1 5 th McMaster University Review Course in INTERNAL MEDICINE What s New in Stroke? Robert Hart, M.D. HHS / McMaster Stroke Program Department of Medicine (Neurology) McMaster University Hamilton, Ontario
2 5 th McMaster University Review Course in INTERNAL MEDICINE Robert Hart perceives no conflicts of interest with this presentation, but in the past 2 years he has worked with or consulted for: Boehringer Ingelheim (dabigatran) Bayer (rivaroxaban)
3 What s New in Stroke 2013? 3 topics 1. Guidelines for anticoagulation in atrial fibrillation: updates endorse novel oral anticoagulants over warfarin; reduced intracranial hemorrhage a key advantage. 2. Endovascular therapies for acute ischemic stroke: mixed results from 5 RCTs (IMS III, SYNTHESIS, MR RESCUE, TREVO 2, SWIFT). 3. Clopidogrel added to aspirin for 21 days after acute minor stroke / TIA reduces early stroke recurrence (CHANCE).
4 Novel Oral Anticoagulants Factor Xa Inhibitors and Direct Thrombin Inhibitors Tissue Factor/VIIa X IX VIIIa Va Xa IXa Rivaroxaban Betrixaban Apixaban YM150 Edoxaban II IIa Dabigatran AZD-0837 Fibrinogen Fibrin Harenberg J. Semin Thromb Hemost. 2009;35:
5 Four Recent Phase III Trials of Novel Oral Anticoagulants in Atrial Fibrillation Trial Agent Comments RE-LY dabigatran 150/110 mg b.i.d. vs. warfarin ROCKET AF rivaroxaban 20 mg daily vs warfarin ARISTOTLE AVERROES apixaban 5 mg b.i.d. vs. warfarin apixaban 5 mg b.i.d. vs. aspirin open-label, TTR= 64%; superior (higher dose), less bleeding (lower dose), reduced mortality (higher dose) double-blind, high-risk pts, TTR=55%; non-inferior with reduced risk of fatal and/or intracranial bleeds. double-blind, TTR=62%; reduced stroke, major bleeding, and death double-blind, unsuitable for warfarin ; huge effect over aspirin with similar intracranial bleeding.
8 Recent Oral An,coagula,on Trials: Hemorrhagic Stroke Dabigatran 110 mg BID Dabigatran 150 mg BID Rivaroxaban 20 mg QD P Value P <.001 P <.001 P =.024 Apixaban 5 mg BID P < New Agent BeLer Connolly SJ, et al. N Engl J Med. 2009;361: Patel MR, et al. N Engl J Med. 2011;365: Granger C, et al. N Eng J Med. 2011;365: HR (95% CI) Warfarin BeLer
9 Intracranial hemorrhages in the RE-LY RCT (Hart RG, Diener H-C et al. Stroke 2012; 43: ) Warfarin Dabigatran 150 mg Dabigatran 110 mg All intracranial Intracerebral - spontaneous - traumatic 46^ Subdural - spontaneous - traumatic Subarachnoid - spontaneous - traumatic *Intention-to-treat results; on-treatment results similar. Red = p<0.05 vs. warfarin. ^Rate = 0.4%/yr
10 Guidelines 2012 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 Camm AJ, et al. Eur Heart J 2012 (On line) Furie KL, et al. Stroke 2012 (On line)
11 Guidelines 2012 Canadian Cardiovascular Society 2012 we suggest that most patients should receive dabigatran, rivaroxaban or apixaban in preference to warfarin... American College of Chest Physicians 2012 we suggest dabigatran 150 mg bid rather than adjusted-dose VKA therapy (2B). You JJ, et al. Chest 2012; 141: e531s-575s Skanes AC, et al. Can J Cardiol 2012; 28:
12 Mechanical thrombectomy for acute ischemic stroke: SWIFT RCT Saver JL et al. Lancet 2012; 380: Solitaire stent retriever vs. Merci coil retriever. - proximal cerebral artery occlusion (most middle cerebral artery) within 8 hrs of onset patients with mod/severe acute stroke (av. NIHSS = 17); av. 5 hrs to Rx, 40% prior i.v. tpa. Good reperfusion without bleeding Good neurological 90 days* Solitaire N = 58 Merci N = 55 P value 61% 24% % 33% days 17% 38% 0.02
13 Mechanical Retrieval and REcanalization of Stroke Clots Using Embolectomy (MR RESCUE) (Kidwell CS et al. N Engl J Med 2013 on-line Feb 8th) RCT of embolectomy (MERCI, Penumbra) vs. standard medical care within 8 hrs of stroke onset. 118 pts, mean NIHSS = 17, mean time to enrollment = 5.5 hrs (> 6 hrs mean time to puncture); 67% recanalized. MRI penumbral pattern did not predict response. Embolectomy N = 64 Standard Care N = 54 Mean 90 d Good 90 d Death 12 13
14 Mechanical Retrieval and REcanalization of Stroke Clots Using Embolectomy (MR RESCUE) (Kidwell CS et al. N Engl J Med 2013 on-line Feb 8th) no significant difference in clinical or imaging outcomes in patients undergoing embolectomy [vs.] standard medical care. A favorable penumbral pattern on neuroimaging did not identify patients who would differentially benefit from endovascular therapy. Caveats: delayed time to treatment (average time > 6 hrs), relatively low achieved rate (67%) of reperfusion.
