1. Ichaemic stroke from cardiologist point of view Petr Jansky University Hospital Motol Prague 5.9.2014

2. Ischaemic vs. haemorrhagic stroke Ischaemic –Caused by obstruction within a blood vessel supplying the brain Clot may form directly in blood vessel or travel from another site (e.g. from the left atrium in patients with atrial fibrillation) Haemorrhagic –Caused by rupture of a weakened vessel and leads to bleeding into or around the brain Intracerebral haemorrhage (bleeding into the brain) – causes include: –Hypertension –Blood vessel abnormalities –Antithrombotic therapy Subarachnoid haemorrhage (bleeding into space between brain and skull) – usually caused by cerebral aneurysm

3. Normal regulation of heart rate and rhythm Contraction is controlled by the sinoatrial node

4. Atrial fibrillation: Electrocardiogram Normal sinus rhythm –Regular rhythm –Normal heart rate –P waves Atrial fibrillation –Irregularly irregular rhythm –Heart rate increased (tachyarrhythmia) –Absence of P waves P Regular rhythm Irregularly irregular rhythm

5. Consequences of atrial fibrillation Reduction in cardiac output can precipitate heart failure, leading to distinctive symptoms such as: –Peripheral oedema –Dyspnoea –Pulmonary oedema –Fatigue –Chest pain Formation of blood clots (thrombosis) on the atrial walls that can dislodge (embolize), leading to stroke and systemic embolism

6. Left atrial appendage and thrombus formation in atrial fibrillation ~90% of atrial thrombi occur in the left atrial appendage LAA is a small muscular pouch attached to the main atrial chamber Atria do not contract properly leading to stasis in the LAA Appendage Clot Path of dislodged clot

7. Transoesophageal echocardiogram Ultrasound transducer positioned close to the heart High-quality images of cardiac structure and function –Particularly the LAA, the most common site of thrombi in AF LAA = left atrial appendage Thrombus in left atrium

8. Atrial fibrillation is a common disorder Responsible for a third of all hospitalizations for cardiac rhythm disturbances 1 Estimated prevalence: –Europe: 4.5 million 1 –USA: 5.1 million 2 Affects approximately 2.0% of the US population 2 1. ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354 & Eur Heart J 2006;27:1979–2030; 2. Miyasaka Y et al. Circulation 2006;114:119–25; 3. Heeringa J et al. Eur Heart J 2006;27:949–53

9. Prevalence of AF increases with age Prevalence at baseline assessed in 6808 participants in a European population-based study Heeringa J et al. Eur Heart J 2006;27:949–53 Women (n=4053) Age (yrs) Prevalence (%) 0 5 10 15 20 55–5960–6465–6970–7475–7980–84>85 Men (n=2590)

10. AF is an increasingly common disorder 60% increase in hospital admissions for AF over the past 20 years 20% increase in prevalence expected over next decade Increasing prevalence driven by: –Increased longevity of populations worldwide –Rising prevalence of chronic heart disease –Rising prevalence of AF risk factors, e.g. diabetes mellitus Benyoucef S et al. Atrial fibrillation. 2008; Friberg J et al. Epidemiology 2003;14:666–72

11. Prevalence of AF predicted to more than double by 2050 Miyasaka Y et al. Circulation 2006;114:119–25 0 8 10 12 16 2050 People with AF in the USA (millions) Year 20002010202020302040 6 4 2 14 Projected incidence of AF assuming no further increase in age-adjusted incidence Projected incidence of AF assuming a continued increase in age-adjusted incidence as evident in 1980–2000

12. Stroke is the leading complication of AF AF increases the risk of all types of stroke 5-fold 1 Without prevention, approximately 1 in 20 patients will have a stroke each year 2 AF is responsible for nearly one-third of all strokes 3 1. Savelieva I et al. Ann Med 2007;39:371–91; 2. Atrial Fibrillation Investigators. Arch Intern Med 1994;154:1449– 57; 3. Hannon N et al. Cerebrovasc Dis 2010;29:43–9

13. Stroke risk assessment with CHADS 2 CHADS 2 criteriaScore Congestive heart failure1 Hypertension1 Age ≥75 yrs1 Diabetes mellitus1 Stroke/transient ischaemic attack 2 Gage BF et al. JAMA 2001;285:2864–70 Annual stroke rate (%)* CHADS 2 score 30 0 2 3 4 5 6 0510152025 1

