The argument against revascularization for asymptomatic carotid stenosis

Transcription

1 The argument against revascularization for asymptomatic carotid stenosis Seemant Chaturvedi, MD, FAHA, FAAN Professor of Clinical Neurology Vice-Chair for VA Programs Univ. of Miami Miller School of Medicine

2 Disclosures Research: Executive committee member for CREST 2 and ACT I studies Research: Boehringer-Ingelheim Speakers bureau: None

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4 Absolute Benefits of Carotid Endarterectomy (CEA) Absolute RR Ipsilateral Stroke/Yr CEA showed only marginal benefits on annual rates of ipsilateral stroke for patients with asymptomatic or moderate lesions. Dramatic benefit was seen for high-grade symptomatic stenoses.

5 Subgroup analysis Do women benefit? Do the elderly benefit?

6 Rothwell, PM and Goldstein, LB. Stroke 2004; 35:

7 Largest asymptomatic carotid stenosis study 650 patients 75 years enrolled No definite benefit seen (For patients age 75 and over) because their normal life expectancy is short, any net benefits would probably be of limited duration. Lancet 2004; 363:

8 ACST study

9 Statin use in previous carotid stenosis studies NASCET 14.5%* ACE 28% ACST 38% *any lipid lowering agent

10 So why are we relying on data from 1995? We are doing patients a disservice by relying on obsolete data Patient safety

11 Events in 1995 Bill Clinton was still in his first term Forrest Gump won the Oscar for best picture Derek Jeter had not even played his first full season in his major league baseball career

12 Medical therapy then and now 1995 Aspirin monotherapy Very little lipid lowering therapy use Suboptimal BP control No organized lifestyle modification approach 2017 Expanded AP therapy High potency statins PCSK9 inhibitors Targeted BP lowering Expanded options for smoking cessation Mediterranean diet Increased physical activity

13 Potential risk reduction with aggressive medical therapy Risk reduction High potency statins 33%* Dual antiplatelet therapy 10-32%** Blood pressure control 20-30% Lifestyle measures 10-30% * Sillesen et al. SPARCL trial; **Wang et al CHANCE trial

14 Aggressive Medical Management Identical in both arms: Aspirin 325 mg / day for entire follow-up Clopidogrel 75mg per day for 90 days Aggressive, protocol driven risk factor management primarily targeting systolic blood pressure < 140 mm Hg (130 mm Hg diabetics) and low density cholesterol < 70 mg / dl Intervent USA a lifestyle modification program

15 Effect of multi-modality therapy

16 Carotid stenosis 2017 Medical Management Newer antiplatelet agents Aggressive use of statins Targeted BP lowering ACE/ARB utilization Smoking cessation Control of other risk factors (DM) Increased physical activity Other lifestyle interventions (Med Diet) PCSK 9 inhibitors

17 Asymptomatic carotid stenosis and current medical therapy Study N Follow up duration Annual stroke rate Oxford Vascular years 0.34% SMART years 0.3% ACES 77 2 years 3.6% with microemboli ACES years 0.7% w/o microemboli Stroke 2010; 41: e11-17; Stroke 2013; 44: ; Lancet Neurol 2010; 9:

18 Decline in stroke rate Naylor, R. Stroke 2011; 42:

19 An important new clinical trial

20 Primary Aim To assess in patients with 70% asymptomatic stenosis: If contemporary MEDICAL alone is not inferior to contemporary revascularization plus contemporary medical management using CEA, and If contemporary MEDICAL alone is not inferior to contemporary revascularization plus contemporary medical management using CAS

21 Primary Outcome Composite of stroke and death within 30 days of enrollment or ipsilateral stroke up to 4 years.

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23 CREST 2 website For further information Your help is urgently needed! Many centers in New England and NY are participating Please refer your patients

24 Ethics of informed consent You cannot honestly consent a patient in 2017 without some knowledge of how CEA/CAS compares to optimal, multi-modal medical therapy Patients deserve to know this Do what is right for the patient To not participate in new asymptomatic carotid stenosis trials would be.