15 Endovascular Therapy for Acute Stroke TREVO 2 RCT of stent retriever (Lancet 2012; 380:1231): similar results as SWIFT. U.S. FDA approved MERCI, TREVO and Solitaire devices to re-open blocked arteries (but no RCTs showing better neuro outcomes). 2013: IMS III, SYNTHESIS and MR RESCUE: endovascular Rx no better than medical controls AHA/ASA guideline (2012): mechanical thrombectomy may be reasonable.. in patients with large-artery occlusion who have not responded to intravenous fibrinolysis. Additional randomized trial data are needed (Class IIb) TREVO and Solitaire better than MERCI, & MERCI appears comparable to standard care, so..?
16 Effect of clopidogrel added to aspirin on stroke: meta-analysis of 13 RCTs (Palacio S, Hart RG et al. International J Stroke 2013 (in press)) OR=0.81, 95% CI 0.74,0.85
17 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 CHARISMA subgroup 2011 CLAIR FASTER Meta-analysis (0.43, 0.94) (Palacio S, Hart RG et al. International J Stroke 2013 (in press))
18 Clopidogrel added to aspirin for stroke prevention: Conclusions of meta-analysis Clopidogrel combined with aspirin reduces ischemic stroke more than aspirin alone for a broad range of patients with vascular disease. For those with recent stroke / TIA (<30 days), the relative risk reduction was 36% (95% CI 6-57) Major bleeding is increased by clopidogrel plus aspirin (RR 1.4, 95%CI , p<0.001) Palacio S, Hart RG et al. International J Stroke 2013 (in press).
19 Clopidogrel in High-risk pts with Acute Nondisabling Cerebrovascular Events (CHANCE) (Wang Y, Johnston SC. Am Heart J 2010; 160: 380-6) Acute (<24 hrs, av. 13 hrs) non-disabling (NIHSS <3) ischemic stroke (72%) or high-risk TIA (ABCD2 >4)(28%). Rationale: restricted to minor stroke to reduce secondary intracerebral bleeding; short-term (21 day) treatment to maximize benefit vs. risk. Double-blind RCT: clopidogrel (300 mg loading dose, then 75 mg/d) plus aspirin ( mg/ d) vs aspirin for 21 days; 21 d to 3 months: aspirin 75 mg/d. Primary outcome: all strokes at 90 days.
20 CHANCE Results (Wang Y, AHA International Stroke Conference, Feb ) 5170 Chinese participants, m. age = 62 yrs, 34% women. All 90 days: 12% aspirin alone vs. 8% clopidogrel + aspirin (HR 0.68, 95% CI ; p = 0.001). Kaplan-Meier plots: parallel after 1 st 21 days. Absolute reduction 3.5%; NNT with dual antiplatelet for 21 days to prevent 1 stroke = 29.
21 CHANCE Results (International Stroke Conference 8 Feb 2013) Aspirin n = 2586 Clopidogrel + aspirin n = 2584 p value Ischemic stroke <0.001 Intracerebral bleed 8 8 ns Myocardial infarct 2 3 ns All deaths ns Any bleeding Severe bleeding 4 4 ns
22 Canadian Best Practice Recommendations for Stroke Care (4th Edition 2012) Short-term concurrent use of acetylsalicylic acid and clopidogrel (up to 90 days) has not shown an increased risk of bleeding [Evidence Level B]; however, longer-term use is not recommended for secondary stroke prevention, unless there is an alternate indication (e.g., drug-eluting carotid artery stent requiring dual antiplatelet therapy), due to an increased risk of bruising and bleeding [Evidence Level A].
23 Key Questions 1. Should atrial fibrillation patients requiring anticoagulant be treated with warfarin or one of the novel oral anticoagulants? 2. Does endovascular therapy benefit selected patients with acute stroke? 3. Is anything better than starting aspirin for acute minor stroke / TIA patients?
24 TAKE HOME MESSAGES 1. Most updated guidelines recommend that atrial fibrillation patients requiring anticoagulation should be treated with a novel oral anticoagulant. 2. Does endovascular therapy benefit selected patients with acute stroke? Technical advances / promising results, but clinical benefits still not certain. 3. Is anything better than starting aspirin for acute minor stroke / TIA patients? Yes: clopidogrel plus aspirin for at least 21 days.
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