4/16/2015 Consulting Merck Novartis Astra Zeneca Joshua - - PowerPoint PPT Presentation

4/16/2015 1 Joshua Beckman, MD

• Consulting

Merck Novartis Astra Zeneca Bristol Myers Squibb

• Stock

Janacare EMX

• Research Grant

Bristol Myers Squibb

• Boards

VIVA Phyiscian’s Group

MI=myocardial infarction; CVA=cerebrovascular accident. Adapted from Bakhai A. Pharmacoeconomics. 2004;22(suppl 4):11-18.

5 10 15 20 Healthy History of MI History of CVA

In the FHS, healthy individuals aged 60 years who did not have atherothrombosis were expected to live a further 20 years to the age of 80 ▪ Comparatively, patients with a history of MI lived 9.2 fewer years ▪ Those with a history of CVA lived 12 fewer years In the FHS, healthy individuals aged 60 years who did not have atherothrombosis were expected to live a further 20 years to the age of 80 ▪ Comparatively, patients with a history of MI lived 9.2 fewer years ▪ Those with a history of CVA lived 12 fewer years

9.2

Fewer years

12

Fewer years

Life Expectancy (Years)

20

Past: Management of Active Disease Present: Management of Asymptomatic

Disease

Future: Risk Stratification

4/16/2015 2

• A. Statins
• B. Anticoagulants
• C. Antiplatelet agents
• D. ACE inhibitors

Statins Anticoagulants Antiplatelet agents ACE inhibitors

12% 28% 0% 60%

Risk Factors for Events: OR Age > 60 y 1.8 Diabetes 2.0 >10 Min TIA2.3 Weakness 1.9 Speech 1.5

Johnston, SC. JAMA. 2000;284:2901-2906

Follow up of 1707 subjects diagnosed with TIA in ED

• 10

10 20 30 40 0-2 2-4 4-12 >12

70-99% Stenosis 50-69% Stenosis Rothwell, PM. Lancet 2004; 363:915

Time from event to randomization (weeks)

ARR Death/ CVA (%)

• 4

6 8 10 12 14 16 ASA DYP ASA-DYP Placebo

J Neurol Sci 1996; 143(1-2):1

• Stroke (%)

6602 pts with recent TIA or CVA followed for 2 years

4/16/2015 3

Aspirin-Dipyridamole vs. Clopidogrel in Stroke Recurrence Prevention

Sacco RL et al. N Engl J Med 2008;359:1238-1251.

20,332 pts with ischemic CVA within 90 days randomly assigned to 25 mg ASA + 200 mg of ER dipyridamole twice daily or 75 mg of clopidogrel daily Stroke

Stroke/MI/Vascular Death

Bath, PMW. Lancet 2001; 358 (9253):702-710 1486 patients CVA within 48 hrs randomized to high-dose tinzaparin, medium-dose tinzaparin, or aspirin (300 mg daily; 491 patients)

1 2 3 4

Years of Follow-Up 6105 Patients with Previous Stroke Treated with Regimen including ACEI or placebo

PROGRESS Collaborative Group. Lancet 2001:358; 1033

20 15 10 5

Stroke %

Active Treatment Placebo

14% 10% 28% RRR

The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators.

SPARCL Investigators. N Engl J Med 2006;355:549-559.

4/16/2015 4

Marquardt, L Stroke. 2010;41:e11-e17

Event Medical Rx 5 yr (%) CEA 5 yr (%) p Ipsilateral & perioperativeCVA & death 11 5.1 .004 Major CVA & Perioperative CVA/death 6 3.4 .12 IpsTIA/CVA, PeriopTIA/CVA 19.2 8.2 <.001 Any CVA/Periop death 17.5 12.4 .09 Any major CVA/Periop Death 9.1 6.4 .26 Any CVA/death 31.9 25.6 .08 Any major CVA/death 25.5 20.7 .16 ACAS Executive Committee JAMA 1995;273:1421-1428

ACST: 3120 pt with carotid stenosis >60%, no symptoms, randomized to CEA vs. medical management. Enrolled from 4/93 to 7/2003

Event Free (%)

85 95 100 90

Years of Follow-Up

Any Stroke or Death Major Stroke or Death

CEA 6.4% Medical 11.8% CEA 3.5% Medical 6.1%

Years of Follow-Up

ACST Collaborative Group. Lancet 2004; 363: 1491 CAS CEA p MI 7 (1.2%) 13 (2.2%) 0.2 All Stroke 15 (2.5%) 8 (1.4%) 0.15 Major Stroke 3 (0.5%) 2 (0.3%) 0.66 Minor Stroke 12 (2.0%) 6 (1.0%) 0.15 Stroke + Death 15 (2.5%) 8 (1.4%) 0.15 Stroke/Death/MI 21 (3.5%) 21 (3.5%) 0.96 Silver, FL. Stroke 2011, 42:675-680

