What s New in Stroke? Top 10 for

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What’s New in Stroke?

Top 10 for 2012-4

Robert Hart, M.D.

Hamilton Health Sciences / McMaster Stroke Program

Population Health Research Institute Department of Medicine (Neurology)

McMaster University Hamilton, Ontario

(2)

Disclosures

Robert G. Hart

Relationships with commercial interests:

Grants: Bayer (COMPASS MIND MRI)

No participation on advisory boards / speakers bureaus; no ownership interest and does not own stocks of any pharmaceutical company.

Potential for conflict(s) of interest:

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Presenter Disclosures

Robert G. Hart

Character flaws

“I will exaggerate a little, but

most of what I will tell you is

the truth.”

(4)

Carotid Stenosis

Small Artery Disease

Atrial Fibrillation

Valve Disease

Ventricular Thrombi Cardiogenic Emboli

Aortic Arch Plaque Carotid Plaque with Emboli

Intracranial Atherosclerosis

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What’s New in Stroke: Top 10

1. Benefit of i.v. tPA confirmed for the very old,

those with large strokes, and for atrial fibrillation patients (IST-3)

2. Short-term clopidogrel + aspirin superior to

aspirin in acute minor stroke & TIA (CHANCE)

3. BP lowering in acute intracerebral hemorrhage is safe and likely beneficial (INTERACT2)

4. Early surgery for acute lobar intracerebral hemorrhage of minimal benefit (STICH II)

5. No clear benefit of endovascular therapies for

acute ischemic stroke (IMS III, SYNTHESIS, MR Rescue)

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What’s New in Stroke: Top

10

6. Novel oral anticoagulants continue to demonstrate superiority to warfarin in atrial fibrillation patients (ENGAGE AF)

7. Warfarin reduces stroke by half for patients with heart failure, but the absolute reduction is small and offset by major hemorrhage (WARCEF)

8. Value of PFO closure in young patients with

cryptogenic stroke remains unproven (CLOSURE I, RESPECT, PC trial)

9. Lowering systolic BP to <130 mmHg likely benefits patients with recent lacunar stroke (SPS3)

10. Intermittent pneumatic compression reduces

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8 additional stroke RCTs 2012-3

• ALIAS (NINDS): albumin infusion for moderate acute ischemic

stroke; negative, not yet published.

• ARCH: warfarin vs. clopidogrel + ASA in stroke/TIA with aortic

arch plaque; underpowered: 11 strokes/172 pts assigned dual antiplatelet vs. 9 strokes/177 warfarin.

• ARUBA (NINDS): medical vs. interventional (surgical,

endovascular) treatment for AVMs; stopped early due complications from interventions.

• CATIS: early BP is lowering (9 mmHg systolic by 24 hrs) in acute ischemic stroke of no benefit.

• SPS3 antiplatelet trial (NINDS): clopidogrel + ASA vs. ASA in

recent lacunar stroke: unexplained higher mortality with dual antiplatelet therapy.

• Tenecteplase vs. tPA: exciting result, but phase II.

• SWIFT & TREVO 2: superiority of stent retrievers over coiled retrievers in acute ischemic stroke.

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The Top 10:

Phenomenological Analysis

• All 14 are randomized clinical trials (RCTs)

= best evidence.

• Total participants: 23,285/13

(av 1790/trial)

+

21,105 edoxaban AF trial

• NEJM – 10, Lancet – 4

• 3 (+2) were “positive” (i.e. one treatment was

proven superior), and 9 RCTs were

“negative” (no difference or equivalent).

• Sponsorship: 4.5 industry, 9.5 government.

• 7 tested devices, 6 drugs, 1 surgery.

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Today’s topics

1. IST-3:

What was learned from this largest, “real-world” RCT testing i.v. tPA for acute ischemic stroke?

2. CHANCE:

Short-term clopidogrel + aspirin superior to aspirin in acute minor stroke & TIA.

3. ENGAGE AF:

factor Xa inhibitor as good or better than high-quality warfarin in atrial

fibrillation patients and current status of new oral anticoagulants

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International Stroke Trial (IST)-3

Lancet 2012: 379: 2352-62.

• 3035 patients with acute ischemic stroke

randomized to 0.9 mg/kg i.v. tPA vs. none

(open-label) within 6 hrs of stroke onset.

• Ethics of placebo <3 hrs:

“uncertainty principle”: individual investigator equipoise.

