Do You Believe in Magic? Anticoagulation for Ischemic Stroke
Gary L. Bernardini, MD, PhD Professor of Neurology Director, Stroke and Neurocritical Care Departments of Neurology and Neurosurgery Albany Medical Center Albany, NY
Disclosures Nothing to disclose “Do You Believe In Magic” by John Sebastian Born March 17, 1944, in Greenwich Village, New York City Founder of The Lovin’ Spoonful Performed at Woodstock ’68, ‘94 Inducted into Rock and Roll Hall of Fame 2000 “Do You Believe In Magic” released in 1965 made it to #9 Billboard Hot 100
Anticoagulation for Ischemic Stroke Yes: – Atrial fibrillation – Carotid/vertebral dissection – Antiphospholipid antibody syndrome – Cerebral Venous Sinus Thrombosis (CVST) – Other sources of thromboembolism – Thromboembolic strokes in pregnancy Maybe… – Aortic arch plaque/descending aortic arch plaque – PFO – Dissection/stump embolism – Brainstem/ vertebro-basilar insufficiency – ?? MRI with ‘ shower of emboli’ with no clear embolic source
Anticoagulation for Ischemic Stroke No: – Recurrent stroke on antiplatelet agent – Intracranial stenosis – Afib/Mechanical valve with recent ICH – Infective Endocarditis
Anticoagulation: we have ways… Unfractionated IV Heparin Warfarin Coumadin Low molecular weight heparins (LMWH) – Dalteparin (Fragmin) – Enoxaparin (Lovenox) – Ardeparin (Normiflo)
Direct Factor Xa/Thrombin inhibitors – – – – –
Hirudin Fondaparinux (Arixtra®) Bivalirudin Argatroban Ximelagatran
Unfractionated Heparin Anticoagulant drug of choice for prevention and treatment thrombosis Limitations of heparin – – – – –
Unpredictable dose response Need for lab monitoring Limited activity against clot-bound thrombin Major bleeding effects Heparin-induced thrombocytopenia (HIT)
Is bridging necessary after cardioembolic stroke? 1,2 1
Zeuthen,, et al. Throm Res 2003;109:241; 2 Hallevi Zeuthen Hallevi,, et al. Arch Neurol 2008;65:1169
Anticoagulation: Yes!
Non-valvular Atrial Fibrillation CHADS2 score: 1 pt: CHF, HTN, age>75; 2pts: h/o stroke or TIA: AC for CHADS2 score = 1 Delayed detection of AF after stroke 1 Risk of symptomatic ICH in Acute Stroke with AF 2 – – – –
1Kamel,
Large infarct Previous hemorrhagic stroke Low platelet count High hsCRP level
et al. J Stroke Cerebrovasc Dis 2009;18:453; 2 Lee, et al. Eur Neurol 2010;64:193.
Non-valvular Atrial Fibrillation AC relatively safe in group >80 yrs 1 Risk factors for stroke in patients with AF on AC 2: – – –
Carotid/vertebral atherosclerosis Diabetes Hyperlipidemia
ACTIVE W study 3 – Oral anticoagulation vs clopidogrel plus aspirin for Afib – Study stopped early because of superiority of oral anticoagulation therapy 1
Benavente, et al. Int Arch Med 2010;5:3. 2 Paciaroni Benavente, Paciaroni,, et al. Atherosclerosis 3 2010;Jun 15 (Epub (Epub); ); The ACTIVE Writing Group, The Lancet 2006; 367:1903.
Anticoagulation for Primary Stroke Prevention in Patients with Atrial Fibrillation 100% Relative Risk Reduction
86% 80%
79% 68%
65% 58%
60% 40%
33%
20% 0% Total patients N=2,461
SPINAF N=571
Hart RG. Ann Intern Med 1999;131:492-501.
