1. Case study – patient presenting with newly diagnosed NVAF Full Prescribing Information is provided at the end of this presentation NVAF: non-valvular atrial fibrillation EUAPI581i, April 2014 15.ELI.22.12 43NL15PR04186-01

2. Patient case Patient: Ingrid* * Patient is fictitious

3. Question 1  What are the CHADS 2 and CHA 2 DS 2 -VASc scores of this patient? 1. CHADS 2 = 1, CHA 2 DS 2 -VASc = 2 2. CHADS 2 = 1, CHA 2 DS 2 -VASc = 3 3. CHADS 2 = 2, CHA 2 DS 2 -VASc = 2 4. CHADS 2 = 2, CHA 2 DS 2 -VASc = 3

4. 1. Gage et al. JAMA 2001;285:2864–2870. 2. Lip et al. Chest 2010;137:263–272. CHADS 2 and CHA 2 DS 2 -VASc risk scoring schemes Adapted from Gage et al. JAMA 2001;285:2864–2870. LV: left ventricular; TIA: transient ischaemic attack; TE: echo time; MI: myocardial infarction; PAD: peripheral arterial disease

5. Question 1  What are the CHADS 2 and CHA 2 DS 2 -VASc scores of this patient? 1. CHADS 2 = 1, CHA 2 DS 2 -VASc = 2 2. CHADS 2 = 1, CHA 2 DS 2 -VASc = 3 3. CHADS 2 = 2, CHA 2 DS 2 -VASc = 2 4. CHADS 2 = 2, CHA 2 DS 2 -VASc = 3

6. Question 2  Ingrid is newly diagnosed with NVAF; has a CHADS 2 score of 1, a CHA 2 DS 2 -VASc score of 3 and moderate renal impairment (CrCl = 49 mL/min)  Which antithrombotic treatment do you propose in this patient? 1. No antithrombotic treatment 2. Aspirin + clopidogrel 3. Warfarin (INR 2.0–3.0) 4. A novel oral anticoagulant INR: international normalized ratio

7.  Our patient has a CHA 2 DS 2 -VASc score of 3 CHA 2 DS 2 RecommendationClass*Level † 0No antithrombotic therapyIB 1 OAC therapy with  Adjusted-dose VKA (INR 2–3); or  A direct thrombin inhibitor (dabigatran); or  An oral factor Xa inhibitor (e.g. rivaroxaban, apixaban) …should be considered IIaA ≥2 OAC therapy with  Adjusted-dose VKA (INR 2–3); or  A direct thrombin inhibitor (dabigatran); or  An oral factor Xa inhibitor (e.g. rivaroxaban, apixaban) …is recommended IA ESC 2012 guideline recommendations 1 1. Camm et al. Europace 2012;14:1385–1413. *Class of recommendation; † Level of evidence ESC: European Society of Cardiology; VKA: vitamin K antagonists Adapted from Camm et al. Europace 2012;14:1385–1413.  ESC 2012 Guidelines also recommend: “…well-controlled VKA therapy (INR 2–3, with a high percentage of TTR, for example, at least 70%) or one of the NOACs”

8. Recommendations for prevention of thromboembolism in NVAF—NOACsClass*Level † Where OAC is recommended, one of the NOACs, either:  A direct thrombin inhibitor (dabigatran); or  An oral factor Xa inhibitor (e.g. rivaroxaban, apixaban) …should be considered rather than adjusted-dose VKA (INR 2–3) for most patients with NVAF, based on their net clinical benefit IIaA 1. Camm et al. Europace 2012;14:1385–1413. ESC 2012 guideline recommendations 1 *Class of recommendation; † Level of evidence NOAC(s): novel oral anticoagulant(s) Adapted from Camm et al. Europace 2012;14:1385–1413.

9. Question 2  Ingrid is newly diagnosed with NVAF; has a CHADS 2 score of 1, a CHA 2 DS 2 -VASc score of 3 and moderate renal impairment (CrCl = 49 mL/min)  Which antithrombotic treatment do you propose in this patient? 1. No antithrombotic treatment 2. Aspirin + clopidogrel 3. Warfarin (INR 2.0–3.0) 4. A novel oral anticoagulant