25 SAD!

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27 Asymptomatic Carotid Disease Argument for Treatment Philip M. Meyers, MD, FACR, FAHA, FSIR, FSNIS Professor, Radiology and Neurological Surgery Columbia University, College of Physicians & Surgeons Director, Neuroendovascular Services New York Presbyterian Hospitals Columbia Neurological Institute of New York Past President, Society of NeuroInterventional Surgery

28 Disclosure Statement of Financial Interest I, Philip Meyers, do not have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation. CREST-2 Registry participant

29 What?! Surgery for Carotid Stenosis?

30 Medical Therapy Only!

31 Executive Summary Argument in Favor of Carotid Revascularization Level 1 Evidence for CEA/CAS despite the lack of consensus Carotid revascularization reduces the risk of stroke Proven repeatedly for symptomatic carotid stenosis Proven repeatedly for asymptomatic carotid stenosis 5-10% of the general population has carotid stenosis 50% 80% of strokes not preceded by symptoms Strokes caused by asymptomatic stenosis could have been treated Screening can identify asymptomatic carotid stenosis Risks of CEA/CAS are declining Data on declining risk of stroke with medical therapy are flawed Mineva PP. Eur J Neurol 9: 383-8, 2002 Inzitari D. NEJM 342: , 2000 Naylor AR. Surgeon 13: 34-43, 2015

32 Executive Summary Reality, not nihilism Class 1 Evidence for carotid revascularization in asymptomatic carotid stenosis without a doubt, it works! CEA reduces the risk of stroke (ACAS, ACST, CREST) CAS is non-inferior to CEA (CREST-1, ACT-1) The effect size is small how small? Depends on numerator appropriate selection for intervention Depends on denominator how many do we want to treat to prevent strokes There is little consensus about indications $2 billion/year industry as practiced based, in part, on scientific guidelines Most strokes cannot be prevented by CEA We still don t know how to identify high risk patients Stroke risk has been declining (until recently) on medical therapy $2 billion/year industry Burton T. Wall Street Journal Sept. 1, 2004 "I wish the medical-industrial complex wouldn't rush us into this" - Robert W. Hobson II

33 Stroke due to carotid artery disease Stroke remains an important cause of adult death and disability 20-35% of strokes are due to carotid disease 2/3 of strokes due to carotid thromboembolic disease do not have associated bifurcation stenosis Only 1/3 of carotid thromboembolic strokes have significant bifurcation stenosis, i.e % narrowing 20% with stenosis have TIA/minor stroke 80% with stenosis have major stroke with no warning signs 11% of major strokes occur due to asymptomatic stenosis 66,000 strokes/year in U.S. Nearly half are disabling <1% of population over age 50 years Inzitari D. NEJM 342: , 2000 Mozaffarian D. Circulation 133: , 2016 Naylor AR. Surgeon 13: 34-43, 2015 Fine-Edelstein JS for Framingham Study. Neurology 44: , 1994

34 Mechanical Thrombectomy for Acute Stroke 2.5% IMS 3 (n=656) Absolute Difference mrs 0-2 at 90 days TICI 2b/3 Recanalization 44% 69% 11% 12% THRACE (n=414) MR CLEAN (n=500) 59% 16% REVASCAT (n=206) 66% 21% 87% PISTE (n=58) 72% 24% 24% ESCAPE (n=316) 88% SWIFT-PRIME (n=196) 31% EXTEND-IA (n=74) 86% 100% 90% 80% 70% 60% 50% 40% 30% Sardar P. Eur Heart J 36: , 2015

35 Substantial Rates of Poor Outcomes 86% 88% mrs 2-6 (Disabled) % Recan 88% 100% 90% 80% 48% 57% 66% 72% 66% 66% 59% 70% 60% 50% 40% 30% 20% 10% EXTEND-IA SWIFT PRIME ESCAPE REVASCAT MR CLEAN 0% Prabhakaran S. JAMA 313: , 2015

36 Goals and limitations of carotid revascularization Identify asymptomatic high risk patients 50-99% carotid stenosis Benefit from CEA/CAS Benefit from aggressive medical therapy Likely a small subgroup 0.06% of US population 0.07% of population over age 50 years Unclear how to identify this subgroup Tests to identify high risk patients remain unproven Best medical therapy remains unproven Superiority of BMT over CEA/CAS remains unproven May be costly to identify high risk group Screening is expensive Surgery is expensive (76,000 = $101,800/stroke prevented) Naylor AR. Nat Rev Cardiol 9:116-24, 2011 Thapar A. J Neurointerv Surg 5: 94-6,

37 CEA for asymptomatic stenosis ACAS 1662 patients Ages yrs Stenosis 60% CEA vs. BMT (aspirin) Median 2.7 yrs follow-up 5-yr risk stroke/death 11% medical therapy 5.1% CEA RRR=54%, p=0.004 NNT=19 No est. difference any major stroke or death, 25.5% vs. 20.7% (p=0.16) ACST patients Ages <75 yrs Stenosis 60% CEA vs. BMT (statins) Median 3.4 yrs follow-up 5-yr risk stroke/death 11.8% medical therapy 6.4% CEA (p<0.001) 10-yr risk stroke/death 17.9% medical therapy 13.4% CEA (p=0.24) RRR=46%, p< NNT=22 ACAS. JAMA 273: , 1995 ACST. Lancet 363: , 2004