CAFA N=378
BAATAF SPAF I AFASAK N=420 N=1,330 N=1,007
Direct Thrombin Inhibitors for Rx of Afib RE-LY Trial: Dabigatran vs Warfarin in Patients with Atrial Fibrillation 1: – Non-inferiority, randomized trial: 18,113 patients – Blinded fashion, fixed does of dabigatran: 110mg or 150mg twice daily or unblinded fashion, adjusted-dose warfarin – Primary outcome: stroke or systemic embolism – Primay outcomes: 1.69%/yr warfarin vs. 1.53% with 110 mg vs. 1.11% with 150 mg dabigatran (P<0.001 for non-inferiority) – Major bleeding: 3.36% warfarin vs. 2.71% 110 mg (P=0.003) vs. 3.11% 150 mg dabigatran (P=0.31) – Rate of hemorrhagic stroke: 0.38% warfarin vs. 0.12% 110 mg vs. 0.10% 150 mg dabigatran (P<0.001, both groups) – Mortality rates: 4.13% warfarin vs. 3.75% 110 mg (P=0.13) vs. 3.64% 150 mg dabigatran (P=0.051) – Rate of MI: higher with both doses of dabigatran vs. warfarin
1Connolly,
et al. N Engl J Med 2009;361:1
Carotid Dissection
Angiographic Features of Dissection of Carotid and Vertebral Arteries
Risk Factors - Dissection Connective Tissue Disorders: – – – – –
Ehlers-Danlos syndrome type IV Autosomal dominant polycystic kidney disease Marfan’s syndrome Osteogensis imperfecta type 1 ? Fibromuscular dysplasia (FMD)/cystic medical necrosis (also associated with variety of systemic disorders)
Behaviors (mechanical stretching): – – – – – – – ‡
Chiropractic manipulation (1 in 20,000 result in stroke; vertebral >>carotid)‡ Taekwondo Roller coaster rides Shiatsu massager Springboard diving “Bottoms-up” dissection “Beauty-parlor stroke”
Smith, et al, Neurology 2003;60:1424
Medical Treatment of Dissection To prevent thromboembolic complications, anticoagulation with intravenous heparin followed by oral warfarin recommended for acute dissections Imaging studies support thromboembolic mechanism (>90%) (vs hemodynamic)1 Distal â&#x20AC;&#x153;stumpâ&#x20AC;? emboli, low -flow zone from ? false lumen Target INR 2.0 -3.0 for at least 3 -6 months ? No evidence that anticoagulants better than aspirin 2 Lucas, et al, Stroke 1998;29:2646; 2Lyrer P, Engelter S. Cochrane Database of Systematic Reviews 2010
1
Antiphospholipid antibody syndrome (APS) Diagnosis of APS by 2006 Sydney criteria1 Comparison of single antiplatelet agent vs combination antiplatelet + anticoagulation for secondary stroke prevention2: – No significant difference in age, gender, NIHSS, mRS at discharge – Stroke incidence statistically higher with single antiplatelet agent than with combination therapy (p=0.026) APASS study: Presence of aPL (LA or aCL) did not predict either: – Increased risk for subsequent vascular occlusive events over 2 years – Differential response to aspirin or warfarin therapy
However, general recommendations remain: APS + thrombotic event (including stroke) = anticoagulation 1Rand.
Am Soc Hematol 2007;1:136; 2Okuma, et al. Int J Med Sci 2009;7:15;
Cerebral Venous Sinus Thrombosis (CVST)
CVST Incidence: 4-6/100,000 1 Risk factors: postinfectious, inherited pro-thrombotic states (prot S/C & AT III deficiencies, factor V Leiden mutation), drugs (androgens, ecstasy, HRT, oral contraceptives), pregnancy/ puerperium Clinical presentation: headache, focal seizures, paresis, papilledema2 Complications: raised dural venous sinus and CSF pressure, parenchymal edema and venous infarction, intracerebral hemorhage Diagnosis: CTV, MRV, angiography Treatment: – IV Heparin3 Improved outcomes No increase in cerebral hemorrhage even in those with prepre -existing bleeds
– LMWH – Catheter based therapy: rt-PA vs urokinase 4
1 3
Kimber. Q J Med 2002;95:137; 2 de Bruin, et al. J Neurol Neurosurg Psychiat 2001;70:105; Kimber. Einhaupl,, et al. Lancet 1991;338:597; 4 Bousser Einhaupl Bousser.. Stroke 1999;30:481.
