Andrew Hudson, MD CCFP

October. 17/2018

Topics in Stroke Management

Program Planning Committee

(PPC) Disclosure

The following steps have been taken to mitigate bias:

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delivery. The coordinator wil l be looking for any signs of bias including use of

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I f bias is detected the PPC would review it and the speaker would be notif ied so

that the bias can be corrected before the presentation is given. I f the bias cannot

be corrected or removed the session would be cancelled.

I f a bias is detected by a planning committee member during the presentation they

would question the speaker about it .

All biases would be reviewed at the next PPC meeting.

Disclosures

I have no personal or financial relationships to disclose.

Objectives

Describe the burden of stroke in Canada

Demonstrate an understanding of current Best Practice

Recommendations

Apply an evidence based approach to individualize stroke

management

Kawarau Bridge, NZ

Stroke: an episode of symptomatic neurological dysfunction, caused by focal brain, spinal cord or retinal ischemia or hemorrhage with evidence of infarction or hemorrhage on imaging and regardless of duration

TIA: transient episode of of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia, without infarction.

*Symptoms resolving < 24 hours still widely used as definition of TIA

-majority resolve within 60 minutes

700, 000 Canadians >20 (2.7%), are living with diagnosed

stroke

10% adults >65 affected

1/3 of strokes occur >80

Mean age of stroke is decreasing, increased proportion <55

Male=female

Clinical Presentation

99% of vertigo not stroke

Initial Assessment

TIA Risk assessment

Minor Stroke/High Risk TIA

10-20% have recurrent stroke within 3 months

½ within first 2 days

80-90% within first 30 days

Initial imaging

CT

CTA

Aortic arch to vertex *include extracranial vessels

Carotid imaging

Include with initial CTA

Carotid ultrasound within 24 hours if CTA not completed

Carotid endarterectomy

To prevent one stroke at 5 years:

NNT=5 if surgery<2 weeks

NNT=125 if surgery >3 mo

For non-disabling stroke/TIA with

70-99% stenosis, CEA should

be performed within first few days

Antiplatelet Therapy

ASA 160mg stat

ASA vs clopidogrel

ASA + clopidogrel

Ticagrelor

2014 Cochrane review, evaluated immediate antiplatelet use (within 2 weeks)

Primary outcome death/dependency @6 months

8 trials, >41,000 participants

ASA 160-300mg within 48 hours sig reduced death/dependency

NNT=79

Small increase in number of hemorrhages. Determined benefit >>Risk

No included studies looked at clopidogrel

Continue with ASA 81-325mg indefinitely

Plavix as an alternative if already on ASA prior to stroke/TIA

-loading dose 300mg in some cases

ASA or clopidogrel or DAPT?

•Published 2013

•N=5170 Chinese, randomized to ASA 75mg + placebo vs ASA 75mg + clopidogrel 75mg

•Age ≥ 40, onset ≤ 24h, NIHSS ≤3, ABCD2 ≥4

•Stop placebo/clopidogrel at 21 days, continue ASA

•Primary outcome stroke at 90 days, 3.5% ARR/30% RRR in DAPT group

•NNT=29

•No increased risk of hemorrhage

•?results applicable to a western population

•Chinese known to have increased intracranial large vessel disease, poorly controlled

risk factors

•POINT trial, f/u to CHANCE

•Published May 2018

•N=4881 NA/Australia/Europe

•Randomized to ASA+placebo vs ASA+clopodigrel 75mg/d x 90 days, then continue ASA

•Onset ≤12 hours, NIHSS ≤3, ABCD2 ≥4

•Primary outcome ischemic stroke/MI/ischemic vascular death @ 90 days

•Study stopped when 84% complete due to hemorrhage in ASA/clopidogrel group

•NNH=200

•Improved primary outcome, NNT=66

•Majority of benefit within first 7 days, 80-90% within first 30 days

•Bleeding risk steady throughout trial period

•Conclusion: suggest benefits > risks, if DAPT limited to maximum 30 days

19,000 pts enrolled with recent CVA, MI or symptomatic PAD

Randomized to ASA 325mg vs clopidogrel 75mg

Composite outcome ischemic stroke, MI, vascular death significantly reduced in clopidogrel group

*majority of benefit seen in PVD group

ESPRIT/ESPS2- ASA/dipyrimadole (Aggrenox) for secondary prevention, showed benefit over

ASA in non-fatal MI, non-fatal stroke, vascular deaths vs ASA

PRoFESS trial, plavix as effective as asa+dipyrimadole for secondary stroke prevention

ASA or Plavix?