• 2000-2011 at 156 hospitals in 12 countries:

Northern Europe -70%; 1891 pts / 62% of

sites with no prior thrombolysis experience.

• Primary outcome: MRS 0-2 @ 6 months by

postal questionnaire or blinded telephone

interview.

Disclosure: I served on the IST-3 Data Monitoring Committee;

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IST-3: Time to randomisation and age

0 200 400 600 800 1000 1200 1400 0-3 3-4.5 4.5-6 Time to randomisation (hrs) N u m b e r <80 yrs >80 yrs 53% of IST III participants >80 yrs

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IST-3: Primary outcome: ‘alive and

independent’

(MRS 0-2)

at 6 months

rt-PA

(n=1515)

control

(n=1520)

n

(%)

n

(%)

554 (37%)

534 (35%)

Absolute difference/1000

= 14 more alive and independent

(95% CI -20 to 48)

p

= NS

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IST-3: Secondary ‘ordinal’ analysis

Ordinal analysis more statistically efficient:

favourable shift in mRS

adjusted common odds ratio

(15)

rt-PA

(n=1515)

Control

(n=1520)

No.

(%)

No.

(%)

104 (7%)

16 (1%)

IST-3: Fatal & non-fatal intracranial

hemorrhage < 7 days

(16)

(interaction)

IST-3 subgroups: Adjusted effect

on primary outcome (mRS 0-2)

The treatment odds ratio in each subgroup has been adjusted for the linear effects of the other

(17)

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Updated systematic review & meta-analysis

Wardlaw JM et al. Lancet 2012: 379: 2364-74.

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Updated systematic review & meta-analysis

Wardlaw JM et al. Lancet 2012: 379: 2364-74.

10 randomized trials with 6887 patients

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IST-3 results

• IST-3 confirms (for any lingering doubters) the benefit of i.v. tPA within 3 hrs - even at

inexperienced centers.

• IST-3 strengthens evidence of benefit for pts >80 y/o, severe strokes (NIHSS scores 15-24 had most

benefit), atrial fibrillation pts.

• Fuels controversy about i.v. tPA benefit between 3-4.5 hrs: adds 1177 patients rx’d in 3-3-4.5 hr window to 2743 pre-IST III patients (U.S. FDA declined to

approve extension of time window).

• 18 month outcomes: greater differences favoring tPA: age >80yrs (p=0.03) and high NIHSS score (p=0.02) but not time to Rx (Lancet Neurol 2013; 12: 768)

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Supported by NIH-NINDS

The Field Administration of Stroke

Therapy - Magnesium (FAST-MAG)

Pre-hospital treatment by EMS based on LA stroke score Physician telephone review and elicit consent

Stroke onset to Rx: 45 min (range 35 – 62 min) Final dx: 73% ischemia, 23% bleed, 4% mimic

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Supported by NIH-NINDS

FAST-MAG

(Field Administration of Stroke Therapy – Magnesium) Abstract, International Stroke Meeting (14 Feb 2014)

CMH test: p = 0.28

(Means 2.7 v 2.7)

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C

lopidogrel in

H

igh-risk pts with

A

cute

N

on-disabling

C

erebrovascular

E

vents (CHANCE)

(Wang Y, Johnston SC.N Engl J Med 2013; 369: 11-19)

• Acute (<24 hrs, av. 13 hrs) non-disabling (NIHSS <3) ischemic stroke (72%) or high-risk TIA

(ABCD2 >4)(28%).

• Double-blind RCT: clopidogrel (300 mg loading dose, then 75 mg/d) plus aspirin (75 – 300 mg/d) vs aspirin for 21 days; 21 d to 3 months: aspirin 75 mg/d vs. clopidogrel 75 mg/d.

• Primary outcome: all strokes at 90 days.

• 5170 Chinese participants, m. age = 62 yrs, 34% women.

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CHANCE Results

(Wang Y et al. N Engl J Med 2013; 369: 11-19)

Aspirin n = 2586 Clopidogrel + Aspirin n = 2584 p value Ischemic stroke 295 (12%) 204 (8%) <0.001 HR 0.67 Intracerebral bleed 8 8 ns Myocardial infarct 2 3 ns All deaths 10 10 ns Any bleeding 41 60 0.09 Severe bleeding 4 4 ns

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CHANCE results:

Probability of stroke-free survival

Days since Randomization

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CHANCE:

Should clopidogrel plus aspirin now be used routinely in acute TIA & minor ischemic stroke?

