Dr Julia Hopyan Stroke Neurologist Sunnybrook Health Sciences Centre

Dr Julia Hopyan Stroke Neurologist Sunnybrook Health Sciences Centre

Objectives To learn what s new in stroke care 2010-11 1) Acute stroke management Carotid artery stenting versus surgery for symptomatic carotid artery disease 2) Stroke Prevention Advances in blood thinning therapy Dabigatran Cilostazol Physical exercise reduces the risk of stroke 3) Stroke Rehabilitation Robots and rehab

Symptomatic Carotid Artery Disease Carotid Endarterectomy is Very Beneficial <50% stenosis Medical therapy 50-69% stenosis Surgery beneficial NNT=7* 70-99% stenosis Surgery very beneficial NNT=3* 100% occluded Medical therapy *if surgery is performed within 2 weeks of presentation

Is Carotid Artery Stenting an Alternative?

Meta-analysis of data comparing CAS versus endarterectomy

Carotid Revascularisation Endarterectomy vs. Stenting Trial (CREST) NEJM Vol. 363(1) 2010 RCT N=2502 patients within 6 months of a stroke or TIA >50% stenosis on angiography or >70% with other modalities Median follow-up 2.5 yrs (max 4 years) Primary composite endpoint: Stroke, myocardial infarction, or death from any cause during the periprocedural period or any ipsilateral stroke within 4 years after randomisation

Results Primary composite endpoint over 4 years not significantly different between the 2 groups: 7.2% CAS vs. 6.8% CEA (p=0.51) 4 year rate of stroke of death was significantly higher in the CAS group: 6.4% vs. 4.7% (p=0.03) Periprocedural rates of stroke were significantly higher in the CAS group: 4.1% vs. 2.3% (p=0.01) Periprocedural rates of MI were significantly higher in the CEA group: 1.1% versus 2.3% (p=0.03)

CAS is associated with higher risk in patients >70 years of age

CREST Conclusions CAS is associated with higher periprocedural rates of stroke, but lower rates of MI compared with CEA Longer term outcomes are similar to CEA over a 4 year follow-up period, except that after the exclusion of MI, stroke and death rates are still higher after 4 years in CAS group

CREST Limitations We can t ignore the results of previous CAS vs. CEA trials that showed inferior outcomes with stenting vs. endarterectomy CAS is more dangerous in the elderly We still don t know longterm effects of stenting beyond 5-10 years of follow-up CEA is still the gold standard of treatment for symptomatic carotid artery disease, but stenting may be considered on an individual basis, esp. for younger patients, patients who are not considered surgical candidates, or who have a history of coronary artery disease

Stroke Prevention Preventing Strokes Due to Atrial Fibrillation

Atrial Fibrillation The Facts 3-4 fold increased risk of stroke after adjustment for other vascular risk factors Prevalence increases with age Responsible for 25% strokes in >80 year olds Only 30-60% of patients with AF receive anticoagulation

CHADS2 Score JAMA 2001;285:2864-2870 C Congestive cardiac failure = 1 point H Hypertension = 1 point A Age >75 years = 1 point D Diabetes = 1 point S Prior Stroke or TIA = 2 points

Risk of Stroke Per Year JAMA 2001;285:2864-2870 Score Risk of Stroke Per 100 Patient Years 0 1.9% 1 2.8% 2 4.0% 3 5.9% 4 8.5% 5 12.5% 6 18.2%

ASA 2007 Management Guidelines CHADS2 Score Treatment Recommendation 0 Aspirin (75-325mg daily) 1 Aspirin (75-325mg daily) or Warfarin (INR 2-3; target 2.5) 2 Warfarin (INR 2-3; target 2.5) Patients with valvular AF should be anticoagulated independent of their CHADS score

Atrial Fibrillation and Stroke Why are patients with AF not treated with warfarin? Drug and dietary interactions Inconvenience of monitoring the INR Compliance issues in the elderly with cognitive decline Fear of falls and bleeding Fear of taking rat poison Why do patients with AF have TIAs or strokes despite treatment with warfarin? Real-world effectiveness averages at 35%

RE-LY Study NEJM 2009;361 Non-inferiority trial; randomised; N=18,113 Patients with AF and 1 risk factor for stroke Dabigatran (blinded) 110mg or 150mg bid OR Warfarin (unblinded) target INR 2-3 Median duration of follow-up = 2 years Primary outcome measures: stroke or systemic embolism

What is dabigatran? Direct, competitive inhibitor of thrombin Blocks the activity of thrombin (both free and clotbound) 6.5% bioavailability 80% renally excreted Rapid onset of action Bid dosing Does not require regular monitoring

Results

Results: Safety Data Drug and dosage Major Bleeding Risk/Yr Warfarin (INR 2-3) 3.36% Dabigatran 110mg bid 2.71% (p=0.003) Dabigatran 150mg bid 3.11% (p=0.31)

Results: Safety Data Drug and Dosage Risk of ICH per year Warfarin (INR 2-3) 0.38% Dabigatran 110mg bid 0.12% (p<0.001) Dabigatran 150mg bid 0.10% (p<0.001)