38 CAS Equivalent to CEA Non-inferiority CREST patients Mean age 68 years Stenosis 70-99% 1:1 CAS:CEA Median 2.5 yrs follow-up 30-d risk stroke/death/mi 5.2% CAS 4.5% CEA (p=0.38) 4-yr risk stroke/death 7.2% CAS 6.8% CEA (p=0.51) ACT patients Ages <80 years Stenosis 70-99%% 2:1 CAS:CEA 5 yrs follow-up 30-d risk stroke/death/mi 3.8% CAS 3.4% CEA (p<0.01) 1-yr risk stroke/death 3.8% CAS 3.4%% CEA (p=0.24) CREST. NEJM 363: 11-23, 2010 ACT1. NEJM 374: , 2016

39 Screening No guideline for carotid screening until 2014 despite widespread use Carotid ultrasound can be inaccurate (up to 61%) Certification process for ultrasound labs Still highly operator-dependent Stenosis progression occurs quickly in 50% AHA/ASA Guidelines (2014) support annual surveillance IF >50% stenosis amenable to medical or surgical treatment has already been identified (Class IIa, LOE C) ACAS and ACST only reduced stroke risk by 50% If treatment of all patients with asymptomatic stenosis, 95% of strokes would still occur Aggressive screening would only reduce the number of strokes by 1-2% Curtis LH. Cir Cardiovasc Qal Outcomes 3: , 2010 Brown OW. J Vasc Surg 39: , 2004 Bock RW. J Vasc Surg 17: 160-9, 1993 Kernan WN. Stroke 45: , 2014

40 Effect Size ACST % absolute risk 10 yrs 46 strokes prevented per 1000 CEA 95% of all procedures are unnecessary In U.S., 90% of CEA are performed in asymptomatic patients >120,000 CEA/CAS procedures per year >115,000 procedures are unnecessary In the SMART study, risk of Vascular Death or MI >> CVA for asymptomatic stenosis 50-99% years Vascular Death: 9% MI: 6% CVA: 2% years CVA: 2.7% (0.4%/yr) Only half were large vessel occlusions (LVOs) Only slightly higher for 70-99% stenosis at 0.5%/yr Patients without prior ischemia McPhee JT. J Vasc Surg 48: , 2008 Goessens BMB. Stroke 38:1470-5, 2007 Den Hartog AG. Stroke 44:1002-7, 2013

41 Effect Size Revisited REACH Registry (Reduction of Atherothrombosis for Continued Health) 30,329 persons without carotid disease 3,164 with asymptomatic carotid disease 70% Based on the premise that RCTs do not accurately depict disease burden Trial-like patients experience different outcome rates Registries offer real-world risk estimates Higher risk of stroke despite modern medical therapy in more than 70% of patients Majority patients treated with statins (>70%), anti-htn (87%) and anti-thrombotics (>90%) Event Type Carotid Stenosis No Stenosis P-value TIA, % CVA, Non-fatal CVA, death MI, death Composite, % Prior cerebral ischemia was a powerful predictor of future events, Aichner FT. Eur J Neurol. 16: 902-8, 2009

42 Temporal Trends in CEA outcomes AHA guideline limit Even if risk is modelled at 0%, 92% (ACAS) to 93% (ACST) of CEA were unnecessary Rerkasem K. Eur J Vasc Endovasc Surg 37: 504, 2009 Bunch CT. Semin Vasc Surg 17: , 2004 Naylor AR. Eu J Vasc Endovasc Surg 37: , 2009

43 BMT increases life expectancy Heart Protection Study Heart Outcomes Prevention Trial Women s Health Study Asymptomatic Cervical Bruit Study 60-70% decline in rate of any stroke in trials Similar declines in the rates of acute MI severity and death Myerson M. Circulation 119: , 2009

44 Declining stroke rate Naylor AR. Stroke 42: , 2011 Abbott AL. Stroke 40: e573-83, 2009

45 Decline in stroke rate stalled

46 Asymptomatic Carotid Stenosis Trials in Progress Study Trial Design Eligibility Primary Outcome Enrollment CREST-2 Dual Arm trial CEA+BMT vs BMT CAS+BMT vs BMT 70% asymptomatic stenosis (NASCET) PeriOp Stroke and Death 4 Yr Ipsilateral Stroke SPACE-2 Dual Arm trial CEA+BMT vs BMT CAS+BMT vs BMT 70% asymptomatic stenosis (NASCET) PeriOp Stroke and Death 5 Yr Ipsilateral Stroke ECST-2 CEA+BMT or CAS+BMT Vs BMT 50% symptomatic stenosis (NASCET) or Symptomatic (NASCET) PeriOp Stroke and Death 2000 AMTEC CEA vs BMT 70-79% asymptomatic carotid stenosis by U/S, 6 79% by CT/MRA 5 Yr Stroke, MI, death 400 Calvet D. Int J Stroke 11: 19-27, 2016