4/16/2015 5

1. Mantese VA, Timaran CH, Chiu D, Begg RJ, Brott TG, Investigators C. The carotid revascularization endarterectomy versus stenting trial (crest): Stenting versus carotid endarterectomy for carotid disease. Stroke. 2010;41:S31-34 2. Silver FL, Mackey A, Clark WM, Brooks W, Timaran CH, Chiu D, Goldstein LB, Meschia JF, Ferguson RD, Moore WS, Howard G, Brott TG, Investigators C. Safety of stenting and endarterectomy by symptomatic status in the carotid revascularization endarterectomy versus stenting trial (crest). Stroke. 2011;42:675-680 3. Howard VJ, Lutsep HL, Mackey A, Demaerschalk BM, Sam AD, 2nd, Gonzales NR, Sheffet AJ, Voeks JH, Meschia JF, Brott TG, investigators C. Influence of sex on outcomes of stenting versus endarterectomy: A subgroup analysis of the carotid revascularization endarterectomy versus stenting trial (crest). Lancet neurology. 2011;10:530-537 4. Blackshear JL, Cutlip DE, Roubin GS, Hill MD, Leimgruber PP, Begg RJ, Cohen DJ, Eidt JF, Narins CR, Prineas RJ, Glasser SP, Voeks JH, Brott TG, Investigators C. Myocardial infarction after carotid stenting and endarterectomy: Results from the carotid revascularization endarterectomy versus stenting trial. Circulation. 2011;123:2571-2578 5. Clark WM, Brott TG. Intracranial hemorrhage complicating carotid artery stenting and carotid endarterectomy. Stroke. 2011;42:2720- 2721 6. Barrett KM, Ossi RG, Brott TG, Meschia JF. Clinical, anatomic, and procedural durability of carotid revascularization. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 2013;22:218-226 7. Cohen DJ, Stolker JM, Wang K, Magnuson EA, Clark WM, Demaerschalk BM, Sam AD, Jr., Elmore JR, Weaver FA, Aronow HD, Goldstein LB, Roubin GS, Howard G, Brott TG, Investigators C. Health-related quality of life after carotid stenting versus carotid endarterectomy: Results from crest (carotid revascularization endarterectomy versus stenting trial). J Am Coll Cardiol. 2011;58:1557-1565 8. Voeks JH, Howard G, Roubin GS, Malas MB, Cohen DJ, Sternbergh WC, 3rd, Aronow HD, Eskandari MK, Sheffet AJ, Lal BK, Meschia JF, Brott TG, Investigators C. Age and outcomes after carotid stenting and endarterectomy: The carotid revascularization endarterectomy versus stenting

• trial. Stroke. 2011;42:3484-3490

9. Vilain KR, Magnuson EA, Li H, Clark WM, Begg RJ, Sam AD, 2nd, Sternbergh WC, 3rd, Weaver FA, Gray WA, Voeks JH, Brott TG, Cohen DJ, Investigators C. 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;43:2408-2416 10. Lal BK, Beach KW, Roubin GS, Lutsep HL, Moore WS, Malas MB, Chiu D, Gonzales NR, Burke JL, Rinaldi M, Elmore JR, Weaver FA, Narins CR, Foster M, Hodgson KJ, Shepard AD, Meschia JF, Bergelin RO, Voeks JH, Howard G, Brott TG, Investigators C. Restenosis after carotid artery stenting and endarterectomy: A secondary analysis of crest, a randomised controlled trial. Lancet neurology. 2012;11:755-763 11. Hill MD, Brooks W, Mackey A, Clark WM, Meschia JF, Morrish WF, Mohr JP, Rhodes JD, Popma JJ, Lal BK, Longbottom ME, Voeks JH, Howard G, Brott TG, Investigators C. Stroke after carotid stenting and endarterectomy in the carotid revascularization endarterectomy versus stenting trial (crest). Circulation. 2012;126:3054-3061 12. Timaran CH, Mantese VA, Malas M, Brown OW, Lal BK, Moore WS, Voeks JH, Brott TG, Investigators C. Differential outcomes of carotid stenting and endarterectomy performed exclusively by vascular surgeons in the carotid revascularization endarterectomy versus stenting trial (crest). J Vasc Surg. 2013;57:303-308

No one knows the hierarchy of minor

secondary endpoints to patients.

• 82 year old man sent for consultation for management of his right

internal carotid artery stenosis.

• He has a significant cardiovascular history with a previous CABG in 1997

and, more recently, PCI in February of this year after being admitted for an NSTEMI.

• Interestingly, he had been worked up for stable angina in December 2013

and had an exercise MIBI, where he exercised for 6 minutes and achieved a heart rate of 134 (96% of max predicted heart rate) with imaging that revealed mild inferior ischemia.

• His cerebrovascular disease is notable for a left carotid endarterectomy in

1994 with subsequent stenting in that artery in 2008 for restenosis.

• In addition, he has also had a left carotid-to-subclavian bypass for

subclavian steal with a known left vertebral artery and right carotid artery stenoses.

• It should be noted that a right ICA stenosis with a current velocity of 472

cm/s in 7/14.