Five caveats

1. Unusually high rate of early recurrence in CHANCE. 2. Different spectrum of stroke subtypes among Chinese (and no information collected).

3. Concomitant stroke care likely different.

4. After 21 days, clopidogrel vs. aspirin (but Kaplan-Meier..)

5. POINT DSMB reviewed interim data on ~1500

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Effect of Adding Clopidogrel to Aspirin in

Patients with Recent Brain Ischemia

(

≤

30 days)

Trial N Ischemic Stroke

CPD+ASA ASA OR (95%CI)

CARESS 2005 107 0 4 0.11 CHARISMA subgroup 2011 1331 32 43 0.74 CLAIR 2010 100 0 2 0.22 FASTER 2007 392 12 21 0.53 Meta-analysis 1930 44 70 0.64 (0.43, 0.94)

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CHANCE:

Should clopidogrel plus aspirin now be used routinely in acute TIA & minor ischemic stroke?

• “I think that …non-Chinese patients with acute TIA and minor ischemic stroke [should continue to be enrolled] in large clinical trials..” G. Hankey, editorial, N Engl J Med 2013; 361: 82.

• “important differences according to ethnicity and environment limit the generalizability of our

results” Wang et al. (CHANCE principal

investigator) NEJM 2013; 361: 1376 (response to letters)

• “extrapolation of the results of the CHANCE trial to the Western population is not warranted…”

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Direct-acting Oral Anticoagulants (DOACs)

Factor Xa Inhibitors & direct thrombin inhibitors

Harenberg J. Semin Thromb Hemost. 2009;35:574-586. Tissue Factor/VIIa IX IXa X Xa VIIIa Va II IIa Fibrinogen Fibrin Rivaroxaban Apixaban Edoxaban Dabigatran v Unlike warfarin,

directly interact with their coagulation protein target

First phase III RCT published in 2003 (ximelagatran)

“xaban” = Xa inhibitor

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ENGAGE AF

Giugliano RP et al. N Engl J Med 2013; 369: 2093-104.

• Double-blind RCT of two dosages of once-daily edoxaban (oral factor Xa inhibitor) vs. warfarin (target INR 2-3) in

21,105 atrial fibrillation patients with >2 CHADS₂ risk

factors (sponsored by Daiichi Sankyo Pharma).

• Recruited from 1393 clinical sites in 46 countries (37% North America / Western Europe) between 2008-2010; mean follow-up = 2.8 yrs.

• Mean time-in-therapeutic range for warfarin = 68%.

• Dosage halved (in 32%) when creatinine clearance 30-50 mL/min, weight <60 kg, or potent p-glycoprotein inhibitor use (e.g. verapamil, quinidine).

• Mean age = 72 yrs, 62% men, 28% prior stroke/TIA, 25%

paroxysmal, mean CHADS₂ score = 2.8, prior use of oral

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ENGAGE AF:

Main results

Giugliano RP et al. N Engl J Med 2013; doi 10.1056/NEJMoa1310907.

Edoxaban 60 mg/day n = 7035 Edoxaban 30 mg/day n = 7034 Warfarin INR 2-3 n = 7036

All strokes & systemic emboli (primary outcome)

296* (1.6%/yr) 383 (2.0%/yr) 337 (1.8%/yr) Ischemic strokes 236 333** 235 Intracerebral bleeds 49** 30** 90

Extracranial major bleeds^ 357 213** 392

All deaths 773* 737** 839

*p= 0.08 vs. warfarin; **p<0.01 vs. warfarin.

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ENGAGE AF

Giugliano RP et al. N Engl J Med 2013; 369: 2093-104.

• Third large phase III RCT testing an oral factor Xa inhibitor against warfarin in atrial fibrillation patients.

(mean CHADS2 scores: ROCKET AF = 3.5 ; ENGAGE AF = 2.8, ARISTOTLE = 2.1)

• High-quality anticoagulation (mean TTR = 68%) and prior warfarin use minimized warfarin-associated bleeding.

• Clear dose-effect evident for ischemic strokes and bleeding. • Edoxaban 60 mg/day noninferior to warfarin re: all stroke

with major bleeding (significantly reduced intracranial bleeds) & trend toward lower mortality (p=0.08).

