1. Case study - patient presenting with newly diagnosed NVAF with prior CAD Full Prescribing Information is provided at the end of this presentation EUAPI581k; Date of preparation: April 2014 NVAF, non-valvular atrial fibrillation; CAD, coronary artery disease 15.ELI.22.14 43NL15PR04188-01

2. Patient profile – Newly diagnosed NVAF * Patient is fictitious MI, myocardial infarction; ECG, electrocardiogram; ASA, acetylsalicylic acid Patient: Jürgen*

3. Jürgen is at significant risk of stroke and major bleeding CHA 2 DS 2 -VASc 1 = 4 Risk Factors 2 Points C Congestive heart failure/ LV dysfunction 1 HHypertension1 A2A2 Age ≥75 years2 DDiabetes mellitus1 S2S2 Stroke/TIA/thromboembolism2 VVascular disease a 1 AAge 65 to 74 years1 ScSex category (female)1 Maximum score9 HAS-BLED 2 = 3 a Vascular disease includes myocardial infarction, complex aortic plaque, and peripheral artery disease b Defined as uncontrolled hypertension (systolic blood pressure >160 mm Hg) LV, left ventricular; TIA, transient ischemic attack; INR, international normalized ratio Clinical CharacteristicsPoints HHypertension b 1 A Abnormal renal or hepatic function (1 point each) 1 or 2 SStroke1 B Bleeding history or predisposition 1 LLabile INRs1 EElderly (age >65 years)1 DDrugs or alcohol (1 point each)1 or 2 1. Lip et al. Chest 2010;137:263–72; 2. Pisters et al. Chest 2010;138:1093–100.

4. Question 1  Jurgen is newly diagnosed with NVAF and has a CHA 2 DS 2 -VASc score of 4 and a HAS-BLED score of 3. According to the 2012 ESC guidelines, a NOAC should be considered rather than adjusted-dose VKA (INR 2–3) 1  Jurgen has hypertension and prior coronary artery disease  Would ELIQUIS®  (apixaban) be a good option for Jürgen’s stroke prevention? 1. Yes 2. No NOAC(s), novel oral anticoagulant(s); VKA, vitamin K antagonist 1. Camm et al. Eur Heart J 2012;33:2719–47.

5.  Jürgen has a high risk of stroke as well as a high risk of bleeding and may benefit most from a therapy that protects against stroke and limits major bleeding  In ARISTOTLE, ELIQUIS® (apixaban) significantly reduced the rates of stroke/SE and major bleeding as compared to warfarin 1 – In addition all-cause mortality was reduced significantly for ELIQUIS® (apixaban) vs warfarin 1 What about ELIQUIS® (apixban) 1. Granger et al. N Engl J Med 2011;365:981–92. n=269 Stroke/ systemic embolism 1 Major bleeding 1 n=212/ 9120 n=265/ 9081 n=327/ 9088 n=462/ 9052 21% RRR p=0.01 31% RRR p<0.001 SE, systemic embolism Adapted from Granger et al. N Engl J Med 2011;365:981–92 Event rate (%/year)

6. B. Major Bleeding 1 Subgroup No. of patients ApixabanWarfarinHazard Ratio (95% CI) P value for interaction No. of events (%/yr) Age 0.63* < 65 yr5,45556 (1.17)72 (1.51) 65 to < 75 yr7,030120 (1.99)166 (2.82) ≥ 75 yr5,655151 (3.33)224 (5.19) 1. Halvorsen et al. Eur Heart J 2014;Feb 20 [epub ahead of print]; 2. Connolly et al. N Engl J Med 2011;364:806–17. Jürgen is 77 years old. What do we know about the ELIQUIS® (apixaban) data (ARISTOTLE) in elderly patients? 1 0.250.501.002.00 Apixaban better Warfarin better A. Primary Efficacy Outcome: Stroke and Systemic Embolism 1 Subgroup No. of patients ApixabanWarfarinHazard Ratio (95% CI) P value for interaction No. of events (%/yr) Age0.11* < 65 yr5,47151 (1.00)44 (0.86) 65 to < 75 yr7,05282 (1.25)112 (1.73) ≥ 75 yr5,67879 (1.56)109 (2.19) 0.25 0.501.002.00 Apixaban better Warfarin better *Interaction P-values based on continuous age Adapted from Halvorsen et al. Eur Hear J 2014;Feb 20 [epub ahead of print]  In addition, in the AVERROES trial the effects of apixaban compared with ASA in the older patient subgroups (age ≤ 75 years) were consistent with the overall study population 2