10. ApixabanWarfarin Hazard Ratio (95% CI) p value for Interaction %/yr (No. of Events) Stroke / systemic embolism0.705 eGFR >80 mL/min * 0.99 (70)1.12 (79) eGFR >50-80 mL/min † 1.24 (87)1.69 (116) eGFR ≤50 mL/min ‡ 2.11 (54)2.67 (69) Major bleeding0.030 eGFR >80 mL/min * 1.46 (96)1.84 (119) eGFR >50-80 mL/min † 2.45 (157)3.21 (199) eGFR ≤50 mL/min ‡ 3.21 (73)6.44 (142) 1. Hohnloser et al. Eur Heart J 2012;22:2821–2830. 2. Apixaban SmPC. Available at http://www.ema.europa.eu. ELIQUIS  (apixaban): Outcomes of ARISTOTLE according to renal function 1 * n=7,518 (42%); † n=7,587 (42%); ‡ n=3,017 (17%) Cockcroft-Gault method displayed here; Results were consistent regardless of methods for GFR estimation Adapted from Hohnloser et al. Eur Heart J 2012;22:2821–2830. 0.250.51.002.0 Apixaban Better Warfarin Better ELIQUIS® (apixaban ) was more effective and was associated with less major bleeding events than warfarin across all ranges of eGFRs Apixaban is not recommended in patients with CrCl of < 15 mL/min or patients undergoing dialysis Patients with serum creatinine ≥1.5 mg/dL (133 micromole/L) associated with age ≥80 years or body weight ≤60 kg should receive the lower dose of apixaban 2.5 mg twice-daily; as well as patients with exclusive criteria of renal impairment (CrCl 15–29 mL/min) 2

11. ELIQUIS® (apixaban): outcomes of AVERROES according to renal function 1 1. Eikelboom et al. J Stroke Cerebrovasc Dis 2012;21:429–435. ApixabanASA Hazard Ratio (95% CI) p value for interaction %/yr (No. of Events) Stroke / systemic embolism0.10 eGFR ≥60 mL/min * 1.7 (34)2.8 (60) eGFR 30–59 mL/min † 1.8 (17)5.6 (51) Major bleeding0.82 eGFR ≥60 mL/min0.9 (19)0.8 (18) eGFR 30–59 mL/min † 2.5 (24)2.2 (20) 0.250.51.002.0 Apixaban Better ASA Better * n=3828, † n=1697 ASA = acetylsalicylic acid eGFRs are in mL/min per 1.73 m 2 Adapted from Eikelboom et al. J Stroke Cerebrovasc Dis. 2012;21:429–35.

12. Our patient has a CHADS 2 score of 1. What do we know about ELIQUIS® (apixaban) in these patients?  ELIQUIS® (apixaban) – 6,183 patients (34%) had a CHADS 2 = 1 in ARISTOTLE 1 – No significant heterogeneity in effects of apixaban vs warfarin in subgroups defined by CHADS 2 scores 1 – 2,026 patients (36.2%) had a CHADS 2 ≤1 in AVERROES 2 – No significant heterogeneity in effects of apixaban vs aspirin in subgroups defined by CHADS 2 scores 2 1. Lopes et al. Lancet. 2012;380:1749–58. 2. Lip et al. Circ Arrhythm Electrophysiol. 2013;6:31–8.

13. ARISTOTLE enrolled patients across a broad range of stroke and bleeding risk 1  Patients with non-valvular AF and at least 1 risk factor for stroke were enrolled 1  CHADS 2 and HAS-BLED scores were correlated in ARISTOTLE: 2 1. Granger et al. N Engl J Med 2011;365:981–992; 2. Lopes et al. Lancet 2012;380:1749–1758. HAS-BLED score 0–12≥3Total CHADS 2 score 13,203 (18%)2,051 (11%)929 (5%)6,183 (34%) 22,807 (15%)2,461 (14%)1,248 (7%)6,516 (36%) ≥31,451 (8%)2,056 (11%)1,995 (11%)5,502 (30%) Total7,461 (41%)6,568 (36%)4,172 (23%)18,201 (100%) Adapted from Lopes et al. Lancet 2012;380:1749–1758.

14. ApixabanWarfarin Hazard Ratio (95% CI) p value No. of Patients %/yr (No. of Events) CHADS 2 Interaction: 0.4457 16,1830.74% (44)0.87% (51) 26,5161.24% (74)1.37% (82) ≥35,5021.95% (94)2.80% (132) CHA 2 DS 2 VASc Interaction: 0.1210 11,6040.62% (10)0.53% (8) 23,7710.85% (30)0.67% (24) ≥312,8261.48% (172)2.03% (233) HAS-BLED Interaction: 0.9422 0–17,4610.92% (65)1.14% (79) 26,5681.39% (83)1.81% (109) ≥34,1721.73% (64)2.14% (77) Overall18,2011.27% (212)1.60% (265) 0.0144 Favours ApixabanFavours Warfarin ARISTOTLE Stroke or systemic embolism according to baseline risk scores 1 1. Lopes et al. Lancet 2012;380:1749–1758. 0.250.501.002.004.00 Adapted from Lopes et al. Lancet 2012;380:1749–1758.