• Edoxaban 30 mg/day noninferior to warfarin re: all stroke with reduced major bleeding & lower mortality; but increase in ischemic strokes.

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Four Phase III DOAC vs. Warfarin Trials in

Atrial Fibrillation

Trial Agent Comments

RE-LY (2009) 18,118 pts dabigatran 150 & 110 mg b.i.d. vs. warf

open-label, TTR= 64%; fewer strokes and reduced mortality (higher dose), non-inferior

with less bleeding (lower dose)

ROCKET AF (2011) 14,264 pts rivaroxaban 20 mg daily vs warfarin

double-blind, high-risk pts, TTR=55%; non-inferior with reduced risk of fatal and/or

intracranial bleeds. ARISTOTLE (2011) 18,201 pts apixaban 5 mg b.i.d. vs. warf

double-blind, TTR=62%; reduced stroke, major bleeding, and death

ENGAGE AF (2013) 21,105 pts edoxaban 60 & 30 mg daily vs warfarin

double-blind, TTR=68%; both doses non-inferior with reduced risk intracranial bleeds

and cardiovascular death

4 DOAC vs. Warf RCTs: 71,683 pts / 2460 strokes 6 Warf vs. control RCTs: 2900 pts / 186 strokes

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DOACs: Key pharmacological features

Feature Dabigatran Apixaban Rivaroxaban Edoxaban

Coagulation target Thrombin Factor Xa Factor Xa Factor Xa

Pro-drug Yes No No No

Bioavailability 6% 70% 80% 60%

Protein binding 35% 90% 90% 55%

Dosing frequency^ twice daily twice daily once daily once daily

Half-life 12-14 hours 12 hours 7-11 hours 8-10 hrs

Drug interactions P-gp 3A4/P-gp 3A4/P-gp 3A4/P-gp

Renal excretion 80% 25% 35% 50%

Dose modification

for stage III CKD* No Yes Yes Yes

^For atrial fibrillation patients. gp = glycoprotein

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Stroke or systemic emboli (primary outcome events) in 4

large randomized trials comparing DOACs with high-quality warfarin anticoagulation

Data shown are for higher dosages of dabigatran (150mg twice daily) and edoxaban (60mg daily).

(37)

Individual outcomes in 4 large randomized trials comparing DOACs with high-quality warfarin

anticoagulation*

Data shown are for higher dosages of dabigatran (150mg twice daily) and edoxaban (60mg daily).

(38)

DOACs are more efficacious than high-quality

warfarin in non-valvular atrial fibrillation

• Meta-analysis 71,683 participants in the 4 phase III RCTs of DOAC vs. warfarin in atrial fibrillation.

• “Higher -dose”DOACs associated with reductions in all stroke (19%, p<0.0001), ischemic stroke (8%,

p=0.10) intracranial hemorrhage (52%, p<0.0001), and all-cause mortality (10%, p<0.001), but with an

increase in major GI bleeding (25%, p=0.04).

• Low-dose NOAC regimens (dabigatran 110mg twice daily, edoxaban 30mg daily) more favorable bleeding profile but significantly more ischemic strokes.

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All-cause mortality in DOAC vs. warfarin phase III RCTs in atrial fibrillation

Drug All deaths Relative

risk reduction p-value DOAC warfarin Dabigatran 150mg BID 438 487 12% 0.05 Dabigatran 110mg BID 446 487 9% 0.13 Apixaban 5mg BID 603 669 11% _0.05 Rivaroxaban 20mg QD* 208 250 15% _0.07 Edoxaban 60mg QD 773 839 8% 0.08 Edoxaban 30mg QD 737 839 13% 0.006 Pooled^ - - 10% 0.0003 .

Connolly SJ, et al. N Engl J Med. 2009;361:1139–51. Patel MR, et al. N Engl J Med. 2011;365:883–91. Granger C, et al. N Eng J Med. 2011;365:981–92. Giugliano RP, et al. N Engl J Med 2013; online Nov 19

*On-treatment analysis.

^ For higher-dosages.Ruff CT et al. Lancet 2013 (on-line Dec 4th_).