7. Prevalence in the REACH Registry 1 Jürgen is put on ELIQUIS® (apixaban) 5 mg twice-daily How does his CAD influence his treatment? 1. Goto et al. Am Heart J 2008;156:855–63. 37,724 stable outpatients with CAD The REACH study was a large-scale international, prospective cohort study of 68,236 stable outpatients with established atherothrombosis or >= 3 atherothrombotic risk factors. Adapted from Goto et al. Am Heart J 2008;156:855–63 Atrial Fibrillation and CAD frequently coincide

8. CAD patients with AF have a higher rate of major clinical events than CAD patients without AF 1 p<0.0001 CV, cardiovascular 1. Goto et al. Am Heart J 2008;156:855–63. Adapted from Goto et al. Am Heart J 2008;156:855–63 37,724 patients with CAD: 12.5% prevalence of atrial fibrillation 1

9. What data for ELIQUIS® (apixaban) in for stroke prevention in NVAF exist in patients with prior CAD? 1  Of the study population in ARISTOTLE, 6,639 (36.5%) of patients had prior CAD  Patients with prior CAD were more often male and were more likely to have prior stroke, diabetes and hypertension as compared with patients without prior CAD  Patients with prior CAD were more likely to be on aspirin at baseline (42.2% vs 24.5%; p<0.001) when compared with patients without prior CAD 1. Bahit et al. Int J Cardiol 2013;170:215–20

10. ApixabanWarfarinHR (95% CI) No CAD CAD Interaction p value Efficacy endpoints Stroke or systemic embolism 1.15 (121) 1.47 (91) 1.63 (171) 1.55 (94) 0.704 (0.558, 0.889) 0.950 (0.712,1,267) 0.11 Stroke 1.06 (112) 1.40 (87) 1.52 (159) 1.50 (91) 0.701 (0.550, 0.892) 0.937 (0.699, 1.258) 0.14 Death (any cause) 3.11 (335) 4.21 (267) 3.68 (395) 4.40 (274) 0.847 (0.732, 0.979) 0.958 (0.809, 1.133) 0.28 MI 0.29 (31) 0.95 (59) 0.39 (41) 1.00 (61) 0.755 (0.473, 1.203) 0.947 (0.662, 1.354) 0.45 Revascularisation (PCI/CABG) 0.70 (74) 1.69 (104) 0.67 (71) 1.89 (114) 1.040 (0.751, 1.441) 0.890 (0.682, 1.161) 0.47 Safety endpoints ISTH major bleeding 1.99 (194) 2.39 (123) 3.12 (297) 3.05 (165) 0.640 (0.534, 0.766) 0.784 (0.624, 0.985) 0.17 Intracranial bleeding 0.37 (37) 0.27 (15) 0.85 (82) 0.73 (40) 0.443 (0.301, 0.654) 0.364 (0.201, 0.659) 0.59 Patients with or without prior CAD in ARISTOTLE 1 1. Bahit et al. Int J Cardiol 2013;170:215–20 Adapted from Bahit et al. Int J Cardiol 2013;170:215–20 0.1110 Favour apixabanFavour warfarin MI, myocardial infarction; ISTH, International Society on Thrombosis and Haemostasis

11. Conclusion of the subanalysis of patients with prior CAD in ARISTOTLE  In patients with NVAF, ELIQUIS® (apixaban) prevents stroke or systemic embolism and causes less major bleeding and death compared with warfarin  These treatment effects were consistent in patients with and without a history of CAD  As the combination of NVAF and CAD commonly occurs and as there are higher rates of CV events and death in these patients, ELIQUIS® (apixaban) may be a better option than warfarin in this high-risk group 1. Bahit et al. Int J Cardiol 2013;170:215–20

12. Question 2  Jürgen is now on ELIQUIS® (apixaban) for stroke prevention in NVAF and is also still taking aspirin given his prior CAD. His CAD has been stable ever since he has had the MI 2 years ago  Can Jürgen discontinue taking ASA? 1. Yes, ASA can be discontinued 2. No, he still needs ASA

13. ELIQUIS® (apixaban) and antiplatelet therapy in NVAF patients  In ARISTOTLE, concomitant use of ASA increased the major bleeding risk: 1 1. Apixaban SmPC. Available at http://www.ema.europa.eu There was limited (2.1%) use of concomitant dual antiplatelet therapy 1 Created from Apixaban SmPC