Other Embolic Sources Oral anticoagulation after MI – – –
AWMI with LV thrombus Reduces stroke Associated more major bleeding compared to aspirin alone1
Oral anticoagulation with CHF2 – Incidence 10 per 100,000 over age 65 yrs – Second after Afib as cause of cardiogenic strokes – Awaiting trial to show overall efficacy and safety of anticoagulation
1Haq,
et al. Am J Med 2010;123:250; 2 Kohsaka Kohsaka,, et al. Expert Rev Cardiovasc Ther 2009;10:1209.
Other Embolic Sources Stroke during pregnancy3 – Overal incidence of stroke during pregnancy 5-67/100,000 – Causes of stroke during pregnancy: preeclampsia and eclampsia, cardioembolism, rupture of cerebral vascular anomaly, peripartum and postpartum cerebral angiopathy, cerebral venous sinus thrombosis
– Anticoagulation during pregnancy for: Arterial or venous thromboembolism Prior venous thromboembolism on long-term AC Antiphospholipid antibody syndrome with prior venous thromboembolism Patients with mechanical heart valve
3
Tang, Expert Rev Neurother 2010;10:205
â&#x20AC;&#x2DC;Shower of emboliâ&#x20AC;&#x2122; on MRI/DWI: Treat with anticoagulation? (without identifiable embolic source?)
Diagnosing cardioembolic sources of ischemic stroke Transthoracic (TTE) vs. Transesophageal echo (TEE)1: – – – – – – –
left atrial spontaneous contrast intracavity thrombus atrial septal aneurysm ventricular septal defect patent foramen ovale intra-aortic atherosclerotic plaques mobile thrombi
– Results: in 28/68 (41%) patients: TEE found abnormal lesion not detected by TTE (i.e., resulted in changed Rx) 1Blum,
et al. Med Sci Monit 2004;10:CR521
Diagnosing cardioembolic sources of ischemic stroke Another TEE study of 503 consecutive stroke patients2 â&#x20AC;&#x201C; â&#x20AC;&#x201C;
Stroke etiology found by routine diagnostics in 226 pts Of remaining 227 pts (undertermined etiology), TEE led to oral anticoagulation in 30% of these pts
2Harloff,
et al. Stroke 2006;37:859.
Anticoagulation: Maybe
Aortic arch plaque Atherosclerotic plaques in AA risk factor for IS Large plaques = 4mm increases stroke risk (2.5-9 fold ? risk) Complex plaques (ulceration, mobile component): anticoagulation advocated in past Study by DiTullio , et al1: – Two year incidence of recurrent stroke or death increases with aortic arch plaque size – Two year incidence of recurrent stroke/death similar b/t warfarin and aspirin treated groups (16.4% vs. 15.8%, respectively;P respectively;P=0.43); =0.43); i.e.,NO i.e., NO difference in treatment arms – *NOTE: recurrent stroke risk HIGH despite warfarin or aspirin – No interaction between warfarin treatment and large plaques on risk of stroke/death
Examples of aortic arch plaque by TEE 1. A, Noncomplex plaque. B, Complex plaque with ulceration of the luminal surface 1Di Tullio, et al. Circulation 2009;119:2376
Descending aortic arch plaque: Source of brain embolus?
