISK 4.3 % (1501 of patients) risk of stroke in control group 3.4 % (1215 of patients) risk of stroke with statin therapy 21% relative risk reduction in stroke 0.9% absolute risk reduction (9 strokes prevented per 1000 patients treated for 5 years). By comparison, meta analyses have shown that, in similar patients with known CHD 17 strokes per 1000 patients prevented with Ramipril treatment for 5 years 17.3 strokes per 1000 patients prevented with antiplatelet agents (45 strokes prevented per 1000 patients treated for 5 years in patients with prior stroke) HOW DOES MAXIMAL MEDICAL THERAPY INFLUENCE STROKE RISK IN ACAS? 5

6 MEDICAL (NONSURGICAL) INTERVENTION ALONE IS NOW BEST FOR PREVENTION OF STROKE ASSOCIATED WITH ASYMPTOMATIC SEVERE CAROTID STENOSIS: RESULTS OF A SYSTEMATIC REVIEW AND ANALYSIS 1. Investigate temporal changes in reported stroke rate among patients with ACAS receiving MMT alone 2. Compare above stroke rate rates with those of patients who received CEA in major randomized surgical trials 3. Compare stroke-prevention cost effectiveness of medical intervention alone with MMT plus CEA. Abbott et al. Stroke ABBOTT, STROKE 2009 Meta-review of studies of severe (> 50%) asymptomatic carotid stenosis Found significant decrease in stroke rate from 1980s to 2000s. Abbott et al. Stroke

7 ABBOTT, STROKE 2009 Author notes that no systematic analysis of reported stroke rate associated with isolated medical management of ACAS has been performed. One of the author s arguments is that the low peri-operative risk associated with CEA in these trials is not comparable to the risk in the community at large. The flip side to this argument is that in order to benefit from the reduced stroke risk associated with MMT, patients must be compliant. In the community at large, is compliance equivalent to that of trial patients? THE EFFECT OF MEDICAL TREATMENTS ON STROKE RISK IN ASYMPTOMATIC CAROTID STENOSIS ACES data 477 patients with ACES Followed Q6mos for 2 yrs King et al King et al

8 THE WORLD AT LARGE or at least a nation SVS VASCULAR REGISTRY REVIEW 2015 Normal Risk patients Age < 80 Absence of clinically significant cardiac disease Absence of severe pulmonary disease Absence of contralateral carotid occlusion Absence of contralateral laryngeal nerve palsy No history of radical neck surgery or radiation to neck No recurrent stenosis SVS REGISTRY 8

9 MODERN DATA ACST-1 10 YEAR FOLLOW UP DATA (2010) Stroke rates were lower in those on lipid-lowering therapy, the absolute difference in the stroke incidence rate produced by allocation to immediate CEA was not as great (0 7 vs 1 3% per year [p<0 0001] for those currently on lipid-lowering therapy, and 1 8 vs 3 3% per year [p<0 0001] for those not The event rates in patients on lipid-lowering therapy suggest somewhat lower perioperative risks and lower absolute benefits, but still with a significant reduction in net risk at year 10. In patients with effective antihypertensive, antithrombotic, and lipid-lowering therapy and with little likelihood of death from other causes within 10 years, the absolute 10-year stroke reduction would be about 5%. If so, the number needed to treat to avoid one stroke would be about 20. Allowance for non-compliance might reduce this number to about 15. MODERN DATA Aggressive Medical Treatment Evaluation for Asymptomatic Carotid Artery Stenosis (AMTEC) Study Group Russia has higher rate of stroke and death than Western countries 55 patients with % asymptomatic stenosis randomized MMT and 31 CEA + MMT MMT defined as Aspirin Statin Anti-hypertensives 9

10 AMTEC Nonfatal stroke and death (1 endpoint) Nonfatal stroke, carotid revascularization, and death (2 endpoint) Major adverse cardiovascular events* Cumulative rate at 3.3 years CEA (%) MMT (%) Nonfatal stroke Death *Death, nonfatal myocardial infarction, nonfatal stroke, carotid revascularization, and coronary revascularization. CONRAD ET AL 900 carotid arteries in 794 patients 87.1% were on a statin throughout the study low-density lipoprotein cholesterol level was always normal (<100 mg/dl) in 37.8% and accordingly, 241 (30.3%) had OMT The 5-year freedom from plaque progression was 61.2% vs 62.1% with no benefit from OMT vs the control group. 11.3% patients developed INS during follow-up (58% of these were strokes) Statins were protective Conclusions: At the 5-year of follow-up, OMT failed to prevent carotid disease progression or development of ipsilateral symptoms in 45% of patients with ACAS. J Vasc Surg 2013;58: CONRAD ONE YEAR LATER 126 asymptomatic but severely stenotic (> 70%) carotid arteries 86% on statin 24.6% developed ipsi neuro event during mean of 27 month follow up Statins not protective against ipsi neuro events or death 10