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DOACs vs. warfarin phase III RCTs in atrial fib: Intracerebral hemorrhage P _Value Dabigatran 110 mg BID P _{< .001} Dabigatran 150 mg BID P _{< .001} Rivaroxaban 20 mg QD P _{= .024} Apixaban 5 mg BID P _{< .001} Edoxaban 60 mg QD P _{< 0.001} Edoxaban 30 mg QD P _{< 0.001} Warfarin better DOAC better

Connolly SJ, et al. N Engl J Med. 2009;361:1139–1151. Patel MR, et al. N Engl J Med. 2011;365:883–891. Granger C, et al. N Eng J Med. 2011;365:981–992. Giugliano RP, et al. N Engl J Med 2013; online Nov 19

0.25 0.50 0.75 1.00 1.25

HR (95% CI)

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Is Warfarin Brain Toxic?

• Tissue factor (TF) is a receptor for factor VIIa found in high concentrations in the brain, where it provide[s] additional hemostatic protection in the case of injury. • Selective protein target of the DOACs vs warfarin: their factor VII sparing effect, supports that vascular-bed-specific hemostasis may be important.

• Alternatively, DOACs act as stoichiometric inhibitors (1:1 blockade of thrombin by dabigatran and 1:1

blockade of factor Xa by apixaban or rivaroxaban) so that higher levels of thrombin generation or factor Xa can overwhelm these anticoagulants

.

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Guidelines 2012

Canadian Cardiovascular Society 2012

“…we suggest…that…most patients should receive dabigatran, rivaroxaban or apixaban in preference to

warfarin...” European Society of Cardiology 2012

“One of the new OACs, either a DTI or an oral fXa

inhibitor should be considered rather than dose-adjusted VKA…for most patients (IIaA)”

AHA/ASA 2012

“Warfarin (1A), dabigatran (1B), apixaban (1B) and rivaroxaban (IIaB) are…indicated for the prevention

of…stroke in…non-valvular AF…”

Skanes AC, et al. Can J Cardiol 2012; 28: 125-136; Camm AJ, et al. Eur

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Which AF patients should receive

warfarin instead of a DOAC?

- Already taking warfarin with very good

INR control.

- Severe chronic kidney disease (eGFR <30

mL/min).

- Low risk of brain hemorrhage (young (<70

years), low blood pressure, no antiplatelets,

low fall risk / head trauma risk)

- Unable to afford a DOAC

(warfarin ~$50/yr plus

costs of INR monitoring; DOACs $2300/yr)

- Prosthetic cardiac valves

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Dabigatran vs. warfarin in patients with

mechanical heart valves (RE-ALIGN)

Eikelboom JW et al. N Engl J Med 2013; on-line 1 Sept.

• 252 with mechanical prosthetic heart valves randomized 1:2 to warfarin (INR 2-3 or 2.5-3.5) vs. dabigatran (150, 220, 300 mg twice daily).

• Stopped early due to excess of bot thromboembolism and major bleeding with dabigatran.

9 ischemic strokes with

(46)

Structured Follow-up of Patients

Prescribed DOACs

Heidbuchel H et al. Eur Heart J 2013: 34: 2094-106

Follow-up every 3 months

1. Assess adherence

2. Thromboembolic events

3. Bleeding or other side effects (e.g. dyspepsia) 4. New drugs prescribed that might interact

(verapamil, aspirin)

5. Re-educate about do’s and don’ts of taking anticoagulants (e.g. alcohol use)

6. Checklist for lab testing

- CBC, creatinine annually

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Things to know about the DOACs

1. More favorable benefit/risk profile vs. warfarin

in atrial fibrillation, with sharply reduced

intracranial bleeding

2. Lack of antidote an over-emphasized.

3. Not just “easy-to-use warfarin”; don’t work for

all anticoagulation indications.

4. Each DOAC has different dosing and specific

issues; how to choose?

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What’s New in Stroke 2012-14

1. IST-3

: i.v. tPA <3hrs works well in less

experienced hands, old patients and large

stroke especially benefit.

2. CHANCE:

Short-term clopidogrel +

aspirin – is it time for routine use? Maybe…

3. ENGAGE AF:

factor Xa inhibitors have

advantages over warfarin in atrial fibrillation.

(49)

This image cannot currently be display ed.

Cryptogenic ischemic stroke

• “otherwise undetermined cause”

• depends on extent of diagnostic work-up • no standard criteria Ischemic Stroke 35% Large Artery Atherosclerosis 20% Small Artery Disease “lacunes” 15% Recognized Cardiogenic Embolism 5% Unusual (e.g. dissections, arteritis) 25% Cryptogenic