1

Natural History of Carotid Artery Disease

Eric Hager, MDAssistant Professor of SurgeryDivision of Vascular surgery

University of Pittsburgh Medical Center

2

Cerebral Vascular Disease“Stroke”

3rd leading cause of death in the United States

Incidence: 795,000 First stroke: 610,000 Recurrent stroke:

185,000 Annual US mortality:

136,000 Morbidity

15-30% permanently disabled

20% require institutional care at 3 months

Sources: Roger VL, et al. `American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics--2011 update: a report from the American Heart Association. Circulation. 2011 Feb 1;123(4):e18-e209. Epub 2010 Dec 15.

3

Cerebral Vascular Disease“Stroke”

Lifetime risk for stroke at 65 years of age Men: 14.5% Women: 16.1%

Economic 2007 direct and indirect

cost of stroke: $40.9 billion

Average lifetime cost of ischemic stroke: $140,048

Sources: Roger VL, et al. `American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics--2011 update: a report from the American Heart Association. Circulation. 2011 Feb 1;123(4):e18-e209. Epub 2010 Dec 15.

4

Extracranial Carotid

8%

In-tracra-

nial Carotid

8%

Lacunar20%

Cardio-embolic20%

Unknown44%

Ischemic stroke causes

Stroke and Extracranial Carotid Artery Occlusive Disease

Stroke Etiology

Hemorrhagic: 13%

Ischemic: 87%

Source: Mackey WC. CHAPTER 92 – Cerebrovascular Disease  :  General Considerations. Rutherford’s Vascular Surgery. 7th Edition. 2010.

5

Extracranial carotid disease is associated with stroke

Symptomatic disease Already experienced

a neurologic event High risk of recurrence Secondary prevention

Asymptomatic disease Incidentally found Low, but significant,

ongoing risk of an event Primary prevention

6

MR and CT imaging: stroke extent and carotid stenosis

Davis SM, Donnan GA. Secondary Prevention after Ischemic Stroke or Transient Ischemic Attack. N Engl J Med 2012;366:1914-22.

7

Cerebral vascular Occlusive Disease

Risk factors: Male gender Advancing age Hypertension Smoking Diabetes Atrial fibrillation History of

cerebrovascular disease

8

Natural History

What is the Natural History of carotid disease? Asymptomatic? Symptomatic?

▪ * No contemporary studies non-medically managed best medical therapy

(BMT)

9

Before BMT: Natural history of asymptomatic disease –

severity of stenosis

1986: 500 patients with asymptomatic carotid bruits and variable stenosis graded by ultrasound

Recorded TIA/Stroke rates

Study period 4 years (mean follow up 26 month)

Sources: Chambers BR. Norris JW. Outcome in patients with asymptomatic neck bruits. N Engl J Med. 1986;3 15:860-865

0-29% 30 - 74% 75 - 99%0.0%

5.0%

10.0%

15.0%

20.0%

Neurologic Events

2.1%

5.7%

19.5%

10

Before BMT: Natural history of asymptomatic disease - echogenicity

1987: 296 patients evaluated Stratified according to:

▪ 1) Degree of stenosis by B-mode US▪ 2) Echogenicity of the carotid lesion

▪ Gray-scale median >32 =dense▪ Gray-scale median <32 = echolucent

Evaluated neurologic events over a 3 year study period

Sources: O’Holleran LW, Kennelly MM, McClurken M, Johnson JM. Natural history of asymptomatic carotid plaque. Am J Surg. 1987; 154:659-662

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<75 % stenosis

>75 % stenosis

Dense Echolucent0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

10%

49%

16%

48%

3%

12%

3%

15%

TIAs

Before BMT: Natural history of asymptomatic disease - echogenicity

1987: 296 patients evaluated Stratified according to:

▪ 1) Degree of stenosis by B-mode US▪ 2) Echogenicity of the carotid lesion

▪ Gray-scale median >32 =dense▪ Gray-scale median <32 = echolucent

Evaluated neurologic events over a 3 year study period

Sources: O’Holleran LW, Kennelly MM, McClurken M, Johnson JM. Natural history of asymptomatic carotid plaque. Am J Surg. 1987; 154:659-662

Support to the NEJM data – degree of stenosis correlates to neurologic event rates.

