Is there a future role for warfarin in stroke prevention for NVAF in 2014 EUAPI581f, April 2014 Full Prescribing Information is provided at the end of this presentation. NVAF: non-valvular atrial fibrillation; 15.ELI NL15PR

The NOACs changed the landscape for stroke prevention in NVAF and impacted the position of VKA 1. Camm et al, Eur Heart J 2012; 33:2719–47.  The 2012 ESC Guidelines state that when oral anticoagulation is recommended, a NOAC should be considered rather than adjusted-dose VKA for most patients with non-valvular AF 1  In this presentation, the preference of NOACs vs VKA for stroke prevention in NVAF will be illustrated in two clinical cases: – A patient on VKA with a time in therapeutic range (TTR) of approx. 72% – A newly diagnosed patient NOAC(s): novel oral anticoagulant(s); VKA: Vitamin K antagonists; AF: atrial fibrillation; ESC: European Society of Cardiology

Patient #1: Elderly patient on warfarin with INRs mostly in therapeutic range *Patient is fictitious. INR: international normalised ratio Patient: Marta*

Marta has a CHA 2 DS 2 -VASc score of 4 and a HAS-BLED score of 1 CHA 2 DS 2 -VASc 1 = 4 Clinical CharacteristicsPoints HHypertension (uncontrolled)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 D Drugs or alcohol (1 point each) 1 or 2 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 1. Lip et al. Chest 2010;137:263–72; 2. Pisters et al. Chest 2010;138:1093–100. HAS-BLED 2 = 1 LV, left ventricular; TIA, transient ischemic attack a Vascular disease includes myocardial infarction, complex aortic plaque, and peripheral artery disease

Question to the audience  Patient Marta: – 76 year old female, NVAF for 3 years – Hypertension (blood pressure 140/81 mmHg) – CHA 2 DS 2 -VASc = 4 – HAS-BLED = 1 – On warfarin for 3 years: – INR frequently in range (TTR = 72%) – No serious bleeding events on warfarin – Marta asks for information about novel agents and is interested in lack of monitoring  Would this patient benefit from switching to ELIQUIS®  (apixaban)? 1. Yes 2. No

1. Granger et al. N Engl J Med 2011;365:981–92. Adapted from Granger et al. N Engl J Med 2011;365:981– % 669/9, % 603/9, % 462/9, % 327/9, % 265/9, % 212/9,120 Median duration of follow-up 1.8 years Superior stroke / systemic embolism prevention Superior profile in reducing major bleeding Superior reduction in all-cause mortality 21% RRR p= % RRR p< % RRR p=0.047 ELIQUIS® (apixaban) has demonstrated superiority vs warfarin in the following three key outcomes 1 RRR: relative risk ratio

ApixabanWarfarin Hazard Ratio (95% CI) No. of Events (%/yr) Stroke/SE 212 (1.27)265 (1.60)0.66–0.95 Stroke 199 (1.19)250 (1.51)0.65–0.95 Ischaemic or unspecified stroke* 162 (0.97)175 (1.05)0.74–1.13 Haemorrhagic stroke 40 (0.24)78 (0.47)0.35–0.75 Disabling or fatal stroke 84 (0.50)117 (0.71)0.54–0.94 ARISTOTLE: efficacy according to type of stroke 1 1. Granger et al. N Engl J Med 2011;365:981–92. SE: systemic embolism; CI: Confidence Interval *Unknown type of stroke occurred in 14 patients in the apixaban group and 21 patients in the warfarin group. Among patients with ischaemic stroke, haemorrhagic transformation occurred in 12 patients with apixaban and 20 with warfarin. Adapted from Granger et al. N Engl J Med 2011;365:981–92. Favours apixaban Favours warfarin

 In ARISTOTLE, 43% of patients (7,800) were warfarin-naive and 57% (10,401) were warfarin experienced  The benefits of apixaban over warfarin on the primary efficacy and safety outcomes were similar in VKA-naive and VKA-experienced patients The outcomes of ELIQUIS® (apixaban) vs warfarin in VKA-experienced patients – primary outcomes 1 1. Garcia et al. Am Heart J. 2013;166:549–58.