15. ApixabanWarfarin Hazard Ratio (95% CI) p value No. of Patients %/yr (No. of Events) CHADS 2 Interaction: 0.4018 16,1691.38% (76) 2.34% (126) 26,4922.30% (125) 3.03% (163) ≥35,4792.88% (126) 4.15% (173) CHA 2 DS 2 VAScInteraction: 0.2059 11,6020.80% (12) 1.21% (17) 23,7591.26% (42) 2.48% (82) ≥312,7792.60% (273) 3.55% (363) HAS-BLEDInteraction: 0.7127 0–17,4331.36% (89) 2.16% (137) 26,5442.25% (123) 3.23% (175) ≥34,1633.46% (115) 4.70% (150) Overall18,1402.13% (327) 3.09% (462) <0.0001 Favours ApixabanFavours Warfarin Major bleeding according to baseline risk scores 1 1. Lopes et al. Lancet 2012;380:1749–1758. 0.250.501.002.004.00 Adapted from Lopes et al. Lancet 2012;380:1749–1758.

16. ApixabanWarfarin Hazard Ratio (95% CI) p value No. of Patients %/yr (No. of Events) CHADS 2 Interaction: 0.1775 16,1690.27% (15) 0.60% (33) 26,4920.38% (21) 0.64% (35) ≥35,4790.36% (16) 1.27% (54) CHA 2 DS 2 VASc Interaction: 0.8478 11,6020.20% (3) 0.35% (5) 23,7590.27% (9) 0.57% (19) ≥312,7790.37% (40) 0.94% (98) HAS-BLED Interaction: 0.0604 0–17,4330.35% (23) 0.53% (34) 26,5440.38% (21) 0.96% (53) ≥34,1630.23% (8) 1.07% (35) Overall18,1400.33% (52) 0.80% (122) <0.0001 Favours ApixabanFavours Warfarin ARISTOTLE Intracranial bleeding according to baseline risk scores 1 1. Lopes et al. Lancet 2012;380:1749–1758. 0.010.11.0010.00 Adapted from Lopes et al. Lancet 2012;380:1749–1758.

17. Apixaban AspirinHazard Ratio (95% CI) p value No. of Patients %/yr (No. of Events) No. of Patients %/yr (No. of Events) CHADS 2 Interaction: 0.54 0–11,0046% (0.5)1,022 16% (1.4) 21,04417% (1.4)954 33% (3.1) 3–675812% (1.5)812 44% (5.0) CHA 2 DS 2 VAScInteraction: 0.35 0–12770% (0)312 5% (1.4) 26893% (0.4)660 7% (0.9) 3–61,65924% (1.3)1,616 62% (3.5) 6–81818% (4.2)200 19% (8.6) Overall2,80635% (1.1)2,788 93% (3.0) 1. Lip et al. Circ Arrhythm Electrophysiol 2013;6:31–38. AVERROES: ischaemic stroke according to baseline risk scores 1 Favours ApixabanFavours Aspirin 0.10.1511.60.20.60.35 Adapted from Lip et al. Circ Arrhytm Electrophysiol 2013;6:31–38.

18. Apixaban AspirinHazard Ratio (95% CI) p value No. of Patients %/yr (No. of Events) No. of Patients %/yr (No. of Events) CHADS 2 Interaction: 0.7 0–11,0046% (0.5)1,022 6% (0.5) 21,04414% (1.2)954 14% (1.3) 3–675824% (2.9)812 19% (2.1) CHA 2 DS 2 VAScInteraction: 0.94 0–12771% (0.3)312 2% (0.6) 26895% (0.7)660 4% (0.5) 3–61,65929% (1.6)1,616 24% (1.3) 6–81819% (4.7)200 9% (4.1) Overall2,80644% (1.4)2,788 39% (1.3) 1. Lip et al. Circ Arrhythm Electrophysiol 2013;6:31–38. AVERROES: major bleeding according to baseline risk scores 1 Favours ApixabanFavours Aspirin 0.010.052.77.40.110.4 Adapted from Lip et al. Circ Arrhytm Electrophysiol 2013;6:31–38.