Dense (calcified) plaque is less likely to cause TIA/strokes

12

Before BMT: Natural history of asymptomatic disease –

stenosis progression

1984: Stroke - Roederer and colleagues examined 167 patients with <80% stenosis

Conclusion: Progressive disease leads to a higher risk of neurologic events

Sources: Roederer GO, Langlois YE, Jager KA, Primozich JF, Beach KW, Phillips DJ, Strandness DE Jr. The natural history of carotid arterial disease in asymptomatic patients with cervical bruits. Stroke 1984;15: 605-613

Stroke risk at 12 months

Stable <80% stenosis 1.5%

Progressive stenosis >80 % 46%

13

Best Medical Therapy

Evolution of Best Medical Therapy (BMT) Smoking cessation Glycemic control Anti-platelet (e.g., aspirin

+/- dipyridamole, clopidogrel)

Lower hypertension (ACE, ARB, b-blocker)

Address dyslipidemia (statins)

14

Natural history with BMT

Study Degree of stenosis

Year

Number of patients

Endpoint Stroke or TIA (%)

Asymptomatic Carotid AtherosclerosisStudy (ACAS)

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Natural history with BMT

Study Degree of stenosis

Year

Number of patients

Endpoint Stroke or TIA (%)

Asymptomatic Carotid AtherosclerosisStudy (ACAS)

60-99% 1995

1662 Ipsilateral stroke

11.0% over 5 years

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Natural history with BMT

Study Degree of stenosis

Year

Number of patients

Endpoint Stroke or TIA (%)

Asymptomatic Carotid AtherosclerosisStudy (ACAS)

60-99% 1995

1662 Ipsilateral stroke

11.0% over 5 years

Asymptomatic Carotid StenosisTrial (ACST)

17

Natural history with BMT

Study Degree of stenosis

Year

Number of patients

Endpoint Stroke or TIA (%)

Asymptomatic Carotid AtherosclerosisStudy (ACAS)

60-99% 1995

1662 Ipsilateral stroke

11.0% over 5 years

Asymptomatic Carotid StenosisTrial (ACST)

60-99% 2004

3120 Any stroke 11.8% over 5 years

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ACST- asymptomaticendarterectomy v. medical therapy

Halliday A, Mansfield A, Marro J, Peto C, Peto R, Potter J, Thomas D; MRC Asymptomatic Carotid Surgery Trial (ACST) Collaborative Group. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomised controlled trial. Lancet. 2004 May 8;363(9420):1491-502.

0 1 2 3 4 5

Patients with >60% stenosis

a) 30 day results: CEA: 2.5% BMT: 0.7%

b) 5 year results: CEA: 6.4% BMT: 11.8% P<0.0001

Years after randomization

CEA

Medical

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Natural history of untreated symptomatic disease

No randomized study is possible today in symptomatic disease

Consequently natural history is based on early observational studies

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Natural history of symptomatic disease – ASA vs. Placebo

Sources: 1) The Canadian Cooperative Study Group. A randomized trial of aspirin and sulfinpyrazone in threatened stroke. N Engl J Med 299: 53-59, 19782) Candelise L, Landi G, Perrone P, Bracchi M and Brambilla G. A randomized trial of aspirin and sulfinpyrazone in patients with TIA. Stroke. 1982;13:175-1793) Fields WS, Lemak NA, Frankowski RF, Hardy RJ: Controlled trial of aspirin in cerebral ischemia. Stroke. 8:301-315 1977 3240364) Bousser MG, Eschwege E, Haguenau M, et al.: “AICLA” controlled trial of aspirin and dipyridamole in secondary prevention of athero-thrombotic cerebral ischemia. Stroke. 14:5-14 1983 6401878

Study Year Number of patients

Mean follow-up

period

Stroke or death risk

Canadian Cooperative Study

Candelise et al.

Fields et al.

Bousser et al.