14. Ischaemic stroke in AF likely to result in persistent disability or death Gladstone DJ et al. Stroke 2009;40:235–40 Outcomes of first ischaemic stroke in high-risk patients with AF (n=597) Persisting disability Modified Rankin scale ≥2 Death 60 40 0 50 30 20 10 Proportion of patients (%) 14 60% 20%

15. Survival times after ischaemic stroke are worse with AF Follow-up of 501 patients with ischaemic stroke in the Framingham study Lin HJ et al. Stroke 1996;27:1760–4 1.0 1.00 0 60 Days after stroke Probability Survival 0.8 0.6 0.4 0.2 0 120180240300360 Patients with AF (n=103) P<0.001 Patients without AF (n=398) By 1 year after ischaemic stroke, two-thirds of patients with AF have died, compared with one-third of those without AF

16. Ischaemic stroke in AF is more likely to recur Marini C et al. Stroke 2005;36:1115–9 Patients with AF (n=869) Patients without AF (n=2661) Recurrent stroke after ischaemic stroke Months after first stroke Cumulative probability of recurrence (%) 10 12 8 6 4 2 0 0246810 P=0.0398

17. Sept 2012 Management of AF has two broad objectives ESC guidelines: Camm J et al. Eur Heart J 2010;31:2369–429; ACCF/AHA/HRS Focused Update Guidelines: Fuster V et al. J Am Coll Cardiol 2011;57:e101–98 Prevention of complications, including thromboembolism (particularly ischaemic stroke) and heart failure Relief of symptoms Choice of antithrombotic therapy should be tailored to the patient based on: Risk of thromboembolism Risk of bleeding

18. Goals for anticoagulation therapy in AF Prevent ischaemic stroke Minimize haemorrhagic stroke (minimize risk of intracranial bleeding)

19. Vitamin K antagonists (warfarin) reduce the risk of stroke in patients with AF Hart RG et al. Ann Intern Med 2007;146:857–67 Favours warfarinFavours placebo RRR (%) 100–100500–50 AFASAK SPAF BAATAF CAFA SPINAF EAFT All trials RRR 64% ( 95% CI: 49  74%)

20. Sept 2012 Therapeutic range 1 International normalized ratio Odds ratio 2 15 8 10 5 0 1 34567 20 Stroke Intracranial bleed VKAs have a narrow therapeutic window VKAs = vitamin K antagonists ACCF/AHA/HRS focused update guidelines: Fuster V et al. Circulation 2011;123:e269-e367; Wann LS et al. Circulation 2011;123:104–23 & Circulation 2011;123:1144–50

21. ICH is the most feared complication of traditional antithrombotic therapy ICH can be life-threatening 1 Traditional antithrombotics increase the risk of ICH*: 1 –Warfarin use doubles risk (INR 2.0–3.0; rate is 0.3–0.6%/yr) –Warfarin use also increases the severity of ICH 2 *Compared with placebo ICH = intracranial haemorrhage; INR = international normalized ratio 1. Hart RG et al. Stroke 2005;36:1588–93; 2. Fang MC et al. Stroke 2012;43:1795–9

22. Warfarin is used in only half of eligible AF patients Go A et al. Ann Intern Med 1999;131:927–34 Proportion of eligiible patients using warfain (%) Age (yrs) 100 <55 80 60 40 20 0 55–6465–7475–84  85 44% 58% 61% 57% 35% Overall use = 55% (n= 11 082) Underuse greatest in elderly patients (who are at highest risk of stroke )

23. Global AF registry Funded by a grant from Boehringer Ingelheim Aim: to compare regional differences in predisposing conditions for AF and its treatment –Focus on BP management and anticoagulation Prospective registry across all continents –Patients enrolled between January 2008 and April 2011 –47 countries, 163 sites, 15 174 patients Includes patients presenting to an emergency department BP = blood pressure Healey J et al. ESC 2011

24. Global AF registry: participating countries RegionSitesPatients North America181802 South America231127 Western Europe191975 Eastern Europe222536 Healey J et al. ESC 2011 RegionSitesPatients Middle East8896 Africa201089 India222520 China201951 Asia111278 Participating country