Results: Safety Data Drug and dosage Mortality rate / year Warfarin (INR 2-3) 4.13% Dabigatran 110mg bid 3.75% (p=0.13) Dabigatran 150mg bid 3.64% (p=0.051)

RE-LY Conclusions In patients with AF, compared with warfarin: Dabigatran 110mg bid is associated with similar rates of stroke and systemic embolism, but lower rates of major hemorrhage Dabigatran 150mg bid is associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage

Limitations of dabigatran No antidote!! Cost: $3.20 per day Contraindicated in patients with renal impairment

2010 Antiplatelet Guidelines Unchanged despite recent publications (PROFESS) ASA 81-325mg/day in patients with TIA/stroke Alternatives include extended-release dipyridamole + ASA, or clopidogrel Clopidogrel is a reasonable alternative in aspirin intolerant patients Long-term combination of ASA + clopidogrel is not recommended For patients who have an ischemic stroke while taking aspirin, there is no evidence that increasing the dose of aspirin provides additional benefit

The truth about antiplatelets Aspirin is the mainstay of therapy NNT = 26-28 in a 2-3y treatment period to prevent one stroke (Antithrombotic Trialists Collaboration Data) Clopidogrel offers an 8% relative risk reduction in stroke, but absolute risk reduction per year is only 0.5% compared with aspirin (CAPRIE Trial data) Aspirin + clopidogrel is not recommended for long-term therapy because of net harm from bleeding side effects (MATCH and CHARISMA Trial data) Aggrenox does not offer any additional benefit to clopidogrel and is less well tolerated (PROFESS Trial data)

Cilostazol for prevention of secondary stroke (CSPS 2) Lancet Neurology Vol 9 October 2010 Cilostazol Inhibits platelet aggregation Has vasodilatory activity Has been used to treat peripheral vascular disease Bid dosing

Cilostazol for prevention of secondary stroke (CSPS 2) Lancet Neurology Vol 9 October 2010 CSPS 2 is an aspirin-controlled, double blind, randomised non-inferiority trial Randomised 2672 patients (20-79 yrs) within 6 mo of an ischemic stroke to Cilostazol 100mg twice daily OR Aspirin 81mg in am and placebo at night Primary endpoint First occurrence of stroke (cerebral infarction, cerebral hemorrhage or subarachnoid hemorrhage) Mean follow-up = 2-3 years

Results 1 - Efficacy (A) Primary endpoint: cerebral infarction, cerebral haemorrhage, or subarachnoid haemorrhage

Results 2 - Efficacy (B) Secondary composite endpoint: stroke (cerebral infarction, cerebral haemorrhage, or subarachnoid haemorrhage), transient ischaemic attack, angina pectoris, myocardial infarction, heart failure, or any haemorrhage requiring hospital admission

Results 3 - Safety (C) Safety endpoint of haemorrhagic events: cerebral haemorrhage, subarachnoid haemorrhage, or haemorrhage requiring hospital admission

Tolerability of Cilostazol

Conclusions: Cilostazol versus Aspirin Stroke patients treated with cilostazol are 25.7% less likely to have a stroke Cilostazol is associated with a lower rate of hemorrhagic complications Cilostazol has higher rates of non-serious adverse events, needs to be taken twice a day, and is more expensive, which may affect compliance Study population was Asian: will the study results be applicable to other ethnicities?

Physical Activity and Risk of Stroke in Women Stroke 2010;41:1243-1250 39,315 healthy US women 45yoa Women reported physical activity at baseline and regularly up to 149 months Over average follow-up of 12 years, the more exercise performed per week in terms of kcal/wk or hours/wk was associated with a lower risk of stroke Walking time and walking pace were inversely related to stroke risk Vigorous exercise was not related to stroke risk

Can robots out-do humans?

Robot-Assisted Therapy for Long-Term Upper-Limb Impairment after Stroke NEJM 362;19 May 13, 2010 Multicentre RCT 127 patients with moderate-severe upper limb impairment 6 months after stroke 49 patients received intensive robot-assisted therapy 50 patients received intensive comparison therapy 28 received usual care 36 1-hour sessions over a period of 12 weeks Primary outcome: Change in motor function at 12 wks (Fugl-Meyer Assessment of Sensorimotor Recovery after Stroke) Secondary outcomes: Scores on the Wolf Motor Function Test and Stroke Impact Scale at 36 wks

MIT-Manus robotic system (Interactive Motion Technologies)

Types of Therapies Robot-assisted: High intensity, repetitive, task-oriented movements directed by video screens Shoulder-elbow unit Wrist unit Grasp hand unit Intensive comparison therapy: Structured protocol using conventional rehab techniques Assisted stretching Shoulder stabilisation techniques Arm exercises Functional reaching tasks Usual care: Medical management Clinic visits as needed Occasionally rehab services

Results and Conclusions Robot-assisted therapy did not significantly improve motor function at 12 weeks, as compared with usual or intensive therapy In secondary analyses, robot-assisted therapy improved outcomes over 36 weeks as compared with usual care but not with intensive therapy Robots cannot out-do humans (yet)!