Total number of plaques in DAo Retrograde flow into TBC into CCA into LSA
97
total (%) 14 (14%) 24 (25%) 65 (67%)
*Clear potential for retrograde embolization from DAo plaques Harloff, et al. Stroke 2010;41:1145-1150
Cryptogenic Stroke & Cardioembolic Risk Factor: PFO Prevalence of PFO in cryptogenic stroke is about 45% vs 15 -20% in general population1 Potential role of rightàleft shunt in IS Best medical management unclear –antiplatelet vs anticoagulation Source of thromboembolus not likely LE DVT; ? Pelvic veins ? ASD itself Percutaneous closure devices currently in trials – RESPECT – CLOSURE I, II 1Ballerini,
et al J Cardiovasc Med 2007;8:34
Starflex device
PFO CLOSURE I Trial: preliminary results: – PFO closure using Starflex device is not superior to best medical management Rx for recurrent stroke or TIA (failed to meet primary end point) – Small but not statistically significant benefit of device closure – Starflex device low rate of adverse events including thrombus formation – Actual closure rates were consistent with other studies – ? No need for PFO closure after stroke
Others… Dissection: antiplatelet agent good enough?? Basilar artery occlusive disease 1,2 – – – – – – – –
1
One study with 60 pts Basilar artery stenosis/occlusion >50% Stroke preceded by TIA in 48% Common presenting s/s: vertigo, dizziness, hemiparesis Most infarcts in pons; BA middle third most frequently affected segment Large artery atherosclerosis most common Anticoagulation treatment of choice Significant improvement in mRS scores at 6 months; 78% mRS 0-2
Caplan,LR . Caplan Caplan,LR. Caplan’’ s stroke: a clinical approach, 2000. 2010;112:233
2
Ciriaco,, et al. Clin Neurol Neurosurg Ciriaco
Anticoagulation: No!
Warfarin vs A spirin for Prevention of Recurrent Ischemic Stroke Study WARSS trial Multicenter, double-blind, randomized control trial comparing warfarin (INR 1.4-2.8) vs aspirin 325 mg in recurrent stroke
Primary end point: death or recurrent ischemic stroke N=2206 pts Over two year period: no difference between aspirin and warfarin in: â&#x20AC;&#x201C; prevention of recurrent stroke or death â&#x20AC;&#x201C; rate of major hemorrhage (2.22/100 pt-yrs for warfarin vs 1.49/100pt-yrs for ASA; p=0.10)
Mohr JP et al. al. N Engl J Med 2001;345:1444 2001;345:1444--51.
Probability of Event (%)
Warfarin-Aspirin for Recurrent Stroke Study (WARSS) 30
1.13 Hazard Ratio P=0.25 95% CI (0.92â&#x20AC;&#x201C;1.38)
20
Warfarin
10
The primary end point occurred in 17.8% of patients in warfarin group and 16.0% in ASA group.
Aspirin
0 0
90
180
270
360
450
540
630
720
Days After Randomization
No. at Risk Warfarin
1,103
1,047 1,013
998
972
956
939
924
885
Aspirin
1,103
1,057 1,032
1,004
984
974
951
932
900
Mohr JP et al. N Engl J Med. 2001;345:1444. Back-up slide
Medical management of intracranial (MCA) large -vessel disease WASID trial1 – 569 patients with TIA or stroke with angiographically determined 50-99% stenosis of major intracranial artery – Randomized to receive ASA 650 mg BID OR warfarin 5mg daily, mean follow-up period 18 mos. – Rate of death vascular causes: 3.2% ASA vs 5.9% warfarin groups (p=0.16); – Primary end point (ischemic stroke, brain hemorrhage, death from vascular causes other than stroke) occurred in: 22.1% ASA vs 21.8% warfarin groups (p=0.83) – Rate of death significantly higher in warfarin (9.7%) vs ASA (4.3%) group – Enrollment stopped early due to concerns about safety of warfarin group
Antiplatelet therapy ?Angioplasty/ stenting 1Chimowitz,
et al. N Engl J Med 2005;352:1305
Wingspan stent™
Afib/Mechanical valve with recent ICH Discontinuation of anticoagulation for 1 -2 weeks with relatively low probability of embolic events in patients with high embolic risk1 â&#x20AC;&#x201C; Afib â&#x20AC;&#x201C; Mechanical heart valve
Early recurrence of ICH low
1Phan,
et al. Arch Neurol 2000;57:1710
Infective Endocarditis (IE) In IE, up to 20% complicated by stroke Native valve IE: 74% ischemic strokes at time of presentation Brain hemorrhages primarily in IV drug users with S. aureus infections Antibiotic therapy: primary treatment for patients with IE and ischemic stroke Anticoagulation NOT warranted due to risk of hemorrhage from infection-related mycotic aneurysms
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