Bottom Line: clopidogrel, asa+dypyridamole MAY be slightly more efficacious than ASA, esp

in pts with known atherosclerotic disease.

-not superior to ASA for prevention stoke/MI/death at 90 days

-Ticagrelor superior to ASA at 90 days for patients with ipsilateral atherosclerotic stenosis

(6.7% vs 9.6%)

-no difference in bleeding rates

*Differences were only seen in patients with lacunar stroke

ASA/Plavix “Failure”

Canadian Stroke Best Practice Recommendations

-Assess for patient compliance

-concomitant use of NSAIDS with ASA

-smoking increased ASA resistance, appears to enhance clopidogrel benefits

Intracranial Atherosclerosis

Symptomatic intracranial large artery stenosis 70-99%-DAPT x

90 days, then d/c one

Medical management superior to stenting

•1/6 stroke attributed to atrial fibrillation

•Strokes are more disabling, 80-90% die or are disabled

•Anticoagulation 64% reduction in risk of stroke, 25% reduction in risk of mortality

•Antiplatelets 22% reduction in risk of stroke

•Anticoagulation strongly recommended

•1/4 strokes labelled ‘cryptogenic’ after standard workup

•Paroxysmal atrial fibrillation often undetected

Atrial fibrillation

EKG

Initial 24 hour EKG monitoring

2 week loop recorder

•572 patients with cryptogenic

stroke after standard w/u

•Repeat 24 hour holter vs 30 day

loop recorder

2017 Best Practice Recommendations

Mechanical valve=

coumadin

Timing of initiation anticoagulation

General recommendations:

Same day after TIA

3 days after mild stroke

6 days after moderate stroke

12-14 days after severe stroke

Bridge with antiplatelet

*individualize based on infarct size, imaging, age, co-

morbidities, estimated recurrence risk

Hemorrhagic transformation 13% to 43% in CT studies

Symptomatic HT 0.6% to 20%

15-20% MCA infarcts

Majority occur within first 48-72 hours

Risk factors:

- Acute massive infarction

- Atrial fibrillation w/ cerebral emboli

- Cortical infarct

- Low platelets

- Poor collaterals on CTA/MRA

- Early CT signs

- Thrombolytic use-repeat CT 24 hours after

PH2 predictor of deterioration and mortality at 3 months

HT management

Hold antiplatelet/anticoag

Restart antiplatelet 24-48 hours and stable imaging

Restart anticoagulation 7-10 days

Consider:

-cryoprecipitate

-antifibrinolytic agents (Tranexamic acid 10mg/kg tid-qid)

Atrial fibrillation and PCI 20% patients with A.fib will requires PCI

2016 CCS Guidelines

2124 patients with A. fib undergoing PCI

1. Rivaroxaban 15mg OD + clopidogrel 75mg/d

2. Rivaroxaban 2.5mg BID + clopidogrel 75mg + ASA 75-100mg

3. Coumadin + clopidogrel 75 mg + ASA 75-100mg

• For the majority of patients of patients risks of standard

triple therapy outweigh benefits

2018 CCS Guidelines

Statins

Best Practice Guidelines 2017

Statins

No evidence (RCTs) to support achievement of any specific

lipid targets, including LDL

High quality evidence supports significant benefit of high

dose statin vs low,

And any dose statin vs no statin

No other LDL lowering method (fibrates, resins, diet,

HDL) have any impact on stroke reduction

All current evidence suggest CVD risk is lowered by statins,

not LDL lowering

Therefore… All patients should likely receive high dose statin (40-80mg

atorvastatin equivalent), or highest dose tolerated, regardless of LDL level

Appears to be no strong benefit to routinely checking LDL levels to guide therapy

**IMPROVE-IT shows ezetimibe added to simvastatin decreased CV death/MI/stroke in high risk post ACS patients vs simvastatin alone

-only study to show small benefit of non-statin

-some suggestion LDL level actually mattered

Hypertension

Single most important modifiable risk factor for stroke

0-72 hours CHEP/Canadian Stroke network Guidelines

*75% of stroke patients are hypertensive at this stage

-Patients receiving thrombolysis: lower BP <185/110 prior to tPA and maintain x 24 hours

-non-thrombolytic patients: Hypertension at this stage should NOT be treated unless extreme, SBP >220 mm Hg or DBP >120 mm Hg

(unless other indication, angina, CHF, etc..)