47 Investigational high risk features Silent cerebral infarcts on CT or MRI 7.4% stroke/yr vs. 3.1%/yr Progression of stenosis Large, irregular or hypo-echoic plaque 14.8% vs. 2.3% TCD HITS Cerebral vaso-reactivity AHA MRI Plaque types 4-6 (lipid or necrotic) Tandem intracranial stenosis Stenosis and cognitive impairment Screening has been suggested in high risk groups with increased prevalence of carotid Peripheral vascular disease 25% Ischemic heart disease 15% Aortic aneurysm 12% Rundek T. Neurology 70: , 2008 Kakkos SK. J Vasc Surg 49: 902-9, 2009 Bertges DJ. Arch Intern Med 163: , 2003 Markus HS. Lancet Neurol 9: , 2010 Hellings EW. Circulation 121: , 2010 Nicolaides AN. J Vasc Surg 52: , 2010 Gupta A. Stroke 43: , 2012 Hirt LS. Stroke 45: 702-6, 2014 Topakian R. Neurol 77: 751-8, 2011 King A. Stroke 42: , 2011 Gupta A. Stroke 44: , 2013 Paraskevask KI. Stroke 45: , 2014 Wallaert JB. Stroke 43: , 2012 Naylor AR. Eur J Vasc Endovasc Surg 48: , 2014

48 Should We Do More Trials? IDENTIFICATION OF TRUE HIGH RISK ASYMPTOMATIC STENOSIS COMPARISON WITH NEW DEVICES IN HIGH SURGICAL RISK ASYMPTOMATICS CEA WITH POSTOP/PERI-OP PLAVIX Phase III Propensity Best Practice

49 Rebuttal

50 Meta-analysis favors CEA over BMT Raman G. Ann Intern Med 158: , 2013

51 Outcomes in CAS Trials Over Time 10% 9% 8% 7% 6% 8.3% 6.9% 7.5% 6.1% 5% 4% 3% 2% 2.9% 3.3% 2.6% 4.1% 3.5% 1.5% 1.4% 3.9% 1.8% 2.3% 1% 0.6% 0% 30 day Composite Stroke, Death, MI 30 day Composite of Death and Major Stroke

52 Broad Variations in Practice % CEA for Asymptomatic Carotid Stenosis Percent In US, up to 20% performed in patients with life-limiting conditions McPhee JT. J Vasc Surg 48: , 2008 Vikatmaa P. Eur J Vasc Ednovasc Surg 44: 11-7, 2012 Wallaert JB. Stroke 43: , 2012 Wang FW. Stroke 42: , 2011

53 AHA Guidelines Screen individuals with asymptomatic stenosis for modifiable risk factors (Class 1, LOE C) Patients should receive aspirin and statin (Class 1, LOE C) Patients should be screened for stroke risk factors (Class 1, LOE C) Institute life-style changes (Class 1, LOE C) Appropriate medical therapy (Class 1, LOE C) Annual imaging surveillance for >50% stenosis (Class 2a, LOE C) Consider CEA for avg risk >70% stenosis (Class 2a, LOE A) If surgical risk is low (<3%) Comparative effectiveness of BMT not established CAS an alternative to CEA in avg risk (Class 2b, LOE B) In highly selected patients with stenosis >60% by angio, >70% by US Comparative effectiveness of BMT not established Goldstein LB. Stroke 42: , 2011

54 Consensus, or lack thereof North Am Multi-disciplinary Similar to AHA guidelines European Stroke Organization CEA not for asymptomatic except high risk for stroke (Class I, LOE C), no CAS (Class IV, GCP) European Society of Cardiology Similar to AHA guidelines: CEA (Class 2a, LOE A); CAS (2b, LOE B) UK National Institute for Health and Care Excel CEA in avg risk, CAS in trials (Class 2a, LOE A) Society of Vascular Surgery CEA for avg risk, medical therapy for high risk (Class I, LOE A) Centers for Medicare Services (CMS) CEA only, not CAS for asymptomatic Australian Intercollegiate Committee CEA only, no CAS in avg risk patient (Class 1, LOE A)

55 The psychology of patient trust Disclosure of bias to patients increases their trust Disclosure of potential sources of bias are meant to protect consumers Patients respond favorably to disclosure of specialty bias by physicians 447 patients at 4 Veterans Administration medical centers Rigorous survey methodology to determine patient decision-making regarding treatment Therefore, much depends on the relationship between patients and their healthcare providers Ironically, perhaps, physicians who speak to the controversy surrounding their biases are more likely to persuade patients to their perspectives Sah S. PNAS 113: , 2016