• Amoxicillin 2000 MG (500MG CAPSULE Take 4) PO 30-60 minutes prior to dental visits PRN, Take

s/p-hip replacement

• Aspirin (ACETYLSALICYLIC Acid) 81 MG (81MG TABLET Take 1) PO QD, Non-coated (labeled

"chewable”)

• Brimonidine Tartrate 0.2 % DROPS Take 1 OU BID x 30 days
• Coenzyme Q10 400 MG CAPSULE PO QD
• Cozaar (LOSARTAN) 50 MG (50MG TABLET Take 1) PO QD
• Crestor (ROSUVASTATIN) 2.5 MG (5 MG TABLET Take 0.5) PO QD
• Fenofibrate, Microparticle (TRIGLIDE) 160 MG (160 MG TABLET Take 1) PO QD
• Finasteride (BPH) 5 MG (5MG TABLET Take 1) PO QD x 90 days
• Fish Oil Capsule (OMEGA-3-FATTY Acids) 4800 MG PO QD
• Folic Acid 0.4 MG (0.4 MG TABLET Take 1) PO QD
• Hctz 25 MG (25MG TABLET Take 1) PO QD
• Hytrin 1 MG (1MG TABLET Take 1) PO QD
• Latanoprost 1 DROP (0.005 % DROPS ) BOTH EYES QPM x 30 days
• Metoprolol Succinate Extended Release 25 MG (25 MG TAB ER 24H Take 1) PO QD
• Nitroglycerin 1/150 (0.4 Mg) 0.4 MG SL Q5MIN PRN Chest Pain, 30
• Plavix (CLOPIDOGREL) 75 MG (75MG TABLET Take 1) PO QD
• Synthroid (LEVOTHYROXINE Sodium) 50 MCG (50 MCG TABLET Take 1) PO QD
• Vitamin B12 (CYANOCOBALAMIN) 50 MCG (50 MCG TABLET Take 1) PO QD
• Vitamin B6 (PYRIDOXINE Hcl) 100 MG (100 MG TABLET Take 1) PO QD

4/16/2015 6

• On exam, 138/96, 56 BPM, 187 pounds.
• Neither wasting nor jaundice. Moist mucus membranes.
• JVP < 9 cm water. 2+ carotid pulsations with a right carotid bruit.
• Lungs clear to auscultation.
• PMI not displaced. Regular rate. Normal S1S2 without S3S4. No murmur
• r rub.
• Soft abdomen. No bruits, AAA, or organomegaly appreciated.
• No edema/cyanosis.
• ECG: Sinus bradycardia with incomplete right bundle branch block.
• A. Medical Management
• B. CAS
• C. CEA?

M e d i c a l M a n a g e m e n t C A S C E A ?

68% 18% 14%

How to decided whether to send him to the OR? Stratify by the likelihood of survival to reach benefit

▪ What is survival after revascularization? ▪ What conditions should suggest a pause before therapy?

Stratify by the risk of stroke

▪ Stenosis ▪ Plaque characteristics ▪ TCD embolic signals ▪ Plaque Progression

How to decided whether to send him to the OR? Stratify by the likelihood of survival to reach benefit

▪ What is survival after revascularization? ▪ What conditions should suggest a pause before therapy?

Stratify by the risk of stroke

▪ Stenosis ▪ Plaque characteristics ▪ TCD embolic signals ▪ Plaque Progression

4/16/2015 7

Halliday, A. Lancet 2010; 376: 1074–84 “Of those allocated deferral, about 4%/ year underwent CEA over the next decade. Only 1/3 were in patients who had had a new ipsilateral stroke or episode of TIA; the main other reason was that patients or doctors changed their minds, not that lesions changed.”

16% 38%

How to decided whether to send him to the OR? Stratify by the likelihood of survival to reach benefit

▪ What is survival after revascularization? ▪ What conditions should suggest a pause before therapy?

Stratify by the risk of stroke

▪ Stenosis ▪ Plaque characteristics ▪ TCD embolic signals ▪ Plaque Progression

11 7 4 5 10 15 5 Year Stroke Risk

60-69 70-79 80-99

ACAS Medical Therapy

9.5 9.5 5 10 15 5 Year Stroke Risk

<80 >80

ACST Medical Therapy

ACST Investigators Lancet 2004 ACAS Investigators JAMA 1995

OR P GSM >25 vs. <25 7.1 0.002 Stenosis (%) >85 vs. < 85 5.8 0.01 Symptom status Yes/No 2.9 0.06 Brain CT Positive Negative 2.5 0.099

Biasi, G. Circulation. 2004;110:756-762 418 cases of CAS had carotid plaque with gray scale median (GSM) measurement made

• preprocedurally. Neurological deficits periprocedure and postprocedurally recorded.

4/16/2015 8

King A , Markus H S Stroke 2009;40:3711-3717 Metanalysis of TCD Microembolic Signals and Risk of Stroke/TIA in Asymptomatic Carotid Disease

Balestrini S et al. Stroke. 2013;44:792-794

523 subjects with unilateral ASX ICA stenosis of 50% to 69% with CUS performed within 12

• months. Subjects were prospectively evaluated for a median period of 42 months. Stroke or

TIA diagnoses verified by a brain CT or MRI.

Asymptomatic carotid is associated with

increased cardiovascular mortality and stroke events

Current risk stratification methods require

prospective multicenter validation for recommendation

Plaque progression is currently the furthest

• ne along