-if treating target 15% (<25%) reduction within 24 hours

HTN Beyond 72 hours Long term BP management is important

Gradually introduce therapy to achieve a target consistently <140/90

ACE (or ARB)/BB/CCB/Thiazide diuretics all options for first line (based on RCTs)

CHEP recommends ACE +/- thiazide diuretic as first line

-based on PROGRESS trial

Treatment to BP targets beneficial regardless of agent used

*Na intake, exercise, reduced etoh all have impact on BP

PFO in Cryptogenic stroke

PFO found in 25-30% of adults (25% age 30-80)

PFO closure suggested if:

-18-60 y/o

-Cryptogenic, embolic ischemic stroke/TIA

Therefore: patients ≤ 60 with cryptogenic stroke consider TEE

*Patients > 60 receive antiplatelet treatment

References 1. Wein T, Lindsay M, Cote R, et al. Canadian Stroke Best Practice Recommendations: Secondary Prevention of Stroke, sixth edition practice

guidelines, update 2017. International Journal of Stoke. 2018, Vol. 13(4), 420-443.

2. Casaubon L, Boulanger JM, Blaquiere D, et al. Canadian Stroke Best Practice Recommendations: Hyperacute Stroke Care Guidelines, Update 2015 International Journal of Stoke. 2015, 10: 924-940

3. Stroke in Canada: Highlights from the Canadian Chronic Disease Surveillance System. https://www.canada.ca/en/public-health/services/publications/diseases-conditions/stroke-canada-fact-sheet.html. (Accessed October 2018)

4. Yew K. Acute Stroke Diagnosis. Am Fam Physician. 2009 July 1; 80(1); 33-40.

5. Johnston SC, Rothwell PM, Huynh-Huynh MN. Validation and Refinement of Scores to Predict Very Early Stroke Risk After Transient Ischemic Attack. Lancet, 2007, 369: 283-292.

6. Rothwell PM, Ellasniw M, Gutnikov SA, et al. Endarterectomy for symptomatic carotid artery stenosis in releation to clinical subgroups and timing of surgery. Lancet, 2004, 363: 915-924.

7. Sandercook PA, Counsell C, Tseng MC, et al. Oral antiplatelet for acute ischemic stroke. Cochrane Database Syst Rev, 2014, March 26(3)

8. Wang Y, Wang Y, Shao X. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. NEJM, 2013, 369: 11-19.

9. Johnston S, Easton D, Farrant M, et al. Clopidogrel andaspirin in acute ischemic stroke and high risk TIA. NEJM, 2018, 379: 215-225.

10. Sacco R, Diener HC, Yusuf S, et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. NEJM, 2008, 359: 1238-1251.

11. Johnston S, Amarenco P, Albers G, et al. Ticegralor vs aspirin in acute stroke or transient ischemic attack. NEJM, 2016, 375: 35-43.

12. Johnston S, Denison H, Albers G, et al. Ticegralor vs aspirin in acute stroke or transient ischemic attack of atherosclerotic origin: a subgroup analysis of SOCRATES. Lancet, 2017, 16 : 301-310.

13. Chimowitz M, Lynn M, Derdyn C, et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. NEJM, 2011, 365: 993-1003.

14. Gladstone D, Dorian P, Spring M, et al. Atrial fibrillation in patients with cryptogenic stroke. NEJM, 2014, 370: 2467-2477.

15. Anticoagulation in non-valvular a. fib. www. Rxfiles.ca. (accessed October 2018)

16. Yanghi S, Willie J, Cucchiara B, et al. Treatment and outcome of hemorrhagic transformation after intravenous alteplase in acute ischemic

stroke. Stroke, 2017, 48: e343-e361.

17. Gibson M, Behran R, Bode C, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. NEJM, 2016, 375: 2423-2434.

18. Prevention and management of cardiovascular disease risk in primary care: Clinical practice guidelines. Towards optimized practice. 2015.

www.topalbertadoctors.org

19. Cannon C, Blazing M, Giugliano R. Ezetimibe added to statin therapy after acute coronary syndrome. NEJM, 2015, 372: 2387-2397.

20. Hypertension Canada 2017 Guidelines. https://guidelines.hypertension.ca/. (accessed October 2018)