14. Concomitant use of ELIQUIS® (apixaban) with antiplatelet agents increases the risk of bleeding 1  Care is to be taken if patients are treated concomitantly with non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid  In patients with NVAF and conditions that warrant mono or dual antiplatelet therapy, a careful assessment of the potential benefits against the potential risks should be made before combining this therapy with apixaban 1. Apixaban SmPC. Available at http://www.ema.europa.eu

15. In ARISTOTLE, concomitant ASA use was left to the discretion of the treating physician 1 On Day 1, 4434 (24%) of patients were taking ASA 1 Event rates for apixaban vs warfarin in patients on ASA vs no ASA: Apixaban benefits vs warfarin were consistent for patients taking or not taking ASA 1 What do we know about the use of concomitant ASA in patients using apixaban? 1. Alexander et al. Eur Heart J 2014;35:224–32 Apixaban event rate (%/year) Warfarin event rate (%/year) HR (95% CI) ASA No ASA Interaction p value Stroke or systemic embolism 41 (1.12) 127 (1.11) 67 (1.91) 149 (1.32) 0.58 (0.39–0.85) 0.84 (0.66–1.07) 0.10 Ischaemic stroke 29 (0.79) 95 (0.83) 40 (1.14) 94 (0.83) 0.69 (0.43–1.11) 1.00 (0.75–1.33) 0.19 Myocardial infarction 33 (0.90) 46 (0.40) 26 (0.74) 58 (0.51) 1.20 (0.71–2.00) 0.78 (0.53–1.14) 0.19 Death 71 (1.93) 188 (1.64) 64 (1.82) 223 (1.97) 1.05 (0.75–1.47) 0.83 (0.68–1.00) 0.23 Major bleeding 114 (3.10) 211 (1.82) 138 (3.92) 317 (2.78) 0.77 (0.60–0.99) 0.65 (0.55–0.78) 0.29 Haemorrhagenic stroke 10 (0.27) 25 (0.22) 24 (0.68) 47 (0.42) 0.40 (0.19–0.83) 0.53 (0.33–0.86) 0.52 Major or CRNM bleeding 199 (5.54) 410 (3.59) 246 (7.18) 620 (5.58) 0.76 (0.63–0.92) 0.65 (0.57–0.73) 0.15 Any bleeding 682 (22.64) 1657 (16.61) 859 (32.84) 2180 (23.72) 0.70 (0.62–0.77) 0.71 (0.67–0.76) 0.70 0.1110 Favour apixabanFavour warfarin

16. EHRA guidance on concomitant ASA 1  Stable CAD patients developing AF should receive anticoagulation, depending on their CHA 2 DS 2 -VASc score  Anticoagulation without additional antiplatelet agents is considered sufficient for most AF patients with stable CAD (acute coronary syndrome ≥1 year ago; elective bare-metal stent ≥1 month; drug- eluting stent ≥6 months)  The advantages of NOACs over VKA are likely to be preserved in stable CAD patients. NOACs may be an appropriate and effective alternative to VKAs 1. Heidbüchel et al. Europace 2013;15:625–51.

17. Question 2  Jürgen is now on ELIQUIS® (apixaban) for stroke prevention in NVAF and is also still taking aspirin given his prior CAD. His CAD has been stable ever since he has had the MI 2 years ago  Can Jürgen discontinue taking ASA? 1. Yes, ASA can be discontinued 2. No, he still needs ASA

18. Patient case: Key learnings 1. Bahit et al. Int J Cardiol 2013;170:215–220; 2. Alexander et al. Eur Heart J 2014;35:224–232; 3. Heidbüchel et al. Europace 2013;15:625–651.  This high-risk patient may benefit most from a therapy that protects against stroke while limiting major bleeding – In ARISTOTLE, ELIQUIS® (apixaban) significantly reduced the risk of stroke/SE and major bleeding as compared to warfarin  The results of the ARISTOTLE trial were consistent in predefined subgroups according to: – Prior coronary artery disease 1 – Use of ASA 2  According to the EHRA practical guide on the use of NOACs in NVAF, anticoagulation without additional antiplatelet agents is considered sufficient for most patients with stable CAD 3

19. ELIQUIS ® (apixaban) 2.5 mg & 5 mg FILM-COATED TABLETS PRESCRIBING INFORMATION SMPC link, click here