Secondary Preven-on of Thromboembolic Stroke: Clinical Data and Recommenda-ons from the ESC Atrial Fibrilla-on Guideline Update 2012

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1 Secondary Preven-on of Thromboembolic Stroke: Clinical Data and Recommenda-ons from the ESC Atrial Fibrilla-on Guideline Update 2012 Professor Dan Atar Head, Dept. of Cardiology Councillor of the ESC, Oslo University Hospital Ullevål Norway

2 Prof. Dan Atar Disclosures Co-author of ESC Guidelines on Atrial Fibrillation Steering Committee member, National Coordinator for Norway, and Co-author of ACTIVE, ARISTOTLE, AVERROES Fees, honoraria from Sanofi-Aventis, Merck (MSD), Boehringer- Ingelheim, Bayer, BMS/ Pfizer, Daiichi-Sankyo, Nycomed-Takeda

3 2012 focused update of the ESC Guidelines for the Management of Atrial Fibrillation An update of the 2010 ESC Guidelines for the Management of Atrial Fibrillation Camm AJ, et al. Eur Heart J :

4 A logical sequence to AF management Camm AJ, et al. Eur Heart J. 2010;31:

5 Two intertwined issues: Stratification as a guide to therapy (Antiplatelet therapy) The CHAD 2 DS 2 VASc score Identifying truly low risk patients The HAS-BLED score Courtesy Prof. R. de Caterina European Heart Journal doi: /eurheartj/ehs253.

6 Adapted from Gage BF, et al. JAMA. 2001; 285: Courtesy Prof. R. de Caterina Camm AJ, et al. Eur Heart J. 2010;31:

7 Problems with the CHADS 2 score Moderate c-statistics (0.58) in the whole cohort to predict stroke Most subjects categorized as moderate risk (score=1) These subjects overall still appear to derive benefit from oral anticoagulants vs aspirin Courtesy Prof. R. de Caterina

8 Courtesy Prof. R. de Caterina Healey JS, et al. Stroke. 2008;39:

9 Problems with the CHADS 2 score (con t) Moderate c-statistics (0.58) in the whole cohort to predict stroke ( but no worse than 11 other risk stratification schemes compared by the Stroke in AF Working Group) Most subjects categorized as moderate risk (score=1) These subjects overall still appear to derive benefit from oral anticoagulants vs aspirin Also, the CHADS2 score does not include many stroke risk factors, and other stroke risk modifiers needed to be considered in a comprehensive stroke risk assessment Courtesy Prof. R. de Caterina

10 Camm AJ, et al. Eur Heart J. 2010;31:

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12 Since 2010, further validation of the CHA2DS2-VASc score Lip GY. J Thromb Haemost 2011;9 Suppl 1: Potpara TS, et al. Circ Arrhythm Electrophysiol 2012;5: Olesen JB, et al. Thromb Haemost 2012;107: Van Staa TP, et al. J Thromb Haemost 2011;9: Abu-Assi E, et al. Int J Cardiol Courtesy Prof. R. de Caterina European Heart Journal doi: /eurheartj/ehs253.

13 ESC AF Guidelines Update Adapted from Olesen JB, et al. Br Med J 2011;342:d142. Camm AJ, et al. Eur Heart J :

14 Proportion of patients free of stroke/thromboembolism The value of the CHA 2 DS 2 -VASc score for refining stroke risk stratification in patients with a CHADS 2 score % 98% 96% 94% 92% 0% Olesen et al Thromb Haemost Jun;107(6): CHA 2 DS 2 -VASc = 0 CHA 2 DS 2 -VASc = 1 CHA 2 DS 2 -VASc = 2 CHA 2 DS 2 -VASc = 3 CHADS 2 = Days from discharge In patients with a CHADS 2 =0, c-statistic was ( ) and increased to ( ) when CHA 2 DS 2 -VASc was included. European Heart Journal doi: /eurheartj/ehs253