Apixaban rate per 100 patient years (n) Warfarin rate per 100 patient years (n) Treatment HR (95% CI) Interaction p value Intracranial bleeding0.02 VKA naive0.48 (32)0.81 (52)0.60 (0.38, 0.93) VKA experienced0.23 (20)0.80 (70)0.28 (0.17, 0.46) Death0.82 VKA naive4.07 (304)4.50 (333)0.91 (0.78, 1.06) VKA experienced3.10 (299)3.51 (336)0.88 (0.76, 1.03) Discontinuation0.26 VKA naive13.94 (930)15.98 (1032)0.87 (0.79, 0.95) VKA experienced11.69 (1041)12.57 (1102)0.93 (0.85, 1.02) The outcomes of ELIQUIS® (apixaban) vs warfarin in VKA-experienced patients – other outcomes 1 1. Garcia et al. Am Heart J. 2013;166:549–58.  Treatment effects of apixaban vs warfarin were not modified by VKA naivety  Key outcomes were numerically lower for apixaban vs warfarin, irrespective of prior VKA use Adapted from Garcia et al. Am Heart J. 2013;166:549–58.

VKA-related intracerebral hemorrhage frequently occurs even when INRs are in therapeutic range 1 1. Berwaerts et al. Stroke. 2000;31:2558–2562; 2. Granger et al. Circulation 2012;125:159–64.  Warfarin has a liability of hemorrhagic stroke that might not be overcome with excellent INR control 2 Std. Dev = 2,10 Mean = 3,6 n= 41, INR Frequency distribution of INR values on admission of patients with intracerebral hemorrhages 1 Frequency Adapted from Berwaerts et al. Stroke. 2000;31:2558–562.

The outcomes of ELIQUIS® (apixaban) vs warfarin according to TTR in warfarin group 1 1. Wallentin et al. Circulation 2013;127:2166–76. In ARISTOTLE, patients in the warfarin group had an INR in the therapeutic range ( ) for a median of 66.0% Median TTR, % TTR: Time in Therapeutic Range Median of Patients’ TTR in different countries in ARISTOTLE 1 Adapted from Wallentin et al. Circulation 2013;127:2166–76.

Primary efficacy and safety outcomes in ARISTOTLE according to cTTR: lower quartiles 1 cTTR = centre’s average TTR Adapted from Wallentin et al. Circulation 2013;127: Wallentin et al. Circulation 2013;127:2166–76.

Primary efficacy and safety outcomes in ARISTOTLE according to cTTR: upper quartiles 1 cTTR = centre’s average TTR Adapted from Wallentin et al. Circulation 2013;127: Wallentin et al. Circulation 2013;127:2166–76.

There is clear guidance on how to switch a patient from a VKA to ELIQUIS® (apixaban) 1. Apixaban SmPC. Available at  Guidance on switching from SmPC 1 Discontinue warfarin or other VKA therapy Monitor INR at regular intervals until INR is < 2.0 Start ELIQUIS® (apixaban) Switching treatment from aspirin and parenteral anticoagulants can be done at the next scheduled dose 1

Take-away messages: patient #1 1. Granger et al. N Engl J Med. 2011;365:981–992; 2. Garcia et al. Am Heart J. 2013;166:549–58; 3. Wallentin et al. Circulation 2013;127:2166–76; 4. Camm et al. Eur Heart J 2012; 33:2719–47.  ARISTOTLE demonstrated that ELIQUIS® (apixaban) was superior to warfarin in reduction of stroke/SE, major bleeding outcomes and all-cause mortality 1  The benefits of ELIQUIS® (apixaban) over warfarin were consistent in warfarin-naïve and warfarin-experienced patients 2  The rates of stroke or systemic embolism and major bleeding were consistently lower with ELIQUIS® (apixaban) than warfarin across the cTTR quartiles, including those >71.2% in TTR 3  NOACs such as ELIQUIS® (apixaban) offer better convenience than VKAs 4  Based on the clinical data shown, there is no reason for reluctance to switch from warfarin to ELIQUIS® (apixaban) in appropriate patients TTR: time in therapeutic range; cTTR: enters’ time in therapeutic range.

