1. The EINSTEIN EXT Study 'Xarelto' for the Long-Term Prevention of Recurrent Venous Thromboembolism

2. Persistent Threat of VTE Recurrence  Patients who experience a thromboembolic event are at continued risk of recurrent VTE  This risk of recurrence is highest in the first 6–12 months after the initial episode, and may continue for as long as 10 years 1  Recurrent episodes are observed in >20% of patients 12 months after discontinuation of anticoagulation 2 Long-term treatment of VTE is an important factor in preventing recurrent events 1. Heit et al, 2000; 2. Kearon et al, 1999 Cumulative event rate of recurrent VTE after discontinuation of therapy in patients with unprovoked VTE 2 Cumulative event rate 40 Time after discontinuation (months) 30 20 10 0 0 4812162024 >20% of patients had a recurrence within 12 months of discontinuing 3 months’ warfarin treatment Point of treatment discontinuation

3. 'Xarelto': Simple and Effective Single-Drug Approach for VTE Treatment  'Xarelto' is fast-acting and has minimal drug–drug interactions 1  'Xarelto' has no need for routine monitoring or frequent dose adjustment 1 1. Perzborn et al, 2011; 2. Kubitza et al, 2013 'Xarelto' acts as fast as enoxaparin and can be given at the initiation of DVT and PE treatment 'Xarelto' exerts similar pharmacodynamic effects to enoxaparin 2 40 30 20 10 0 0 4812162024 Anti-Factor Xa activity (ng/ml enoxaparin) Time (hours) Enoxaparin (n=10) 'Xarelto' (n=11)

4. The EINSTEIN EXT Study Design  Compared 'Xarelto' (as a once-daily 20 mg dose) with placebo for the long-term prevention of recurrent symptomatic VTE  Patients enrolled were those for whom the decision to continue or stop treatment was unclear, and who had previously received anticoagulation with 'Xarelto' or a VKA  Primary efficacy outcome: symptomatic recurrent VTE (composite of recurrent DVT, non-fatal PE or fatal PE)  Principal safety outcome: major bleeding The EINSTEIN Investigators, 2010 Confirmed symptomatic DVT or PE completing 6–12 months of 'Xarelto' or VKA in the EINSTEIN programme N=1197 Placebo Predefined treatment period of 6 or 12 months 'Xarelto' 20 mg od R 30-day observation period Confirmed symptomatic DVT or PE completing 6–12 months of VKA ~53% ~47% Day 1

5. Effective Long-Term Treatment Matters ITT population; *some patients had more than one event The EINSTEIN Investigators, 2010 Time to event (days) 10 5 2 1 Cumulative event rate (%) 3 4 9 6 7 8 0 0306090120150180210240270300330360 HR=0.184; p<0.0001 (superiority) RRR=82% 'Xarelto' N=602 Placebo N=594 'Xarelto' showed a relative risk reduction of 82% 'Xarelto' (N=602)Placebo (N=594) n(%)n Symptomatic recurrent VTE*8(1.3)42(7.1) Recurrent DVT5(0.8)31(5.2) Non-fatal PE2(0.3)13(2.2) Fatal PE001(0.2) Unexplained death (where PE cannot be excluded) 1(0.2)00

6. 'Xarelto' (N=598) Placebo (N=590) p-value n(%)n Major bleeding4(0.7) 0 00.11 Bleeding contributing to death0000 Bleeding in a critical site0000 Associated with fall in haemoglobin  2 g/dl and/or transfusion 4(0.7)00 Gastrointestinal bleeding3(0.5)00 Menorrhagia1(0.2)00 Major or clinically relevant non-major bleeding 36(6.0)7(1.2)<0.001 Clinically relevant non-major bleeding32(5.4)7(1.2) Safety Matters: No Significant Increase in Major Bleeding Safety population The EINSTEIN Investigators, 2010

7. ITT population 'Xarelto' (N=602)Placebo (N=594) n(%)n Cardiovascular outcomes 4(0.7)4 STEMI 1(0.2)00 Unstable angina 3(0.5)1(0.2) Transient ischaemic attack 001(0.2) Ischaemic stroke 001(0.2) Non-CNS systemic embolism 001(0.2) Total mortality 1(0.2)2(0.3) PE, or unexplained death where PE cannot be excluded 1(0.2)1 Cancer001(0.2) Safety Matters: Low Rates of Mortality and Cardiovascular Outcomes The EINSTEIN Investigators, 2010

8. 'Xarelto' (N=602), % Placebo (N=594), % HR (95% CI)p-value Net clinical benefit* 2.07.10.28 (0.15–0.53)<0.001 Favourable Benefit–Risk Balance Matters The EINSTEIN Investigators, 2010 *Defined as the composite of the primary efficacy outcome and major bleeding A total of 34 recurrent events were prevented, at the cost of 4 major bleeding events RRR 72% (p<0.001) 7.1 2.0

9. 'Xarelto': Simple Sustained Protection from Hospital to Home EINSTEIN EXT confirmed the benefits of the simple, single-drug approach with 'Xarelto' for long-term treatment of DVT/PE No significant increase in major bleeding events or vascular events Significant reductions in recurrent VTE compared with placebo – an 82% relative risk reduction An acceptable benefit–risk balance for patients receiving long-term treatment in whom there is no clear decision whether to continue or stop anticoagulation

10. Pack Shot

12. BACK-UP SLIDES

13. 'Xarelto' (N=602) Placebo (N=594) Males (%)58.857.1 Age, mean (years)58.258.4 Weight (%) ≤50 kg1.70.8 >50–100 kg81.682.2 >100 kg14.114.6 Creatinine clearance (ml/min) (%) <3000.8 30–<496.17.4 50–<8022.320.5 ≥8062.062.8 Index event* (%) DVT64.159.9 PE35.940.1 Active cancer (%)4.74.4 Unprovoked VTE (%)73.174.2 Patient Characteristics: Similar in Both Study Arms in EINSTEIN EXT The EINSTEIN Investigators, 2010 ITT population; *index event not confirmed in all patients

14. Bleeding Management in Clinical Practice  If bleeding events occur while patients are receiving 'Xarelto', they can be managed easily by measures used in clinical practice 1,2  There is no specific reversal agent currently available for 'Xarelto'; however, studies are ongoing 3–5 1. Siegal et al, 2012; 2. Bauer KA, 2012; 3. Eerenberg et al, 2012; 4. Marlu et al, 2012; 5. Lu et al, 2013 Bleeding during anticoagulant treatment with 'Xarelto' Minor bleeding e.g. gum or nose bleed Major bleeding Bleeding that cannot be controlled by general or supportive measures General measures  Delay next dose or discontinue treatment Supportive measures  Mechanical compression  Fluid replacement  Haemodynamic support or blood products Consider haemostatic procoagulant agents  Prothrombin complex concentrate  Activated prothrombin complex  Factor VIIa