15 Figure 1 Choice of an-coagulant Atrial fibrilla*on Yes Valvular AF* Yes No (i.e. non- valvular AF) < 65 years and lone AF (including females) No Assess risk of stroke (CHA 2 DS 2 - VASc score) 0 1** 2 Oral an*coagulant therapy Assess bleeding risk (HAS- BLED score) Consider pa*ent values and preferences No an*thrombo*c therapy NOAC VKA * Includes rheuma-c valvular AF, hypertrophic cardiomyopathy, etc. ** An-platelet therapy with aspirin plus clopidogrel, or less effec-vely aspirin only, may be considered in pa-ents who refuse any OAC. Colour: CHA 2 DS 2 - VASc score; green = 1, blue = 2, red = 2. Line: Solid: best op-on; Dashed: alterna-ve op-on. If absolute contraindica-ons to any OAC or an-- platelet therapy, lex atrial appendage closure device can be considered. AF = atrial fibrilla-on; CHA 2 DS 2 - VASc = see text; HAS- BLED = see text; NOAC = novel an-coagulants; VKA = vitamin K antagonist.

16 Male or female! European Heart Journal doi: /eurheartj/ehs253.

17 Conclusions The ESC 2012 AF Guideline Update emphasizes the need for stroke risk assessment in AF The focus is on identification of truly low-risk patients All others: Oral Anticoagulation (OAC) recommended. Aspirin no longer recommended OAC can be either Warfarin or NOAC The 2012 ESC guideline update encourages the use of NOAC as the preferred option in suitable patients after thorough identification of potential contra-indications European Heart Journal doi: /eurheartj/ehs253.

18 Secondary Prevention Prior stroke subgroup analysis

19 RE-LY

20 Prior stroke subgroup analysis: stroke or systemic embolism Higher rate of stroke/systemic embolism in patients with prior stroke/tia vs those without across treatment groups (2.38% vs 1.22%/yr; P<0.001) No significant interaction between previous stroke/tia and treatment effects on primary outcome Dabigatran 110 mg BID Dabigatran 150 mg BID Warfarin Prior stroke/tia Annual rate, % RR (95% CI) vs warfarin 0.84 ( ) 0.75 ( ) No prior stroke/tia Annual rate, % RR (95% CI) vs warfarin 0.93 ( ) 0.60 ( ) P value for interaction BID = twice daily; RR = relative risk; TIA = transient ischaemic attack Diener HC, et al. Lancet Neurol. 2010;9:

21 Prior stroke subgroup analysis: time to stroke or systemic embolism in patients with previous stroke or TIA Cumulative hazard rates Dabigatran 110 mg BID Dabigatran 150 mg BID Warfarin Number at risk Follow-up (years) Dabigatran 110 mg Dabigatran 150 mg Warfarin BID = twice daily; TIA = transient ischaemic attack Diener HC, et al. Lancet Neurol. 2010;9:

22 Prior stroke subgroup analysis: haemorrhagic stroke Lower stroke risk in patients with prior stroke/tia receiving dabigatran vs warfarin mainly due to decrease in haemorrhagic stroke Dabigatran 110 mg BID Dabigatran 150 mg BID Warfarin Prior stroke/tia Annual rate, % RR (95% CI) vs warfarin 0.11 ( ) 0.27 ( ) No prior stroke/tia Annual rate, % RR (95% CI) vs warfarin 0.44 ( ) 0.25 ( ) P value for interaction BID = twice daily; TIA = transient ischaemic attack Diener HC, et al. Lancet Neurol. 2010;9:

23 Prior stroke subgroup analysis: major bleeding Dabigatran 110 mg BID Dabigatran 150 mg BID Warfarin Prior stroke/tia Annual rate, % RR (95% CI) vs warfarin 0.66 ( ) 1.01 ( ) No prior stroke/tia Annual rate, % RR (95% CI) vs warfarin 0.85 ( ) 0.91 ( ) P value for interaction BID = twice daily; TIA = transient ischaemic attack Diener HC, et al. Lancet Neurol. 2010;9:

24 Prior stroke subgroup analysis: intracranial bleeding Dabigatran 110 mg BID Dabigatran 150 mg BID Warfarin Prior stroke/tia Annual rate, % RR (95% CI) vs warfarin 0.20 ( ) 0.41 ( ) No prior stroke/tia Annual rate, % RR (95% CI) vs warfarin 0.35 ( ) 0.43 ( ) P value for interaction BID = twice daily; TIA = transient ischaemic attack Diener HC, et al. Lancet Neurol. 2010;9:

25 ARISTOTLE

26 Primary outcome: Stroke (ischaemic or haemorrhagic) or systemic embolism 10 8 Warfarin / Prior Stroke Percent with Event Apixaban / Prior Stroke Warfarin / No Prior Stroke Treatment Apixaban Warfarin Apixaban Warfarin Prior Months Stoke Yes Yes No No Adapted from Easton JD, et al. Lancet Neurol. 2012; 11: Apixaban / No Prior Stroke

27 Major efficacy study outcomes Prior stroke or TIA No prior stroke or TIA Number of events (% per year) Apixaban Warfarin HR (95% CI) Interaction p Stroke or 73 (2.46) 98 (3.24) 0.76 ( ) systemic embolism 139 (1.01) 167 (1.23) 0.82 ( ) 0.71 Stroke 67 (2.26) 96 (3.17) 0.71 ( ) 132 (0.96) 154 (1.14) 0.84 ( ) 0.40 Ischaemic or 57 (1.92) 68 (2.23) 0.86 ( ) unknown stroke 105 (0.76) 107 (0.79) 0.97 ( ) 0.61 Haemorrhagic 12 (0.40) 31 (1.00) 0.40 ( ) Stroke 28 (0.20) 47 (0.34) 0.59 ( ) 0.35 Death from 129 (4.22) 150 (4.77) 0.89 ( ) any cause 474 (3.37) 519 (3.75) 0.90 ( ) Adapted from Easton JD et al. Lancet Neurol. 2012; 11:

28 Major safety study outcomes (con t) Prior stroke or TIA No prior stroke or TIA Number of events (% per year) Interaction Apixaban Warfarin HR (95% CI) p Total bleeding 457 (19.86) 619 (29.12) 0.70 ( ) (17.70) 2441 (25.11) 0.72 ( ) Major bleeding 77 (2.84) 106 (3.91) 0.73 ( ) (1.98) 356 (2.91) 0.68 ( ) Intracranial 15 (0.55) 41 (1.49) 0.37 ( ) 0.60 bleeding 37 (0.29) 81 (0.65) 0.44 ( ) GI major 18 (0.66) 22 (0.80) 0.83 ( ) bleeding 87 (0.68) 97 (0.78) 0.87 ( ) Adapted from Easton JD et al. Lancet Neurol. 2012; 11:

29 Outcomes in secondary prevention: patients with prior stroke or TIA AVERROES Baseline characteristic Apixaban Aspirin Randomized Age (mean and SD) 70 ± 9 yrs 70 ± 10 yrs Male 59% 58% CHADS2 score (mean and SD) ± % 37% 27% 2.1 ± % 34% 29% Prior stroke/tia 14% 13% TIA=transient ischaemic attack Connolly SJ, et al. N Engl J Med. 2011;364: AVERROES

30 AVERROES: Primary endpoints for patients with prior stroke/tia Connolly SJ, et al. N Engl J Med. 2011;364:

31 AVERROES: Major bleeding in patients with prior stroke/tia Connolly SJ, et al. N Engl J Med. 2011;364:

32 ROCKET AF subanalysis: secondary prevention Cohorts: - History of stroke/tia (stroke cohort) versus - No history of stroke/tia (non-stroke cohort) 7468 (52%) patients had a previous stroke (n=4907; 65%) or TIA (n=2561; 34%) Hankey GJ, et al. Lancet Neurol. 2012;11: ROCKET-AF