25. Global AF registry: use of oral anticoagulants was low and varied between regions CHADS 2 = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, prior Stroke, or TIA (2); OAC = oral anticoagulation; TIA = transient ischaemic attack Healey J et al. ESC 2011 100 80 60 40 20 0 North America OAC use, CHADS 2 ≥ 2 (% patients) *P≤0.005 vs North America South America Western Europe Eastern Europe Middle East AfricaIndiaChinaAsia Patients with a prior history of AF * * * * * * *

26. Global AF registry: INR control was poor and varied between countries INR = international normalized ratio Healey J et al. ESC 2011 100 80 60 40 20 0 North America % patients *P≤0.005 vs North America South America Western Europe Eastern Europe Middle East AfricaIndiaChinaAsia Based on three most recent INR values (%) INR >3.0INR 2.0–3.0INR <2.0 54 44 67 59 4740 34 36 38 ******

27. Sept 2012 Targets for new-generation antithrombotic agents in the coagulation cascade 1 AT= antithrombin; Ph = Phase 1. Adapted from Turpie AG. Eur Heart J 2008;29:155–65; 2. Ellis DJ et al. Circulation 2009;120:1029–35; 3. Bousser MG et al. Lancet 2008;371:315–21; 4. NCT00580216; available at www.ClinicalTrials.gov; accessed March 2012; 5. Connolly SJ et al. N Engl J Med 2011;364:806–17; 6. Granger CB et al. N Engl J Med 2011;365:981–92; 7. Patel MR et al. N Engl J Med 2011;365:883–91; 8. NCT00781391; available at www.ClinicalTrials.gov; accessed March 2012; 9. NCT00742859; available at www.ClinicalTrials.gov; accessed March 2012; 10. Connolly SJ et al. N Engl J Med 2009;361:1139–51; 11. Olsson SB et al. Lancet 2003;362:1691–8; 12. Albers GW et al. JAMA 2005;293:690–8; 13. Lip GY et al. Eur Heart J 2009;30:2897–907 Fibrin IX IXa X VIIIa Thrombin Fibrinogen Direct Factor Xa inhibitors: Apixaban (Ph III completed) 5,6 Rivaroxaban (Ph III completed) 7 Edoxaban (Ph III completed) 8 Betrixaban (Ph II completed) 9 Va Xa II AT Direct thrombin inhibitors: Dabigatran etexilate (Ph III completed) 10 Ximelagatran (withdrawn 2006) 11,12 AZD0837 (Ph II completed) 13 Indirect Factor Xa inhibitors: Idraparinux (Ph III terminated) 3 SSR 126517 (withdrawn 2009) 4 Vitamin K antagonists: Tissue factor/VIIa

28. Anticoagulation therapy in prevention of stroke in atrial fibrillation in atrial fibrillation 6 studies 1989-1993 RE-LY ( Dabigatran ) 2009 ROCKET AF ( Rivaroxaban ) 2010 ARISTOTLE ( Apixaban ) 2011 ENGAGE AF-TIMI 48 ( Edoxaban ) ( Edoxaban )2013 Warfarin vs. placebo 2 900 patients NOACs vs. warfarin 71 683 patients

29. 0.12 0.02 0.581 0.024 0.02 Rivaroxaban reduces the risk of haemorrhagic stroke and ICH with similar rates of stroke/SE vs warfarin HR = hazard ratio; ICH = intracranial haemorrhage; ITT = intention-to-treat; OT = on-treatment; SE = systemic embolism Enrolled patients were at moderate-to-high risk of stroke (CHADS 2 score ≥2) Patel MR et al. N Engl J Med 2011;365:883–91 Event rate (per 100 patient-yrs) RivaroxabanWarfarin Stroke/SE ITT OT 2.1 1.7 2.4 2.2 Ischaemic stroke1.341.42 Haemorrhagic stroke0.260.44 ICH0.50.7 0.1 1.50–0.51.00.5 Rivaroxaban vs warfarin HR (95% CI)P value Favours warfarin Favours rivaroxaban

30. Apixaban reduces the risk of stroke/SE, haemorrhagic stroke, and ICH vs warfarin HR = hazard ratio; ICH = intracranial haemorrhage; SE = systemic embolism Granger CB et al. N Engl J Med 2011;365:981–92 0.1 Event rate (%/yr) ApixabanWarfarin Stroke/SE1.271.60 Ischaemic or uncertain stroke 0.971.05 Haemorrhagic stroke0.240.47 ICH0.330.80 1.50–0.51.00.5 0.011 0.42 <0.001 Apixaban vs warfarin HR (95% CI)P value Favours warfarin Favours apixaban