11 ASYMPTOMATIC CAROTID STENOSIS: RISK OF PROGRESSION AND DEVELOPMENT OF SYMPTOMS Retrospective review of 214 consecutive patients 97% statins 95% anti-hypertensives 99% aspirin 68% progression of stenosis 21% develop ipsilateral symptoms in long term follow up Mean of 6 years to development of symptoms Risk factors for symptom development Degree of stenosis at diagnosis Intracranial stenosis Plaque ulceration Silent infarction Prior history of TIA/stroke Cerebrovasc Dis 2015;40: WHAT IS GOING ON? DEFINITION OF SEVERE CAROTID STENOSIS Abbott et al : > 50% ACAS: > 60% by either angio or duplex VA: >50% by angio SVS guidelines 60% Common practice 70% 11

12 SMOKING Although the world-wide prevalence of tobacco use has decreased, the total number of smokers has increased due to population growth. Certain countries have rates of tobacco use >50% in men (i.e Russia). LENGTH OF FOLLOW UP Cerebrovasc Dis 2015;40: IS THERE A SELECTION BIAS? Medical compliance Smoking cessation 12

13 WHAT ABOUT COST? INDEX HOSPITALIZATION COSTS CAS VS CEA (CREST TRIAL) CAS CEA Difference P Value Procedure $6782 ± 1412 $5743 ± 1370 $1039 < Post procedure $6759 ± 4815 $7122 ± $ Physician fees $1514 ± 446 $1951 ± $437 < Total index hospitalization $15,055 ± 5539 $14,816 ± 7709 $ NUMBER NEEDED TO TREAT 9 strokes prevented per 1000 patients treated with statins for 5 years NNT = 111 ACST-1 data reported needed to treat patients to prevent one stroke. NNT = 20 13

14 COST COMPARISON Statins Lipitor $4000 / year x 5 years = 20,000 x 111 patients = CEA / CAS $15, 000 per procedure x 20 procedures = $ 2,220,000 to prevent 1 stroke $ 300,000 prevent 1 stroke CLOSING THOUGHTS SPACE-2 Designed as three armed randomized trial to compare best medical therapy alone, best medical therapy plus CAS and best medical therapy plus CEA Low recruitment has halted the study (Jan 2015) Plans to analyze and report out available data later this year. 14

15 CREST-2 Randomized trial of patients with asymptomatic carotid stenosis 70% Medical treatment alone versus medical treatment and endarterectomy Medical treatment alone versus medical treatment and stenting Recruiting 2480 patients in US and Canada COGNITIVE EFFECTS OF CEA Patients with asymptomatic severe carotid stenosis perform poorer on tests of cognitive function than controls. Carotid revascularization improves memory and attention within the first 6 postoperative months in patients with >80% ACAS. Kougias, P et al. J Vasc Surg 2015;62: REFERENCES Amarenco P & Tonkin AM. Circulation. Statins for Stroke Prevention Disappointment and Hope 2004;109:III-44 III-49. Benavente O, et al. Carotid endarterectomy for asymptomatic carotid stenosis:a metaanalysis. BMJ 1998;317: Bhatt DL, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354: Bonati LH, et al. Long-term outcomes after stenting versus endarterectomy for treatment of symptomatic carotid stenosis: the International Carotid Stenting Study (ICSS) randomised trial. Lancet 2015; 385: 529 Brothers, TE et al. Contemporary results of carotid endarterectomy in normal-risk patients from the Society for Vascular Surgery Vascular Registry. J Vasc Surg 2015;62: CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348: Conrad, MF et al. Progression of asymptomatic carotid stenosis despite optimal medical therapy. J Vasc Surg 2013;58: Conrad, MF et al. The natural history of asymptomatic severe carotid artery stenosis. J Vasc Surg 2014;60: Diener HC, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo controlled trial. Lancet 2004;364: Endarterectomy for asymptomatic carotid stenosis. JAMA 1995;273: Halliday A, et al. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomised controlled trial. Lancet. 2004;363:

16 REFERENCES Hobson, RW et al. Efficacy of carotid endarterectomy for asymptomatic carotid stenosis. NEJM 1993;328: King, A et al. The Effect of Medical Treatments on Stroke Risk in Asymptomatic Carotid Stenosis. Stroke. 2013;44: Kolos, I et al. Modern medical treatment with or without carotid endarterectomy for severe asymptomatic carotid atherosclerosis. J Vasc Surg 2015;62: Kougias, P et al. Comparison of domain-specific cognitive function after carotid endarterectomy and stenting. J Vasc Surg 2015;62: Martinic-Popovic, I et al. Advanced Asymptomatic Carotid Disease and Cognitive Impairment: An Understated Link? Stroke Research and Treatment Volume 2012, Nicolaides AN, et al. Effect of image normalization on carotid plaque classification and the risk of ipsilateral hemispheric ischemic events: results from the asymptomatic carotid stenosis and risk of stroke study. Vascular 2005; 13: Rijbroek, A et al. Asymptomatic Carotid Artery Stenosis: Past, Present and Future. Eur Neurol 2006;56: Singh TD, et al. Asymptomatic Carotid Stenosis: Risk of Progression and Development of Symptoms. Cerebrovasc Dis 2015;40: Vilain, KR et al. Costs and Cost-Effectiveness of Carotid Stenting versus Endarterectomy for Patients at Standard Surgical Risk: Results from the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST). Stroke. 2012; 43: Yadav, JS et al. Protected Carotid-Artery Stenting versus Endarterectomy in High-Risk Patients. N Engl J Med 2004;351: