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Stroke, Part I - An Evidence-Based Review of Risk Factors and Prevention Laurence J. Kinsella, M.D., F.A.A.N.

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Presentation on theme: "Stroke, Part I - An Evidence-Based Review of Risk Factors and Prevention Laurence J. Kinsella, M.D., F.A.A.N."— Presentation transcript:

1 Stroke, Part I - An Evidence-Based Review of Risk Factors and Prevention Laurence J. Kinsella, M.D., F.A.A.N.

2 Stroke: Incidence and Cost in the United States 795,000 new or recurrent cases yearly 1 stroke every 40 seconds #3 cause of death $73 billion annual health cost 4,400,000 stroke survivors at high risk for recurrence 75 yo M with multiple Large artery territory infarctions, typical of cardiogenic embolus AHA Heart and Stroke Statistics Update Available at 1982%20Heart%20and%20Stroke%20Update pdf

3 Cost of Stroke 20% institutionalized after 3 months 15-30% permanently disabled $73 billion in direct and indirect costs Average lifetime cost of stroke in the U.S. estimated to be $140,000. Stroke 2011;42:

4 Causes of Stroke 85% Infarction 30-60% Cerebrovascular atherosclerosis 20% Penetrating artery disease (lacunes) 15-30% Cardiogenic Embolism (higher 80) 5% Other, unusual causes Hemorrhage - Intracerebral - Subarachnoid 15%

5 Well-Documented and Modifiable Risk Factors Hypertension exposure to cigarette smoke diabetes atrial fibrillation and certain other cardiac conditions dyslipidemia Carotid artery stenosis Sickle cell disease Postmenopausal hormone therapy Poor diet physical inactivity Obesity body fat distribution Stroke 2011;42:

6 Less well-documented or potentially modifiable Risk Factors Metabolic syndrome Excessive alcohol consumption Drug abuse Sleep-disordered breathing Migraine Hyperhomocysteinemia Elevated lipoprotein(a) Use of oral contraceptives Hypercoagulability Inflammation Infection Stroke 2011;42:

7 Stroke risk varies by clinical setting Risk FactorAnnual Risk AFIB, Low Risk1% Amaurosis Fugax2-3% Asx carotid > 60%2-3% TIA5-6% AFIB, High Risk8% Prior Stroke6-10% Sx carotid > 70%16% Gorelick P. Arch Neurol 1995;52:

8 Causes of Stroke: Cerebrovascular Atherosclerosis 85% Infarction 30-60% Cerebrovascular atherosclerosis 20% Penetrating artery disease (lacunes) 15-30% Cardiogenic embolism 5% Other, unusual causes Hemorrhage - Intracerebral - Subarachnoid 15%

9 Vascular Territories of the Cerebral Hemisphere

10 Circle of Willis: Key Collateral Circulation Antero-posterior Axial

11 Carotid Ultrasound Internal carotid artery Common carotid artery

12 Critical Internal Carotid artery stenosis Most frequent cause of recurrent or crescendo TIAs Mechanism is stenosis with flow reduction Ulcerated plaque with artery to artery embolism

13 Causes of Stroke: Penetrating Artery Disease (Lacunes) 85% Infarction 60% Cerebrovascular atherosclerosis 20% Penetrating artery disease (lacunes) 15% Cardiogenic embolism 5% Other, unusual causes Hemorrhage - Intracerebral - Subarachnoid 15%

14 Lacunar Stroke Thalamic Lacune Subcortical White matter lacunes

15 Lacunar Infarction Vessels undergo lipohyalinosis 4 most common locations Internal capsule Thalamus Pons Cerebellum

16 Lacunar Infarcts (Small Subcortical Strokes): Summary Diagnosis: Clinical syndrome (e.g., pure motor or pure sensory) plus CT/MRI confirmation Risk factor management: Hypertension, diabetes Carotid stenosis: Present in only 10% Rate of re-occurrence: High (10%/yr) Antiplatelet agents probably effective

17 Causes of Stroke: Cardiogenic Embolism 85% Infarction 60% Cerebrovascular atherosclerosis 20% Penetrating artery disease (lacunes) 15% Cardiogenic embolism* 5% Other, unusual causes Hemorrhage - Intracerebral - Subarachnoid 15%

18 Cardiogenic Embolism Nonvalvular atrial fibrillation (45%) Acute MI (15%) Other,less common sources (10%) Prosthetic cardiac valves (10%) Rheumatic heart disease (10%) Ventricular aneurysm (10%)

19 Atrial Fibrillation (AF) Predisposes to Stroke Mean Onset Age 64, > 2 Million People 35% Have Stroke During Lifetime 5% /Yr Stroke Rate, 12% after TIA > 75,000 Strokes/Yr in U.S. 30% of all strokes > 80 years old Gorelick P. Arch Neurol 1995;52:

20 Stroke: Other, Unusual Causes *Dissection, migraine, oral contraceptive use in smokers, meningovascular syphilis, cocaine and amphetamine use, associated with prothrombotic states (e.g., sickle cell anemia) 5% Other, unusual causes 85% Infarction 60% Cerebrovascular atherosclerosis 20% Penetrating artery disease (lacunes) 15% Cardiogenic embolism Hemorrhage - Intracerebral - Subarachnoid 15%

21 Hemorrhagic Stroke 85% Infarction 60% Cerebrovascular atherosclerosis 20% Penetrating artery disease (lacunes) 15% Cardiogenic embolism 5% Other, unusual causes Hemorrhage - Intracerebral - Subarachnoid 15%

22 Subdural hematoma Not considered a stroke, but may have focal signs from mass effect Obvious right SDH with mass effect Subtle SDH in 75 yo M with confusion, myoclonus after falling at home s/p trimalleolar fracture repair

23 Hypertensive Intracerebral Hemorrhage Same locations as lacunes Thalamus, basal ganglia, pons, cerebellum Lipohyalinosis, microaneurysms Amyloid angiopathy may have similar appearance Prognosis dependent on volume of blood and Glasgow Coma Scale Intraventricular blood - poor prognostic sign Ritter MA, Droste DW, et al. Role of cerebral amyloid angiopathy in intracerebral hemorrhage in hypertensive patients. Neurology. 2005;64:1233–7. Clarke JL. Neurocrit Care. 2004;1:53-60.

24 Lobar Hemorrhages Present in frontal, parietal, temporal lobes Rarely due to HTN Consider - hemorrhagic embolic infarction tumor AVM amyloid septic embolus 57 yo Hunter with sudden onset headache, minimal left hand weakness. Qureshi AI, Tuhrim S, et al. Spontaneous intracerebral hemorrhage. N Engl J Med.2001;344:1450–60

25 Subarachnoid Hemorrhage 30,000 per year 80% due to aneurysm 20% non-aneurysmal (venous rupture?) 1% of all ED headaches Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage Stroke. 2009;40:

26 Risk Factor Modification is critical >77% of all strokes are first time events without a warning TIA Risk factor control for hypertension, diabetes, smoking, hyperlipidemia, etc. Antiplatelet agents for cerebrovascular disease. Anticoagulation for atrial fibrillation and other selected heart diseases. Endarterectomy vs stenting for high-grade symptomatic carotid stenosis

27 Reduction in Stroke in SHEP 36% reduction in stroke (p = 0.003) Placebo Active Treatment months Cumulative Stroke Rate per 100 Population JAMA Jun 26;265(24):

28 Therapeutic Goals for Antihypertensive Rx Condition Pre-Hypertension Uncomplicated Diabetic or Kidney Dz African-American Goal BP 120/80-129/89 140/90 130/80 135/85 JNC VII, Hypertension 2003

29 Stroke reduction published in the large statin trials Trial % reduction GREACE 47 4S 37 CARE 31 ASCOT-LLA27 HPS 25 LIPID 19 ALHAT-LLA 9

30 Guidelines for Cholesterol With CHD or symptomatic athero, target goal is LDL < 100 mg/dl, < 70 for high risk patients (DM, smoking) Patients with TIA or stroke with normal cholesterol levels will benefit from statin therapy Low HDL may be treated with gemfibrozil or niacin Sacco RL, et al. Guidelines for prevention of stroke. Stroke 2006;37:

31 Statins and ACEI in Secondary Stroke Prevention SPARCL trial 80 mg atorvastatin in 4731 pts after TIA or stroke LDL 73 mg/dl in Tx, 129 mg/dl in placebo 11.2 vs. 13.1% had fatal/non-fatal stroke (p <.03) 20% RRR for all major cardiac events Increased hemorrhages in those with prior ICH Dagenais Metanalysis of 3 clinical trials of ACE inhibitors (ACEI) 29,805 patients Reduced all cause mortality 7.8 vs 8.9% placebo Amerenco P. SPARCL: high dose atorvastatin after stroke or transient ischemic attack. NEJM 2006;355: Dagenais GR, et al. ACE inhibitors in stable vascular disease without LV dysfunction or CHF. Lancet 2006;368:

32 Vitamins and Stroke - Does Homocysteine Suppression work? Homocysteine lowering with folic acid, pyridoxine (B6), and cobalamin (B12) Reduced average by 2.5 µmol/liter No difference in vascular events despite significant lowering of homocysteine Same results as VISP 2004 trial - no effect The Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. N Engl J Med 2006; 354:

33 Aspirin - what dose and when? mg qd has shown statistical benefit. (25% RRR) Not as effective after TIA (13% RRR) 325 mg paralyzes all platelets immediately when chewed and swallowed, therefore this is ideal in acute settings (TIA and Stroke) 81 mg is appropriate as “maintenance therapy” - may reduce bleeding risk 8 th ACCP Guidelines. Chest 2008

34 Combination ASA and Clopidogrel MATCH trial shows increased risk of hemorrhage with combination. ASA-clopidogrel arm dropped from the ProFESS trial Combination not recommended for the secondary prevention of stroke due to hemorrhage risk J Am Coll Cardiol 2011 Feb 22; 57:1002. Diener et al, Lancet 2004.

35 Combination of ASA and Clopidogrel in AFIB Low dose ASA mg daily vs ASA plus clopidogrel 75 mg daily No reduction seen in vascular outcomes Stroke, MI, vascular death rates unaffected Found to be more effective at stroke reduction than ASA alone for AFIB in patients who are poor candidates for anticoagulation Bhatt DL, et al. N Engl J Med 2006;354. ACTIVE-A,NEJM 2009;360:

36 Problems with Clopidogrel? Requires P450 2C19 metabolism 2-3% are deficient in the enzyme, therefore no antiplatelet effect 2C19 Inhibited by proton pump inhibitors (omeprazole, etc), reducing efficacy of clopidogrel Frere C et al, Effect of cytochrome P450 polymorphisms on platelet reactivity after treatment with clopidogrel in acute coronary syndrome. Am J Cardiol 2008; 101: Gilard M et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole Clopidogrel Aspirin) Study. J Am Coll Cardiol 2008: 51:

37 Dipyridamole and ASA 2 ESPRIT 1363 pts randomized to ASA mg alone, 1376 ASA with dipyridamole 200 mg bid w/in 6 mos of TIA or stroke Primary outcome - death, stroke, MI or bleeding at 3.5 yrs ARR 1% per year NNT 100 pts to prevent outcome per year, 5 yrs ESPRIT study group. Lancet 2006;367:

38 ASA-dipyridamole vs Clopidogrel PROFESS trial Combination pill no better than clopidogrel in preventing recurrent stroke. No neuroprotective effect seen for dipyridamole (Persantine ® ) or telmisartan (Micardis ® ) Sacco RL, et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med. 2008;359:

39 Antiplatelets and AFIB Warfarin reduces stroke by 64% and ASA 26% 50% of patients with Afib are not treated with warfarin- risk of bleeding, fall risk, etc. ASA + Clopidogrel demonstrated additional 28% reduction in stroke and MI, but increased hemorrhages over ASA alone (2%/yr) ASA + Clopidogrel is an option for warfarin intolerant patients with afib, with risks Active-A. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med May 14;360(20):

40 When to use Coumadin in Afib CHADS2 score C HF - any history H TN - prior history A ge > 75 D iabetes S econdary prevention after systemic embolization 1 2 Go AS, et al. JAMA 2003;290:2685 Gage BF, et al. JAMA 2001;285:2864.

41 When to use Warfarin in afib CHADS2 score Event rate/yr Warfarin Event rate/yr No warfarin NNT * * * * * Go AS, et al. JAMA 2003;290:2685 Gage BF, et al. JAMA 2001;285:2864. *consider warfarin therapy

42 Dabigatran Direct thrombin inhibitor 110mg equally effective than warfarin at stroke prevention with fewer hemorrhages 150mg superior to warfarin, similar hemorrhages No drug interactions No monitoring expensive relative to warfarin RELY Trial NEJM 2010

43 Stroke Prevention in AFIB 2011 RiskRecommendation s Alternatives lone AF < 65 yrASA 325 mg/d--- low risk yrASA 325 mg/d -Warfarin INR 2-3 -ASA 81mg plus clopidogrel 75mg -Dabigatran 110mg high risk or > 75 yr Warfarin INR 2-3 Or Dabigatran 110mg -ASA plus clopidogrel if warfarin is Contraindicated -Dabigatran 110mg Active A Trial. NEJM 2009;360:

44 Carotid Endarterectomy: Symptomatic vs. Asymptomatic Carotid Stenosis Stroke Rate (%/yr) Symptomatic Carotid Stenosis ( > 70% ) Asymptomatic Carotid Stenosis ( > 60% ) Medical Rx Carotid Endarterectomy Symptomatic Carotid Stenosis ( 50-69% ) Circulation. 2006;113:e409-e449. Lancet May 8;363(9420):

45 Carotid Endarterectomy - How soon after stroke/TIA? NASCET Data analysis For > 50% symptomatic stenosis NNT to prevent one ipsilateral stroke in 5 yrs: 5 for those within 2 weeks of last ischemic event 125 if randomized after 12 weeks. 9 for men vs 36 for women 5 for > 75 years 18 for < 65 years Rothwell PM. Lancet. 2004;363:

46 Steps to reduce Morbidity and Mortality in Stroke Control fever and glucose IV tPA within 4.5 hours of onset - 30% increased chance of little or no deficit at 3 months. Aspirin 325 mg within 48 hrs - 10/1000 reduction in deaths at 6 months Admission to Stroke Unit - 40% reduction in death Don’t withdraw statins Use an ACE inhibitor NPO and Swallowing eval within 24 hrs - prevents pneumonia, fever, prolonged LOS, ?deaths DVT prophylaxis - calf SCDs, Subq Heparin No BP Rx for < 200/120 for 48 hours (<185/110 w tPA) 80 mg Atorvastatin acutely after TIA and Stroke, not hemorrhage Acute Stroke Treatment 2010 emedicine.medscape.com/article/ treatment#Table4 Adams H et al. Stroke. 2007;38: Blanco M et al. Neurology Aug 28;69(9):904-10

47 2011 Guidelines Risk Factor Modification BP <140/90 or BP <130/80 with DM, renal disease EtOH

48 Questions from the Audience?

49 References 1.Guideline on the management of patients with extracranial carotid and vertebral artery disease. J Am Coll Cardiol 2011 Feb 22; 57: Sacco RL, etal. Guidelines for prevention of stroke. Stroke 2006;37: Albers GW, Amarenco P, Easton JD, Sacco RL, Teal P. Antithrombotic and thrombolytic therapy for ischemic stroke: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest Sep;126(3 Suppl):483S-512S. 4.Halliday A, Mansfield A, Marro J, et al. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomized controlled trial. Lancet May 8;363(9420): NASCET: beneficial effect of carotid endarterectomy in symptomatic patients with high grade stenosis. N Engl J Med 1991;325: ACAS Study group: Endarterectomy for asymptomatic carotid stenosis. JAMA 1995;273: Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage. Stroke. 2009;40: Diener H-C, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomized, double-blind, placebo- controlled trial Lancet 2004;364:


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