19. Patient case Patient: Ingrid* * Patient is fictitious

20. Question 3  Patient is to undergo total hip replacement (THR)  At what time before the planned surgery would you discontinue ELIQUIS® (apixaban)? 1. Not at all 2. At least 24 hours prior to surgery 3. At least 48 hours prior to surgery 4. At least 72 hours prior to surgery

21. Surgical interventions / invasive procedures in patients with AF  Trials have shown that approx. 25% of AF patients in need of anticoagulation therapy require temporary cessation within 2 years 1  Due to long half life of VKAs: – Discontinue 5 days before major procedure 2 – Bridging therapy if moderate/high thromboembolic risk 2 – Additional costs, inconvenience and risk 1,3,4  Patient characteristics (eg kidney function, age, history of bleeding complications, concomitant medication) and surgical factors are to be taken into account on when to discontinue and restart the NOAC 5  Bridging is not necessary in NOAC-treated patients since the predictable waning of the effect allows properly timed cessation and re-initiation of NOAC therapy before and after surgery 5 1. Healey et al. Circulation 2012;126:343–348; 2. Douketis et al. Chest 2008;133(6 Suppl):299S–339S; 3. Broderick et al. Stroke 2011;42:2509 –2514; 4. Robinson et al. Pacing Clin Electrophysiol 2009;32:378–382; 5. Heidüchel et al. Europace 2013;15:625–651. AF: atrial fibrillation

22. When to stop ELIQUIS® (apixaban) before elective surgical intervention  Guidance from SmPC: 1 – ELIQUIS® (apixaban) should be discontinued at least 48 hours prior to surgery with a moderate or high risk of bleeding – ELIQUIS® (apixaban) should be discontinued at least 24 hours prior to surgery with a low risk of bleeding  EHRA guidance: 2 1. Apixaban SmPC. Available at http://www.ema.europa.eu; 2. Heidbüchel et al. Europace. 2013;15:625–651. Apixaban is not recommended in patients with CrCl of < 15 mL/min or patients undergoing dialysis. Patients with serum creatinine ≥1.5 mg/dL (133 µmol/L) associated with age ≥80 years or body weight ≤60 kg should receive the lower dose of apixaban 2.5 mg twice daily; as well as patients with exclusive criteria of renal impairment (CrCl 15–29 mL/min) 2 EHRA: European Heart Rhythm Association; Adapted from Heidbüchel et al. Europace 2013;15:625–651.

23. Low riskHigh risk  Endoscopy with biopsy  Prostate or bladder biopsy  Electrophysiological study or radiofrequency catheter ablation for supraventricular tachycardia (including left sided ablation via single transseptal puncture)  Angiography  Pacemaker or ICD implantation (unless complex anatomical setting e.g. congenital heart disease)  Complex left-sided ablation: pulmonary vein isolation, VT ablation  Spinal or epidural anaesthesia; lumbar diagnostic puncture  Thoracic surgery  Abdominal surgery  Major orthopaedic surgery  Liver biopsy  Transurethral prostate resection  Kidney biopsy 1. Heidbüchel et al. Europace 2013;15:625–651. EHRA guidance: classification of surgical interventions according to bleeding risk 1 Adapted from Heidbüchel et al. Europace. 2013;15:625–651. ICD: implantable cardioverter defibrillator, VT: ventricular tachycardia

24. Question 3  Patient is to undergo total hip replacement (THR)  At what time before the planned surgery would you discontinue ELIQUIS® (apixaban)? 1. Not at all 2. At least 24 hours prior to surgery 3. At least 48 hours prior to surgery 4. At least 72 hours prior to surgery

25. When to restart ELIQUIS® (apixaban) after surgery  ELIQUIS® (apixaban) SmPC: 1 – ELIQUIS® (apixaban) should be restarted after the invasive procedure / surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established – Lapses in therapy should be avoided  therapy should be restarted as soon as possible  EHRA guidance: 2 – There are no data on safety and efficacy of NOACs for prevention of VTE after knee / hip surgery in patients with AF 1. Apixaban SmPC. Available at http://www.ema.europa.eu; 2. Heidbüchel et al. Europace 2013;15:625–651. LWMH: low molecular weight heparin Adapted from Heidbüchel et al. Europace 2013;15:625–651.

26. Patient case – summary Patient: Ingrid* * Patient is fictitious

27. Patient case: key learnings 1. Camm et al. Europace 2012;14:1385–1413; 2. Granger et al. N Engl J Med 2011;365:981–992; 3. Hohnloser et al. Eur Heart J 2012;22:2821–2830; 4. Apixaban SmPC. Available at http://www.ema.europa.eu; 5. Heidbüchel et al. Europace 2013;15:625–651.  The ESC guidelines state that when OAC is recommended for stroke prevention in NVAF, NOACs are preferred over VKA unless contra-indicated 1  The outcomes of ELIQUIS® (apixaban) vs warfarin in the ARISTOTLE trial were consistent in predefined subgroups according to: – Level of renal impairment 2,3 – Risk factors for stroke 2  Practical guidance on how to manage ELQUIS® (apixaban) around surgical interventions / invasive procedures is available 4,5 – This includes when to stop treatment before an intervention and when to resume treatment afterwards

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