What s New in Stroke? Top 10 for 2012-4

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 lr017feb2014

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: Bayer product (rivaroxaban) will be mentioned.

Presenter Disclosures Robert G. Hart Character flaws I will exaggerate a little, but most of what I will tell you is the truth. Mark Twain

Stroke is not one disease Intracranial Atherosclerosis Small Artery Disease Carotid Plaque with Emboli Carotid Stenosis Aortic Arch Plaque Atrial Fibrillation Valve Disease Cardiogenic Emboli Ventricular Thrombi

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)

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 venous thromboembolism after stroke (CLOTS 3)

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.

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.

Today s topics 1. IST-3: What was learned from this largest, realworld 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

Lancet 2012: 379: 2352-62

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; no remuneration.

IST-3: Time to randomisation and age 1400 1200 1000 Number 800 600 400 200 0 0-3 3-4.5 4.5-6 Time to randomisation (hrs) <80 yrs >80 yrs 53% of IST III participants >80 yrs

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

IST-3: Secondary ordinal analysis Ordinal analysis more statistically efficient: favourable shift in mrs adjusted common odds ratio 1 27 (95% CI 1 10-1 47), p=0 001

IST-3: Fatal & non-fatal intracranial hemorrhage < 7 days rt-pa (n=1515) Control (n=1520) No. (%) No. (%) 104 (7%) 16 (1%) P < 0.0001

IST-3 subgroups: Adjusted effect on primary outcome (mrs 0-2) (interaction) The treatment odds ratio in each subgroup has been adjusted for the linear effects of the other key variables

Updated systematic review & meta-analysis Wardlaw JM et al. Lancet 2012: 379: 2364-74. 12 randomized trials with 7012 patients (43% from IST III)

Updated systematic review & meta-analysis Wardlaw JM et al. Lancet 2012: 379: 2364-74. Age vs. time to treatment on good outcome (mrs 0-2) 10 randomized trials with 6887 patients

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 3-4.5 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)

Abstract, AHA International Stroke Meeting (14 Feb 2014) 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 Supported by NIH-NINDS

FAST-MAG (Field Administration of Stroke Therapy Magnesium) Abstract, International Stroke Meeting (14 Feb 2014) Disability at 3 Months (modified Rankin Scale) CMH test: p = 0.28 (Means 2.7 v 2.7) Supported by NIH-NINDS

Clopidogrel in High-risk pts with Acute Non-disabling Cerebrovascular Events (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.

CHANCE Results (Wang Y et al. N Engl J Med 2013; 369: 11-19) Aspirin n = 2586 Clopidogrel + Aspirin n = 2584 Ischemic stroke 295 (12%) 204 (8%) p value <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

CHANCE results: Probability of stroke-free survival Days since Randomization Wang Y et al. N Engl J Med 2013; 369: 11-19.

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 participants in May 2013 & recommended continuing.

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 1331 32 43 0.74 subgroup 2011 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) (Palacio S, Hart RG et al. International J Stroke 2013 (in press))

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 D.Y. Huang & W.G.Eisert, Stroke 2013; 44: 3623-4.

Direct-acting Oral Anticoagulants (DOACs) Factor Xa Inhibitors & direct thrombin inhibitors First phase III RCT published in 2003 (ximelagatran) X Tissue Factor/VIIa IX Unlike warfarin, directly interact with their coagulation protein target v xaban = Xa inhibitor II VIIIa Va Xa IIa IXa Rivaroxaban Apixaban Edoxaban Dabigatran Fibrinogen Fibrin Harenberg J. Semin Thromb Hemost. 2009;35:574-586.

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 CHADS 2 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 CHADS 2 score = 2.8, prior use of oral vitamin K antagonists by 59%.

ENGAGE AF: Main results Giugliano RP et al. N Engl J Med 2013; doi 10.1056/NEJMoa1310907. All strokes & systemic emboli (primary outcome) Edoxaban 60 mg/day n = 7035 296* (1.6%/yr) Edoxaban 30 mg/day n = 7034 383 (2.0%/yr) Warfarin INR 2-3 n = 7036 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. ^Estimated by subtracting all intracranial bleeds from major bleeds.

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.

Four Phase III DOAC vs. Warfarin Trials in Atrial Fibrillation Trial Agent Comments RE-LY (2009) 18,118 pts ROCKET AF (2011) 14,264 pts ARISTOTLE (2011) 18,201 pts ENGAGE AF (2013) 21,105 pts dabigatran 150 & 110 mg b.i.d. vs. warf rivaroxaban 20 mg daily vs warfarin apixaban 5 mg b.i.d. vs. warf edoxaban 60 & 30 mg daily vs warfarin open-label, TTR= 64%; fewer strokes and reduced mortality (higher dose), non-inferior with less bleeding (lower dose) double-blind, high-risk pts, TTR=55%; noninferior with reduced risk of fatal and/or intracranial bleeds. double-blind, TTR=62%; reduced stroke, major bleeding, and death double-blind, TTR=68%; both doses noninferior 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

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 * None are approved for patients with end-stage renal disease.

Stroke or systemic emboli (primary outcome events) in 4 large randomized trials comparing DOACs with highquality warfarin anticoagulation Data shown are for higher dosages of dabigatran (150mg twice daily) and edoxaban (60mg daily). Ruff CT et al. Lancet 2013 (on-line Dec 4 th )

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). Ruff CT et al. Lancet 2013 (on-line Dec 4 th )

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. Ruff CT, et al. Lancet 2013; on-line Dec 4 th.

All-cause mortality in DOAC vs. warfarin phase III RCTs in atrial fibrillation Drug All deaths Relative risk DOAC warfarin reduction p-value 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 *On-treatment analysis. ^ For higher-dosages.. Ruff CT et al. Lancet 2013 (on-line Dec 4 th ). 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

Intracerebral Hemorrhage

DOACs vs. warfarin phase III RCTs in atrial fib: Intracerebral hemorrhage PValue Dabigatran 110 mg BID P<.001 Dabigatran 150 mg BID P<.001 Rivaroxaban20 mg QD P=.024 Apixaban5 mg BID P<.001 Edoxaban60 mg QD P< 0.001 Edoxaban30 mg QD P< 0.001 0.00 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 DOAC better HR (95% CI) Warfarin better

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 vascularbed-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.

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 Heart J 2012; Furie KL et al. Stroke 2012.

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 - Hx of gastrointestinal bleeding (hmmm?)

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 dabigatran vs. 0 with warfarin

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 - creatinine quarterly if egfr <50 ml/min

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? 5. Regular follow-up is required.

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. 4. DOACs are here to stay.

This image cannot currently be displayed. 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 25% Cryptogenic 15% Recognized Cardiogenic Embolism 5% Unusual (e.g. dissections, arteritis)

Embolic Strokes of Undetermined Source (ESUS) Most cryptogenic strokes are embolic (cardioembolic, arteriogenic, paradoxic). For secondary prevention of ESUS, anticoagulants are likely to be more efficacious than antiplatelet therapy. Extensive diagnostic efforts to define the specific cause may be futile and unnecessary. Lancet Neurol 2014 (April) Thrombi overlying aortic arch plaque