Patient #2: Newly diagnosed NVAF patient Patient: Jose* *Patient is fictitious.

There are two options for Jose: VKA or a NOAC What are relevant considerations? My job means that I have to travel extensively I’m not always able to follow dosing instructions of my medications I am a vegetarian and I especially love Asian food I often have to reschedule appointments with my physician My mother was on warfarin and seemed well- controlled I am worried about bleeding Patient is fictitious

Example of challenges with VKAs in attaining a therapeutic INR 1,2 1. Merli et al. J Thromb Thrombolysis. 2009;27: ; 2. Haas. J Thromb Thrombolysis. 2008;25:52–60. Adapted from Merli GJ et al. G. J Thromb Thrombolysis. 2009;27(3):293–99 and Haas S. J Thromb Thrombolysis. 2008;25(1):52–60. Confusion with complex dosing instructions INR >3; dose adjusted down INR <2; dose adjusted up INR <2; dose adjusted up INR <2; dose adjusted up Lack of coordinated care INR >3; dose adjusted down Drug and diet interactions Therapeutic INR Newly diagnosed patient initiated on VKA therapy Inter-individual variability in dose response

Assume that apixaban has been on the market for 5 years 1. Granger et al. N Engl J Med. 2011;365:981–92; 2. Connolly et al. New Engl J Med. 2009;361:1139–1151; 3. Dlott et al. Circulation Feb 3 [Epub ahead of print]; 4. Diener et al. Int J Stroke 2012;7:139–41.  Compared to ELIQUIS® (apixaban), assuming warfarin is a new drug, the new drug has: – 25% increased relative risk of stroke/systemic embolism 1 – Nearly 50% increased relative risk of major bleeding 1 – Approx. 2.5 times the rate of ICH 1 – Requirement for monthly monitoring to adjust dose 1 – Falls out of target anticoagulation one third of the time in highly controlled trials 1,2 and nearly one half the time in general practice 3 – Many food and drug interactions 1,4 – 10% increased relative risk of mortality 1  Would warfarin be approved by regulatory authorities now? ICH = intracranial hemorrhage

1. Granger et al. N Engl J Med 2011;365:981–92. Adapted from Granger et al. N Engl J Med 2011;365:981– % 669/9, % 603/9, % 462/9, % 327/9, % 265/9, % 212/9,120 Median duration of follow-up 1.8 years Superior stroke / systemic embolism prevention Superior profile in reducing major bleeding Superior reduction in all-cause mortality 21% RRR p= % RRR p< % RRR p=0.047 ELIQUIS® (apixaban) has demonstrated superiority vs warfarin in the following three key outcomes 1

1. Granger et al. N Engl J Med 2011;365:981– Garcia et al. Am Heart J. 2013;166:549–58 Adapted from Granger et al. N Engl J Med 2011;365:981– % 669/9, % 603/9, % 462/9, % 327/9, % 265/9, % 212/9,120 Median duration of follow-up 1.8 years Superior stroke / systemic embolism prevention Superior profile in reducing major bleeding Superior reduction in all-cause mortality 21% RRR p= % RRR p< % RRR p=0.047 ELIQUIS® (apixaban) has demonstrated superiority vs warfarin in the following three key outcomes 1 The safety profile of ELIQUIS® (apixaban) was consistent across all major patient subgroups in AVERROES and ARISTOTLE 1,2

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