33 ROCKET AF subanalysis: secondary prevention Results: Primary efficacy outcome Kaplan Meier survival curve showing time to the primary outcome (stroke or systemic embolism) Cumulative event rate stroke or systemic embolism (%) Intention-to-treat population Hankey GJ, et al. Lancet Neurol. 2012;11: Months from randomisation 30 Previous stroke/ TIA, warfarin Previous stroke/ TIA, rivaroxaban No previous stroke/ TIA, warfarin No previous stroke/ TIA, rivaroxaban

34 ROCKET AF subanalysis: secondary prevention Results: Efficacy outcome (ITT) Rivaroxaban Events/yr (nr*) Warfarin Events/yr (nr*) No previous stroke or TIA Previous stroke or TIA HR (95% CI) p-value* Stroke or systemic embolism 1.44 (90) 2.79 (179) 1.88 (119) 2.96 (187) 0.77 ( ) 0.94 ( ) 0.23 Any stroke 1.31 (82) 2.66 (171) 1.72 (109) 2.71 (172) 0.76 ( ) 0.98 ( ) 0.16 Haemorrhagic stroke 0.17 (11) 0.34 (22) 0.42 (27) 0.46 (30) 0.41 ( ) 0.73 ( ) 0.21 Ischaemic or unknown stroke 1.13 (71) 2.34 (151) 1.29 (82) 2.27 (144) 0.88 ( ) 1.03 ( ) 0.41 Non-disabling stroke (MRS 0 2) 0.67 (42) 1.13 (73) 0.61 (39) 1.05 (67) 1.09 ( ) 1.08 ( ) 0.97 Disabling or fatal stroke (MRS 3 6) 0.59 (37) 1.41 (92) 1.00 (64) 1.53 (98) 0.58 ( ) 0.93 ( ) 0.07 Disabling stroke (MRS 3 5) 0.25 (16) 0.71 (46) 0.39 (25) 0.79 (51) 0.65 ( ) 0.89 ( ) 0.40 Intention-to-treat population *nr=number of events Favours rivaroxaban Favours warfarin Hankey GJ, et al. Lancet Neurol. 2012;11:

35 ROCKET AF subanalysis: secondary prevention Safety outcome (Safety on-treatment*) Rivaroxaban Events/yr (nr*) Warfarin Events/yr (nr*) No previous stroke or TIA Previous stroke or TIA HR (95% CI) p-value* Principal safety bleeding endpoint (785) (690) (743) (706) 1.10 ( ) 0.96 ( ) 0.08 Major bleeding 4.10 (217) 3.13 (178) 3.69 (203) 3.22 (183) 1.11 ( ) 0.97 ( ) 0.36 Fatal bleeding 0.22 (12) 0.26 (15) 0.48 (27) 0.49 (28) 0.46 ( ) 0.54 ( ) 0.74 Intracranial 0.39 (21) haemorrhage 0.59 (34) 0.68 (38) 0.80 (46) 0.57 ( ) 0.74 ( ) 0.47 Intracerebral 0.24 (13) haemorrhage 0.45 (26) 0.52 (29) 0.54 (31) 0.46 ( ) 0.84 ( ) 0.16 Extracerebral 0.18 (10) haemorrhage 0.17 (10) 0.30 (17) 0.35 (20) 0.61 ( ) 0.50 ( ) 0.73 Non-major clinically relevant bleeding (620) (565) (585) (566) 1.10 ( ) 0.99 ( ) 0.20 Safety on-treatment population *nr=number of events Hankey GJ, et al. Lancet Neurol. 2012;11: Favours rivaroxaban Favours warfarin

36 Conclusion The relative effects on stroke or systemic embolism, major bleeding and all-cause mortality with NOACs versus warfarin are consistent in AF patients with and without previous stroke/tia Given the higher risk for these outcomes in patients with previous stroke, the absolute benefits with NOACs are even greater in this population 36

37 Thank you for your attention 37