31. Sept 2012 In addition to a significant reduction in stroke/SE, haemorrhagic stroke, and ICH Dabigatran is the only new-generation agent to also reduce the risk of ischaemic stroke vs warfarin ICH = intracranial haemorrhage; NI = non-inferiority; RR = relative risk; RRR = relative risk reduction; SE = systemic embolism; Sup = superiority Connolly SJ et al. N Engl J Med 2010;363:1875–6 Event rate (%/yr) Dabigatran 110 mg BID vs warfarin Dabigatran 150 mg BID vs warfarin D110D150Warfarin RR (95% CI) P value RR (95% CI) P value Stroke/SE1.541.111.71 <0.001 (NI) <0.001 (Sup) Ischaemic stroke1.280.861.140.31 0.03 (Sup) Haemorrhagic stroke 0.120.100.38 <0.001 (Sup) <0.001 (Sup) ICH0.230.320.76 <0.001 (Sup) 1.501.00.51.501.00.5 Favours warfarin Favours dabigatran Favours warfarin Favours dabigatran

32. All-Cause Mortality Myocardial Infarction Hemorrhagic Stroke Ischemic Stroke 0.90 (0.85 - 0.95) 0.97 (0.78 - 1.20) 0.49 (0.38 - 0.64) 0.92 (0.83 - 1.02) Risk Ratio (95% CI) p=0.0003 p=0.77 p<0.0001 p=0.10 Favors NOAC Favors Warfarin 0.2 0.5 1 2 Novel Oral Anticoagulants: Efficacy Outcomes Heterogeneity p=NS for all outcomes Ruff CT, et al. Lancet 2014

33. Apixaban Rivaroxaban Combined Favors NOAC Favors Warfarin Risk Ratio (95% CI) 0.80 (0.71 - 0.90) 0.71 (0.61 - 0.81) 1.03 (0.90 - 1.18) 0.94 (0.82 - 1.07) 0.86 (0.73 - 1.00) 0.512 Novel Oral Anticoagulants: Major Bleeding [Random Effects Model] N=58,498 p=0.06 Dabigatran [150 mg] Edoxaban [60 mg] Ruff CT, et al. Lancet 2014

34. Sept 2012 European Society of Cardiology 2012 focused update: choice of antithrombotic therapy in atrial fibrillation *Includes rheumatic valvular disease and prosthetic valves; ESC = European Society of Cardiology; NOAC = novel oral anticoagulant; VKA = vitamin K antagonist Camm AJ et al. Eur Heart J 2012;33:2719–47 Yes Atrial fibrillation Valvular AF* <65 years and lone AF (including females) Assess risk of stroke CHA 2 DS 2 -VASc score Assess bleeding risk (HAS-BLED score) Consider patient values and preferences No antithrombotic therapy Oral anticoagulant therapy NOAC VKA 0 1 No (i.e. nonvalvular) Yes No ≥2 = CHA 2 DS 2 -VASc 0 = best option = CHA 2 DS 2 -VASc 1 = CHA 2 DS 2 -VASc ≥2 = alternative option

35. Atrial fibrillation (AF) and stroke: summary AF is an increasingly common disorder –Prevalence set to double by 2050 Stroke is the leading complication of AF –5-fold increase in stroke risk –Risk persists in asymptomatic/paroxysmal AF Most AF-related strokes are ischaemic –Likely to result in permanent disability or death Factors increasing stroke risk include: –Previous stroke or TIA –Advancing age –Hypertension –Diabetes mellitus Assessing stroke risk is important to guide antithrombotic therapy

36. The importance of ischaemic stroke prevention in patients with atrial fibrillation – summary Goal of antithrombotic therapy in AF should be to prevent ischemic stroke and minimize the risk of bleeding and haemorrhagic stroke (ICH) Traditional agents for stroke prevention in AF have limitations, including the risk of ICH –Many patients receive suboptimal anticoagulation New-generation OACs could optimize stroke protection in AF –Dabigatran, rivaroxaban and apixaban all significantly reduce the risk of haemorrhagic stroke and ICH vs warfarin –Dabigatran 150 mg BID significantly reduced the risk of ischaemic stroke vs warfarin –NOACs reduce major bleeding and all-cause mortality

37. Thank you !