21

Natural history of symptomatic disease – ASA vs. Placebo

Sources: 1) The Canadian Cooperative Study Group. A randomized trial of aspirin and sulfinpyrazone in threatened stroke. N Engl J Med 299: 53-59, 19782) Candelise L, Landi G, Perrone P, Bracchi M and Brambilla G. A randomized trial of aspirin and sulfinpyrazone in patients with TIA. Stroke. 1982;13:175-1793) Fields WS, Lemak NA, Frankowski RF, Hardy RJ: Controlled trial of aspirin in cerebral ischemia. Stroke. 8:301-315 1977 3240364) Bousser MG, Eschwege E, Haguenau M, et al.: “AICLA” controlled trial of aspirin and dipyridamole in secondary prevention of athero-thrombotic cerebral ischemia. Stroke. 14:5-14 1983 6401878

Study Year Number of patients

Mean follow-up

period

Stroke or death risk

Canadian Cooperative Study

1978

Candelise et al.

1982

Fields et al. 1977

Bousser et al. 1983

22

Natural history of symptomatic disease – ASA vs. Placebo

Sources: 1) The Canadian Cooperative Study Group. A randomized trial of aspirin and sulfinpyrazone in threatened stroke. N Engl J Med 299: 53-59, 19782) Candelise L, Landi G, Perrone P, Bracchi M and Brambilla G. A randomized trial of aspirin and sulfinpyrazone in patients with TIA. Stroke. 1982;13:175-1793) Fields WS, Lemak NA, Frankowski RF, Hardy RJ: Controlled trial of aspirin in cerebral ischemia. Stroke. 8:301-315 1977 3240364) Bousser MG, Eschwege E, Haguenau M, et al.: “AICLA” controlled trial of aspirin and dipyridamole in secondary prevention of athero-thrombotic cerebral ischemia. Stroke. 14:5-14 1983 6401878

Study Year Number of patients

Mean follow-up

period

Stroke or death risk

Canadian Cooperative Study

1978 139 26 months 21%

Candelise et al.

1982 76 11 months 17%

Fields et al. 1977 604 36 months 18%

Bousser et al. 1983 90 6 months 21%

In all trials there was a reduction of stroke rates with aspirin therapy. No further placebo trials have been conducted since.

23

North American Symptomatic Carotid Endarterectomy Trial

1991- NASCET trial sought to compare outcomes of surgery vs. best medical management 659 patients with

symptomatic carotid disease

Stroke risk was directly related to degree of stenosis

North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med. 1991 Aug 15;325(7):445-53.

30-49% 50-69% 70-99%0.0%

5.0%

10.0%

15.0%

20.0%

25.0%

30.0%

18.7%

22.2%26.0%

Stroke risk

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North American Symptomatic Carotid Endarterectomy Trial

Stroke risk also correlated to number of risk factors: Age >70 SBP >160 DBP>90 Recent stroke Stenosis >80% Ulcerated plaque Hx of tobacco use Diabetes Claudication HyperlipidemaNorth American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med. 1991 Aug 15;325(7):445-53.

0-5 6 >60.0%

5.0%

10.0%

15.0%

20.0%

25.0%

30.0%

35.0%

40.0%

17.0%

23.0%

39.0%

Stroke risk

The study was stopped early due to the high stroke rates of medically managed patients. All patients recommended to have CEA

25

North American Symptomatic Carotid Endarterectomy Trial

659 patients 30 day results

CEA: 5.8% BMT: 3.3%

2 year results CEA: 9% BMT: 26%

North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med. 1991 Aug 15;325(7):445-53.

26

Treatment of patients with asymptomatic disease

Patient with asymptomatic

carotid stenosis ≥ 80%

(>3 year life expectancy)

BMT + Open surgery (CEA)

High risk for open surgery?• Medical comorbidities• Difficult anatomy

Best medical therapy (BMT)

YES

NO

27

Treatment of symptomatic patients

Patient with symptomatic

carotid stenosis ≥ 60%

BMT + Endarterectomy

High risk for open surgery?• Medical comorbidities• Difficult anatomy

BMT + Stenting

YES

NO

28

Conclusion:

The natural history of asymptomatic and symptomatic carotid disease is well understood

Asymptomatic patients, there is ongoing debate whether surgical intervention is ever warranted due to improved BMT

Most symptomatic carotid stenosis should undergo intervention